Published online before print February 26, 2009, doi: 10.1161/STROKEAHA.108.529883
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
(Stroke. 2009;40:1195.)
© 2009 American Heart Association, Inc.
Original Contributions |
Analysis of 1008 Consecutive Patients Aged 15 to 49 With First-Ever Ischemic Stroke
The Helsinki Young Stroke Registry
From the Department of Neurology, Helsinki University Central Hospital, Helsinki, Finland.
Correspondence to Dr Jukka Putaala, Department of Neurology, Helsinki University Central Hospital, Haartmaninkatu 4, FIN-00290, Helsinki, Finland. E-mail jukka.putaala{at}hus.fi
 |
Abstract |
|---|
 Top Abstract IntroductionPatients and MethodsResultsDiscussionReferences |
|---|
Background and Purpose— To analyze trends in occurrence, risk factors, etiology, and neuroimaging features of ischemic stroke in young adults in a large cohort.
Methods— We evaluated all 1008 consecutive ischemic stroke patients aged 15 to 49 admitted to Helsinki University Central Hospital, 1994 to 2007. Etiology was classified by Trial of Org 10172 in Acute Stroke Treatment criteria. Comparisons were done between groups stratified by gender and age.
Results— Estimated annual occurrence was 10.8/100 000 (range 8.4 to 13.0), increasing exponentially with aging. Of our 628 male and 380 female (ratio 1.7:1) patients, females were preponderant among those <30, whereas male dominance rapidly increased around age of 44. The most frequent risk factors were dyslipidemia (60%), smoking (44%), and hypertension (39%). Males and patients >44 clearly had more risk factors. Cardioembolism (20%) and cervicocerebral artery dissection (15%) were the most frequent etiologic subgroups. Proportions of large-artery atherosclerosis (8%) and small-vessel disease (14%) began to enlarge at age 35, whereas frequency of undetermined etiology (33%) decreased along aging. Posterior circulation infarcts were more common among patients <45 years of age. Left hemisphere infarcts were more frequent in general. There were 235 (23%) patients with multiple and 126 (13%) with silent infarcts, and 55 (5%) patients had leukoaraiosis.
Conclusions— The frequency of ischemic stroke increases sharply at age 40. Etiology and risk factors start resembling those seen in the elderly in early midlife but causes defined in younger patients still are frequent in those aged 45 to 49. Subclinical infarcts were surprisingly common in the young.
Key Words: cerebral infarct • imaging • risk factors • stroke in young adults • young, stroke in
|
Introduction |
|---|
|
TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
|---|
Ischemic stroke is an important cause of morbidity and mortality. It often has devastating consequences with respect to quality of life and work ability, which holds true especially at younger ages. As it is well established, incidence, risk factors, and etiology in young adults differ notably from those seen in older patients. In previous series of young brain infarct patients, males have commonly predominated,1–7 but opposite reports also exist.8–11 Females usually outnumber males among patients under 30.1,3,8,10,11 More detailed occurrence data from large patient cohorts are sparse, however. Traditional vascular risk factors as well as migraine and oral contraceptive use have been reported as frequent in previous series.2,4–8,10–13 As prior studies involved rather modest number of patients and more evidence of both well established and less well-documented risk factors constantly accumulates,14 there is a clear need for an update. Furthermore, only a handful of studies have presented neuroimaging data on young brain infarct patients, the earliest involving mainly patients diagnosed by computed tomography (CT).2–4,8,11 Localization was analyzed more thoroughly in one CT-study.8 To satisfy the need for a larger up-to-date study assessing features of ischemic stroke in the young, we established a comprehensive database. The Helsinki Young Stroke Registry includes all ischemic stroke patients under age 50 diagnosed and treated at our department since the beginning of 1994. In the present study, we sought to determine the trends in occurrence, risk factors, etiology and its evolution, as well as detailed neuroimaging features of these patients.
