Trigger factors in patients with a patent foramen ovale-associated stroke: A case-crossover study.

BACKGROUND: Patent foramen ovale (PFO) is a congenital anatomical variant which is associated with strokes in young adults. Contrary to vascular risk factors and atherosclerosis, a PFO is present from birth. However, it is completely unknown how an anatomical structure that is already present at birth in a large proportion of the population can convert into a PFO that causes stroke in a few. Recent studies reported a significant association between certain trigger factors and ischemic stroke in young adults. This study aims to investigate these triggers in PFO-associated stroke. METHODS: The ODYSSEY study, a multicenter prospective cohort study between 2013 and 2021, included patients aged 18-49 years experiencing their first-ever ischemic event. Participants completed a questionnaire about exposure to potential trigger factors. A case-crossover design was used to assess the relative risks (RR) with 95% confidence intervals (95% CI). The primary outcome was the RR of potential trigger factors for PFO-associated stroke. RESULTS: Overall, 1043 patients completed the questionnaire and had an ischemic stroke, of which 124 patients had a PFO-associated stroke (median age 42.1 years, 45.2% men). For patients with PFO-associated stroke, the RR was 26.0 (95% CI 8.0-128.2) for fever, 24.2 (95% CI 8.5-68.7) for flu-like disease, and 3.31 (95% CI 2.2-5.1) for vigorous exercise. CONCLUSION: In conclusion, flu-like disease, fever, and vigorous exercise may convert an asymptomatic PFO into a stroke-causing PFO in young adults. DATA ACCESS STATEMENT: The raw and anonymized data used in this study can be made available to other researchers on request. Written proposals can be addressed to the corresponding author and will be assessed by the ODYSSEY investigators for appropriateness of use, and a data sharing agreement in accordance with Dutch regulations will be put in place before data are shared.

Short-Term and Long-Term Risk of Recurrent Vascular Event by Cause After Ischemic Stroke in Young Adults.

Importance: Cause of ischemic stroke in young people is highly variable; however, the risk of recurrence is often presented with all subtypes of stroke grouped together in classification systems such as the Trial of ORG (danaparoid sodium [Orgaran]) 10172 in Acute Stroke Treatment (TOAST) criteria, which limits the ability to individually inform young patients with stroke about their risk of recurrence. Objective: To determine the short-term and long-term risk of recurrent vascular events after ischemic stroke at a young age by stroke cause and to identify factors associated with recurrence. Design, Setting, and Participants: This cohort study used data from the Observational Dutch Young Symptomatic Stroke Study, a prospective, multicenter, hospital-based cohort study, conducted at 17 hospitals in the Netherlands between 2013 and 2021. Eligible participants included 30-day survivors of an initial, neuroimaging-proven ischemic stroke (aged 18-49 years). Data analysis was conducted from June to July 2023. Exposure: Diagnosis of a first-ever, ischemic stroke via neuroimaging. Main Outcome and Measures: The primary outcome was short-term (within 6 months) and long-term (within 5 years) recurrence risk of any vascular event, defined as fatal or nonfatal recurrent ischemic stroke, transient ischemic attack, myocardial infarction, and revascularization procedure. Predefined characteristics were chosen to identify factors associated with risk of recurrence (cause of stroke, age, sex, stroke severity, and cardiovascular health factors). Results: A total of 1216 patients (median [IQR] age, 44.2 [38.4-47.7] years; 632 male [52.0%]; 584 female [48.0%]) were included, with a median (IQR) follow-up of 4.3 (2.6-6.0) years. The 6-month risk of any recurrent ischemic event was 6.7% (95% CI, 5.3%-8.1%), and the 5-year risk was 12.2% (95% CI, 10.2%-14.2%)The short-term risk was highest for patients with cervical artery dissections (13.2%; 95% CI, 7.6%-18.7%). Other factors associated with a recurrent short-term event were atherothrombotic stroke, rare causes of stroke, and hypertension. The long-term cumulative risk was highest for patients with atherothrombotic stroke (22.7%; 95% CI, 10.6%-34.7%) and lowest for patients with cryptogenic stroke (5.8%; 95% CI, 3.0%-8.5%). Cardioembolic stroke was associated with a recurrent long-term event, as were diabetes and alcohol abuse. Conclusions and Relevance: The findings of this cohort study of 1216 patients with an ischemic stroke at a young age suggest that the risk of recurrent vascular events was high and varied by cause of stroke both for short-term and long-term follow-up, including causes that remained concealed when combined into 1 category in the routinely used TOAST criteria. This knowledge will allow for more personalized counseling of young patients with stroke.

