Less well-documented risk factors

With these factors, evidence is considerably weaker since the results may be inconsistent between studies or dose- and time-dependency might be incompletely shown. Less well-documented risk factors are overall fairly frequent in the healthy population as well.

Cardiac interatrial abnormalities

PFO, a slit-like communication in the interatrial septum, is a fetal remnant that remains functional in approximately 25% of adults based on autopsy studies.⁷² With two thin membranes on both sides of the septum, it can open in certain circumstances, such as during an activity inducing the Valsalva maneuver—resulting in a transient right-to-left shunt in systemic circulation. The maneuver causes right atrial pressure to exceed left atrial pressure, opening the slit, while in normal circumstances the positive left-to-right pressure gradient keeps the membranes closed. PFO can occur with or without atrial septal aneurysm (ASA), which is diagnosed when a fixed displacement or mobile excursion of the fossa ovalis bulges to either one of the atriums.⁷³ After increasing evidence of supporting benefits of PFO closure in secondary prevention after cryptogenic ischemic stroke, however, a term “PFO-associated stroke” was proposed, applicable for all etiological classification systems (TOAST, ASCOD, and CCS).⁷⁴

The best-characterized connection to ischemic stroke is paradoxical embolism, where an embolus from the venous circulation passes through the PFO. Although the association between PFO and cryptogenic stroke has been demonstrated also for older patients (age ≥55 years) in case-control studies, it appears stronger for younger individuals. Compared with patients with a known stroke etiology, in an older study, OR for having a PFO was 4.7 (95% CI 1.9-11.7) among younger patients (<55 years) and 2.9 (95% CI 1.7-5.0) among older patients (≥55 years) with unknown stroke etiology.⁷⁵ Later trials exploring the efficacy and safety of percutaneous closure of PFO to prevent recurrent ischemic strokes in younger IS patients have reinforced the causality of PFO and stroke in cryptogenic ischemic stroke.^76-78 However, PFO may remain only an innocent bystander in a large proportion of patients, documented after completed diagnostic work-up; only in a few cases can the actual paradoxical embolism be detected. This uncertainty of PFO’s role has been studied in several systematic meta-analyses. One of them proposed that the overall probability of PFO being incidental in cryptogenic strokes is 33%, being approximately 20% in patients younger than 55 years and 48%

in patients older than 55 years.⁷⁹

Several PFO characteristics, such as PFO size, tunnel length, magnitude of the shunt, presence of concomitant ASA, and prothrombotic mutations, have been suggested as factors increasing the PFO-related stroke risk.^80,81 In 2013, a 10-point Risk of Paradoxical Embolism (RoPE) score was introduced, including such variables as age, presence of a cortical stroke on imaging, hypertension, smoking, and diabetes. Score higher than six indicates that the PFO might be pathogenic and closure should be considered.⁸²

Migraine

Migraine is characterized by recurrent unilateral pulsatile headaches lasting 4-72 hours and of moderate to severe intensity. These headaches can be associated with sensitivity to light and sound, nausea, and vomiting. Furthermore, migraine attacks may be preceded by visual, somatosensory, motor, vestibular or speech-related aura.⁸³ The population prevalence of migraine is about 12%, approximately 6% in men and 18% in women—with the highest societal burden in the second, third, fourth, and fifth decades of life.⁸⁴ Comorbidities in migraine include stroke, myocardial infarction, epilepsy, sleep disorders, and depression.⁸⁴ Since the first epidemiological study published in 1975 demonstrating that migraine could be an independent risk factor for stroke,⁸⁵ a number of hospital-based or population-hospital-based case-control and cohort studies mostly including young patients have addressed this hypothesis.

Potential mechanisms explaining the increased risk of ischemic stroke in individuals with migraine with aura (MA) include vasospasm in the larger intracerebral arteries, cortical spreading depression leading to cerebral microcirculatory vasoconstriction, endothelial dysfunction, increased platelet aggregation, use of non-steroidal anti-inflammatory drugs, immobilization, and paradoxical embolism via PFO.^86-89 Indeed, studies have also suggested that PFO, migraine, and cryptogenic ischemic stroke are intertwined based on findings that MA is approximately 3-fold more common in individuals with PFO than in those without PFO.^90-92 In cryptogenic ischemic stroke specifically, those patients harboring PFO also more frequently had MA or any type of migraine than patients without PFO.^91-94 Other explanations for the increased risk of ischemic stroke in PFO patients with migraine might be serotonin-induced platelet activation and increased expression of plasminogen activator-1 and suppression of fibrinolysis caused by transient hypoxemia.^86,87 Finally, there might be a shared genetic background that links migraine to several cardiovascular diseases, including ischemic stroke.^95-97 However, evidence for all of these associations and mechanisms is controversial and more research is warranted.

