Juvenile Stroke: A Practice-Oriented Overview
A practice-oriented overview
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Background: So-called juvenile stroke, i.e., stroke in a person aged 18 to 55, affects approximately 30 000 persons per year in Germany and is thus an important cause of mortality and permanent morbidity. The spectrum of causes of stroke is broader in this age group than in older patients and is also differently distributed.
Methods: This review is based on pertinent publications retrieved by a selective search in PubMed and on current guideline recommendations.
Results: Juvenile strokes are often caused by cardiogenic emboli (ca. 25%) and by vascular dissection (ca. 20%). Approximately 10% are due to rare causes such as vasculitis or thrombophilia, 25–50% remain cryptogenic, and 20–30% meet the criteria for an embolic stroke of undetermined source (ESUS). A rational diagnostic algorithm should be applied that is based on the relative frequencies of the potential causes. The acute treatment of ischemic stroke is the same for patients of all ages: the patient must be transferred as soon as possible to a hospital where a vascular recanalization procedure can be performed. From age 40 onward, there is a steep rise in vascular risk factors and therefore also in the resulting macro- and microangiopathy, which lead, in turn, to stroke. Only 40% of patients with juvenile stroke are ever able to return to their original occupation, and approximately one-third remain permanently unable to work.
Conclusion: The high rates of cryptogenic stroke and ESUS among patients with juvenile stroke indicate that uncertainties remain in the diagnosis and treatment of this entity. The identification of rare causes of juvenile stroke requires a major diagnostic effort. Which diagnostic tests are useful or necessary in which patients is a matter that is currently decided on an individual basis. This is true, above all, of the indication for long-term cardiac monitoring.
There is no uniform age definition of “juvenile” stroke in young adults: in the literature, age ranges of 18 to 40, 45, 50, or 55 years have been given for juvenile stroke (1). The incidence of arterial ischemic stroke increases exponentially with age and is comparatively low in young and middle-aged adults compared to the elderly (2.4 per 100 000 for 20- to 24-year-olds, 20 per 100 000 for 35- to 44-year-olds, and 1200 per 100 000 for 75- to 84-year-olds) (2, 3). About 15% of strokes in Germany occur in persons younger than 55 years, corresponding to about 30 000 strokes in young adults per year (3–5). The health and psychosocial effects are particularly severe in this young age group
Types of young adult strokes include arterial ischemic stroke (approximately 70%; range, 42 to 98%), intracerebral hemorrhage (approximately 10%; range, 0 to 29%), subarachnoid hemorrhage (approximately 20%; range, 0 to 45%), and cerebral venous sinus thrombosis (0.5 to 1%) (6, 7). This review focuses on arterial ischemic stroke in young adults.
Etiological classification of young adult stroke is a major challenge for the treating physicians, as the spectrum of underlying causes is more heterogeneous, with a different frequency distribution, than in older stroke patients.
Acute care after ischemic stroke is independent of age and consists of the fastest possible transport to a hospital, where a vascular recanalization procedure (systemic thrombolysis and/or endovascular thrombectomy) and treatment in a stroke unit are possible (8, 9).
In this review, the possible causes of stroke in young adults are presented. The most frequent, and therefore most clinically relevant, etiologies and their guideline-appropriate therapies are described in detail in separate sections.
A selective literature search was carried out in PubMed for papers published from 1990, based on the clinical experience of the authors. Reviews, meta-analyses, randomized controlled studies, cohort studies, case–control studies, and case reports were included. The current guidelines of the German Society of Neurology (Deutsche Gesellschaft für Neurologie, DGN), the European Stroke Organization (ESO), and the American Academy of Neurology (AAN) were taken into account throughout the text.
Etiology of young adult arterial ischemic stroke
Classification of strokes according to the underlying etiology is usually based on the TOAST (“Trial of ORG 10172 in Acute Stroke Treatment”) classification, which is divided into five main categories: large-artery atherosclerosis, cardioembolism, small-vessel occlusion, stroke of other determined etiology, and stroke of undetermined or cryptogenic etiology (10).
The TOAST classification of strokes should be interpreted carefully, making sure that both well-known and less-certain cardioembolic sources have been included under the heading of “cardioembolic stroke”; for instance, artial fibrillation (AF) is a well-known embolic source, while patent foramen ovale (PFO) is a more controversial one (Table). Further, the category of “cryptogenic” in the TOAST classification is inconsistent, as not only strokes with no clear cause but also strokes with competing causes have been grouped together. The ESUS concept (“embolic stroke of undetermined source”), which in contrast to “cryptogenic stroke” has a positive (operative) definition, is increasingly being used as a subcategory of cryptogenic stroke.
