Papers by Catharina Klijn
JAMA, Jun 4, 2019
IMPORTANCE Stroke remains the second leading cause of death worldwide. Approximately 10% to 15% o... more IMPORTANCE Stroke remains the second leading cause of death worldwide. Approximately 10% to 15% of all strokes occur in young adults. Information on prognosis and mortality specifically in young adults is limited. OBJECTIVE To determine short-and long-term mortality risk after stroke in young adults, according to age, sex, and stroke subtype; time trends in mortality; and causes of death. DESIGN, SETTING, AND PARTICIPANTS Registry-and population-based study in the Netherlands of 15 527 patients aged 18 to 49 years with first stroke between 1998 and 2010, and follow-up until January 1, 2017. Patients and outcomes were identified through linkage of the national Hospital Discharge Registry, national Cause of Death Registry, and the Dutch Population Register. EXPOSURES First stroke occurring at age 18 to 49 years, documented using International Classification of Diseases, Ninth Revision, and International Statistical Classification of Diseases and Related Health Problems, Tenth Revision, codes for ischemic stroke, intracerebral hemorrhage, and stroke not otherwise specified. MAIN OUTCOMES AND MEASURES Primary outcome was all-cause cumulative mortality in 30-day survivors at end of follow-up, stratified by age, sex, and stroke subtype, and compared with all-cause cumulative mortality in the general population. RESULTS The study population included 15 527 patients with stroke (median age, 44 years [interquartile range, 38-47 years]; 53.3% women). At end of follow-up, a total of 3540 cumulative deaths had occurred, including 1776 deaths within 30 days after stroke and 1764 deaths (23.2%) during a median duration of follow-up of 9.3 years (interquartile range, 5.9-13.1 years). The 15-year mortality in 30-day survivors was 17.0% (95% CI, 16.2%-17.9%). The standardized mortality rate compared with the general population was 5.1 (95% CI, 4.7-5.4) for ischemic stroke (observed mortality rate 12.0/1000 person-years [95% CI, 11.2-12.9/1000 person-years]; expected rate, 2.4/1000 person-years; excess rate, 9.6/1000 person-years) and the standardized mortality rate for intracerebral hemorrhage was 8.4 (95% CI, 7.4-9.3; observed rate, 18.7/1000 person-years [95% CI, 16.7-21.0/1000 person-years]; expected rate, 2.2/1000 person-years; excess rate, 16.4/1000 person-years). CONCLUSIONS AND RELEVANCE Among young adults aged 18 to 49 years in the Netherlands who were 30-day survivors of first stroke, mortality risk compared with the general population remained elevated up to 15 years later.
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PubMed, Dec 15, 2016
- In virtually all age groups, the incidence of ischemic stroke is higher in men. However, in wom... more - In virtually all age groups, the incidence of ischemic stroke is higher in men. However, in women aged between 25-49 years the prevalence is higher than in men. Female-specific risk factors and disorders may explain this peak.- Pregnancy and the post-partum period are associated with physiological changes which can increase blood coagulation. Complications during pregnancy may also increase the risk of ischaemic stroke.- Migraine with aura and antiphospholipid syndrome are disorders which are also associated with an increased risk of ischaemic stroke. These disorders are more common in women compared to men. Furthermore, hormonal contraceptives containing oestrogen are also identified to increase the incidence of ischaemic stroke.- The acute treatment and secondary prevention of ischaemic stroke in young women is identical to that in elderly stroke patients, be it men or women, although thrombolysis and platelet aggregation inhibition in pregnant women should be approached with care.- Clinical outcomes after stroke for women under the age of 50 are worse compared to age-matched men.
