Endothelial Repair in Childhood Arterial Ischaemic Stroke with Cerebral Arteriopathy.
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ABSTRACT: Background
We have previously shown that recurrent arterial ischaemic stroke (AIS) in children with cerebral arteriopathy is associated with increased circulating endothelial cells and endothelial microparticles, consistent with ongoing endothelial injury. To date, however, little is known about endothelial repair responses in childhood AIS. We examined the relationship between the number and function of circulating endothelial progenitor cells (EPC), the levels of brain-derived neurotrophic factor (BDNF) and AIS recurrence.Methods
Flow cytometry was used to identify peripheral blood mononuclear cells positive for CD34/kinase insert domain-containing receptor (KDR). In a subgroup of patients (5 in each group selected at random), monocytic EPC function was assessed by colony-forming unit (EPC-CFU) capacity and incorporation into endothelial cell networks in Matrigel. BDNF was measured using ELISA.Results
Thirty-five children, aged 12 years (range: 5-16.5; 9 males), with AIS and cerebral arteriopathy were studied; 10 had recurrent AIS. CD34+/KDR+ cells were significantly higher in recurrent AIS compared to non-recurrent AIS patients (p = 0.005) and controls (p = 0.0002). EPC-CFU and EPC incorporation into endothelial cell networks were significantly reduced in recurrent compared to non-recurrent AIS patients (p = 0.04 and p = 0.01, respectively). Levels of BDNF were significantly higher in recurrent compared to non-recurrent AIS patients (p = 0.0008) and controls (p = 0.0002).Conclusions
Children with recurrent AIS and cerebral arteriopathy had increased circulating CD34+/KDR+ cells and BDNF consistent with an endothelial repair response. However, EPC function was impaired. Future studies are needed to examine whether suboptimal endothelial repair contributes to childhood AIS recurrence.
SUBMITTER: Eleftheriou D
PROVIDER: S-EPMC4478301 | biostudies-literature | 2015 May-Aug
REPOSITORIES: biostudies-literature
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Project description:ObjectiveCirculating endothelial cells (CECs) and microparticles (MPs) have been reported to reflect endothelial injury, cellular activation, and MP-mediated thrombin generation. We tested the hypothesis that these indices differ between children with cerebral arteriopathy and arterial ischemic stroke (AIS) recurrence, and those with a single event.MethodsThis was a single-center cross-sectional study of 46 children with AIS and cerebral arteriopathy matched with pediatric controls. AIS recurrence was defined as new acute neurologic deficit with radiologic evidence of further cerebral infarction. CECs and MPs were identified with immunomagnetic bead extraction and flow cytometry, respectively. MP function as assessed by thrombin generation was determined using a fluorogenic assay.ResultsTen children had AIS recurrence while 36 had a single AIS event. CECs were raised in children with recurrent AIS, compared to those with no recurrence (p = 0.0001), and in controls (p = 0.0001). Total circulating annexin V+ MPs were significantly greater in children with recurrence than in those with no recurrence (p = 0.0020). These MPs were of endothelial or platelet origin, and a subpopulation expressed tissue factor. Finally, MP-mediated thrombin generation was enhanced in children with recurrent AIS compared to those with no recurrence (p = 0.0001), providing a link between inflammation, endothelial injury, and increased thrombotic tendency.ConclusionDespite the wide spectrum of clinical and radiologic presentation of childhood AIS, indices of endothelial injury and cellular activation are different in patients with single and recurrent events. This novel approach has potential for furthering understanding of AIS pathophysiology and prognosis.
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Project description:Cerebral arteriopathies, including an idiopathic focal cerebral arteriopathy of childhood (FCA), are common in children with arterial ischemic stroke and strongly predictive of recurrence. To better understand these lesions, we measured predictors of arteriopathy within a large international series of children with arterial ischemic stroke.Between January 2003 and July 2007, 30 centers within the International Pediatric Stroke Study enrolled 667 children (age, 29 days to 19 years) with arterial ischemic stroke and abstracted clinical and radiographic data. Cerebral arteriopathy and its subtypes were defined using published definitions; FCA was defined as cerebral arterial stenosis not attributed to specific diagnoses such as moyamoya, arterial dissection, vasculitis, or postvaricella angiopathy. We used multivariate logistic regression techniques to determine predictors of arteriopathy and FCA among those subjects who received vascular imaging. Of 667 subjects, 525 had known vascular imaging results, and 53% of those (n=277) had an arteriopathy. The most common arteriopathies were FCA (n=69, 25%), moyamoya (n=61, 22%), and arterial dissection (n=56, 20%). Predictors of arteriopathy include early school age (5 to 9 years), recent upper respiratory infections, and sickle cell disease, whereas prior cardiac disease and sepsis reduced the risk of arteriopathy. The only predictor of FCA was recent upper respiratory infection.Arteriopathy is prevalent among children with arterial ischemic stroke, particularly those presenting in early school age, and those with a history of sickle cell disease. Recent upper respiratory infection predicted cerebral arteriopathy and FCA in particular, suggesting a possible role for infection in the pathogenesis of these lesions.