The Table shows the frequency distribution of stroke cases based on the TOAST classification, comparing young and older adults. Cervical artery dissection is a very common cause of stroke in young adults, and PFO is more associated with cryptogenic stroke in young than older adults. In contrast, the classic stroke etiologies, such as macro- and microangiopathy and AF, play a minor role in the younger age group. However, young adult stroke patients show a marked increase in macroangiopathy and acquired microangiopathy in the age group of 40–55 years (Figure 1).
Specific etiology—diagnostics, therapy, and prognosis
Spontaneous cervical artery dissection
Although spontaneous cervical artery dissections are rare overall, with an incidence of about 3 per 100 000 per year, they represent one of the most common causes of young adult stroke, of 10–25% (11). The causes of spontaneous dissections are still not conclusively clarified and are presumably multifactorial. In addition to genetic predisposition, environmental factors, such as trivial traumas or infections, play a role (11). Approximately 15% of patients present multiple dissections in which more than one carotid artery is affected.
The most frequent clinical symptoms are headache and sore throat (30–70%), Horner’s syndrome (15–35%), cerebrospinal nerve disruption—especially of hypoglossal and vagal nerves (up to 10%), and tinnitus (up to 10%) (12, 13, e1). Stroke occurs in clinical cohorts in up to 90% of cases, although this figure does not adequately reflect reality due to the high number of undiagnosed asymptomatic dissections (11, 14, e2).
The gold standard for diagnostics is an MRI scan of the neck with T1 sequences after fat suppression. The vessel wall hematoma can be directly visualized in nearly all cases using this method, from 2 to 4 days to several weeks following the event. Multislice spiral CT angiography and color-coded duplex sonography also allow dissection to be diagnosed in 90 to 100% of the cases (15, 16, e3).
Randomized studies on acute therapy are not available. Case series suggest that, similar to ischemic stroke events of other etiologies, systemic thrombolysis therapy as well as mechanical thrombectomy can be performed (14, 17). For secondary prophylaxis, the one randomized study that was found showed no comparative differences between antiplatelet drugs (APD) and oral anticoagulation with vitamin K antagonists, in the context of a very low recurrence rate of ischemic stroke events of 1 to 2% per year (18). Ischemic patients should be treated with APD for life. Patients who had only local symptoms without cerebral ischemia can usually finish taking secondary prophylaxis after 6 to 12 months (19).
Cardioembolic causes and patent foramen ovale (PFO)
Between 5 to 25% of strokes in young adults are attributed to cardiac embolism (1, 2). Atrial fibrillation (AF) is one of the most common causes of stroke in the elderly, accounting for 25 to 35% of cases. An intensive search for AF is also recommended for young adults with stroke. However, in young adults, an AF is found relatively rarely, in only about 5% of cases (e4). The relationship between AF and stroke is currently undergoing a fundamental reinterpretation. On the one hand, AF is a strong independent risk factor for the onset of stroke, and oral anticoagulation is a very effective method for stroke prevention (20, e5). On the other hand, recent studies have given rise to doubts about a simple relationship between AF and stroke. For instance, there is only a weak temporal relationship between AF and stroke (21). Additionally, intensive long-term cardiac monitoring has led to more frequent detection of AF, yet AF is detected not only in patients after stroke but also in completely asymptomatic patients (22, 23, e6).
In younger stroke patients, transesophageal echocardiography (TEE) is usually performed in case of unclear etiology. Valvular heart disease, infectious and non-infectious endocarditis, or (in very rare cases) tumors (atrial myxomas, fibroelastomas) can be the cause of cardioembolism (1).
The role of PFO is controversial. This relic from the embryonic stage is present in about 25% of people. In young adult stroke, however, it is detected in 30 to 50% of patients (24–26). PFO as the cause of a cardiac right-to-left shunt appears to be pathophysiologically plausible: thrombus material would pass from the venous system into the arterial system as a paradoxical embolism (for example, for deep venous thrombosis). Alternative causes that have been discussed are the direct formation of intracardiac thrombi with additional atrial septal aneurysm (ASA), a low-flow situation within a PFO, or thrombus formation by paroxysmal arrhythmias (1).