European stroke journal, Aug 25, 2021
Introduction: It is unclear why cerebral small vessel disease (SVD) leads to lacunar stroke in so... more Introduction: It is unclear why cerebral small vessel disease (SVD) leads to lacunar stroke in some and to non-lobar intracerebral hemorrhage (ICH) in others. We investigated differences in MRI markers of SVD in patients with lacunar stroke or non-lobar ICH. Patients and methods: We included patients from two prospective cohort studies with either lacunar stroke (RUN DMC) or non-lobar ICH (FETCH). Differences in SVD markers (white matter hyperintensities [WMH], lacunes, cerebral microbleeds [CMB]) between groups were investigated with univariable tests; multivariable logistic regression analysis, adjusted for age, sex, and vascular risk factors; spatial correlation analysis and voxel-wise lesion symptom mapping. Results: We included 82 patients with lacunar stroke (median age 63, IQR 57-72) and 54 with non-lobar ICH (66, 59-75). WMH volumes and distribution were not different between groups. Lacunes were more frequent in patients with a lacunar stroke (44% vs. 17%, adjusted odds ratio [aOR] 5.69, 95% CI [1.66-22.75]) compared to patients with a non-lobar ICH. CMB were more frequent in patients with a non-lobar ICH (71% vs. 23%, aOR for lacunar stroke vs non-lobar ICH 0.08 95% CI [0.02-0.26]), and more often located in non-lobar regions compared to CMB in lacunar stroke. Discussion: Although we obserd different types of MRI markers of SVD within the same patient, ischemic markers of SVD were more frequent in the ischemic type of lacunar stroke, and hemorrhagic markers were more prevalent in the hemorrhagic phenotype of non-lobar ICH. Conclusion: There are differences between MRI markers of SVD between patients with a lacunar stroke and those with a non-lobar ICH.
Neurology, Sep 17, 2019
Objective To investigate the prevalence of asymptomatic diffusion-weighted imaging-positive (DWI+... more Objective To investigate the prevalence of asymptomatic diffusion-weighted imaging-positive (DWI+) lesions in individuals with cerebral small vessel disease (SVD) and identify their role in the origin of SVD markers on MRI.
Frontiers in Neurology, Nov 12, 2018
Background and Purpose: Hypertensive vasculopathy and cerebral amyloid angiopathy are the two mos... more Background and Purpose: Hypertensive vasculopathy and cerebral amyloid angiopathy are the two most common forms of cerebral small vessel disease. Both forms are associated with the development of primary intracerebral hemorrhage, but the pathophysiological mechanisms underlying spontaneous vessel rupture remain unknown. This work constitutes a systematic review on blood-brain barrier dysfunction in the etiology of spontaneous intracerebral hemorrhage due to cerebral small vessel disease. Methods: We searched Medline (1946-2018) and Embase (1974-2018) for animal and human studies reporting on blood-brain barrier dysfunction associated with intracerebral hemorrhage or cerebral microbleeds. Results: Of 26 eligible studies, 10 were animal studies and 16 were in humans. The authors found indications for blood-brain barrier dysfunction in all four animal studies addressing hypertensive vasculopathy-related intracerebral hemorrhage (n = 32 hypertensive animals included in all four studies combined), and in four of six studies on cerebral amyloid angiopathy-related intracerebral hemorrhage (n = 47). Of the studies in humans, five of six studies in patients with cerebral amyloid angiopathy-related intracerebral hemorrhage (n = 117) and seven out of nine studies examining intracerebral hemorrhage with mixed or unspecified underlying etiology (n = 489) found indications for blood-brain barrier dysfunction. One post-mortem study in hypertensive vasculopathy-related intracerebral hemorrhage (n = 82) found no evidence for blood-brain barrier abnormalities. Conclusions: Signs of blood-brain barrier dysfunction were found in 20 out of 26 studies. Blood-brain barrier integrity deserves further investigation with a view to identification of potential treatment targets for spontaneous intracerebral hemorrhage.
Alzheimers & Dementia, Dec 7, 2021
Background: Cerebrospinal fluid (CSF) platelet-derived growth factor receptor-β (PDGFRβ) has been... more Background: Cerebrospinal fluid (CSF) platelet-derived growth factor receptor-β (PDGFRβ) has been proposed as a biomarker of blood-brain barrier (BBB) breakdown. We studied PDGFRβ levels as a biomarker for cerebral amyloid angiopathy (CAA), amnestic mild cognitive impairment (aMCI), or Alzheimer's disease (AD).
JAMA Network Open
ImportanceStroke may be a first manifestation of an occult cancer or may be an indicator of an in... more ImportanceStroke 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.ObjectivesTo 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 ParticipantsThis 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.E...
Neurology
Background and Objectives Causes of stroke in young adults differ from those in the elderly indiv... more 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 isc...
