Acute treatment
Acute management of ischemic stroke is generally similar in young and older patients, including physiologic management, e.g. blood pressure, temperature, glucose, and oxygenation, as well as acute reperfusion treatments. Younger patients benefit from access to stroke expertise and should be admitted to comprehensive stroke centers with neurocritical care units.181 It has been suggested that the increased survival rates and lower levels of dependency associated with stroke unit admission are the greatest among the age group of 18-64 years,182 although no significant differences have emerged between the age groups for duration of
33 hospital stay. However, these results might be somewhat biased by several confounding factors, e.g. younger patients admitted to stroke units more frequently in the first place and treated more actively overall.
Intravenous thrombolysis appears effective in young adults (˂50 years).183,184 Age-stratified analyses suggest an inverse relation of age and effectiveness, being highest in very young patients (<30 years),183 and the young have lower symptomatic intracranial hemorrhage rates, higher likelihood to achieve functional independence at 3 months, and lower 3-month fatality than older patients.185 Chances for favorable outcome after acute stroke and endovascular stroke therapy decline continuously in a linear manner with advancing age,186 and younger stroke patients seem to have less thrombectomy-related complications than older patients.187 Age is a crucial factor in predicting functional outcome even after hemicraniectomy performed within 48 hours after stroke onset in patients with large middle cerebral artery territory infarction, as especially patients below the age of 60 years were shown to have lower mortality (number needed to treat [NNT] 2) and better functional outcome (modified Ranking scale [mRS] ≤3, NNT 4).188
Long-term secondary prevention
Secondary stroke prevention is directed towards stroke etiology as well as treatment of additional risk factors such as hypertension, overweight, physical inactivity, smoking, and dyslipidemia. Recommendations for secondary prevention with antithrombotics, statins, and antihypertensives in young patients do not differ significantly from older ischemic stroke patients. However, the lack of younger patients in prior randomized controlled trials exploring the effect of secondary prevention must be acknowledged. Nevertheless, antiplatelets are the main therapy for preventing recurrent ischemic events also in early-onset stroke patients without high risk for CE.
Especially in stroke patients with migraine, aspirin could be considered instead of e.g.
clopidogrel or dipyridamole since it might also reduce the frequency of migraine attacks,189 although it is still unclear whether this further reduces the risk of recurrent ischemic stroke.
However, in Finland, clopidogrel and a combination of aspirin and dipyridamole are recommended as the first-line antiplatelets after ischemic stroke. In young stroke patients with migraine, triptans and ergotamines are not recommended due to their effect on vasoconstriction.
34 Evidence on statins is still controversial, but lifestyle changes and statin treatment are recommended especially for patients with atherosclerotic risk factors.190 Interestingly, a study based on the Helsinki Young Stroke Registry (HYSR) demonstrated that young cryptogenic ischemic stroke patients treated for any period with statins had lower rates of new vascular events in a long-term follow-up than those not treated with statins.191 A few studies have shown that, as with the elderly, high adherence to secondary prevention medications is associated with lower risk of recurrent stroke and overall mortality than in non-users.192,193 However, in these two studies, the purchase of statins could be considered as a surrogate marker, as it did not completely guarantee the actual intake of statins or adequate lowering of LDL or total cholesterol levels. Also endothelial function could be improved with lifestyle modifications as well as with statins, angiotensin receptor blockers, and angiotensin-converting enzyme inhibitors.178 Especially statins have beneficial pleotropic effects that are independent of their effect on lipid levels.194,195 Furthermore, other lipid-lowering medications, such as ezetimibe and proprotein convertase subtilisin/kexin type 9 inhibitors, should be kept in mind.
There are limited randomized data on the secondary prevention of cervical and intracranial artery dissection, the most common solitary mechanism of ischemic stroke in the young. A randomized open-label multicenter trial, the Cervical Artery Dissection in Stroke Study (CADISS), reported no difference between antiplatelet and anticoagulation for extracranial dissection regarding recurrent stroke, any other outcome, or the rate of recanalization during the one-year follow-up.196,197 However, the CADISS trial had some limitations, e.g. in 52 cases the diagnosis of dissection was not confirmed and 26 randomized patients (10.4%) did not have an ischemic event prior to randomization. Nevertheless, these results were further supported by an open-label, randomized, non-inferiority trial, the aspirin versus anticoagulation in cervical artery dissection (TREAT-CAD) trial, including 194 patients with MRI-verified cervical artery dissection showing that 300 mg aspirin once daily was not inferior to vitamin K antagonists.198 Currently, there are no double-blinded randomized controlled trials that have shown the superiority of anticoagulation over antiplatelet treatment after ischemic stroke caused by carotid dissection.
Three multicenter, randomized, open-label controlled trials published in 2017 comparing transcatheter PFO closure and best medical treatment with medical treatment alone showed that PFO closure in patients with a previous cryptogenic stroke reduces the risk of recurrent strokes.76-78 A systematic review and meta-analysis from Ntaios and colleagues included these three and two earlier trials comparing PFO closure with medical treatment alone in patients
35 with cryptogenic stroke or transient ischemic attack.199 They showed that patients treated with PFO closure had significantly lower risk for recurrent ischemic stroke than in the medical treatment arm (OR 0.43; 95% CI 0.21-0.90). The benefit was even higher in patients with high-risk PFO (at least moderate shunt or concomitant ASA), with an OR of 0.39 (95% CI 0.16-0.96). These results were also supported by another meta-analysis of six trials with 1889 patients randomized to PFO closure and 1858 patients to best medical treatment.200 However, in PFO closure arm, new-onset AF occurred more frequently (OR 5.15; 95% CI 2.18-12.15), yet in 75% of cases AF resolved within 45 days.
Recent meta-analyses also suggested that even in patients with no PFO closure, anticoagulation does not seem to be superior to antiplatelet treatment.201,202 The benefit of PFO closure has to be kept in mind especially in young cryptogenic ischemic stroke patients, and as described above, RoPE score may be used to assess the probability that PFO would be causally associated with the cryptogenic ischemic stroke. The decision whether to proceed with PFO closure should be carefully considered in a neuro-cardiology team, and this should be done only after excluding other well-defined etiologies with timely minimum and extensive diagnostic work-up. Evidence thus far recommends continuing antiplatelet treatment even after PFO closure.
Regarding secondary prevention after ESUS in all-aged population, results have been published from two large multi-center randomized controlled trials: NAVIGATE ESUS (New Approach Rivaroxaban Inhibition of Factor Xa in a Global Trial versus ASA to Prevent Embolism in Embolic Stroke of Undetermined Source) and RE-SPECT ESUS (Randomized, Double-Blind, Evaluation in Secondary Stroke Prevention Comparing the Efficacy and Safety of the Oral Thrombin Inhibitor Dabigatran Etexilate Versus Acetylsalicylic Acid in Patients With Embolic Stroke of Undetermined Source).203,204 Both of these trials compared anticoagulation (rivaroxaban and dabigatran, respectively) to aspirin 100 mg once daily. They both showed that the rate of recurrent stroke was similar in both study arms. However, in NAVIGATE ESUS, patients treated with rivaroxaban had more major bleeding, whereas in RE-SPECT ESUS the rate of major bleeding was similar in both groups. Neither of these trials focused exclusively on early-onset ESUS. An exploratory analysis of both NAVIGATE ESUS and RE-SPECT ESUS, including only patients with PFO, yielded similar results to the main analyses.205,206 Results from a third trial, ATTICUS (Apixaban for Treatment of Embolic Stroke of Undetermined Source), comparing apixaban with aspirin, have not yet been published (NCT02427126).
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