Case fatality and long-term mortality
The 30-day mortality, i.e. case fatality, for early-onset ischemic stroke patients ranges between 2.7% and 9.3%.207-210 In one older study from the US, the case fatality was shown to be unchanged in the 1990s.211 Previous studies have revealed that long-term cumulative mortality in young stroke patients was 2.4-6.3% at one year, 7.7% at three years, and 5.8-10.7% at five years.209,212-214 For cryptogenic stroke patients, cumulative mortality at five years was 6%.209 Two follow-up studies found a 10-year mortality of 12.1-13.5% and a 20-year mortality of 21.7-26.8%.214,215 In a Finnish study, the 15-year incidence rate for vascular death was 4.1 cases per 1000 person years in cryptogenic stroke alone.216 As with the elderly, the mortality rate is highest during the first year after stroke. Compared with their age mates, the 20-year mortality ratio was 3.9 times the expected.215 One must acknowledge, however, that many of these studies were published over ten years ago and more updated data are warranted.
Factors associated with long-term mortality in young stroke patients are recurrent stroke, male sex, increasing age, active malignancy, type 1 diabetes mellitus, heart failure, other cardiac diseases, heavy drinking, cigarette smoking, increasing NIHSS score, increased C-reactive protein (CRP) and homocysteine levels, infections, leukoaraiosis, and certain stroke etiologies.116,213,214,217-220 Unfavorable outcome is associated with LAA and CE, and the best prognoses with dissections and cardioembolism from low-risk causes.209,214,216 The accumulation of many risk factors increases mortality.221,222
Risk of recurrent stroke and future cardiovascular events
A Swedish study has shown a decreasing risk of recurrence of ischemic stroke in young adults over the last decades.223 As with mortality, the risk for recurrent stroke is highest during the first year after index stroke, up to 3%, but then decreases during the follow-up to 1-2%.224 Nevertheless, many studies have established that the cumulative risk for a recurrence remains higher than in stroke-free individuals, being approximately 10% at 5 years,224 15% at 10 years,53 17% at 15 years,216 and even 30% at 25 years,225 with somewhat differing stroke definitions used in these studies. In one study, the 15-year incident rate for recurrent stroke in patients with cryptogenic first-ever stroke was 11.0 cases per 1000 person-years and for composite vascular event up to 22.3 cases per 1000 person-years.216 In the same study, the
15-37 year incident rate for recurrent stroke was e.g. in LAA 37.7 and in CE 21.7 cases per 1000 person-years. Furthermore, the FUTURE study showed the 20-year cumulative risk for recurrent stroke to be 12.1% and for composite event (stroke or other arterial events) 21.3% in cryptogenic stroke.21 In the longest follow-up study thus far, there was a 45% cumulative risk for any ischemic event 25 years after the index event (transient ischemic attack, ischemic stroke, myocardial infarction, coronary artery bypass grafting, percutaneous coronary intervention, carotid endarterectomy, or peripheral artery revascularization procedure).225 Etiology of LAA and CE also have the highest risk for recurrent cardiovascular events.216,224,226
Other factors associated with stroke recurrence include diabetes, increasing age, history of transient ischemic attack, cardiac diseases, male gender, kidney dysfunction, MA, family history of stroke, APS, discontinuation of antiplatelets and antihypertensives, and cancer.53,218,224,227,228 Some studies have found certain factors to be associated only with other cardiovascular events, excluding stroke, in young stroke populations; these include heart failure, cigarette smoking, and certain pathological ECG markers.213,215,224,229 Genetic testing and genetic risk scores may yield additional information for identifying patients with a high risk of recurrence.230 As with mortality, patients with multiple risk factors seem to have the highest cumulative risk for recurrent cardiovascular events.221,222
Functional outcome
Apart from stroke severity, one of the strongest predictors of functional outcome is the patient’s age; younger age predicts better functional outcome in both severe and mild strokes in a follow-up extending follow-up to 12 years.212,214,231 Previous studies have shown that 63-71% of early-onset ischemic stroke survivors recover well (mRS 0-1) and 84-94% can live independently (mRS 0-2).26,212,214,232-234 Also older studies show that relatively small proportion of young patients remain severely disabled and need help from others in their daily routine.26,212,231
Pain after ischemic stroke