Cognitive trajectory in the first year after first-ever ischaemic stroke in young adults: the ODYSSEY study.

BACKGROUND: Limited data exists on cognitive recovery in young stroke patients. We aimed to investigate the longitudinal course of cognitive performance during the first year after stroke at young age and identify predictors for cognitive recovery. METHODS: We conducted a multicentre prospective cohort study between 2013 and 2021, enrolling patients aged 18-49 years with first-ever ischaemic stroke. Cognitive assessments were performed within 6 months and after 1 year following the index event, covering seven cognitive domains. Composite Z-scores using normative data determined cognitive impairment (Z-score<-1.5). A Reliable Change Index (RCI) assessed cognitive recovery (RCI>1.96) or decline (RCI<-1.96). RESULTS: 393 patients (median age 44.3 years, IQR 38.4-47.2) completed cognitive assessments with a median time interval of 403 days (IQR 364-474) between assessments. Based on RCI, a similar proportion of patients showed improvement and decline in each cognitive domain, while the majority exhibited no cognitive change. Among cognitively impaired patients at baseline, improvements were observed in processing speed (23.1%), visuoconstruction (40.1%) and executive functioning (20.0%). Younger age was associated with better cognitive recovery in visuoconstruction, and larger lesion volume was related to cognitive recovery in processing speed. No other predictors for cognitive recovery were identified. CONCLUSIONS: Cognitive impairment remains prevalent in young stroke even 1 year after the event. Most patients showed no cognitive change, however, recovery may have occurred in the early weeks after stroke, which was not assessed in our study. Among initially cognitively impaired patients, cognitive recovery is observed in processing speed, visuoconstruction and executive functioning. It is still not possible to predict cognitive recovery in individual patients.

Functional brain connectivity in young adults with post-stroke epilepsy.

Approximately 1 in 10 young stroke patients (18-50 years) will develop post-stroke epilepsy, which is associated with cognitive impairment. While previous studies have shown altered brain connectivity in patients with epilepsy, little is however known about the changes in functional brain connectivity in young stroke patients with post-stroke epilepsy and their relationship with cognitive impairment. Therefore, we aimed to investigate whether young ischaemic stroke patients have altered functional networks and whether this alteration is related to cognitive impairment. We included 164 participants with a first-ever cerebral infarction at young age (18-50 years), along with 77 age- and sex-matched controls, from the Follow-Up of Transient Ischemic Attack and Stroke patients and Unelucidated Risk Factor Evaluation study. All participants underwent neuropsychological testing and resting-state functional MRI to generate functional connectivity networks. At follow-up (10.5 years after the index event), 23 participants developed post-stroke epilepsy. Graph theoretical analysis revealed functional network reorganization in participants with post-stroke epilepsy, in whom a weaker (i.e. network strength), less-integrated (i.e. global efficiency) and less-segregated (i.e. clustering coefficient and local efficiency) functional network was observed compared with the participants without post-stroke epilepsy group and the controls (P < 0.05). Regional analysis showed a trend towards decreased clustering coefficient, local efficiency and nodal efficiency in contralesional brain regions, including the caudal anterior cingulate cortex, posterior cingulate cortex, precuneus, superior frontal gyrus and insula in participants with post-stroke epilepsy compared with those without post-stroke epilepsy. Furthermore, participants with post-stroke epilepsy more often had impairment in the processing speed domain than the group without post-stroke epilepsy, in whom the network properties of the precuneus were positively associated with processing speed performance. Our findings suggest that post-stroke epilepsy is associated with functional reorganization of the brain network after stroke that is characterized by a weaker, less-integrated and less-segregated brain network in young ischaemic stroke patients compared with patients without post-stroke epilepsy. The contralesional brain regions, which are mostly considered as hub regions, might be particularly involved in the altered functional network and may contribute to cognitive impairment in post-stroke epilepsy patients. Overall, our findings provide additional evidence for a potential role of disrupted functional network as underlying pathophysiological mechanism for cognitive impairment in patients with post-stroke epilepsy.

Subacute cognitive impairment after first-ever transient ischemic attack or ischemic stroke in young adults: The ODYSSEY study.