|
Patients and Methods |
|---|
|
TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
|---|
This retrospective study was approved by the relevant authorities and carried out at the Department of Neurology, Helsinki University Central Hospital, which serves as the only neurological emergency unit for a population of 1.5 million. We reviewed the medical records of all consecutive patients aged 15 to 49 in whom ischemic stroke was suspected between January 1994 and May 2007. The upper age cut-off of 50 was chosen to allow comparisons of differences between younger and older young adults. We found cases by computer search of the hospital database according to the following criteria: (1) patient living in the catchment area; (2) age 15 to 49 at stroke onset; and (3) discharge diagnosis of ischemic stroke. All medical and laboratory records, as well as brain imaging studies, were reviewed by a team of stroke neurologists. Data were abstracted according to a predefined protocol. Only patients with first-ever ischemic stroke with overt clinical symptoms were included. Excluded were those with transient ischemic attack (TIA), cerebral venous thrombosis, stroke attributable to direct head trauma or strangulation, ischemic lesion attributable to immediate complications originating from subarachnoidal hemorrhage, and any iatrogenic stroke as a consequence of angiographic imaging or major surgery (supplemental Table I, available online at http://stroke.ahajournals.org). We defined ischemic stroke as an episode of focal neurological deficits with acute onset and lasting >24 hours (or lasting <24 hours with imaging evidence of stroke corresponding with current symptoms). TIA was defined similarly but with symptoms lasting <24 hours and without corresponding imaging evidence of ischemic lesion. The hospital discharge register from the National Research and Development Centre for Welfare and Health allowed us to ascertain that our hospital register covers nearly all young stroke patients in our catchment area. Demographic data came from Statistics Finland.
|
Patients were initially examined by neurologists at the emergency unit and neurological wards reflecting our institutional protocol currently applied and evaluation was carried out on a case by case basis. All patients underwent routinely a range of blood tests, a chest x-ray, ECG, and brain imaging at admission (supplemental Table II
). All brain imaging studies were evaluated by neuroradiologists. Vascular imaging of intracranial or extracranial vessels or both were done for 929 (92%) patients. Specific coagulation testing was performed on selected patients. Cardiac evaluation was done on 602 (60%) patients by cardiologists. In our center, a dye dilution test, specific and sensitive for the screening of patent foramen ovale (PFO),15 is often combined with transthoracal echocardiography (TTE). Transesophageal echocardiography (TEE) is then performed for confirmation when a cardiac right-to-left shunt is detected. All patients were invariably under continuous ECG monitoring at acute phase. A prolonged ECG recording or other more specific diagnostic testing, eg, in search for vasculitis, were performed when clinically judged necessary.
|
|
The evaluated stroke risk factors and applied definitions are shown in supplemental Table II
. We retrospectively applied consistent definitions for risk factors over the study period. Furthermore, we categorized risk factors according to the existing evidence.14 Stroke subtypes were classified according to the Trial of Org 10172 in Acute Stroke Treatment (TOAST) criteria.16 Stroke subtype was assigned to each patient by pairs of investigators, and in case of discrepancy the patient records were reviewed by a senior investigator and the final categorization was based on consensus agreement of all these. Rare etiologies with uncertain causality, such as clotting abnormalities, were considered as a cause if diagnostic testing was exhaustive and other possible causes absent. PFO with or without atrial septal aneurysm (ASA) was considered similarly causative in the absence of other possible mechanisms. Migrainous infarct was defined according to International Headache Society (IHS) criteria.17
Arterial territory of stroke was classified according to imaging findings or clinical signs. We registered laterality of current visualized ischemic lesions and categorized localization as follows: hemisphere (including basal ganglia and thalamic regions), cerebellum, and brain stem. We defined silent infarcts as imaging evidence of 
1 infarcts without a history of a corresponding stroke or TIA. Multiplicity of all visualized infarcts (including silent infarcts) and leukoaraiosis were registered as well.
Average occurrence rates were calculated based on average population from 1994 to 2006. An exponential regression model served to measure the correlation between occurrence and aging. Pearson Chi-Sq and Fisher Exact tests were used to compare categorical variables across groups, and Student t test to compare means. The binomial test for proportions based on Z approximation allowed comparison of laterality of ischemic lesions. All statistical analyses used SPSS 15.0 for Microsoft Windows (SPSS Inc). Two-sided values of P<0.05 were considered statistically significant.