Background Stakeholder engagement in evaluation of medical devices is crucial for aligning device... more Background Stakeholder engagement in evaluation of medical devices is crucial for aligning devices with stakeholders’ views, needs, and values. Methods for these engagements have however not been compared to analyse their relative merits for medical device evaluation. Therefore, we systematically compared these three methods in terms of themes, interaction, and time-investment. Methods We compared focus groups, interviews and an online survey in a case-study on minimally invasive endoscopy-guided surgery for patients with intracerebral haemorrhage. The focus groups and interviews featured two rounds, one explorative focussing on individual perspectives, and one interactive focussing on the exchange of perspectives between participants. The comparison between methods was made in terms of number and content of themes, how participants interact, and hours invested by all researchers. Results The focus groups generated 34 themes, the interviews 58, and the survey 42. Various improvement...
Annals of Neurology
ObjectiveVascular amyloid β (Aβ) accumulation is the hallmark of cerebral amyloid angiopathy (CAA... more ObjectiveVascular amyloid β (Aβ) accumulation is the hallmark of cerebral amyloid angiopathy (CAA). The composition of cerebrospinal fluid (CSF) of CAA patients may serve as a diagnostic biomarker of CAA. We studied the diagnostic potential of the peptides Aβ38, Aβ40, Aβ42, and Aβ43 in patients with sporadic CAA (sCAA), hereditary Dutch‐type CAA (D‐CAA), and Alzheimer disease (AD).MethodsAβ peptides were quantified by immunoassays in a discovery group (26 patients with sCAA and 40 controls), a validation group (40 patients with sCAA, 40 patients with AD, and 37 controls), and a group of 22 patients with D‐CAA and 54 controls. To determine the diagnostic accuracy, the area under the curve (AUC) was calculated using a receiver operating characteristic curve with 95% confidence interval (CI).ResultsWe found decreased levels of all Aβ peptides in sCAA patients and D‐CAA patients compared to controls. The difference was most prominent for Aβ42 (AUC of sCAA vs controls for discovery: 0.90...
Cochrane Database of Systematic Reviews
Neurology
Background and Objectives The ULTRA trial showed that ultra-early and short-term tranexamic acid ... more Background and Objectives The ULTRA trial showed that ultra-early and short-term tranexamic acid treatment after subarachnoid hemorrhage did not improve clinical outcome at 6 months. An expected proportion of the included patients experienced nonaneurysmal subarachnoid hemorrhage. In this post hoc study, we will investigate whether ultra-early and short-term tranexamic acid treatment in patients with aneurysmal subarachnoid hemorrhage improves clinical outcome at 6 months. Methods The ULTRA trial is a multicenter, prospective, randomized, controlled, open-label trial with blinded outcome assessment, conducted between July 24, 2013, and January 20, 2020. After confirmation of subarachnoid hemorrhage on noncontrast CT, patients were allocated to either ultra-early and short-term tranexamic acid treatment with usual care or usual care only. In this post hoc analysis, we included all ULTRA participants with a confirmed aneurysm on CT angiography and/or digital subtraction angiography. T...
Neurology
Background and ObjectivesGuidelines recommend antithrombotic medication as secondary prevention f... more Background and ObjectivesGuidelines 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.MethodsWe 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 se...
Journal of Neurosurgery
OBJECTIVE Patients with moyamoya vasculopathy often experience cognitive impairments. In this pro... more OBJECTIVE Patients with moyamoya vasculopathy often experience cognitive impairments. In this prospective single-center study, the authors investigated the profile of neurocognitive impairment and its relation with the severity of ischemic brain lesions and hemodynamic compromise. METHODS Patients treated in a Dutch tertiary referral center were prospectively included. All patients underwent standardized neuropsychological evaluation, MRI, digital subtraction angiography, and [15O]H2O-PET (to measure cerebrovascular reactivity [CVR]). The authors determined z-scores for 7 cognitive domains and the proportion of patients with cognitive impairment (z-score < −1.5 SD in at least one domain). The authors explored associations between patient characteristics, imaging and CVR findings, and cognitive scores per domain by using multivariable linear regression and Bayesian regression analysis. RESULTS A total of 40 patients (22 children; 75% females) were included. The median age for chil...