Introduction: We aimed to investigate the prevalence of cognitive impairment in the subacute phase after transient ischemic attack (TIA) and ischemic stroke (IS), factors associated with a vascular cognitive disorder, and the prevalence of subjective cognitive complaints and their relation with objective cognitive performance. Patients and methods: In this multicenter prospective cohort study, we recruited patients with first-ever TIA and IS, aged 18-49 years, between 2013 and 2021 for cognitive assessment up to 6 months after index event. We calculated composite Z-scores for seven cognitive domains. We defined cognitive impairment as a composite Z-score < -1.5. We defined major vascular cognitive disorder as a Z-score < -2.0 in one or more cognitive domains. Results: Fifty three TIA and 545 IS patients completed cognitive assessment with mean time to assessment of 89.7 (SD 40.7) days. The median NIHSS at admission was 3 (interquartile range, 1-5). Cognitive impairment was common in five domains (up to 37%), with similar proportion in TIA and IS patients. Patients with major vascular cognitive disorder had a lower education level, higher NIHSS scores and more frequent lesions in the left frontotemporal lobe than without vascular cognitive disorder (p < 0.05 FDR-corrected). Subjective memory and executive cognitive complaints were present in about two-thirds of the patients, but were weakly associated with objective cognitive performance (ß: -0.32 and -0.21, respectively). Discussion and conclusion: In the subacute phase after TIA or stroke in young adults, cognitive impairment and subjective cognitive complaints are prevalent, but they are weakly associated with each other.

Risk Factors and Causes of Ischemic Stroke in 1322 Young Adults.

BACKGROUND: Identification of risk factors and causes of stroke is key to optimize treatment and prevent recurrence. Up to one-third of young patients with stroke have a cryptogenic stroke according to current classification systems (Trial of ORG 10172 in Acute Stroke Treatment [TOAST] and atherosclerosis, small vessel disease, cardiac pathology, other causes, dissection [ASCOD]). The aim was to identify risk factors and leads for (new) causes of cryptogenic ischemic stroke in young adults, using the pediatric classification system from the IPSS study (International Pediatric Stroke Study). METHODS: This is a multicenter prospective cohort study conducted in 17 hospitals in the Netherlands, consisting of 1322 patients aged 18 to 49 years with first-ever, imaging confirmed, ischemic stroke between 2013 and 2021. The main outcome was distribution of risk factors according to IPSS classification in patients with cryptogenic and noncryptogenic stroke according to the TOAST and ASCOD classification. RESULTS: The median age was 44.2 years, and 697 (52.7%) were men. Of these 1322 patients, 333 (25.2%) had a cryptogenic stroke according to the TOAST classification. Additional classification using the ASCOD criteria reduced the number patients with cryptogenic stroke from 333 to 260 (19.7%). When risk factors according to the IPSS were taken into account, the number of patients with no potential cause or risk factor for stroke reduced to 10 (0.8%). CONCLUSIONS: Among young adults aged 18 to 49 years with a cryptogenic ischemic stroke according to the TOAST classification, risk factors for stroke are highly prevalent. Using a pediatric classification system provides new leads for the possible causes in cryptogenic stroke, and could potentially lead to more tailored treatment for young individuals with stroke.

Trigger Factors for Stroke in Young Adults: A Case-Crossover Study.

BACKGROUND AND OBJECTIVES: Causes of stroke in young adults differ from those in the elderly individuals, and in a larger percentage, no cause can be determined. To gain more insight into the etiology of (cryptogenic) stroke in the young population, we investigated whether trigger factors, such as short-lasting exposure to toxins or infection, may play a role. METHODS: Patients aged 18-49 years with a first-ever ischemic stroke or intracerebral hemorrhage (ICH) in 17 participating centers in the Netherlands completed a questionnaire about exposure to 9 potential trigger factors in hazard periods and on a regular yearly basis. A case-crossover design was used to assess relative risks (RRs) with 95% confidence intervals (95% CIs) by the Mantel-Haenszel case-crossover method, for any stroke (ischemic stroke and ICH combined) and for different etiologic subgroups of ischemic stroke. RESULTS: One thousand one hundred forty-six patients completed the questionnaire (1,043 patients with an ischemic stroke and 103 with an ICH, median age 44.0 years, 52.6% men). For any stroke, an increased risk emerged within 1 hour of cola consumption (RR 2.0, 95% CI 1.5-2.8) and vigorous physical exercise (RR 2.6, 95% CI 2.2-3.0), within 2 hours after sexual activity (RR 2.4, 95% CI 1.6-3.5), within 4 hours after illicit drug use (RR 2.8, 95% CI 1.7-4.9), and within 24 hours after fever or flu-like disease (RR 14.1, 95% CI 10.5-31.2; RR 13.9, 95% CI 8.9-21.9). Four trigger factors increased the risk of other determined and cryptogenic ischemic stroke, 3 that of cardioembolic stroke, 2 that of large vessel atherosclerosis and likely atherothrombotic stroke combined and stroke with multiple causes, and none that of stroke due to small vessel disease. DISCUSSION: We identified cola consumption, vigorous physical exercise, sexual activity, illicit drug use, fever, and flu-like disease as potential trigger factors for stroke in the young population and found differences in the type and number of trigger factors associated with different etiologic subgroups of ischemic stroke. These findings might help in better understanding the pathophysiologic mechanisms of (cryptogenic) stroke in the young population.

