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.

Brody Disease, an Early-Onset Myopathy With Delayed Relaxation and Abnormal Gait: A Case Series of 9 Children.

Brody disease is a rare autosomal recessive myopathy, caused by pathogenic variants in the ATP2A1 gene. It is characterized by an exercise-induced delay in muscle relaxation, often reported as muscle stiffness. Children may manifest with an abnormal gait and difficulty running. Delayed relaxation is commonly undetected, resulting in a long diagnostic delay. Almost all published cases so far were adults with childhood onset and adult diagnosis. With diagnostic next-generation sequencing, an increasing number of patients are diagnosed in childhood. We describe the clinical and genetic features of 9 children from 6 families with Brody disease. All presented with exercise-induced delayed relaxation, reported as difficulty running and performing sports. Muscle strength and mass was normal, and several children even had an athletic appearance. However, the walking and running patterns were abnormal. The diagnostic delay ranged between 2 and 7 years. Uniformly, a wide range of other disorders were considered before genetic testing was performed, revealing pathogenic genetic variants in ATP2A1. To conclude, this case series is expected to improve clinical recognition and timely diagnosis of Brody disease in children. We propose that ATP2A1 should be added to gene panels for congenital myopathies, developmental and movement disorders, and muscle channelopathies.

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.

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.

Association of Stroke at Young Age With New Cancer in the Years After Stroke Among Patients in the Netherlands.

Importance: Stroke may be a first manifestation of an occult cancer or may be an indicator of an increased cancer risk in later life. However, data, especially for younger adults, are limited. Objectives: To assess the association of stroke with new cancer diagnoses after a first stroke, stratified by stroke subtype, age, and sex, and to compare this association with that in the general population. Design, Setting, and Participants: This registry- and population-based study included 390 398 patients in the Netherlands aged 15 years or older without a history of cancer and with a first-ever ischemic stroke or intracerebral hemorrhage (ICH) between January 1, 1998, and January 1, 2019. Patients and outcomes were identified through linkage of the Dutch Population Register, the Dutch National Hospital Discharge Register, and National Cause of Death Register. Reference data were gathered from the Dutch Cancer Registry. Statistical analysis was performed from January 6, 2021, to January 2, 2022. Exposure: First-ever ischemic stroke or ICH. Patients were identified by administrative codes from the International Classification of Diseases, Ninth Revision, and the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision. Main Outcomes and Measures: The primary outcome was the cumulative incidence of first-ever cancer after index stroke, stratified by stroke subtype, age, and sex, compared with age-, sex- and calendar year-matched peers from the general population. Results: The study included 27 616 patients aged 15 to 49 years (median age, 44.5 years [IQR, 39.1-47.6 years]; 13 916 women [50.4%]; 22 622 [81.9%] with ischemic stroke) and 362 782 patients aged 50 years or older (median age, 75.8 years [IQR, 66.9-82.9 years]; 181 847 women [50.1%]; 307 739 [84.8%] with ischemic stroke). The cumulative incidence of new cancer at 10 years was 3.7% (95% CI, 3.4%-4.0%) among patients aged 15 to 49 years and 8.5% (95% CI, 8.4%-8.6%) among patients aged 50 years or older. The cumulative incidence of new cancer after any stroke among patients aged 15 to 49 years was higher among women than men (Gray test statistic, 22.2; P < .001), whereas among those aged 50 years or older, the cumulative incidence of new cancer after any stroke was higher among men (Gray test statistic, 943.1; P < .001). In the first year after stroke, compared with peers from the general population, patients aged 15 to 49 years were more likely to receive a diagnosis of a new cancer after ischemic stroke (standardized incidence ratio [SIR], 2.6 [95% CI, 2.2-3.1]) and ICH (SIR, 5.4 [95% CI, 3.8-7.3]). For patients aged 50 years or older, the SIR was 1.2 (95% CI, 1.2-1.2) after ischemic stroke and 1.2 (95% CI, 1.1-1.2) after ICH. Conclusions and Relevance: This study suggests that, compared with the general population, patients aged 15 to 49 years who have had a stroke may have a 3- to 5-fold increased risk of cancer in the first year after stroke, whereas this risk is only slightly elevated for patients aged 50 years or older. Whether this finding has implications for screening remains to be investigated.

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.

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.

Long-term Risk of Bleeding and Ischemic Events After Ischemic Stroke or Transient Ischemic Attack in Young Adults.