|
Results |
|---|
|
TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
|---|
We identified 1194 potential candidates, of whom 1008 fulfilled the inclusion criteria (supplemental Table I). We had an overall male preponderance (male:female ratio 1.7:1), but patients aged under 30 were more commonly females (females versus males: 56%, n=59 versus 44%, n=47; P<0.001), whereas those 45 to 49 were mostly males (males versus females: 69%, n=319 versus 31%, n=145; P<0.001; Figure 1). Females were significantly younger (95% confidence intervals, CI, 39.1 to 40.7 versus 41.5 to 42.6, respectively; Table 1). Occurrence increased exponentially, correlating with age (Figure 1). Patients <45 and those >44 formed almost equal cohorts and at around age 44 trends in occurrence between males and females clearly separate. Therefore, we divided the study population into 2 cohorts at age 44 for further comparisons. Average annual occurrence rates were 10.8/100 000 (range 8.4 to 13.0) overall, 13.3 (10.2 to 17.3) for males, and 7.8 (5.6 to 9.5) for females. To allow comparisons with several prior studies, occurrence rates were calculated for the age-group 15 to 44 years: 6.6 (range 5.0 to 9.6) overall, 7.5 (5.7 to 10.3) for males, and 5.7 (3.3 to 8.9) for females.
|
|
Frequencies of risk factors are presented in Table 1. Particularly traditional stroke risk factors were more frequent among males and those over 44. In only 51 (5.1%) cases no obvious risk factors were identified. The most common well-documented risk factor was dyslipidemia, followed by smoking, hypertension, and obesity. Males were more often heavy drinkers, whereas migraine as a risk factor was more common in females. Illicit drug use and migraine were more frequent in the younger group. The population included 6 pregnant females and another 4 suffering a postpartum stroke, their age ranging from 20 to 37. Oral contraceptive use and gravidity or postpartum period were the only risk factors more frequent among patients aged <30 (P<0.001 for both).
Stroke etiology is shown in Tables 2, 3, and 4. Cardioembolism (19.6%) and cervicocerebral artery dissection (15.4%) were the most commonly identified causes. Among patients <45, dissection was an even more common cause (n=101, 18.6%) and vertebral artery dissections (including 2 with basilar artery dissection) were more frequent compared with those >44 (n=60, 11% versus n=24, 5%; P=0.001). Such difference between the age-groups was not observed in patients with carotid artery dissection (n=40, 7% versus n=39, 8%; P=0.6). Large-artery atherosclerosis patients (7.5%) were older compared with others (age range 34 to 49 years; mean 45.7 versus 40.9; P<0.001; 95% CI of the difference, 3.9 to 5.7), and they were mostly males. Expectedly, also small-vessel disease patients (13.8%) were older (range 35 to 49; mean 45.4 versus 40.6; P<0.001; 95% CI 4.0 to 5.6). In contrast, patients with other determined etiology (25.7%) were younger (mean 39.8 versus 41.8; P=0.001; 95% CI 0.9 to 3.1). Multiple possible causes were present in 21 patients. Eleven of these had PFO combined with coagulation abnormality (n=6) or migrainous infarct (n=5). Despite comprehensive evaluation, 226 (22.4%) had no identified cause. These patients were younger as well (mean 38.9 versus 42.0; P<0.001; 95% CI 1.8 to 4.3). Diagnostic workup was incomplete in 8.5%, more commonly in those >44. Figure 2 illustrates the evolution of etiologic spectrum as a function of age in the patient population. The most striking change over the study period was a constant decrease in the proportion of the incomplete diagnostics group (TOAST 5c). In contrast, the percentages of other determined etiology and cardioembolism showed increasing trends (supplemental Figure I, available online at http://stroke.ahajournals.org).
|
|
|
|
|
Brain imaging revealed one or more ischemic lesions correlating with current symptoms in 921 (91%) patients. Anterior circulation infarcts were more common among older patients, whereas posterior territory infarcts in those <45, the latter being mostly attributable to cerebellar lesions. Infarcts occurred more often in the left cerebral hemisphere (P<0.001), independent of gender and age (P
0.02). Right-side cerebellar infarcts were more frequent among males (P=0.004) and among all under the age of 45 (P=0.007). Brain stem infarcts occurred more often on the right side as well (P=0.007), particularly in the younger group (P=0.04). Clinically silent brain infarcts were rather frequent (n=126, 13%) and occurred mainly in the older age group, who also more often had leukoaraiosis (5%). Multiple infarcts were also common (23%), with no differences by demographic subgroup (Table 2).
|
Discussion |
|---|
|
TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
|---|
We report a descriptive study with more than 1000 consecutive young patients suffering from first-ever ischemic stroke treated in a single teaching hospital. Large studies using modern imaging techniques and a wide array of ancillary testing, and allowing representation of populations with diverse ethnic and geographic backgrounds, are necessary.