Neuroimaging Parameters Are Not Associated With Chronic Post-stroke Fatigue in Young Stroke Patients.

Introduction: Post-stroke fatigue is frequently present in young adults, but its underlying mechanism is still unclear. The aim of the study was to investigate the association between lesion location, network efficiency and chronic post-stroke fatigue based on voxel-based lesion-symptom mapping and structural network connectivity analysis. Patients and Methods: One hundred and thirty five young patients, aged 18-50 years, with a first-ever transient ischemic attack or cerebral infarction from the Follow-Up of Transient ischemic attack and stroke patients and Unelucidated Risk factor Evaluation (FUTURE) study, underwent 1.5T MRI and were assessed for fatigue using the self-report Checklist Individual Strength. Stroke lesions were manually segmented, and structural network efficiency was calculated using the diffusion MRI-based brain networks and graph theory for each patient. Univariate and multivariate analyses was performed to study the associations between MRI parameters and chronic post-stroke fatigue. In addition, we used voxel-based lesion-symptom mapping to analyze the relationship between the lesion location and chronic post-stroke fatigue. Results: Mean age at index event was 39.0 years (SD ± 8.2), and mean follow-up duration was 11.0 years (SD ± 8.0). 50 patients (37%) had post-stroke fatigue. Voxel-based lesion-symptom mapping showed no significant relation between stroke lesions and the presence of chronic post-stroke fatigue. Furthermore, there were no significant associations between the lesion size or network efficiency, and the presence of chronic post-stroke fatigue. Discussion: We did not find any association between stroke characteristics (lesion location and size) and chronic post-stroke fatigue (CIS20-R), nor associations between structural brain network connectivity and post-stroke fatigue on the long term in young stroke patients.

Increased Risk of Pregnancy Complications After Stroke: The FUTURE Study (Follow-Up of Transient Ischemic Attack and Stroke Patients and Unelucidated Risk Factor Evaluation).

BACKGROUND AND PURPOSE: The study goal was to investigate the prevalence of pregnancy complications and pregnancy loss in women before, during, and after young ischemic stroke/transient ischemic attack. METHODS: In the FUTURE study (Follow-Up of Transient Ischemic Attack and Stroke Patients and Unelucidated Risk Factor Evaluation), a prospective young stroke study, we assessed the occurrence of pregnancy, miscarriages, and pregnancy complications in 223 women aged 18 to 50 years with a first-ever ischemic stroke/transient ischemic attack. Pregnancy complications (gestational hypertension, diabetes mellitus, preeclampsia, and hemolysis, elevated liver enzymes, low platelet count syndrome) were assessed before, during, and after stroke using standardized questionnaires. Primary outcome was occurrence of pregnancy complications and the rate of pregnancy loss compared with the Dutch population. Secondary outcome was the risk of recurrent vascular events after stroke, stratified by a history of hypertensive disorder in pregnancy. RESULTS: Data were available for 213 patients. Mean age at event was 39.6 years (SD=7.8) and mean follow-up 9.5 years (SD=8.5). Miscarriages occurred in 35.2% and fetal death in 6.2% versus 13.5% and 0.9% in the Dutch population, respectively (P<0.05). In nulliparous women after stroke (n=22), in comparison with Dutch population, there was a high prevalence of hypertensive disorders in pregnancy (33.3 versus 12.2%; P<0.05), hemolysis, elevated liver enzymes, low platelet count syndrome (9.5 versus 0.5%; P<0.05), and early preterm delivery <32 weeks (9.0 versus 1.4%; P<0.05). In primi/multiparous women (n=141) after stroke, 29 events occurred (20-year cumulative risk 35.2%; 95% confidence interval, 21.3-49.0), none during subsequent pregnancies, and a history of a hypertensive disorder in pregnancy did not modify this risk (log-rank P=0.62). CONCLUSIONS: When compared with the general population, women with young stroke show higher rates of pregnancy loss throughout their lives. Also, after stroke, nulliparous women more frequently experienced serious pregnancy complications.

Prothrombotic factors do not increase the risk of recurrent ischemic events after cryptogenic stroke at young age: the FUTURE study.

