Treatment of arterial ischemic stroke in children

Stroke is a rare but increasingly recognized disorder in children. Current therapies for arterial ischemic stroke include thrombolytic, antithrombotic and antiplatelet agents, blood transfusion and surgery. Adult studies, pediatric case studies and expert opinion form the basis for these treatment strategies. Thrombolytic agents are increasingly used but, as in adults, the majority of arterial ischemic strokes in children are treated with antiplatelet and antithrombotic agents. Sickle-cell patients, a distinct subset of the pediatric stroke population, are treated primarily with transfusion therapy. Pediatric arterial ischemic stroke studies are needed to determine the most appropriate course of treatment. An international study is currently in progress to formally study the incidence, risk factors, treatment strategies and outcomes of stroke in children.     

Investigation of risk factors in children with arterial ischemic stroke

We present data on the known risk factors encountered in children presenting with a first arterial ischemic stroke to a single tertiary center over 22 years. Two hundred twelve patients (54% male; median age, 5 years) were identified. One hundred fifteen (54%) were previously healthy. Cerebral arterial imaging was undertaken in 185 patients (87%) and was abnormal in 79%. Of 104 previously healthy patients investigated with echocardiography, only 8 had abnormal studies. Genetic or acquired conditions causing thrombophilia were rare. Forty percent of patients were anemic, and 21% either had elevated total plasma homocysteine or were homozygous for the t-MTHFR mutation. Trauma and previous varicella zoster infection were significantly more common in the previously healthy group. There was a significant association between cerebral arterial abnormalities and systolic blood pressure greater than 90th percentile and a trend for an association with varicella within the previous year. Clinical history and examination usually identify underlying risk factors and precipitating triggers for arterial ischemic stroke in childhood. Cerebral arterial imaging is usually abnormal, but echocardiography and prothrombotic screening are commonly negative.     

Risk factors for arterial ischemic stroke in children

Since early recurrence occurs in at least 10% of patients presenting with their first stroke in childhood in the reported series, the search for modifiable risk factors should be a priority. Risk factors for stroke in adults include hypertension, diabetes, and smoking, as well as cardiac disease and sickle cell anemia; asymptomatic cerebrovascular disease and transient ischemic events may predict stroke in this age group. The investigation of a child with a stroke has traditionally focused on finding a single cause rather than looking for risk factors to which the patient may be exposed life long. Approximately half of children presenting with stroke have a known predisposing condition, but some have unexpected pathologies such as primary cerebrovascular disease associated with congenital heart anomalies, or may have modifiable risk factors such as hypertension associated with sickle cell disease. The literature on children presenting with initially unexplained (cryptogenic) stroke suggests that there is a daunting list of possible causes, but since the series have mainly been small, it has been difficult to evaluate the relative importance of the reported associations. This paper reviews the literature on congenital, genetic, and acquired risk factors for stroke in childhood, and includes data from the large series of patients seen at Great Ormond Street Hospital over the past 10 years. The majority have arteriographic abnormalities and there is little evidence for asymptomatic cardiac disease. Genetic predisposition, trauma, infection, and nutritional deficiencies appear to be important, although case-control studies will be required to prove causation. Appropriate screening for modifiable risk factors may lead to prevention of recurrence in some patients. In the long term, an understanding of the multiple etiologies of childhood cerebrovascular disease and ischemic stroke may lead to primary prevention in this age group, and perhaps in adults.     

Prethrombotic disorders in children with arterial ischemic stroke and sinovenous thrombosis.