Meta-analyses have produced different results on the association between migraine and ischemic stroke. Etminan et al. showed that the pooled relative risk for all-aged ischemic stroke (of any subtype) in any type of migraine was 2.2 (95% CI 1.9-2.5), for migraine with aura (MA) 2.3 (95%

CI 1.6-3.2), and for migraine without aura (MO) 1.8 (95% CI 1.1-3.2).⁹⁸ By contrast, Schurks et al.

or Spector et al. found no association for MO (relative risk 1.2; 95% CI 1.7 and 1.2; 95% CI 0.9-1.8, respectively).^99,100 Spector et al. included 13 case-control studies and 8 cohort studies with more than 620 000 patients and were able to address several confounding factors such as hypertension, smoking, COCs, cholesterol, cardiac disease, and family history of migraine or stroke. In that study, the pooled adjusted OR for ischemic stroke in patients with any type of migraine was 2.0 (95% CI 1.7-2.4) and for MA 2.3 (95% CI 1.5-3.3).¹⁰⁰ A more recent nationwide, population-based cohort study with approximately 51 000 patients with migraine and 510 000 age- and sex-matched controls showed that migraine was positively associated with ischemic stroke with an adjusted hazard ratio (HR) of 2.3 (95% CI 2.1-2.4).¹⁰¹ In general, risk was higher for MA than for MO, but aura status was available only in 59% of patients. Therefore, based on these studies, especially MA can be considered a risk factor for early-onset ischemic stroke, while MO has been recently proven to be more common, especially in older patients with cryptogenic strokes.¹⁰² Thus far, only three studies have explored the strength of the association between migraine and cryptogenic ischemic stroke specifically (Table 3).

However, these comparisons were not examined independently of known vascular comorbidities.

Furthermore, of these studies one compared cryptogenic ischemic stroke patients with stroke patients with determined etiology and two with stroke-free patients.^102-104

These earlier studies exploring the association between migraine and ischemic stroke may have suffered from small sample sizes, inaccuracies in migraine ascertainment (e.g. based on self-reporting or registries), and not assessing the association in defined subtypes of ischemic stroke. It is also important to recognize that most studies have included mainly women because of their higher migraine prevalence, and therefore, the association is more uncertain in men.

Table 3. Characteristics of studies assessing the strength of the association between migraine and cryptogenic ischemic stroke. Permission to reproduce parts of the table is granted under John Wiley and Sons’ general terms.

CI, confidence interval; IHS, International Headache Society; OR, odds ratio; TIA, transient ischemic attack

Estrogen-containing contraceptives

COCs are associated with an increased activity of the fibrinolytic inhibitors plasminogen activator inhibitor (PAI) -1 and -2, an increase in many coagulation factors, and a reduced anticoagulant response.¹⁰⁵ A recent systematic Cochrane review with 24 studies showed an overall increased risk for myocardial infarction or ischemic stroke for COCs with increasing doses of estrogen, with the highest for COCs containing ≥50 ug of estrogen (risk ratio 2.14, 95% CI 1.8-3.3). The overall risk ratio for ischemic stroke was 1.7 (95% CI 1.5-1.9) with no dose-response data available. The risk of myocardial infarction or ischemic stroke did not differ significantly according to the generation of progestagen or to progestagen type.¹⁰⁶

Pregnancy and puerperium

Physiological changes as such may increase the risk of ischemic stroke during pregnancy and puerperium, including increasing levels of clotting factors and fibrinogen throughout pregnancy and decreasing levels in natural anticoagulants. Kittner et al. showed in their study including 46 hospitals in the Baltimore-Washington area that the relative risk of ischemic stroke was up to 8.7 (95% CI 4.6-16.7) in the postpartum period 6 weeks after delivery, but no elevated risk was present during pregnancy.⁶ Another more recent study with over 1 600 000 women with a first recorded delivery showed that the risk of ischemic stroke during the postpartum period of 6 weeks was significantly higher than in the same period one year later (OR 8.5, 95% CI 4.9-14.8).¹⁰⁷

The most important risk factors for ischemic stroke during pregnancy and puerperium include previously diagnosed conditions such as hypertension, diabetes, cardiac diseases, genetic or acquired coagulopathies, sickle-cell disease, and migraine. Other temporal risk factors comprise complications of pregnancy, including preeclampsia, eclampsia, and gestational diabetes, or complications of labor or delivery, including postpartum hemorrhage, fluid, electrolyte or acid-base disorders, anemia, blood transfusion, and thrombocytopenia.^108,109

Other less well-documented risk factors

Excessive alcohol consumption, both recent and long-term as well as binge drinking, can act as a transient trigger⁵⁸ and as a chronic risk factor^61,110 for ischemic stroke at young ages. With long-term heavy drinking, up to 8- to 15-fold increases in the stroke risk in young patients have been shown.