BACKGROUND: The role of hypercoagulable states and preceding infections in the etiology of young stroke and their role in developing recurrent ischemic events remains unclear. Our aim is to determine the prevalence of these conditions in patients with cryptogenic stroke at young age and to assess the long-term risk of recurrent ischemic events in patients with and without a hypercoagulable state or a recent pre-stroke infection with Borrelia or Syphilis. PATIENTS AND METHODS: We prospectively included patients with a first-ever transient ischemic attack or ischemic stroke, aged 18-50, admitted to our hospital between 1995 and 2010. A retrospective analysis was conducted of prothrombotic factors and preceding infections. Outcome was recurrent ischemic events. RESULTS: Prevalence of prothrombotic factors did not significantly differ between patients with a cryptogenic stroke and with an identified cause (24/120 (20.0%) and 32/174 (18.4%) respectively). In patients with a cryptogenic stroke the long-term risk [mean follow-up of 8.9 years (SD 4.6)] of any recurrent ischemic event or recurrent cerebral ischemia did not significantly differ between patients with and without a hypercoagulable state or a recent infection. In patients with a cryptogenic stroke 15-years cumulative risk of any recurrent ischemic event was 24 and 23% in patients with and without any prothrombotic factor respectively. CONCLUSIONS: The prevalence of prothrombotic factors and preceding infections did not significantly differ between stroke patients with a cryptogenic versus an identified cause of stroke and neither is significantly associated with an increased risk of recurrent ischemic events after cryptogenic stroke.

Risk factors and mechanisms of stroke in young adults: The FUTURE study.

Incidence of ischemic stroke and transient ischemic attack in young adults is rising. However, etiology remains unknown in 30-40% of these patients when current classification systems designed for the elderly are used. Our aim was to identify risk factors according to a pediatric approach, which might lead to both better identification of risk factors and provide a stepping stone for the understanding of disease mechanism, particularly in patients currently classified as "unknown etiology". Risk factors of 656 young stroke patients (aged 18-50) of the FUTURE study were categorized according to the "International Pediatric Stroke Study" (IPSS), with stratification on gender, age and stroke of "unknown etiology". Categorization of risk factors into ≥1 IPSS category was possible in 94% of young stroke patients. Chronic systemic conditions were more present in patients aged <35 compared to patients ≥35 (32.6% vs. 15.6%, p < 0.05). Among 226 patients classified as "stroke of unknown etiology" using TOAST, we found risk factors in 199 patients (88%) with the IPSS approach. We identified multiple risk factors linked to other mechanisms of stroke in the young than in the elderly . This can be a valuable starting point to develop an etiologic classification system specifically designed for young stroke patients.

Effect of Formal Education on Vascular Cognitive Impairment after Stroke: A Meta-analysis and Study in Young-Stroke Patients.

OBJECTIVES: The extent of vascular cognitive impairment (VCI) after stroke varies greatly across individuals, even when the same amount of brain damage is present. Education level is a potentially protective factor explaining these differences, but results on its effects on VCI are inconclusive. METHODS: First, we performed a meta-analysis on formal education and VCI, identifying 21 studies (N=7770). Second, we examined the effect of formal education on VCI in young-stroke patients who were cognitively assessed on average 11.0 (SD=8.2) years post-stroke (the FUTURE study cohort). The total sample consisted of 277 young-stroke patients with a mean age at follow-up 50.9 (SD=10.3). Age and education-adjusted expected scores were computed using 146 matched stroke-free controls. RESULTS: The meta-analysis showed an overall effect size (z') of 0.25 (95% confidence interval [0.18-0.31]), indicating that formal education level had a small to medium effect on VCI. Analyses of the FUTURE data showed that the effect of education on post-stroke executive dysfunction was mediated by age (ß age -0.015; p<.05). Below-average performance in the attention domain was more frequent for low-education patients (χ2(2)=9.8; p<.05). CONCLUSIONS: While education level was found to be related to post-stroke VCI in previous research, the effects were small. Further analysis in a large stroke cohort showed that these education effects were fully mediated by age, even in relatively young stroke patients. Education level in and of itself does not appear to be a valid indicator of cognitive reserve. Multi-indicator methods may be more valid, but have not been studied in relation to VCI. (JINS, 2017, 23, 223-238).

Remote Lower White Matter Integrity Increases the Risk of Long-Term Cognitive Impairment After Ischemic Stroke in Young Adults.