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Project description:Background and purposeAlthough arteriopathies are the most common cause of childhood arterial ischemic stroke, and the strongest predictor of recurrent stroke, they are difficult to diagnose. We studied the role of clinical data and follow-up imaging in diagnosing cerebral and cervical arteriopathy in children with arterial ischemic stroke.MethodsVascular effects of infection in pediatric stroke, an international prospective study, enrolled 355 cases of arterial ischemic stroke (age, 29 days to 18 years) at 39 centers. A neuroradiologist and stroke neurologist independently reviewed vascular imaging of the brain (mandatory for inclusion) and neck to establish a diagnosis of arteriopathy (definite, possible, or absent) in 3 steps: (1) baseline imaging alone; (2) plus clinical data; (3) plus follow-up imaging. A 4-person committee, including a second neuroradiologist and stroke neurologist, adjudicated disagreements. Using the final diagnosis as the gold standard, we calculated the sensitivity and specificity of each step.ResultsCases were aged median 7.6 years (interquartile range, 2.8-14 years); 56% boys. The majority (52%) was previously healthy; 41% had follow-up vascular imaging. Only 56 (16%) required adjudication. The gold standard diagnosis was definite arteriopathy in 127 (36%), possible in 34 (9.6%), and absent in 194 (55%). Sensitivity was 79% at step 1, 90% at step 2, and 94% at step 3; specificity was high throughout (99%, 100%, and 100%), as was agreement between reviewers (κ=0.77, 0.81, and 0.78).ConclusionsClinical data and follow-up imaging help, yet uncertainty in the diagnosis of childhood arteriopathy remains. This presents a challenge to better understanding the mechanisms underlying these arteriopathies and designing strategies for prevention of childhood arterial ischemic stroke.
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Project description:BACKGROUND:Cerebral arteriopathy is a risk factor for incident and recurrent childhood AIS. There are no standardized criteria to quantify arteriopathy severity. AIMS:To evaluate a method of scoring severity of steno-occlusive arteriopathy in childhood arterial ischemic stroke (AIS) and its association with recurrence. METHODS:In a single-center prospectively enrolled cohort of 49 children with first AIS and arteriopathy, a composite cerebrovascular stenosis score (CVSS) was measured by two independent raters as the sum of stenosis scores in each of 18 intracranial large and medium arteries, where 0 = none; 1 = low-grade, 1-50%; 2 = high-grade, >50-99%; 3 = occlusion, 100%. Cox proportional-hazards models were used to determine the association of CVSS with recurrence. The analysis was stratified by presence or absence of moyamoya arteriopathy (syndrome or disease). RESULTS:At a median follow-up period of 2.5 years (range: 0.8-9), 18/49 children (37%) experienced a recurrence. Median time to recurrence was 0.2 (range: 0.02-2.8) years. Interrater agreement was good, with an intraclass correlation coefficient of 0.77 [95% confidence interval (CI) 0.63-0.87, P < 0.001). Higher CVSS was associated with higher recurrence rate [hazard ratio (HR) per point 1.09, 95% CI 1.04-1.16, P = 0.001]. Among those with moyamoya arteriopathy, CVSS was associated with recurrence (HR per point of CVSS 1.11, 95% CI 1.03-1.19, P = 0.004), but there was no association in those without moyamoya arteriopathy (HR per point of CVSS 0.91, 95% CI 0.75-1.09, P = 0.32). CONCLUSIONS:The CVSS is a reliable measure of severity of steno-occlusive arteriopathy in childhood stroke. This preliminary study suggests that higher CVSS is associated with stroke recurrence in children with moyamoya arteriopathy.