BACKGROUND: Arterial ischemic stroke (AIS) and sinovenous thrombosis (SVT) are relatively rare events in children. The contribution of prethrombotic disorders to the etiology of these entities has not been completely elucidated. OBJECTIVES: To determine the frequency of inherited and acquired prethrombotic disorders in a pediatric population with AIS and SVT and to report clinical and radiological features. METHODS: From May 1992 to April 1997, 30 consecutive children with AIS and 10 children with SVT were assisted at a single institution. Hemostatic evaluation was performed for all the children. Evaluation included the following assays: protein C, protein S, antithrombin, plasminogen, activated protein C resistance, factor V Leiden mutation, and the detection of antiphospholipid antibodies. Data concerning baseline demographics, risk factors, presenting features, family history of thrombosis, and radiological findings were also recorded. RESULTS: One or more prethrombotic disorders were present in 9 children (30%) with AIS (inherited protein S deficiency, 2 patients; inherited protein C deficiency, 1 patient; acquired antithrombin deficiency, 2 patients; antiphospholipid antibodies, 3 patients; and antiphospholipid antibodies and plaminogen deficiency, 1 patient) and in 5 children (50%) with SVT (inherited protein S deficiency, 1 patient; acquired antithrombin deficiency, 3 patients; and antiphospholipid antibodies, 1 patient). CONCLUSIONS: Most children studied presented both a variety of risk factors for thrombosis and concomitant prethrombotic disorders. Therefore, a complete hemostatic evaluation for all children with AIS and SVT should be performed, despite the presence of obvious clinical risk factors or lack of family history of thrombosis.     

Risk factors and treatment outcomes for children with arterial ischemic stroke

To investigate the risk factors and treatment outcomes for ischemic stroke in children, we reviewed the charts of 93 children with ischemic stroke seen at our hospital between 1997 and 2006. Age at stroke, sex, medical history, family history, clinical findings upon admission, history of seizure, and radiological findings were recorded. Mean age at onset of the initial stroke was 56.6 ± 46.9 months, ranging from 1 month to 14 years. The male:female ratio was 1.6:1. Cardiac and infectious disease were the most common risk factors (37.7%). There were five children (5.4%) who had recurrent stroke and three (3.2%) who had multiple risk factors. Cardiac and infectious causes appeared to be the most important risk factors for ischemic stroke in children in the Adana region of Turkey.     

Association of cerebral palsy with other disabilities in children with perinatal arterial ischemic stroke

The association of cerebral palsy with other disabilities in children with perinatal stroke has not been well-studied. We examined this association in 111 children with perinatal stroke: 67 with neonatal presentation, and 44 with delayed presentation. Seventy-six children (68%) had cerebral palsy, which was hemiplegic in 66 and tri- or quadriplegic in 10. Fifty-five (72%) children with cerebral palsy had at least one other disability: 45 (59%) had a cognitive/speech impairment (moderate-severe in 20), and 36 (47%) had epilepsy (moderate-severe in 11). In children with neonatal presentation, cerebral palsy was associated with epilepsy (P = 0.0076) and cognitive impairment (P = 0.0001). These associations could not be tested in children with delayed presentation because almost all children in this group had cerebral palsy. In another analysis with multivariate logistic regression for children with cerebral palsy, children who had both neonatal presentation and history of cesarean-section delivery were more likely to have epilepsy (P = 0.001). Children with cerebral palsy after perinatal stroke who had neonatal presentation were more likely to have severe cognitive impairment (odds ratio, 7.78; 95% confidence interval, 1.80-47.32) or severe epilepsy (odds ratio, 6.64; 95% confidence interval, 1.21-69.21) than children with delayed presentation. Children with cerebral palsy after perinatal stroke are likely to have an additional disability; those with neonatal presentation are more likely to have a severe disability.     

Pharmacology in childhood arterial ischemic stroke

In recent years, there has been increasing recognition of the impact of childhood stroke and interest in the role of drugs in the acute, chronic, and prophylactic management of this condition. Most treatment strategies are based on studies in adults with stroke, and the relative infrequency of stroke and the heterogeneity of etiologies in childhood compared with adults present significant challenges in study design for childhood stroke studies. The presence of thrombophilia has been associated with stroke in children, strengthening the concept that antithrombotic, antiplatelet, and even thrombolytic agents have a role in stroke treatment and prevention. There are several potential roles for drugs in the treatment of childhood stroke including hyperacute therapy, antithrombotic medication, antiplatelet medication, and disease-specific medications. Herein, we review the use and rationale of these medications in childhood arterial ischemic stroke.     