BACKGROUND AND PURPOSE: Poststroke cognitive impairment occurs frequently in young patients with ischemic stroke (18 through 50 years of age). Accumulating data suggest that stroke is associated with lower white matter integrity remote from the stroke impact area, which might explain why some patients have good long-term cognitive outcome and others do not. Given the life expectancy of decades in young patients, we therefore investigated remote white matter in relation to long-term cognitive function. METHODS: We included all consecutive first-ever ischemic stroke patients, left/right hemisphere, without recurrent stroke or transient ischemic attack during follow-up, aged 18 through 50 years, admitted to our university medical center between 1980 and 2010. One hundred seventeen patients underwent magnetic resonance imaging scanning including a T1-weighted scan, a diffusion tensor imaging scan, and completed a neuropsychological assessment. Patients were compared with a matched stroke-free control group (age, sex, and education matched). Cognitive impairment was defined as >1.5 SD below the mean cognitive index score of controls and no cognitive impairment as ≤1 SD. Tract-Based Spatial Statistics was used to assess the white matter integrity (fractional anisotropy and mean diffusivity). RESULTS: About 11 years after ischemic stroke, lower remote white matter integrity was associated with a worse long-term cognitive performance. A lower remote white matter integrity, even in the contralesional hemisphere, was observed in cognitively impaired patients (n=25) compared with cognitively unimpaired patients (n=71). CONCLUSIONS: These findings indicate that although stroke has an acute onset, it might have long lasting effects on remote white matter integrity and thereby increases the risk of long-term cognitive impairment.

Accelerated development of cerebral small vessel disease in young stroke patients.

OBJECTIVE: To study the long-term prevalence of small vessel disease after young stroke and to compare this to healthy controls. METHODS: This prospective cohort study comprises 337 patients with an ischemic stroke or TIA, aged 18-50 years, without a history of TIA or stroke. In addition, 90 age- and sex-matched controls were included. At follow-up, lacunes, microbleeds, and white matter hyperintensity (WMH) volume were assessed using MRI. To investigate the relation between risk factors and small vessel disease, logistic and linear regression were used. RESULTS: After mean follow-up of 9.9 (SD 8.1) years, 337 patients were included (227 with an ischemic stroke and 110 with a TIA). Mean age of patients was 49.8 years (SD 10.3) and 45.4% were men; for controls, mean age was 49.4 years (SD 11.9) and 45.6% were men. Compared with controls, patients more often had at least 1 lacune (24.0% vs 4.5%, p < 0.0001). In addition, they had a higher WMH volume (median 1.5 mL [interquartile range (IQR) 0.5-3.7] vs 0.4 mL [IQR 0.0-1.0], p < 0.001). Compared with controls, patients had the same volume WMHs on average 10-20 years earlier. In the patient group, age at stroke (ß = 0.03, 95% confidence interval [CI] 0.02-0.04) hypertension (ß = 0.22, 95% CI 0.04-0.39), and smoking (ß = 0.18, 95% CI 0.01-0.34) at baseline were associated with WMH volume. CONCLUSIONS: Patients with a young stroke have a higher burden of small vessel disease than controls adjusted for confounders. Cerebral aging seems accelerated by 10-20 years in these patients, which may suggest an increased vulnerability to vascular risk factors.

Kidney Dysfunction Increases Mortality and Incident Events after Young Stroke: The FUTURE Study.

BACKGROUND: In about 30% of young stroke patients, no cause can be identified. In elderly patients, kidney dysfunction has been suggested as a contributing risk factor for mortality as well as stroke. There are hypotheses that novel non-traditional risk factors, like chronic inflammation and oxidative stress, are involved in chronic kidney disease, affecting the cerebral microvasculature that would in turn lead to stroke. Our objective is to investigate the influence of kidney dysfunction on long-term mortality and incident vascular events after stroke in young adults aged 18 through 50 and if this relationship would be independent of other cardiovascular risk factors. METHODS: We prospectively included 460 young stroke patients with an ischemic stroke or transient ischemic attack admitted to our department between January 1, 1980 and November 1, 2010. Follow-up was done between 2014 and 2015. Estimated glomerular filtration rate (eGFR) was calculated from baseline creatinine levels and was divided in 3 subgroups: eGFR <60, 60-120 and >120 ml/min/1.73 m2. Cox proportional hazard models were used to determine the effect of kidney dysfunction on mortality and incident vascular events, adjusting for cardiovascular risk factors. RESULTS: An eGFR <60 (HR 4.6; 95% CI 2.6-8.2) was associated with an increased risk of death and an increased risk of incident stroke (HR 4.1; 95% CI 1.9-9.0) independent of cardiovascular risk factors, but it was not associated with other vascular events. The point estimate for the 15-year cumulative mortality was 70% (95% CI 46-94) for patients with a low eGFR, 24% (95% CI 18-30) for patients with a normal eGFR and 30% (95% CI 12-48) for patients with a high eGFR. The point estimate for the 15-year cumulative risk of incident stroke was 45% (95% CI 16-74) for patients with a low eGFR, 13% (95% CI 9-17) for patients with a normal eGFR and 8% (95% CI 0-18) for patients with a high eGFR. CONCLUSIONS: Kidney dysfunction is related to long-term mortality and stroke recurrence, but not to incident cardiovascular disease, on average 11 years after young stroke. This warrants a more intensive follow-up of young stroke patients with signs of kidney dysfunction in the early phase. In addition, the clear association between kidney dysfunction and incident stroke seen in our young stroke population might be a first step in the recognition of kidney dysfunction as a new risk factor for the development of stroke at young age. Also, it can lead to new insights in the etiological differences between cardiovascular and cerebrovascular disease.