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Project description:Background and Purpose- Focal cerebral arteriopathy (FCA)-a common cause of arterial ischemic stroke in previously healthy children-often progresses over days to weeks, increasing the risk of recurrent stroke. We developed a novel severity scoring system designed to quantify FCA progression and correlate with clinical outcomes. Methods- The VIPS study (Vascular Effects of Infection in Pediatric Stroke) prospectively enrolled 355 children with arterial ischemic stroke (2010-2014), including 41 with centrally confirmed FCA. Two neuroradiologists independently reviewed FCA cerebrovascular imaging, assigning a graded severity score of zero (no involvement) to 4 (occlusion) to individual arterial segments. The FCA severity score (FCASS) was the unweighted sum. In an iterative process, we modeled scores derived from different combinations of arterial segments to identify the model that optimized correlation with clinical outcome, simplicity, and reliability. Results- The optimal FCASS summed scores from 5 arterial segments: supraclinoid internal carotid artery, A1, A2, M1, and M2. The median (interquartile range) baseline FCASS was 4 (2-6). Of 33 children with follow-up imaging, the maximum FCASS (at any time point) was 7 (5-9). Twenty-four (73%) had FCA progression on follow-up with their maximum FCASS at a median of 8 (5-35.5) days poststroke; their median FCASS increase was 4 (2.5-6). FCASS did not correlate with recurrent arterial ischemic stroke. Maximum (but not baseline) FCASS correlated with 1-year pediatric stroke outcome measures ( P=0.037). Conclusions- Our novel scoring system for FCA severity correlates with neurological outcomes in the VIPS cohort and provides a tool for FCA treatment trials under development.
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Project description:Arteriopathies are the commonest cause of arterial ischaemic stroke (AIS) in children. Repeated vascular imaging in children with AIS demonstrated the existence of a 'transient cerebral arteriopathy' (TCA), characterized by lenticulostriate infarction due to non-progressive unilateral arterial disease affecting the supraclinoid internal carotid artery and its proximal branches. To further characterize the course of childhood arteriopathies, and to differentiate TCA from progressive arterial disease, we studied the long-term evolution of unilateral anterior circulation arteriopathy, and explored predictors of stroke outcome and recurrence. From three consecutive cohorts in London, Paris and Utrecht, we reviewed radiological studies and clinical charts of 79 previously healthy children with anterior circulation AIS and unilateral intracranial arteriopathy of the internal carotid bifurcation, who underwent repeated vascular imaging. The long-term evolution of arteriopathy was classified as progressive or TCA. Clinical and imaging characteristics were compared between both groups. Logistic regression modelling was used to determine possible predictors of the course of arteriopathy, functional outcome and recurrence. After a median follow-up of 1.4 years, 5 of 79 children (6%) had progressive arteriopathy, with increasing unilateral disease or bilateral involvement. In the others (94%), the course of arteriopathy was classified as TCA. In 23% of TCA patients, follow-up vascular imaging showed complete normalization, the remaining 77% had residual arterial abnormalities, with improvement in 45% and stabilization in 32%. Stroke was preceded by chickenpox in 44% of TCA patients, and in none of the patients with progressive arteriopathies. Most infarcts were localized in the basal ganglia. In 14 (19%) of TCA patients, transient worsening of the arterial lesion was demonstrated before the arteriopathy stabilized or improved. Thirteen TCA patients (18%) had a recurrent stroke or TIA. Thirty TCA patients (41%) had a good neurological outcome, compared with none of the five patients with progressive arteriopathy. Arterial occlusion, moyamoya vessels and ACA involvement were more frequent in progressive arteriopathies. Cortical infarct localization was significantly associated with poor neurological outcome (OR 6.14, 95% CI 1.29-29.22, P = 0.02), while there was a trend for occlusive arterial disease to predict poor outcome (OR 3.00, 95% CI 0.98-9.23, P = 0.06). Progressive arteriopathy was associated with recurrence (OR 18.77, 95%CI 1.94-181.97, P = 0.01). The majority of childhood unilateral intracranial anterior circulation arteriopathies (94%) have a course that is consistent with TCA, in which transient worsening is common. Although the arterial inflammation probably causing TCA is 'transient', most children are left with permanent arterial abnormalities and residual neurological deficits.