Depending on various factors, reported incidence of ischemic stroke in the young have ranged from 3 to 23 per 100 000 over the last 3 decades.18,19 We missed only a few patients annually treated in regional hospitals, as revealed by statistics from the National Research and Development Centre for Welfare and Health. We did not search nonhospitalized patients or those who possibly died before admission, which may cause some additional underestimation of occurrence rates. Standard practice in Finland is to treat all stroke patients in neurological units, irrespective of stroke severity. Therefore, despite its hospital-based setting, our study could be considered nearly a population based. Our average rates are thus closely comparable to those in earlier hospital-based or population-based reports.2,3,10,19 As in two other northern European studies,2,3 males were overrepresented, and as in several studies, females outnumbered men among those under 30.1,3,8,10,11
The accumulation of traditional risk factors in males and with aging is likely to explain the male predominance among older patients and the steep exponential increase in occurrence (Figure 1). Our findings suggest that the risk factor profile and etiology start to merge those seen in older patients already in early midlife, while this shift accelerates at around age 44 (Figure 2). On the other hand, the larger proportions of undetermined etiology in younger age-groups may be explained by inadequately recognized predisposing genetic factors or poorly understood risk factor interactions. We chose 50 as the upper age limit to conceptualize the change in stroke risk factors and etiology in this population as a function of age. Stroke mechanisms defined in younger patients still were frequently seen in those aged 45 to 49. These etiologies may well be applicable to older stroke patients as well, but in clinical practice the causes of stroke defined in younger patients may possibly be less easily teased out in the elderly because of their high prevalence of risk factors and degenerative causes. Based on our data and previous literature, "stroke in the young" defined as occurring at age 44 or less is relevant in research settings. However, the upper age cut-off may be shifting upwards as expected longevity increases worldwide, particularly in industrialized nations.
The unexpectedly high frequencies of modifiable risk factors indicate a need for aggressive primary and secondary prevention strategies. Although the association of dyslipidemia and ischemic stroke is not as clear as in coronary artery disease, evidence is compelling that increased stroke risk is associated with high levels of total cholesterol and low-density lipoprotein, and low high-density lipoprotein levels in males.14,20 By the modern criteria, dyslipidemia was clearly the most prominent well-documented risk factor in our series. Furthermore, our prevalence of traditional risk factors was among the highest reported in industrialized countries, albeit variation in criteria complicates comparisons.2,4,6–8,10,12,13
Many of the less well-documented risk factors may have fairly modest impact alone, but the effect may be significant if being present in combination or if associated with "more potent" factors such as smoking. Based on the overall high frequency of stroke risk factors detected in our patients, such interactions are very likely. An example of well-defined potentiation is seen among women with migraine as relative stroke risk of migraine is strongly increased by oral contraceptive use and smoking.21 PFO, with or without ASA, and its association with migraine22 or prothrombotic mutations23 demonstrates another complex interaction of factors with low primary risk alone. However, PFO with or without ASA, or ASA alone, should be considered as potential sources of cardioembolism in young adults—despite the difficulties of confirming the paradoxical embolism, in situ thrombosis, or transient atrial arrythmia.24 We registered a lower rate of PFO than is found in normal population,25 which is probably attributable to underutilization of TEE and dye-dilution tests. Considering the frequency in normal population, more than 200 to 300 hundred of our patient cohort would likely harbor a PFO.
As it is well recognized, both paternal or maternal history of stroke is associated with increased stroke risk.26 A family history of any stroke occurring at 65 years is an independent risk factor for ischemic stroke.27 In our patients, family history was more often positive in patients over 44 possibly indicating that the risk could be mediated mostly through conventional risk factors. Mechanisms of stroke heritability are complex, and they reflect the sharing of cultural, environmental, and lifestyle factors as well.28 Our patients with family history of stroke may provide useful data for planning future studies on genetic and environmental factors predisposing to brain infarct in the young.