Women have a poorer very long-term functional outcome after stroke among adults aged 18-50 years: the FUTURE study.

Due to their young age young stroke survivors have to cope with a dramatic impact on their life for the decades to come. We investigated the sex-specific very long-term functional outcome after transient ischemic attack (TIA) and ischemic stroke (IS) in adults aged 18-50 years. This study is part of a cohort study among 619 first-ever young ischemic stroke patients, admitted to our department between January 1, 1980 and November 1, 2010. Functional outcome was assessed during follow-up in 2009-2011 and in 2014-2015 with the modified Rankin Scale (mRS) and instrumental Activities of Daily Living scale (iADL). Risk factors for a poor functional outcome (mRS > 2 and iADL < 8) were calculated by logistic regression analysis. After a mean follow-up of 13.9 (SD 8.2) years, 24.5 % of TIA patients and 44.7 % of IS patients had a poor functional outcome (mRS > 2). When assessing the survivors, 15.2 % of TIA patients and 22.9 % of IS patients had a poor outcome as assessed by iADL. The strongest baseline predictors of poor outcome were female sex (OR 2.7, 95 % CI 1.5-5.0) and baseline NIHSS (OR 1.1, 95 % CI 1.1-1.2 per point increase). In conclusion, 14 years after an ischemic cerebrovascular event in young adults, one out of five IS survivors and one out of ten TIA survivors is still dependent in daily life, with a two to threefold higher risk of a poor outcome in women. This includes a period of life, during which important decisions regarding work and family life have to be made.

The very long-term risk and predictors of recurrent ischaemic events after a stroke at a young age: The FUTURE study.

INTRODUCTION: Patients who suffer a stroke at a young age, remain at a substantial risk of developing recurrent vascular events and information on very long-term prognosis and its risk factors is indispensable. Our aim is to investigate this very long-term risk and associated risk factors up to 35 years after stroke. PATIENTS AND METHODS: Prospective cohort study among 656 patients with a first-ever ischaemic stroke or transient ischaemic stroke (TIA), aged 18-50, who visited our hospital (1980-2010). Outcomes assessed at follow-up (2014-2015) included TIA or ischaemic stroke and other arterial events, whichever occurred first. Kaplan-Meier analysis quantified cumulative risks. A prediction model was constructed to assess risk factors independently associated with any ischaemic event using Cox proportional hazard analyses followed by bootstrap validation procedure to avoid overestimation. RESULTS: Mean follow-up was 12.4 (SD 8.2) years (8105 person-years). Twenty-five years cumulative risk was 45.4% (95%CI: 39.4-51.5) for any ischaemic event, 30.1% (95%CI: 24.8-35.4) for cerebral ischaemia and 27.0% (95%CI: 21.1-33.0) for other arterial events. Risk factors retained in the prediction model were smoking (HR 1.35, 95%CI: 1.04-1.74), poor kidney function (HR 2.10, 95%CI: 1.32-3.35), history of peripheral arterial disease (HR 2.10, 95%CI: 1.08-3.76) and cardiac disease (HR 1.84, 95%CI: 1.06-3.18) (C-statistic 0.59 (95%CI: 0.55-0.64)). DISCUSSION AND CONCLUSION: Young stroke patients remain at a substantial risk for recurrent events; almost 1 of 2 develops a recurrent ischaemic event and 1 of 3 develops a recurrent stroke or TIA during 25 years of follow-up. Risk factors independently associated with recurrent events were poor kidney function, smoking, history of peripheral arterial disease and cardiac disease.

Lower Ipsilateral Hippocampal Integrity after Ischemic Stroke in Young Adults: A Long-Term Follow-Up Study.