Alzheimer's & Dementia, 2020
BackgroundThere is a lack of biomarkers for the early detection of Alzheimer’s disease (AD). Cere... more BackgroundThere is a lack of biomarkers for the early detection of Alzheimer’s disease (AD). Cerebral amyloid angiopathy (CAA), which is characterized by the accumulation of amyloid‐β (Aβ) in the cerebral vasculature, is commonly found in AD. Platelet‐derived growth factor receptor‐β (PDGFRβ) is expressed by pericytes and since blood‐brain barrier (BBB) dysfunction is associated with pericyte degeneration, release of PDGFRβ protein may be a biomarker for BBB dysfunction, that is expected in CAA. Indeed, it has recently been described that PDGFRβ levels are elevated in cerebrospinal fluid (CSF) from patients with mild cognitive impairment (MCI) as compared to controls1. The aim of our study was to investigate the diagnostic and discriminative value of PDGFRβ in CSF in patients at various clinical stages of AD and in patients with CAA.MethodCSF PDGFRβ, Aβ42, total tau (t‐tau) and phosphorylated tau (p‐tau) levels were quantified by ELISA. Cohorts of controls (n=47), CAA patients (n=27...
Alzheimer's & Dementia, 2021
Background: Current diagnostic criteria for cerebral amyloid angiopathy (CAA) are predominantly b... more Background: Current diagnostic criteria for cerebral amyloid angiopathy (CAA) are predominantly based on radiological identification of evidence of CAA (micro-or macrobleeds). These criteria present only end-stage manifestations of the disease, however. The development of transgenic rat models for CAA, carrying the E693Q/D694N mutations in APP (rTg-DI rats), has the potential of discovery of novel biomarkers for CAA. Shotgun proteomics analysis of rTg-DI tissue, compared to wild-type rats has yielded elevated levels of urokinase plasminogen activator (uPA) in CAA. uPA is a serine protease active in the conversion of plasminogen to plasmin, a fibrinolytic factor. We investigated the potential of uPA in a pilot biomarker discovery study for the diagnosis of CAA by analyzing uPA concentrations in cerebrospinal fluid (CSF) of patients with CAA compared to control patients. Method: CSF was obtained from patients with possible or probable CAA (according to the current diagnostic imaging tool, the Boston Criteria) (n=28), and control subjects (n=42). uPA levels in CSF were determined using a uPA Quantikine ELISA (R&D Systems, Minneapolis, USA). Total protein levels were assayed using a Pierce® BCA Protein Assay (Thermo Fisher, Waltham, USA). Associations of uPA with known concentrations of other neurological markers, including aβ peptides and tau proteins were also analysed. Result: The concentration of uPA was significantly increased in the CSF of CAA patients compared to controls (303 ± 23.2 vs. 227 ± 12.5 pg/mL; p=0.001). CSF uPA levels (very) weakly correlated with age at lumbar puncture (r SP =0.33, p=0.005) and total protein content (r SP =0.24, p=0.042). uPA levels in controls were correlated in a weak-to-moderate extent with Aβ-38, 40, 42, and total-and phosphorylated tau protein (r SP =0.46, 0.63, 0.47, 0.53 and 0.41 respectively, p<0.02), whereas this correlation was practically absent in the CAA group. Conclusion: Comparison of CSF levels of uPA shows a significant elevation in CAA patients compared against controls. CAA patients show lower levels of correlation of uPA with circulating aβ peptides and tau protein variants as compared to controls. This reinforces the potential of uPA as an effective biomarker in the diagnosis of CAA patients and incentivizes further research into this biomarker.
International Journal of Stroke, 2022
Background: Patients who suffer intracerebral hemorrhage (ICH) are at very high risk of recurrent... more Background: Patients who suffer intracerebral hemorrhage (ICH) are at very high risk of recurrent ICH and other serious cardiovascular events. A single-pill combination (SPC) of blood pressure (BP) lowering drugs offers a potentially powerful but simple strategy to optimize secondary prevention. Objectives: The Triple Therapy Prevention of Recurrent Intracerebral Disease Events Trial (TRIDENT) aims to determine the effects of a novel SPC “Triple Pill,” three generic antihypertensive drugs with demonstrated efficacy and complementary mechanisms of action at half standard dose (telmisartan 20 mg, amlodipine 2.5 mg, and indapamide 1.25 mg), with placebo for the prevention of recurrent stroke, cardiovascular events, and cognitive impairment after ICH. Design: An international, double-blind, placebo-controlled, randomized trial in adults with ICH and mild-moderate hypertension (systolic BP: 130–160 mmHg), who are not taking any Triple Pill component drug at greater than half-dose. A tota...
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Papers by Catharina Klijn