Two children with both arm ischemia and arterial ischemic stroke during the perinatal period

It is rare for both limb ischemia and arterial ischemic stroke to occur in the same child during the perinatal period. Two children who appear to have had perinatal emboli to both an arm and a middle cerebral artery territory are presented here. One child required amputation of the ischemic limb below the shoulder, and the other required skin grafts to the distal ischemic fingers. Each of these children later received cerebral magnetic resonance imaging for evaluation of developmental delay and was found to have what appeared to be old perinatal arterial ischemic stroke. Both children were homozygous for the methylenetetrahydrofolate reductase C677T gene variant. Eight other children with perinatal limb ischemia and stroke were found on literature review; several also had delayed diagnosis of perinatal stroke. This report examines the approach to diagnosis and treatment in each of these and makes suggestions for the similar cases in the future.     

Common genetic variants of homocysteine metabolism in ischemic stroke: a case–control study

Hyperhomocysteinemia is a risk factor for ischemic stroke. We investigated five functional polymorphisms involved in homocysteine metabolism in each 159 stroke patients and controls. The folate-sensitive polymorphism methylenetetrahydrofolate reductase (MTHFR) c. 677 C > T (A222V) referred a non-significant risk of ischemic stroke (odds ratio: 1.20) in all patients, and homozygosity for MTHFR c. 677 C > T was associated with an earlier onset of stroke selectively in patients younger than 60 years (38 +/- 3 years vs. 45 +/- 1 years; P = 0.043). This study suggests that the investigated polymorphisms are no major risk factors for stroke, although MTHFR c. 677 C > T could be a minor factor of vulnerability especially in young patients (TT genotype), which might be helpful for the clinical work-up of stroke cases and for preventive dietary strategies.     

5-脂氧合酶激活蛋白基因和白介素-1A基因多态与缺血性脑卒中的相关性

目的 探讨中国北方地区汉族人群5-脂氧合酶激活蛋白(ALOX5AP)基因和白介素-1A(IL-1A)基因多态与缺血性脑卒中(IS)的相关性.方法 采用病例-对照研究,检测构建ALOX5AP基因单倍型HapA的4个位点:SG13S25、SG13S32、SG13S89、SG13S114和IL-1A基因-889位点在对照组、IS组及IS亚组中多态的分布.结果 ALOXSAP基因SG13S114位点AA基因型可能是血栓性脑梗死独立的风险因素(OR=1.479,95% CI 1.024～2.135,P=0.037),且其风险性主要来源于A等位基因(OR=1.313,95% CI 1.017～1.693,P=0.036);IL-IA基因-889位点T等位基因可能是血栓性脑梗死的易患等位基因(OR=1.540,95% CI 1.075～2.204,P=0.023).HapA单倍型和IS没有相关性,GCGA单倍型可能是IS的危险单倍型(OR=1.683,95% CI 1.138～2.487,P=0.008).同时携带ALOX5AP基因GCGA单倍型和IL-1A-889T等位基因的个体患IS的风险性显著增加(OR=1.608,95% CI 1.607～2.423,P=0.022).结论 ALOXSAP基因、IL-1A基因的多态与IS具有相关性,二者的协同作用可显著增加IS的患病风险.     

