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.

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.

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.

Ipsilateral hippocampal atrophy is associated with long-term memory dysfunction after ischemic stroke in young adults.

Memory impairment after stroke in young adults is poorly understood. In elderly stroke survivors memory impairments and the concomitant loss of hippocampal volume are usually explained by coexisting neurodegenerative disease (e.g., amyloid pathology) in interaction with stroke. However, neurodegenerative disease, such as amyloid pathology, is generally absent at young age. Accumulating evidence suggests that infarction itself may cause secondary neurodegeneration in remote areas. Therefore, we investigated the relation between long-term memory performance and hippocampal volume in young patients with first-ever ischemic stroke. We studied all consecutive first-ever ischemic stroke patients, aged 18-50 years, admitted to our academic hospital center between 1980 and 2010. Episodic memory of 173 patients was assessed using the Rey Auditory Verbal Learning Test and the Rey Complex Figure and compared with 87 stroke-free controls. Hippocampal volume was determined using FSL-FIRST, with manual correction. On average 10 years after stroke, patients had smaller ipsilateral hippocampal volumes compared with controls after left-hemispheric stroke (5.4%) and right-hemispheric stroke (7.7%), with most apparent memory dysfunctioning after left-hemispheric stroke. A larger hemispheric stroke was associated with a smaller ipsilateral hippocampal volume (b=-0.003, P<0.0001). Longer follow-up duration was associated with smaller ipsilateral hippocampal volume after left-hemispheric stroke (b=-0.028 ml, P=0.002) and right-hemispheric stroke (b=-0.015 ml, P=0.03). Our results suggest that infarction is associated with remote injury to the hippocampus, which may lower or expedite the threshold for cognitive impairment or even dementia later in life.

Long-term cognitive impairment after first-ever ischemic stroke in young adults.

BACKGROUND AND PURPOSE: Up to 14% of all ischemic strokes occur in young adults (<50 years). Poststroke cognitive performance is a decisive determinant of their quality of life. However, virtually no studies report on cognition after young stroke, especially not on the long term. This long-term perspective is important because young patients have a long life expectancy during which they start forming a family, have an active social life, and make decisive career moves. We aimed to evaluate the long-term cognitive outcome. METHODS: All consecutive patients between January 1, 1980, and November 1, 2010, with a first-ever young ischemic stroke were recruited for cognitive assessment, using a matched stroke-free population as a reference. Composite Z scores for 7 cognitive domains were calculated and the ANCOVA model was used (Bonferroni correction). A below average performance was defined as >1.0 SD below the age-adjusted mean of the controls and cognitive impairment as >1.5 SD. RESULTS: Two hundred seventy-seven patients and 146 matched controls completed cognitive assessment (mean follow-up, 11.0 years, SD, 8.2; age, 50.9 years, SD, 10.3). Long-term cognitive outcome after an ischemic stroke was worse in most cognitive domains compared with a nonstroke population. Up to 50% of the patients had a below average performance or cognitive impairment. Deficits in processing speed, working memory, and attention were most common. CONCLUSIONS: Even 11 years after ischemic stroke in young adults, a substantial proportion of patients must cope with permanent cognitive deficits. These results have implications for information given to patients and rehabilitation services.

Ischemic neuropathy and rhabdomyolysis as presenting symptoms of postpartum cardiomyopathy.

Rhabdomyolysis and peripheral neuropathy are two distinct disease entities which are rarely encountered in combination. We present a woman with rhabdomyolysis and peripheral neuropathy 3 weeks postpartum. Her symptoms were caused by bilateral femoral artery thrombosis due to postpartum cardiomyopathy (PPCM). This demonstrates that PPCM may present with predominantly non-cardial symptoms and underscores the importance of rapidly recognizing this disorder.

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.

Cardiovascular disease is the main cause of long-term excess mortality after ischemic stroke in young adults.

Adults with stroke at a young age (18-50 years) remain at an increased risk of death for decades. It is unclear what cause underlies this long-term excess mortality and whether this is sex and time specific. Therefore, we investigated sex-specific temporal changes in cause of death after transient ischemic attack or ischemic stroke in young adults aged 18 to 50 years. We included all 845 consecutive 30-day survivors, of a first-ever transient ischemic attack (n=261) or ischemic stroke (n=584), admitted to our hospital between 1980 and 2010. Survival status was assessed at April 1, 2013. Observed cause-specific mortality was compared with expected mortality, derived from mortality rates in the general population with similar age, sex, and calendar-year characteristics. During a median follow-up of 9.2 years, 146 patients (17.3%) died, such that 29 years of life was lost by each individual. For all causes of death, observed mortality exceeded expected mortality. The absolute excess risk of death was for 74% attributable to a vascular cause (absolute excess risk, 2.8 per 1000 person-years [95% confidence interval, 1.8-4.1] for stroke and absolute excess risk, 4.3 per 1000 person-years [95% confidence interval, 2.9-5.9] for other vascular causes). The absolute excess risk was highest between 10 and 15 years after stroke and this peak was most pronounced in men and mainly attributable to vascular death. Long-term excess death after stroke in young adults is mainly attributable to a vascular cause and most pronounced in men. Attempts to reduce the risk of vascular disease after stroke in young adults should extend beyond the acute phase into the long term.

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.

Clinical characteristics and outcome of intracerebral hemorrhage in young adults.