In our series, the proportion of large-artery atherosclerosis was smaller,1,2,7,9,10,13 and small-vessel disease larger,2,5,7,10 than is usually reported. However, our rate of small-vessel disease was below that reported in young Asians (20%).6 Our results regarding the proportions of cardiac embolism1,4,6,7,9 and stroke of other determined etiology1,2,4,10 are in line with most findings. Most recent studies report ratios of cryptogenic stroke from 24% to 36%,4,6,7,9,10 akin to our series’ ranges. The proportion of cervical artery dissections ranged from the 2%9 seen earlier, to 24% in a recent prospective study.4 In the present data, dissections comprised approximately 15% of all patients and about 19% of those under 45 years. Urgent vascular imaging should thus be routine among young patients.29 In series of young ischemic stroke patients, migraine has been thought to be the cause in up to 20%.8 In more recent studies, the percentage is about 1% to 2%,2,4,6,9,10 but in large series may be as high as 3% to 5%.1,7,11 Our data suggest a considerably lower frequency (n=9, <1%) of migrainous infarct defined by IHS criteria.17
We might underestimate the frequency of strokes originating from arterial vasospasm, such as reversible cerebral vasoconstriction syndrome (RCVS), because all patients did not undergo immediate angiography of cerebral vessels, and patients with subarachnoidal hemorrhage or infarcts related to surgical procedures were excluded. In addition, substance abuse was rare in our patient population. Brain infarcts associated with RCVS are reported to be rather infrequent, however.30 Fabry disease might explain a considerable proportion of cryptogenic strokes31 but has appeared in only few Finnish families, none of which were represented in our series. Sickle-cell disease is absent in people of Finnish origin. Moreover, rheumatic valve disease has practically disappeared in Finland, a frequent cause of stroke among young adults in developing countries.11
A few reports involve the topography of brain infarcts in the young,2–4,8 with anterior circulation infarcts found to predominate, akin to our findings. In contrast to previous findings,3,4,8 we found a considerably larger amount of infarcts in posterior territory among patients under 45 (46% versus 29% to 36%). The percentage was actually only slightly lower than that of anterior territory. This finding may be attributable to frequent use of MRI and because more vertebral artery dissections were causing the brain infarcts in this age group. Additionally, some poorly recognized factors may be causing pathological changes in vertebrobasilar vessels.31 The hemispheric asymmetry of infarcts is an important finding per se, and is in accordance with previous findings, suggesting difficulties in recognition of right hemispheric stroke symptoms.32,33 Additionally, it has been hypothesized that because of hemodynamic differences, there may exist a selectivity favoring a cardiac embolus entering more often the left common carotid artery34 or that atherosclerosis might be more frequent in left carotid artery.33 These theories should be further tested in independent large-scale studies, however.
Data are limited for young adults regarding silent infarcts, leukoaraiosis, and multiple infarcts. Silent infarcts, usually reflecting small-vessel disease, are detected in 20% of healthy elderly people, and in up to 50% in selected series with patients having stroke risk factors.35 They are associated with subtle physical and cognitive deficits and increase the risk for subsequent stroke and dementia in the general population.35 In our series, these subclinical brain infarcts were surprisingly common even in patients <45 years of age, possibly suggesting that the young might have distinctive underlying pathophysiological mechanisms compared with the elderly. We may slightly overestimate the frequency of silent infarcts because of the study design but, on the other hand, we also might have missed small subclinical infarcts in those not scanned with MRI. In addition, our findings indicate that multiple infarcts in young patients clearly are more common than previously presented.2,8
Retrospective nature was the main restriction of our study. It covers a very long time period and therefore is subject to variability in imaging technology and diagnostic testing. Treatment recommendations for vascular risk factors have changed during the study period, whereas we applied the same definitions for all patients. Furthermore, all patients were not tested for clotting abnormalities or did not undergo complete cardiac examinations which, in addition to rather robust and strictly applied TOAST classification system, may have expanded the undetermined group. The size of the incomplete diagnostics group mostly reflects the patients’ compliance to diagnostic testing, but may additionally in part serve as a surrogate for diagnostic quality. Our patients in this group amounted to 8.5%, but they were mainly treated during the earliest years of the study, because only 13 patients were added during the final 6 years reflecting an improvement in diagnostics (supplemental Figure I).