CX37基因I1297D多态性与缺血性脑卒中及临床分型的关系探讨

目的探讨连接蛋白37(connexins37,CX37)基因I1297D多态性位点与缺血性脑卒中及其亚型的关系。方法采用限制性片段长度多态性分析技术,检测缺血性脑卒中组232例(根据诊断分为动脉粥样硬化性血栓性脑梗死组115例,脑栓塞组31例,腔隙性脑梗死组86例)和健康对照组235例CX37基因I1297D多态的分布。结果 CX37基因I1297D多态性,缺血性脑卒中组和对照组中均以II基因型和I等位基因为主。基因型(II型I、D型、DD型)I、和D等位基因分布频率在缺血性脑卒中组分别为46.56%、39.22%、14.22%、66.16%和33.84%,对照组分别为47.66%、43.40%、8.94%、69.36%和30.64%,2组比较差异无统计学意义(P>0.05),且其基因型、等位基因分布频率在缺血性脑卒中各亚型之间与对照组比较,差异无统计学意义(P>0.05)。结论 CX37基因I1297D的多态性与缺血性脑卒中易感性无关。     

Relation between homocysteine and non-fatal stroke in peripheral arterial disease

There are currently no data on whether high total serum homocysteine (tHcy) is predictive for cerebrovascular events in patients with symptomatic peripheral arterial disease (PAD). Therefore, the purpose of this study was to determine whether high tHcy levels were related to the evidence of non-fatal stroke in PAD. Evidence of non-fatal atherothrombotic stroke events was verified in 450 consecutive male patients, admitted for inpatient treatment of symptomatic PAD. The extent of carotid stenosis was evaluated by colour duplex Doppler measurement and fasting tHcy was determined by high-performance liquid chromatography. Within the population of 450 PAD patients a documented history of ischaemic stroke was evident in 50 subjects. The median tHcy values were significantly higher in PAD patients with stroke (18.6 micromol/l) than in PAD patients without stroke (15.1 micromol/l, P < 0.001). Logistic regression analysis revealed that tHcy was an independent and significant predictor (P=0.001) with an odds ratio (OR) of 1.37 for an increment of 5 micromol/l. In this multivariate model, diabetes mellitus (OR=2.34, P=0.011) and carotid stenosis > or =50% (OR=2.59, P=0.005) were also independently related to clinical cerebrovascular disease in PAD. In conclusion, the present study demonstrates an association of tHcy and evidence of non-fatal atherothrombotic stroke in patients with symptomatic PAD. This could be important, as a reduction of elevated tHcy concentrations by vitamin supplement might decrease the high frequency of cerebrovascular complications in PAD patients.     

同型半光氨酸及超敏C反应蛋白与进展性缺血性脑卒中的相关性

目的探讨同型半胱氨酸(Hcy)及超敏C反应蛋白(hs-CRP)在进展性缺血性脑卒中患者中的临床意义。方法急性脑梗死患者70例,分为进展性组35例和完全组35例,并选择35例门诊健康体检者,用全自动生化分析仪器分别测定3组的第1、2、3、7、14天Hcy和hs-CRP的水平。结果进展性脑卒中组的Hcy和hsCRP显著高于完全脑卒中患者(P<0.01)。结论 Hcy和hs-CRP水平增高与进展性脑梗死的发生相关。     

Doppler examination and cerebral arterial stricture in patients with ischemic stroke