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Project description:AimsTo undertake a systematic review of the literature reporting the prevalence of thrombophilia in children with a first arterial ischaemic stroke (AIS).MethodsSystematic review of case-control studies reporting data for prevalence of protein C, S, and antithrombin (AT) deficiencies, activated protein C resistance (APCr), total plasma homocysteine >95th centile, the thrombophilic mutations factor V1691 GA, prothrombin 20210GA, and MTHFR C677T in children with first, radiologically confirmed, AIS.ResultsOf 1437 potentially relevant citations, 18 met inclusion criteria. A total of 3235 patients and 9019 controls had been studied. Results of meta-analyses were expressed as pooled odds ratios (OR) relating the prevalence of the thrombophilic condition in children with AIS to that in controls. The pooled OR (and 95% CI) were: protein C deficiency, 6.49 (2.96 to 14.27); protein S deficiency, 1.14 (0.34 to 3.80); AT deficiency, 1.02 (0.28 to 3.67); APCr, 1.34 (0.16 to 11.52); FV1691 GA, 1.22 (0.80 to 1.87); PT20210GA, 1.10 (0.51 to 2.34); MTHFR C677T, 1.70 (1.23 to 2.34); and total plasma homocysteine >95th centile, 1.36 (0.53 to 3.51). There was no statistical heterogeneity within these data.ConclusionsAll factors examined were more common in children with first AIS than in controls, and significantly so for protein C deficiency and the MTHFR C677T mutation. The implications of thrombophilia for prognosis and recurrence need to be established before clinical recommendations can be made regarding investigation and treatment of children with AIS.
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Project description:BackgroundMost disabling strokes are due to a blockage of a large artery in the brain by a blood clot. Prompt removal of the clot with intra-arterial thrombolytic drugs or mechanical devices, or both, can restore blood flow before major brain damage has occurred, leading to improved recovery. However, these so-called endovascular interventions can cause bleeding in the brain. This is a review of randomised controlled trials of endovascular thrombectomy or intra-arterial thrombolysis, or both, for acute ischaemic stroke.ObjectivesTo assess whether endovascular thrombectomy or intra-arterial interventions, or both, plus medical treatment are superior to medical treatment alone in people with acute ischaemic stroke.Search methodsWe searched the Trials Registers of the Cochrane Stroke Group and Cochrane Vascular Group (last searched 1 September 2020), CENTRAL (the Cochrane Library, 1 September 2020), MEDLINE (May 2010 to 1 September 2020), and Embase (May 2010 to 1 September 2020). We also searched trials registers, screened reference lists, and contacted researchers.Selection criteriaRandomised controlled trials (RCTs) of any endovascular intervention plus medical treatment compared with medical treatment alone in people with definite ischaemic stroke.Data collection and analysisTwo review authors (MBR and MJ) applied the inclusion criteria, extracted data, and assessed trial quality. Two review authors (MBR and HL) assessed risk of bias, and the certainty of the evidence using GRADE. We obtained both published and unpublished data if available. Our primary outcome was favourable functional outcome at the end of the scheduled follow-up period, defined as a modified Rankin Scale score of 0 to 2. Eighteen trials (i.e. all but one included trial) reported their outcome at 90 days. Secondary outcomes were death from all causes at in the acute phase and by the end of follow-up, symptomatic intracranial haemorrhage in the acute phase and by the end of follow-up, neurological status at the end of follow-up, and degree of recanalisation.Main resultsWe included 19 studies with a total of 3793 participants. The majority of participants had large artery occlusion in the anterior circulation, and were treated within six hours of symptom onset with endovascular thrombectomy. Treatment increased the chance of achieving a good functional outcome, defined as a modified Rankin Scale score of 0 to 2: risk ratio (RR) 1.50 (95% confidence interval (CI) 1.37 to 1.63; 3715 participants, 18 RCTs; high-certainty evidence). Treatment also reduced the risk of death at end of follow-up: RR 0.85 (95% CI 0.75 to 0.97; 3793 participants, 19 RCTs; high-certainty evidence) without increasing the risk of symptomatic intracranial haemorrhage in the acute phase: RR 1.46 (95% CI 0.91 to 2.36; 1559 participants, 6 RCTs; high-certainty evidence) or by end of follow-up: RR 1.05 (95% CI 0.72 to 1.52; 1752 participants, 10 RCTs; high-certainty evidence); however, the wide confidence intervals preclude any firm conclusion. Neurological recovery to National Institutes of Health Stroke Scale (NIHSS) score 0 to 1 and degree of recanalisation rates were better in the treatment group: RR 2.03 (95% CI 1.21 to 3.40; 334 participants, 3 RCTs; high-certainty evidence) and RR 3.11 (95% CI 2.18 to 4.42; 268 participants, 3 RCTs; high-certainty evidence), respectively.Authors' conclusionsIn individuals with acute ischaemic stroke due to large artery occlusion in the anterior circulation, endovascular thrombectomy can increase the chance of survival with a good functional outcome without increasing the risk of intracerebral haemorrhage or death.
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