Summary
Our findings contribute to the understanding of the spectrum of risk factors, mechanisms, and imaging features in young brain infarct patients. Traditional stroke risk factors were common in this patient population, but in the young a meticulous search for each patient’s all potential risk factors is crucial for appropriate secondary prevention. These data suggest that the evolution of etiology takes place mainly because of accumulation of vascular risk factors along aging. In addition, poorly recognized genetic factors may be explaining the higher frequency of undetermined etiology, as well as the larger proportion of posterior territory infarcts among younger patients. In some young individuals, a combination of several risk factors might be sufficient to explain the stroke—mostly by currently unclear mechanisms, however. Relatively many of these young patients had asymptomatic strokes, of which clinical and prognostic implications are to be clarified. Moreover, these data pave the way for future studies needed on long-term outcome—and how to improve it—in young ischemic stroke patients.
|
Acknowledgments |
|---|
We are indebted to Marja Metso, RN, for her dedication and technical support.
Sources of Funding
This work was supported by the Helsinki University Central Hospital (TYH2008253) and the University of Helsinki (2103034).
Disclosures
None.
|
Footnotes |
|---|
Continuing medical education (CME) credit is available for this article. Go to http://cme.ahajournals.org to take the quiz.
Received June 25, 2008; revision received August 11, 2007; accepted September 8, 2008.
|
References |
|---|
|
TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
|---|
1. Adams HP Jr, Kappelle LJ, Biller J, Gordon DL, Love BB, Gomez F, Heffner M. Ischemic stroke in young adults. Experience in 329 patients enrolled in the Iowa Registry of stroke in young adults. Arch Neurol. 1995; 52: 491–495.
2. Kristensen B, Malm J, Carlberg B, Stegmayr B, Backman C, Fagerlund M, Olsson T. Epidemiology and etiology of ischemic stroke in young adults aged 18 to 44 years in northern Sweden. Stroke. 1997; 28: 1702–1709.
3. Naess H, Nyland HI, Thomassen L, Aarseth J, Nyland G, Myhr KM. Incidence and short-term outcome of cerebral infarction in young adults in western Norway. Stroke. 2002; 33: 2105–2108.
4. Nedeltchev K, der Maur TA, Georgiadis D, Arnold M, Caso V, Mattle HP, Schroth G, Remonda L, Sturzenegger M, Fischer U, Baumgartner RW. Ischaemic stroke in young adults: predictors of outcome and recurrence. J Neurol Neurosurg Psychiatry. 2005; 76: 191–195.
5. Leys D, Bandu L, Henon H, Lucas C, Mounier-Vehier F, Rondepierre P, Godefroy O. Clinical outcome in 287 consecutive young adults (15 to 45 years) with ischemic stroke. Neurology. 2002; 59: 26–33.
6. Lee TH, Hsu WC, Chen CJ, Chen ST. Etiologic study of young ischemic stroke in Taiwan. Stroke. 2002; 33: 1950–1955.
7. Varona JF, Guerra JM, Bermejo F, Molina JA, Gomez de la Camara, A. Causes of ischemic stroke in young adults, and evolution of the etiological diagnosis over the long term. Eur Neurol. 2007; 57: 212–218.[CrossRef][Medline] [Order article via Infotrieve]
8. Bogousslavsky J, Pierre P. Ischemic stroke in patients under age 45. Neurol Clin. 1992; 10: 113–124.[Medline] [Order article via Infotrieve]
9. Kittner SJ, Stern BJ, Wozniak M, Buchholz DW, Earley CJ, Feeser BR, Johnson CJ, Macko RF, McCarter RJ, Price TR, Sherwin R, Sloan MA, Wityk RJ. Cerebral infarction in young adults: the Baltimore-Washington Cooperative Young Stroke Study. Neurology. 1998; 50: 890–894.
10. Rasura M, Spalloni A, Ferrari M, De Castro S, Patella R, Lisi F, Beccia M. A case series of young stroke in Rome. Eur J Neurol. 2006; 13: 146–152.[CrossRef][Medline] [Order article via Infotrieve]
11. Barinagarrementeria F, Figueroa T, Huebe J, Cantú C. Cerebral infarction in people under 40 years I. Etiologic analysis of 300 cases prospectively evaluated. Cerebrovasc Dis. 1996; 6: 75–79.[CrossRef]
12. Rohr J, Kittner S, Feeser B, Hebel JR, Whyte MG, Weinstein A, Kanarak N, Buchholz D, Earley C, Johnson C, Macko R, Price T, Sloan M, Stern B, Wityk R, Wozniak M, Sherwin R. Traditional risk factors and ischemic stroke in young adults: the Baltimore-Washington Cooperative Young Stroke Study. Arch Neurol. 1996; 53: 603–607.