BACKGROUND AND OBJECTIVES: Guidelines recommend antithrombotic medication as secondary prevention for patients with ischemic stroke or transient ischemic attack (TIA) at young age based on results from trials in older patients. We investigated the long-term risk of bleeding and ischemic events in young patients after ischemic stroke or TIA. METHODS: We included 30-day survivors of first-ever ischemic stroke or TIA aged 18-50 years from the Follow-Up of TIA and Stroke Patients and Unelucidated Risk Factor Evaluation (FUTURE) study, a prospective cohort study of stroke at young age. We obtained information on recurrent ischemia based on structured data collection from 1995 until 2014 as part of the FUTURE study follow-up, complemented with information on any bleeding and ischemic events by retrospective chart review from baseline until last medical consultation or June 2020. Primary outcome was any bleeding; secondary outcome any ischemic event during follow-up. Both were stratified for sex, age, etiology, and use of antithrombotic medication at discharge. Bleeding and ischemic events were classified according to location and bleeding events also by severity. RESULTS: We included 544 patients (56.1% women, median age of 42.2; interquartile range [IQR] 36.5-46.7 years) with a median follow-up of 9.6 (IQR 2.5-14.3) years. Ten-year cumulative risk of any bleeding event was 21.8% (95% CI 17.4-26.0) and 33.9% (95% CI 28.3-37.5) of any ischemic event. Risk of bleeding was higher in women with a cumulative risk of 28.2% (95% CI 21.6-34.3) vs 13.7% (95% CI 8.2-18.9) in men (p < 0.01), mainly because of gynecologic bleeds. Female sex (p < 0.001) and age between 40 and 49 years (p = 0.04) were independent predictors of bleeding. DISCUSSION: Young patients after ischemic stroke or TIA have a substantial long-term risk of both bleeding (especially women) and ischemic events. Future studies should investigate the effects of long-term antithrombotics in young patients, taking into account the risk of bleeding complications.

Long-term mortality in young patients with spontaneous intracerebral haemorrhage: Predictors and causes of death.

INTRODUCTION: Intracerebral haemorrhage (ICH) in young adults is rare but has devastating consequences. We investigated long-term mortality rates, causes of death and predictors of long-term mortality in young spontaneous ICH survivors. PATIENTS AND METHODS: We included consecutive patients aged 18-55 years from the Prognosis of Intracerebral Haemorrhage cohort (PITCH), a prospective observational cohort of patients admitted to Lille University Hospital (2004-2009), who survived at least 30 days after spontaneous ICH. We studied long-term mortality with Kaplan-Meier analyses, collected causes of death, performed uni-/multivariable Cox-regression analyses for the association of baseline characteristics with long-term mortality. RESULTS: Of 560 patients enrolled in the PITCH, 75 patients (75% men) met our inclusion criteria (median age 50 years, interquartile range [IQR] 44-53 years). During a median follow-up of 8.2 years (IQR 5.0-10.1), 26 patients died (35%), with a standardized mortality ratio of 13.0 (95% confidence interval [95% CI] 8.5-18.0) compared to peers from the general population. Causes of death were vascular in 7 (27%) patients, non-vascular in 13 (50%) and unknown in 6 (23%). Global cerebral atrophy (hazard ratio [HR] 3.0, 95% CI 1.1-8.6), modified Rankin Score >2 before ICH (HR 3.4, 95% CI 1.0-11.0), and excessive alcohol consumption (HR 3.3, 95% CI 1.1-10.2) were independently associated with long-term mortality. DISCUSSION: We found a 13-fold higher mortality risk for young ICH survivors compared to the general French population. Predictors of long-term mortality were pre-existing conditions, not ICH-characteristics. CONCLUSION: Young ICH survivors remain at increased mortality risk of vascular and non-vascular death for years after ICH.

Ambient air pollution and the risk of ischaemic and haemorrhagic stroke.

Stroke is a leading cause of disability and the second most common cause of death worldwide. Increasing evidence suggests that air pollution is an emerging risk factor for stroke. Over the past decades, air pollution levels have continuously increased and are now estimated to be responsible for 14% of all stroke-associated deaths. Interpretation of previous literature is difficult because stroke was usually not distinguished as ischaemic or haemorrhagic, nor by cause. This Review summarises the evidence on the association between air pollution and the different causes of ischaemic stroke and haemorrhagic stroke, to clarify which people are most at risk. The risk for ischaemic stroke is increased after short-term or long-term exposure to air pollution. This effect is most pronounced in people with cardiovascular burden and stroke due to large artery disease or small vessel disease. Short-term exposure to air pollution increases the risk of intracerebral haemorrhage, a subtype of haemorrhagic stroke, whereas the effects of long-term exposure are less clear. Limitations of the current evidence are that studies are prone to misclassification of exposure, often rely on administrative data, and have insufficient clinical detail. In this Review, we provide an outlook on new research opportunities, such as those provided by the decreased levels of air pollution due to the current COVID-19 pandemic.

Clinical, morphological and genetic characterization of Brody disease: an international study of 40 patients.