Data on determinants of prognosis after intracerebral hemorrhage (ICH) in young adults are scarce. Our aim was to identify clinical determinants of prognosis after ICH in adults aged 18-50. We investigated 98 consecutive patients with an ICH, aged 18-50 years, admitted to our hospital between 1980 and 2010. Collected ICH characteristics included presenting symptoms, etiology, location, severity and Glasgow Coma Scale (GCS). Outcomes were case-fatality (death within 30 days), poor functional outcome (modified Rankin Scale >2), long-term mortality and recurrent ICH. We assessed discriminatory power of factors associated with case-fatality [area under receiver operating curve (AUC)]. Case-fatality was 20.4 % (n = 20) and well predicted by the GCS (AUC 0.83). Among 30-day survivors, a poor functional outcome at discharge was present in 51.3 %. During a mean follow-up of 11.3 years mortality was only increased in patients aged 40-50 years [standardized mortality ratio 4.8 (95 % CI 2.3-8.6)], but not in patients aged 18-40 years. Recurrent ICH occurred in 6 patients [10-year cumulative incidence 12.2 % (95 % CI 1.5-22.9 %)], all with the index ICH attributable to structural vascular malformations. Prognosis after ICH in young adults is poor, mainly due to high case-fatality, that is well predicted by the GCS. An exception is 30-day survivors <40 years, who have a similar risk of dying as the general population. Recurrence risk is especially present in patients with structural vascular malformations, whereas risk seems to be very low in other patients.

Long-term increased risk of unemployment after young stroke: a long-term follow-up study.

OBJECTIVE: To investigate the prevalence, excess risk, and risk factors of unemployment in patients after a TIA, ischemic stroke, or intracerebral hemorrhage at ages 18 through 50 years, compared with nationwide controls. METHODS: We performed a hospital-based cohort study among 694 patients, aged 18-50 years, with a first-ever TIA, ischemic stroke, or intracerebral hemorrhage. After a mean follow-up duration of 8.1 (SD 7.7) years, we used logistic regression analysis to calculate odds ratio (OR) with 95% confidence interval (CI) for being unemployed as a young stroke patient, compared with the Dutch population of vocational age (n = 7,803,000), with subsequent assessment of risk factors of unemployment. RESULTS: Young stroke patients had a higher risk of being unemployed than their peers in the Dutch population: women OR 2.3 (1.8-2.9), men OR 3.2 (2.5-4.0). A higher NIH Stroke Scale score at admission (OR 1.1 [95% CI 1.0-1.1]) and a longer follow-up duration (middle tertile OR 2.8 [95% CI 1.7-4.7], upper tertile OR 3.4 [95% CI 1.9-6.1]) were associated with a higher risk of being unemployed. CONCLUSION: Young stroke patients had a 2-3 times higher risk of unemployment after 8 years of follow-up. Return-to-work programs should be developed, adjusted, and evaluated in order to diminish the negative effects that unemployment can have on patients' life satisfaction and to limit the socioeconomic consequences.

Subjective cognitive failures after stroke in young adults: prevalent but not related to cognitive impairment.

Few studies exist on subjective cognitive failures after a stroke in young adults (≤50 years) and their relation to objective cognitive performance is unknown. Therefore, we investigated the prevalence of subjective cognitive failures in patients with a stroke in young adulthood and their relation with objective cognitive impairment. This study is part of the "Follow-Up of Transient ischemic attack and stroke patients and Unelucidated Risk factor Evaluation"-study (FUTURE study), including patients, aged 18-50 years, admitted to our hospital between 1980 and 2010 with a first-ever TIA or ischemic stroke. The prevalence of subjective cognitive failures in patients was determined and compared with 146 age- and sex-matched stroke-free controls. The relation of subjective failures with objective cognitive performance was investigated with linear and logistic regression analysis. 160 patients with a TIA and 277 with an ischemic stroke were included. After a mean follow-up of 10.1 (SD 8.3) years, the prevalence of subjective memory failures was 86.4% and that of subjective executive failures was 67.4% in patients, versus 69.7% (p = 0.008) and 41.4% (p = 0.002) in controls. A weak association between subjective memory failures and objective immediate (beta -0.12, p = 0.011) and delayed memory performance (beta -0.13, p = 0.010) was observed in patients. Subjective cognitive failures are prevalent after stroke in young adults, but not strongly related to objective cognitive impairment. Therefore, extensive neuropsychological assessment is essential for determination of objective cognitive impairment. However, it is important that subjective cognitive failures are recognized as they may indicate underlying psychosocial problems.

Epilepsy after TIA or stroke in young patients impairs long-term functional outcome: the FUTURE Study.

OBJECTIVE: To determine the influence of poststroke epilepsy on long-term functional outcome in young stroke survivors. METHODS: This study is a prospective cohort study among 537 stroke survivors with a first-ever TIA, ischemic stroke, or intracerebral hemorrhagic (ICH) stroke, aged 18 to 50 years. After a mean follow-up of 9.8 years (SD 8.4), we performed a follow-up assessment that included an evaluation for poststroke epilepsy and functional outcome. Odds ratios for poor outcome on the modified Rankin Scale (mRS) (score >2) and Instrumental Activities of Daily Living (IADL) (score <8) were calculated using logistic regression analysis. RESULTS: Forty patients (12.7%) with ischemic stroke, 4 patients (2.2%) with TIA, and 10 patients (25.6%) with ICH developed poststroke epilepsy. Ischemic stroke patients with epilepsy more often had a poor functional outcome than those without, both on the mRS and IADL (mRS score >2: 27.5% vs 9.8%, p = 0.001; IADL <8: 27.8% vs 12.6%, p = 0.02). Epilepsy was not related to functional outcome in patients with TIA and ICH. Multiple regression analysis revealed that epilepsy was an independent predictor of poor functional outcome after ischemic stroke assessed by mRS (mRS score >2: odds ratio 3.38, 95% confidence interval 1.33-8.60). In contrast, there was no such relation for IADL. CONCLUSIONS: Epilepsy after stroke in young patients is a common problem that negatively affects functional outcome, even more than 10 years after ischemic stroke.