No previous study that has investigated an interventional closure of PFO as compared to drug treatment for relapse prevention has shown any advantage of the intervention (27, e7, e8). An important result of these studies, however, was that the recurrence rate for stroke was extremely low, at 1% per year. However, the number needed to treat by PFO closure to prevent another stroke is 67 (e9). It should also be noted that the rate of newly diagnosed AF in the intervention group was significantly higher, although it is not known whether this has a causal relationship. Further, the consequences of PFO for stroke risk are also unclear, as long-term data is lacking (8). Antiplatelet drugs (APD), such as acetylsalicylic acid, are currently recommended for secondary prophylaxis in the presence of a PFO. In case of a second event while using APD or if a paradoxical (venous) embolism has been reliably demonstrated, oral anticoagulant therapy with phenprocoumone is recommended (Box) (28). PFO closure can be discussed as a treatment at the individual level, especially if the patient is young and the risk of paradoxical embolism (RoPE) is likely (due to a previous Valsalva maneuver and the detection of deep venous thrombosis). The individual risk of repeated stroke in PFO can be assessed using the so-called RoPE score (29).
Classical vascular risk factors
The importance of classical cardiovascular risk factors increases significantly with age. Young adult stroke patients are also more likely to have cases of macro- and microangiopathy starting from the age of 40, even though these played almost no role in the previous years (1, 2). The main risk factors are: arterial hypertension (25–50%), cigarette smoking (35–50%), fat metabolism disorders (40–70%), and diabetes mellitus (5–20%) (e10). Frequently, several risk factors exist in parallel, which increases the risk exponentially (e10).
Other rare and very rare causes
A number of other rare causes must also be taken into account in young adult stroke, which cause at least 10% of these strokes.
Pregnancy is associated with an increased rate of stroke, especially in late pregnancy and the weeks after birth (puerperium) (e11, e12). In addition to immediate stroke, there are a number of neurological complications that are indirectly associated with stroke: pre-eclampsia, reversible cerebral vasoconstriction syndrome (RCVS), posterior reversible encephalopathy syndrome (PRES), and cerebral venous sinus thrombosis. However, experiencing a stroke during pregnancy is not a fundamental reason to refrain from further pregnancies (30).
Migraine, and in particular migraine with aura, increases the risk of stroke by a factor of 2. This is especially true for women younger than 55 years. The risk of stroke increases with the number of migraine attacks (hazard ratio: 4.25; 95% confidence interval [1.36; 13.29]) (e13). There is currently no clear strategy for primary prevention (31, e14).
The influence of oral contraceptives and hormone replacement therapy on the development of stroke is unclear. Observational studies suggest a link between estrogen and stroke incidence (e15). The route of administration also appears to play a role: transdermal administration is less associated with vascular events than the oral dosage form (32). Guidelines recommend that women with additional risk factors (for example, migraine with aura, cigarette smoking) do not use oral contraceptives that contain estrogens (33).
The use of illicit drugs can cause stroke: sympathomimetic drugs carry a risk of hypertensive crises, cerebral vasospasm, vasculitis, and a disturbed rheology; intravenous substance abuse is associated with an increased risk of thromboembolic events, for instance in the case of endocarditis (34, e16).
Other rare to very rare causes of young adult stroke are presented in the eTable.
Based on the cause spectrum and the frequency distribution, a stepwise diagnosis is recommended for young adult stroke, consisting of basic diagnostics, advanced diagnostics, and ultimately, specialized diagnostics (Figure 2). It must be emphasized, however, that this is a guide for orientation rather than a standardized algorithm. Especially for the detection of very rare causes, targeted specialized diagnostics that are based on a clinical-anamnestic suspicion are sensible and clinically feasible.
The cryptogenic stroke
In up to 50% of strokes in young adults, no definitive cause can be determined (1, 35). However, the term “cryptogenic” is also unspecific: strokes can be classified as cryptogenic if no clear etiology is revealed after either the basic, advanced, or specialized diagnostic step (Figure 2). To date, it is unclear which anamnestic, clinical, or diagnostic combinations trigger further diagnostics, or how much non-informative diagnostic results are necessary to define a “true” cryptogenic stroke (36).
In this context, the importance of non-diagnosed AF has been discussed intensively. Recent studies have shown that in patients with cryptogenic stroke, an increased rate of AF can be detected by intensive long-term cardiac monitoring (for example, by an implantable event recorder) (22, 23). Until now, however, it is unclear which patients benefit from long-term cardiac monitoring—all patients with cryptogenic stroke or only patients selected after risk assessment? The latest findings indicate that, for patients with a vascular risk profile but without prior stroke, an event recorder detects clinically silent AF in up to one-third of cases (e6). Thus, the question of causality between undiagnosed AF and cryptogenic stroke remains unanswered.