Brody disease is an autosomal recessive myopathy characterized by exercise-induced muscle stiffness due to mutations in the ATP2A1 gene. Almost 50 years after the initial case presentation, only 18 patients have been reported and many questions regarding the clinical phenotype and results of ancillary investigations remain unanswered, likely leading to incomplete recognition and consequently under-diagnosis. Additionally, little is known about the natural history of the disorder, genotype-phenotype correlations, and the effects of symptomatic treatment. We studied the largest cohort of Brody disease patients to date (n = 40), consisting of 22 new patients (19 novel mutations) and all 18 previously published patients. This observational study shows that the main feature of Brody disease is an exercise-induced muscle stiffness of the limbs, and often of the eyelids. Onset begins in childhood and there was no or only mild progression of symptoms over time. Four patients had episodes resembling malignant hyperthermia. The key finding at physical examination was delayed relaxation after repetitive contractions. Additionally, no atrophy was seen, muscle strength was generally preserved, and some patients had a remarkable athletic build. Symptomatic treatment was mostly ineffective or produced unacceptable side effects. EMG showed silent contractures in approximately half of the patients and no myotonia. Creatine kinase was normal or mildly elevated, and muscle biopsy showed mild myopathic changes with selective type II atrophy. Sarcoplasmic/endoplasmic reticulum Ca2+ ATPase (SERCA) activity was reduced and western blot analysis showed decreased or absent SERCA1 protein. Based on this cohort, we conclude that Brody disease should be considered in cases of exercise-induced muscle stiffness. When physical examination shows delayed relaxation, and there are no myotonic discharges at electromyography, we recommend direct sequencing of the ATP2A1 gene or next generation sequencing with a myopathy panel. Aside from clinical features, SERCA activity measurement and SERCA1 western blot can assist in proving the pathogenicity of novel ATP2A1 mutations. Finally, patients with Brody disease may be at risk for malignant hyperthermia-like episodes, and therefore appropriate perioperative measures are recommended. This study will help improve understanding and recognition of Brody disease as a distinct myopathy in the broader field of calcium-related myopathies.

Long-term prognosis after intracerebral haemorrhage.

INTRODUCTION: The aim of this study was to determine the risk of recurrent intracerebral haemorrhage (ICH), ischaemic stroke, all stroke, any vascular event and all-cause mortality in 30-day survivors of ICH, according to age and sex. PATIENTS AND METHODS: We linked national hospital discharge, population and cause of death registers to obtain a cohort of Dutch 30-day survivors of ICH from 1998 to 2010. We calculated cumulative incidences of recurrent ICH, ischaemic stroke, all stroke and composite vascular outcome, adjusted for competing risk of death and all-cause mortality. Additionally, we compared survival with the general population. RESULTS: We included 19,444 ICH-survivors (52% male; median age 72 years, interquartile range 61-79; 78,654 patient-years of follow-up). First-year cumulative incidence of recurrent ICH ranged from 1.5% (95% confidence interval 0.9-2.3; men 35-54 years) to 2.4% (2.0-2.9; women 75-94 years). Depending on age and sex, 10-year risk of recurrent ICH ranged from 3.7% (2.6-5.1; men 35-54 years) to 8.1% (6.9-9.4; women 55-74 years); ischaemic stroke 2.6% to 7.0%, of all stroke 9.9% to 26.2% and of any vascular event 15.0% to 40.4%. Ten-year mortality ranged from 16.7% (35-54 years) to 90.0% (75-94 years). Relative survival was lower in all age-groups of both sexes, ranging from 0.83 (0.80-0.87) in 35- to 54-year-old men to 0.28 (0.24-0.32) in 75- to 94-year-old women. DISCUSSION: ICH-survivors are at high risk of recurrent ICH, of ischaemic stroke and other vascular events, and have a sustained reduced survival rate compared to the general population. CONCLUSION: The high risk of recurrent ICH, other vascular events and prolonged reduced survival-rates warrant clinical trials to determine optimal secondary prevention treatment after ICH.

Stroke incidence in young adults according to age, subtype, sex, and time trends.

OBJECTIVE: To investigate incidence of stroke and its subtypes in young adults, according to sex and age, and to study trends over time. METHODS: We established a nationwide cohort through linkage of national registries (hospital discharge, cause of death, and population register) with patients aged 18-50 years and those ≥50 years with first-ever ischemic stroke, intracerebral hemorrhage, or unspecified stroke, using ICD-9/ICD-10 codes between 1998 and 2010 in the Netherlands. Outcomes were yearly incidence of stroke stratified by age, sex, and stroke subtype, its changes over time, and comparison of incidence in patients 18-50 years to patients ≥50 years. RESULTS: We identified 15,257 patients (53% women; mean age 41.8 years). Incidence increased exponentially with age (R 2 = 0.99) and was higher for women than men, most prominently in the youngest patients (18-44 years). The relative proportion of ischemic stroke increased with age (18-24 years: 38.3%; 44-49 years: 56.5%), whereas the relative proportion of intracerebral hemorrhage decreased (18-24 years: 34.0%; 44-49 years: 18.3%). Incidence of any stroke in young adults increased (1998: 14.0/100,000 person-years: 2010: 17.2; +23%; p < 0.001), driven by an increase in those aged over 35 years and ischemic stroke incidence (46%), whereas incidence decreased in those ≥50 years (329.1%-292.2%; -11%; p = 0.009). CONCLUSIONS: Incidence of any stroke in the young increases with age in patients over 35, is higher in women than men aged 18-44 years, and has increased by 23% in one decade, through an increase in ischemic stroke. Incidence of intracerebral hemorrhage is comparable for women and men and remained stable over time.