With the development of interventional therapy, it is necessary for evaluating cerebral vessels to instruct treatment and determine prognosis of patients with ischemic stroke; however, correlation of distribution of infarction focus and clinical symptoms with degrees of cerebrovasoular stricture is still unclear.OBJECTIVE: To evaluate the characteristics of cerebral arterial stricture of patients with ischemic stroke with transcranial Doppler (TCD) and color duplex flow imaging (CDFI) and compare the correlation between distribution of cerebral infarction focus and clinical types with magnetic resonance imaging (MRI).DESIGN: Contrast observation.SETTING: Department of Neurology, the First Hospital of Jilin University.PARTICIPANTS: A total of 159 patients with ischemic stroke were selected from the Department of Neurology, the First Hospital of Jilin University from January to December 2005, including 106 males and 53 females aged from 27 to 88 years. Bases on diagnostic criteria of cerebrovascular disease established by Rao et al, clinical manifestations of all patients were evaluated with CT or nuclear magnetic resonance. All patients provided the confirmed consent.METHODS: The accepted patients received TCD and CDFI examination at 1 week after onset of ischemic stroke. Among them, 112 patients received cerebrovascular imaging examination simultaneously. MRI was used to check cerebral infarction focus and cerebrovascular stricture ＞ 50% was regarded as the accepted vessels. In addition, DWI-T2 TCD (Germany) was used to check middle cerebral artery, and degrees of middle cerebral artery were classified into mild, moderate and severe stricture based on blood velocity (140 cm/s,180 cm/s). Stroke was classified based on characteristics of infarction focus and clinical symptoms showed with MRI and correlation with degrees of cerebrovascular stricture was analyzed simultaneously.MAIN OUTCOME MEASURES: Correlation between the characteristics of ischemic stroke and clinical symptoms checked with TCD and CDFI.RESULTS: A total of 159 patients with ischemic stroke were involved in the final analysis; in addition, 112 oases received cerebrovascular imaging examination simultaneously. ① MRI results of 159 patients with cerebral artery occlusive disease (CAOD): There were 131 patients (82.3%) with cerebral infarction, 40 (25.2%)with transient ischemic attack and 4 (2.5%) with subclavian steal syndrome (SSS). ② Infarction types with MRI examination: There were 33 patients (20.8%) with solitary cerebral infarction and 98 (61.6%) with multiple-cerebral infarction. ③ Results of TCD, CDFI, MRI angiography, CT angiography and digital subtraction angiography (DSA): Among 112 patients, 181 lesion sites (61 .8%) were located in cranium and 112 lesion sites were located out of cranium; especially, lesion site was mostly observed in stem of middle cerebral artery (31.2%) and watershed of basilar artery (7.2%) in cranium and the beginning site of internal carotid artery (21 .4%) out of cranium. ④ Correlation of vascular stricture checking with TCD, MRI and clinical diagnosis: On one hand, MRI and clinical diagnosis demonstrated that 68 patients had a watershed infarction; meanwhile,TCD examination indicated that there were 3 patients with mild vascular stricture, 24 with moderate vascular stricture and 36 with severe vascular stricture. On the other hand, among 68 patients with non-watershed infarction, there were 27 patient with mild vascular stricture, 26 with moderate vascular stricture and 15 with severe vascular stricture. There were significant differences (x2 =26.854, P =0.001 ). Clinical diagnosis indicated that 40 patients had transient ischemic attack and TCD examination demonstrated that there were 8 patient with mild vascular stricture, 12 with moderate vascular stricture and 20 with severe vascular stricture. There were significant differences as compared with 68 patients with watershed infarction (x2 =21.258, P =0.001). ⑤Correlation of vascular stricture checking with CDFI, MRI and clinical diagnosis: On one hand, among patients who were determined as watershed infarction with MRI and clinical diagnosis, CDFI examination indicated that there were 32 patients with mild vascular stricture at neck, 25 with moderate vascular stricture and 6 with severe vascular stricture. On the other hand, among patients with non-watershed infarction, there were 48 patient with mild vascular stricture, 18 with moderate vascular stricture and 2 with severe vascular stricture.There were significant differences (x2 =6.018, P =0.019). Among patients with transient ischemic attack checking with clinical diagnosis, there were 23 patient with mild vascular stricture, 9 with moderate vascular stricture and 8 with severe vascular stricture. There were no significant differences as compared with patients with non-watershed infarction (x2 =0.597, P=0.440).CONCLUSION: ① TCD and CDFI are effective marks to determine cerebral arterial stricture and hemodynamical changes. ② Infarction and transient ischemic attack at watershed are generally clinical phenotypes of CAOD patients and infarction at watershed is correlated with degrees of cerebrovascular stricture.③ TCD, MRI and clinical analysis of stroke types are significant for instructing treatment and evaluate prognosis.