BACKGROUND AND PURPOSE: Memory impairment after stroke is poorly understood as stroke rarely occurs in the hippocampus. Previous studies have observed smaller ipsilateral hippocampal volumes after stroke compared with controls. Possibly, these findings on macroscopic level are not the first occurrence of structural damage and are preceded by microscopic changes that may already be associated with a worse memory function. We therefore examined the relationship between hippocampal integrity, volume, and memory performance long after first-ever ischemic stroke in young adults. METHODS: We included all consecutive first-ever ischemic stroke patients, without hippocampal strokes or recurrent stroke/TIA, aged 18-50 years, admitted to our academic hospital between 1980 and 2010. One hundred and forty-six patients underwent T1 MPRAGE, DTI scanning and completed the Rey Auditory Verbal Learning Test and were compared with 84 stroke-free controls. After manual correction of hippocampal automatic segmentation, we calculated mean hippocampal fractional anisotropy (FA) and diffusivity (MD). RESULTS: On average 10 years after ischemic stroke, lesion volume was associated with lower ipsilateral hippocampal integrity (p<0.05), independent of hippocampal volume. In patients with a normal ipsilateral hippocampal volume (volume is less than or equal to 1.5 SD below the mean volume of controls) significant differences in ipsilateral hippocampal MD were observed (p<0.0001). However, patients with a normal hippocampal volume and high hippocampal MD did not show a worse memory performance compared with patients with a normal volume and low hippocampal MD (p>0.05). CONCLUSIONS: Patients with average ipsilateral hippocampal volume could already have lower ipsilateral hippocampal integrity, although at present with no attendant worse memory performance compared with patients with high hippocampal integrity. Longitudinal studies are needed to investigate whether a low hippocampal integrity after stroke might lead to exacerbated memory decline with increasing age.

Cognitive performance and poor long-term functional outcome after young stroke.

OBJECTIVE: To investigate the influence of cognitive performance on long-term functional outcome after ischemic stroke (IS) in young adults aged 18 through 50 years (young IS). METHODS: This study is part of a prospective cohort study among 277 stroke survivors with a young IS admitted to our department between January 1, 1980, and November 1, 2010. Functional outcome was assessed during follow-up between 2009 and 2012 with the modified Rankin Scale (mRS) and Instrumental Activities of Daily Living scale (IADL). Extensive neuropsychological investigation was performed. Logistic regression was used to calculate odds ratios (ORs) for a poor functional outcome (mRS >2 or IADL <8) for the 7 cognitive domains adjudicated for confounders. Cognitive function (continuous) as well as cognitive impairment (dichotomous) were studied. RESULTS: Only decline in working memory (OR 0.3, 95% confidence interval [CI] 0.1-0.6) was associated with poor functional outcome on the mRS. Except for decline in processing speed (OR 0.5, 95% CI 0.3-0.8) and working memory (OR 0.4, 95% CI 0.2-0.7), no relation was found with poor functional outcome on IADL. Impairment in none of the individual cognitive domains was related to long-term functional outcome, although impairment in global cognitive function was related to a poor functional outcome on the IADL (OR 4.8, 95% CI 1.7-14.0). CONCLUSIONS: On average, 11 years after young IS there was no clear relationship between long-term cognitive deficits and long-term functional outcome or IADL, stressing the need for further prospective studies with further development of sensitive measures of functional prognosis.

Poststroke Epilepsy Is Associated With a High Mortality After a Stroke at Young Age: Follow-Up of Transient Ischemic Attack and Stroke Patients and Unelucidated Risk Factor Evaluation Study.

BACKGROUND AND PURPOSE: Poststroke epilepsy is a common complication after a young stroke. We investigated the association between poststroke epilepsy and mortality. METHODS: We performed a prospective cohort study among 631 patients with a first-ever transient ischemic attack or ischemic stroke, aged 18 to 50 years. Survival analysis and Cox proportional hazard analysis were used to estimate cumulative mortality and hazard ratios for patients with and without epilepsy. RESULTS: After mean follow-up of 12.5 years (SD 8.6), 76 (12.0%) developed poststroke epilepsy. Case fatality was 27.4% for patients with poststroke epilepsy and 2.1% for those without. Poststroke epilepsy was associated with 30-day mortality (hazard ratio, 4.8; 95% confidence interval, 1.7-14.0) and long-term mortality (hazard ratio, 1.8; 95% confidence interval, 1.2-2.9). CONCLUSIONS: Epilepsy is a common problem after a young stroke and is associated with an increased short-term and long-term mortality.