13. Naess H, Nyland HI, Thomassen L, Aarseth J, Myhr KM. Etiology of and risk factors for cerebral infarction in young adults in western Norway: a population-based case-control study. Eur J Neurol. 2004; 11: 25–30.[CrossRef][Medline] [Order article via Infotrieve]
14. Goldstein LB, Adams R, Alberts MJ, Appel LJ, Brass LM, Bushnell CD, Culebras A, DeGraba TJ, Gorelick PB, Guyton JR, Hart RG, Howard G, Kelly-Hayes M, Nixon JV, Sacco RL. American Heart Association, American Stroke Association Stroke Council. Primary prevention of ischemic stroke: a guideline from the American Heart Association/American Stroke Association Stroke Council: cosponsored by the Atherosclerotic Peripheral Vascular Disease Interdisciplinary Working Group; Cardiovascular Nursing Council; Clinical Cardiology Council; Nutrition, Physical Activity, and Metabolism Council; and the Quality of Care and Outcomes Research Interdisciplinary Working Group. Circulation. 2006; 113: e873–923.
15. Karttunen V, Ventila M, Ikaheimo M, Niemela M, Hillbom M. Ear oximetry: a noninvasive method for detection of patent foramen ovale: a study comparing dye dilution method and oximetry with contrast transesophageal echocardiography. Stroke. 2001; 32: 448–453.
16. Adams HP Jr, Bendixen BH, Kappelle LJ, Biller J, Love BB, Gordon DL, Marsh EE, III. Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in Acute Stroke Treatment. Stroke. 1993; 24: 35–41.
17. Headache Classification Committee of the International Headache Society. The International Classification of Headache Disorders, II edition. Cephalalgia. 2004; 24: 9–160.[CrossRef][Medline] [Order article via Infotrieve]
18. Harmsen P, Berglund G, Larsson O, Tibblin G, Wilhelmsen L. Stroke registration in Goteborg, Sweden, 1970–75. Incidence and fatality rates. Acta Med Scand. 1979; 206: 337–344.[Medline] [Order article via Infotrieve]
19. Kittner SJ, McCarter RJ, Sherwin RW, Sloan MA, Stern BJ, Johnson CJ, Buchholz D, Seipp MJ, Price TR. Black-white differences in stroke risk among young adults. Stroke. 1993; 24: I13–15.[Medline] [Order article via Infotrieve]
20. Amarenco P, Bogousslavsky J, Callahan A, III, Goldstein LB, Hennerici M, Rudolph AE, Sillesen H, Simunovic L, Szarek M, Welch KM, Zivin JA. Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) Investigators. High-dose atorvastatin after stroke or transient ischemic attack. N Engl J Med. 2006; 355: 549–559.
21. Bousser MG. Estrogens, migraine, and stroke. Stroke. 2004; 35: 2652–2656.
22. Lamy C, Giannesini C, Zuber M, Arquizan C, Meder JF, Trystram D, Coste J, Mas JL. Clinical and imaging findings in cryptogenic stroke patients with and without patent foramen ovale: the PFO-ASA Study. Atrial Septal Aneurysm. Stroke. 2002; 33: 706–711.
23. Botto N, Spadoni I, Giusti S, Ait-Ali L, Sicari R, Andreassi MG. Prothrombotic mutations as risk factors for cryptogenic ischemic cerebrovascular events in young subjects with patent foramen ovale. Stroke. 2007; 38: 2070–2073.
24. Kizer JR, Devereux RB. Clinical practice. Patent foramen ovale in young adults with unexplained stroke. N Engl J Med. 2005; 353: 2361–2372.
25. Hagen PT, Scholz DG, Edwards WD. Incidence and size of patent foramen ovale during the first 10 decades of life: an autopsy study of 965 normal hearts. Mayo Clin Proc. 1984; 59: 17–20.[Medline] [Order article via Infotrieve]
26. Kiely DK, Wolf PA, Cupples LA, Beiser AS, Myers RH. Familial aggregation of stroke. The Framingham Study. Stroke. 1993; 24: 1366–1371.