Mechanisms associated with high alcohol consumption and ischemic stroke include adverse effects

on fibrinolytics, hemostasis, and blood clotting, and cardiac arrhythmias.¹¹¹ One study also showed that mild-to-moderate alcohol intake might be associated with a lower risk of ischemic stroke in young women.¹¹² This finding was supported by a large systematic review and meta-analysis with 27 prospective studies on ischemic stroke, indicating that light-to-moderate alcohol intake might associated with a lower risk of ischemic stroke, whereas heavy drinking was associated with an increased risk.¹¹³ As discussed in this review, further evidence is needed to better understand the genetic variation in alcohol metabolism and its effect on the risk of stroke, especially in the single-nucleotide polymorphism of the alcohol dehydrogenase 1B gene.

Cannabis, opiates, amphetamine and related substances, and cocaine can cause ischemic stroke by several mechanisms, including direct vasoconstriction, platelet activation, septicemia, and endocarditis. Kaku et al. showed that among young drug abusers the stroke risk was 6.5-fold (95%

CI 3.1-13.6).¹¹⁴ Acute cocaine use, especially crack cocaine, within 24 hours had as high as 6-fold risk of ischemic stroke relative to individuals not using cocaine in one study.¹¹⁵

Heikinheimo et al. showed in their study of 681 young stroke patients that 10.7% had preceding infections within four weeks prior to first-ever ischemic stroke, including upper respiratory tract infections, skin or mucous membrane infections, and gastrointestinal infections.¹¹⁶ However, only a few studies have demonstrated the association between microbial pathogens and ischemic stroke in the young. The best-documented chronic and acute infections include dental infections, chronic and active Chlamydia pneumoniae infection, and human immunodeficiency virus.^117-119 In endemic areas, also tuberculosis, syphilis, and neurocysticercosis must be considered.¹²⁰ Infections may predispose to ischemic stroke by e.g. modifying the platelet function, causing endothelial dysfunction or leading to coagulation disorders.

Antiphospholipid syndrome (APS) or antiphospholipid antibodies alone without fulfilling criteria for APS increase the risk for early-onset ischemic stroke. In APS, two blood samples at least 12 weeks apart should demonstrate the presence of antiphospholipid antibodies, most frequently anticardiolipin antibodies, lupus anticoagulant, or anti-β2 glycoprotein I antibodies. The risk for early-onset ischemic stroke is further amplified when a patient is using COCs or smoking (OR 201.0, 95% CI 22.1-1828.0 and OR 87.0, 95% CI 14.5-523.0, respectively).¹²¹ Other inherited hematologic conditions must also be borne in mind, including sickle cell disease and genetic thrombophilias such as V Leiden G1691A and prothrombin G20210A mutations.¹²² Rare monogenic causes of early-onset ischemic stroke include e.g. MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke), CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and

leukoencephalopathy), and Fabry disease. However, these or other rare genetic disorders will not be presented in this review in detail.

Furthermore, such risk factors as air pollution, carotid artery webs, and intrinsic coagulation factors combined with COCs warrant more attention in future studies.^123-126 Also preterm birth might be associated with early-onset stroke.^127,128 One longitudinal study including individuals with obstructive sleep apnea suggested a higher stroke risk for women aged ≤35 years than for older age groups and a relatively higher risk for women overall.¹²⁹ There are also incidental reports of the associations of psychosocial distress,¹³⁰ both unipolar and bipolar depression, and anxiety disorders with ischemic stroke at young age.^131,132 Finally, especially in cryptogenic stroke, cancer must be kept in mind. A Finnish study with 1002 young patients showed that 3.9% had cancer-diagnosed prestroke.³⁸ A population-based study from the United Kingdom with 180 000 young cancer patients reported a 50% higher than expected incidence of ischemic stroke.¹³³

Several less well-documented risk factors are listed in Table 4.

Table 4. Examples of risk factors for ischemic stroke that may be considered specific to young adults.

Table adapted from Putaala, Eur Stroke J (2016)⁵ and updated.

Risk factor Estimated prevalence in patients†

Strength of association‡

Comment

Pregnancy/puerperium⁶ 7.5% in women RR 8.7 during puerperium No significant association shown for

Migraine^98-100 20-27% OR 2.3 for migraine with

aura

24-50% OR 5.1 for age <55 years No association found in population-based

years); Increasing risk with oral contraceptive use

Periodontitis¹¹⁹ Unknown OR 6.1 for >6 mm attachment loss

Air pollution¹²⁶ NA OR 1.1 for particulate

matter <10 μm Heavy drinking58,61,149,150 12-59% OR 15.3 for long-term

alcohol consumption of

≥60 g/d

Association might be stronger for younger adults

Illicit drug use115,151-154 9-20% OR 1.2 for cannabis OR 2.6 for cocaine

*In absence of antiphospholipid antibody syndrome or systemic lupus erythematosus.

OR, odds ratio; RR, relative risk.

†Variability in prevalence is primarily due to selection of cohorts and usually higher for cryptogenic cases.

‡Pooled estimate of the risk if meta-analysis level of data available.

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