To address the difficulties not only in the definition, but also in the diagnosis and therapy, of cryptogenic stroke, the so-called ESUS concept (ESUS, embolic stroke of undetermined source) was developed in 2014. This is a “positively defined” term, requiring:
- Presence of an embolic stroke pattern (in contrast to lacunar ischemia)
- Absence of a high-grade stenosis of the vessel supplying the area of ischaemia
- No AF detected in long-term ECG
- No other specific alternative etiology.
ESUS accounts for 80 to 90% of cryptogenic strokes. Currently, clinical trials are being conducted to compare the safety and efficacy of new oral anticoagulants (NOAC) versus standard acetylsalicylic acid (ASA) therapy in ESUS patients with respect to recurrence rates (37). If NOAC proves to be superior for ESUS, the urgency of the search for undiagnosed AF might be relativized.
Health and psychosocial effects
Overall, the mortality and recurrence rate of arterial ischemic stroke in young adults is significantly lower than that for older adults (e17). For instance, the 1-year mortality rate for young adult stroke is 4.5%, and the 1-year recurrence rate, 1.5% (e17). In contrast, the 1-year mortality in older adults is 15 to 35%, and the 1-year recurrence rate, 2 to 15% (38, 39). Also the functional outcome, as measured by the modified Rankin scale (mRS), is significantly better on average for young adults than for older adult stroke patients (40). Nonetheless, 11% of young adult patients will still have severe impairment (mRS 4 to 5), and 59%, mild-to-moderate impairment (mRS 1 to 3). A complete recovery without symptoms (mRS 0) occurs in 30% of affected patients (40). However, the psychosocial effects are usually more far-reaching and are not sufficiently represented by the purely medical outcome parameters; for instance, only 40% of young adult stroke patients return to their original workplace, 27% have to change workplace, and 33% remain permanently unable to work (40).
Conflict of interest statement
Prof. Ringleb has received consultant fees from Boehringer Ingelheim; congress and training course fee reimbursement from Boehringer Ingelheim and Bayer; travel expenses from Boehringer Ingelheim, Bayer, and Pfizer; speaking honoraria from Boehringer Ingelheim; and funding for a research project (initiated by him) from Boehringer Ingelheim.
PD Wakili has received consultant fees and travel expenses from Daiichi Sankyo, Bayer, and Boston Scientific; consultant fees from Biotronik; funding for research projects (initiated by him) from Bristol-Myers Squibb, Pfizer, and Boston Scientific; and speaking honoraria from Boehringer-Ingelheim, Boston Scientific, Bristol-Myers Squibb, Pfizer, and Daiichi Sankyo.
Dr. Poli has received consultant fees from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Pfizer, and Daiichi Sankyo; travel expenses and congress participation fee reimbursement and speaking honoraria from Bayer and Boehringer Ingelheim; and speaking honoraria from Bristol-Myers Squibb, Pfizer, and Daiichi Sankyo.
PD Wollenweber has received consultant fees from Boehringer Ingelheim, Bayer, and Daiichi Sankyo; speaking honoraria from Pfizer; and funding for a clinical study commissioned by Boehringer Ingelheim.
PD Kellert has received consultant fees from Bayer, Boehringer Ingelheim, and Daiichi Sankyo; travel expenses and congress participation fee reimbursement from Bayer, Daiichi Sankyo, and Pfizer; and speaking honoraria from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, and Pfizer.
Dr. Schöberl declares that no conflict of interest exists.
Manuscript received on 27 February 2017, reivsed version accepted on
10 May 2017.
Translated from the original German by Veronica A. Raker, PhD.
PD Dr. med. Lars Kellert
Neurologische Klinik und Poliklinik
Klinikum der Universität München
81377 München, Germany
For eReferences please refer to:
005-spontane-dissektionen-der-extrakraniellen-und-intrakraniellen-hirnversorgenden-arterien-2016 (last accessed on 22 April 2017).
Dr. med. Schöberl, PD Dr. med. Wollenweber, PD Dr. med. Kellert
Neurological Clinic, Heidelberg University Hospital: Prof. Dr. med. Ringleb, PD Dr. med. Kellert
Medical Clinic and Policlinic I, Großhadern Hospital, Ludwig-Maximilians-Universität München; German Centre for Cardiovascular Research (DZHK), partner site Munich Heart Alliance, München; Department of Cardiology and Angiology, Westdeutsches Herz- und Gefäßzentrum Essen, Essen University Hospital: PD Dr. med. Wakili
Clinic of Neurology, Hertie Institute for Clinical Brain Research (HIH), University Hospital Tübingen:
Dr. med. Poli
Institute for Stroke and Dementia Research (ISD), Großhadern Hospital, Ludwig-Maximilians-Universität München: PD Dr. med. Wollenweber
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