Many young ischemic stroke survivors suffer from long-standing post-stroke pain, including pain from shoulder subluxation, peripheral neuropathic pain, pain caused by spasticity, or central post-stroke pain.235 The older the patients, the more common non-specific pain syndromes. However, younger stroke patients seem to suffer relatively more frequently from
38 central post-stroke pain; in one study, the prevalence of central post-stroke pain was 5.9%
during a median 8.5-year follow-up.235,236 This pain was often associated with moderate and severe stroke symptoms and lesion size, but not with lesion location.236 Central post-stroke pain was also frequently associated with peripheral pain syndromes.236
Post-stroke epilepsy
A small proportion (2.4-3.5%) of young stroke patients have epileptic seizure(s) during the first week after the ischemic stroke. In one study, the prevalence of post-stroke epilepsy was up to 11.5% in a 10-year follow-up.237,238 The predicting factors for both early seizures and post-stroke epilepsy were anterior or cortical cerebral post-stroke, hemorrhagic transformation in ischemic stroke, and severe stroke symptoms.237,238 Etiology of carotid artery dissection is associated with a higher risk of post-stroke epilepsy, which is likely due to the larger volume of the stroke. Post-stroke epilepsy is associated with unfavorable functional outcome.239 Again, these results must be interpreted cautiously since the definition of post-stroke epilepsy varies significantly between studies. For example, in one study, post-stroke epilepsy was diagnosed even if the patient only had early seizure within one week of the index event.239
Neuropsychological, psychiatric challenges after stroke, and return to work
A Dutch case-control study reported that during an 11-year follow up, 50% of young stroke or transient ischemic attack patients had a subjective decline in their cognitive skills.240 The same study also reported that 41% of these patients (controls 18%) reported post-stroke fatigue during a median follow-up of 9.8 years.241 This was more prevalent with unfavorable motor recovery and impairment in information processing speed.241 Furthermore, a decade after the stroke 17% (controls 6%) of patients were depressed and 23% (controls 12%) anxious.242 Again, these were associated with weaker functional outcome.
The proportion of young stroke patients returning to work varies significantly between studies, ranging from 30% to 80%.231,243-246 Factors associated with not returning to work were ethnicity, low income, large anterior strokes, specific stroke etiologies (such as LAA, CE, and rare causes other than dissection), a higher NIHSS score at admission, early cognitive deficits, and a long follow-up.243-246
39 Effect on family life and future pregnancies
Currently, limited data exist on the effect of ischemic stroke on family life. In one study, 7%
of patients reported having divorced during a 3-year follow-up after ischemic stroke.212 Almost one-third of stroke survivors experienced impaired sexual activity one year after stroke in another study.247
In a French study including ischemic stroke and cerebral venous thrombosis patients, the risk of stroke recurrence was higher with a definite cause of stroke, with 11 recurrent strokes occurring outside of pregnancy and two during a subsequent pregnancy. The outcome of the 187 pregnancies in stroke patients were similar to those in the general population. Altogether 34% of women did not have subsequent pregnancies because of concern of stroke recurrence, medical advice against a new pregnancy, and residual deficit.248 One retrospective study from Spain identified 32 new pregnancies in 192 women who had suffered a transient ischemic attack, stroke, or cerebral venous thrombosis, with no stroke recurrence during subsequent pregnancies.249 A Dutch study showed that after the index stroke young stroke patients had higher rates of pregnancy loss and young nulliparous women experienced more pregnancy-related complications than the stroke-free population.250 Similarly, Aarnio et al. showed in their case-control study that women with prior stroke had a higher incidence of pregnancy- and delivery-related complications.251
40
3 AIMS OF THE STUDY
I. To retrospectively characterize clinical features and long-term risks of vascular events and all-cause mortality in early-onset cryptogenic ischemic stroke patients (aged 18-49 years), with subgroup analysis of ESUS subtype;
II. To design and pilot a prospective international case-control study to assess risk factors and potential mechanisms of early-onset cryptogenic ischemic stroke;
III. To assess the association between migraine and early-onset cryptogenic ischemic stroke in a prospective case-control study;
IV. To assess the association between endothelial function and early-onset cryptogenic ischemic stroke in a prospective case-control study.