27. Hassan A, Sham PC, Markus HS. Planning genetic studies in human stroke: sample size estimates based on family history data. Neurology. 2002; 58: 1483–1488.
28. Liao D, Myers R, Hunt S, Shahar E, Paton C, Burke G, Province M, Heiss G. Familial history of stroke and stroke risk. The Family Heart Study. Stroke. 1997; 28: 1908–1912.
29. Engelter ST, Brandt T, Debette S, Caso V, Lichy C, Pezzini A, Abboud S, Bersano A, Dittrich R, Grond-Ginsbach C, Hausser I, Kloss M, Grau AJ, Tatlisumak T, Leys D, Lyrer PA; for the Cervical Artery Dissection in Ischemic Stroke Patients (CADISP) Study Group. Antiplatelets versus anticoagulation in cervical artery dissection. Stroke. 2007; 38: 2605–2611.
30. Ducros A, Boukobza M, Porcher R, Sarov M, Valade D, Bousser MG. The clinical and radiological spectrum of reversible cerebral vasoconstriction syndrome. A prospective series of 67 patients. Brain. 2007; 130: 3091–3101.
31. Rolfs A, Bottcher T, Zschiesche M, Morris P, Winchester B, Bauer P, Walter U, Mix E, Lohr M, Harzer K, Strauss U, Pahnke J, Grossmann A, Benecke R. Prevalence of Fabry disease in patients with cryptogenic stroke: a prospective study. Lancet. 2005; 366: 1794–1796.[CrossRef][Medline] [Order article via Infotrieve]
32. Foerch C, Misselwitz B, Sitzer M, Berger K, Steinmetz H, Neumann-Haefelin T. Arbeitsgruppe Schlaganfall Hessen. Difference in recognition of right and left hemispheric stroke. Lancet. 2005; 366: 392–393.[CrossRef][Medline] [Order article via Infotrieve]
33. Naess H, Waje-Andreassen U, Thomassen L, Myhr KM. High incidence of infarction in the left cerebral hemisphere among young adults. J Stroke Cerebrovasc Dis. 2006; 15: 241–244.[CrossRef][Medline] [Order article via Infotrieve]
34. Kaps M, Seidel G, Berg J. Is there a hemispheric side preference of cardiac valvular emboli? Ultrasound Med Biol. 1995; 21: 753–756.[CrossRef][Medline] [Order article via Infotrieve]
35. Vermeer SE, Longstreth WT Jr, Koudstaal PJ. Silent brain infarcts: a systematic review. Lancet Neurol. 2007; 6: 611–619.[CrossRef][Medline] [Order article via Infotrieve]
This article has been cited by other articles:
 |
|
 |
|
  A. J. Metso, T. M. Metso, and T. Tatlisumak Local Symptoms and Recanalization in Spontaneous Carotid Artery Dissection Stroke, November 1, 2009; 40(11): e629 - e629. [Full Text] [PDF]
|
|
|
|
|
|
J. Putaala, S. Curtze, S. Hiltunen, H. Tolppanen, M. Kaste, and T. Tatlisumak Causes of Death and Predictors of 5-Year Mortality in Young Adults After First-Ever Ischemic Stroke: The Helsinki Young Stroke Registry Stroke, August 1, 2009; 40(8): 2698 - 2703. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Spengos and K. N. Vemmos Female Predominance at Very Young Ages and Other Similarities Between Finnish and Greek Young Ischemic Stroke Patients Stroke, July 1, 2009; 40(7): e491 - e491. [Full Text] [PDF]
|
|
|
|
|
|
J. Putaala and T. Tatlisumak Response to Letter by Spengos and Vemmos Stroke, July 1, 2009; 40(7): e492 - e492. [Full Text] [PDF]
|
|
|
|
 |
|
 J. Putaala, M. Kurkinen, V. Tarvos, O. Salonen, M. Kaste, and T. Tatlisumak Silent brain infarcts and leukoaraiosis in young adults with first-ever ischemic stroke Neurology, May 26, 2009; 72(21): 1823 - 1829. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. L. Cucchiara Evaluation and management of stroke Hematology, January 1, 2009; 2009(1): 293 - 301. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||