Role of endogenous testosterone concentration in pediatric stroke.

Previous studies have indicated a male predominance in pediatric stroke. To elucidate this gender disparity, total testosterone concentration was measured in children with arterial ischemic stroke (AIS; n = 72), children with cerebral sinovenous thrombosis (CSVT; n = 52), and 109 healthy controls. Testosterone levels above the 90th percentile for age and gender were documented in 10 children with AIS (13.9%) and 10 with CSVT (19.2%), totaling 16.7% of patients with cerebral thromboembolism overall, as compared with only 2 of 109 controls (1.8%; p = 0.002). In multivariate analysis with adjustment for total cholesterol level, hematocrit, and pubertal status, elevated testosterone was independently associated with increased disease risk (odds ratio [95% confidence interval]: overall = 3.98 [1.38-11.45]; AIS = 3.88 [1.13-13.35]; CSVT = 5.50 [1.65-18.32]). Further adjusted analyses revealed that, for each 1nmol/l increase in testosterone in boys, the odds of cerebral thromboembolism were increased 1.3-fold.

Predictive value of clinical and EEG features in the diagnosis of stroke and hypoxic ischemic encephalopathy in neonates with seizures.

BACKGROUND AND PURPOSE: In neonates, the differentiation of stroke and hypoxic ischemic encephalopathy (HIE) is important. Neuroimaging presents technical challenges in unstable neonates, resulting in frequently delayed or missed diagnosis of stroke. Differentiating clinical and electroencephalographic (EEG) features would assist physicians in the timely diagnosis. We sought to determine, in neonates with seizures, clinical and EEG features that differentiate stroke and HIE. METHODS: Retrospective cohort study comparing clinical, seizure, and EEG features in term neonates with ischemic stroke or HIE and seizures within 7 days after birth, admitted at The Hospital for Sick Children. Putative clinical and EEG predictors of stroke were analyzed with univariate and multivariate methods. RESULTS: Sixty-two newborns with stroke (n=27) or HIE (n=35) were studied. With univariate analysis, predictors of stroke included delayed seizure onset (>or=12-hours after birth) (P<0.0001; OR, 26.4; 95% CI, 6.8, 102.5), focal motor seizures (P=0.001; OR, 7.2; 95% CI, 2.0, 26.0) and pattern of neurological abnormalities (P<0.0001). With multivariate analysis, delayed seizure onset (P<0.0001; OR 39.7; 95% CI, 7.3, 217.0) and focal motor seizures (P=0.007; OR, 13.4; 95% CI, 2.1, 87.9) predicted stroke. Presence of both predictors had 100% positive predictive value and specificity, 61% negative predictive value and 37% sensitivity. CONCLUSIONS: In neonates, onset of seizures beyond 12 hours of birth and clinically observed focal seizures are predictive of stroke. These preinvestigation indicators of stroke may facilitate earlier diagnosis and institution of specific management strategies.

Systemic thromboembolism in children. Data from the 1-800-NO-CLOTS Consultation Service.

Thromboembolism (TE) has recently been recognized as a clinical entity in children. Determining the clinical characteristics of pediatric TE is an important first step in dealing with this new disorder. The paper summarizes 1776 consecutive children with systemic TE referred to 1-800-NO-CLOTS telephone consultation service. 1-800-NO-CLOTS is a free consultation service for clinicians managing pediatric TE. Patient information was collected immediately using standardized forms. In children with systemic TE, infants under one year of age (47%) including neonates (26%) represented the largest distinct pediatric age group. Age-related differences were seen in TE locations, associated conditions, and risk factors. However, venous TE was the most frequent manifestation (74%). Neonates and children with cardiac disorders were more likely to have an arterial TE than a venous TE Beyond the neonatal period, venous TE associated with a central line is more likely to occur than arterial TE. Children with ALL were 5.7 times more likely to have a venous TE than an arterial TE. TE were infrequent in otherwise healthy children with 90% of children having at least one risk factor. Central catheters were the single most common risk factor associated with TE, present in 2/3 of children. Ultrasound was most frequently employed for diagnosis of TE. Finally, there was marked heterogeneity in treatment of children with TE. In children, neonates form the largest single group with TE. TE usually occur only in the presence of one or more risk factors with catheters being the single most important factor.

Predictors of mortality and neurological morbidity in children undergoing extracorporeal life support for cardiac disease.

OBJECTIVES: The objective of this study was to determine the incidence and risk factors for death and adverse neurological outcomes in children receiving extracorporeal life support (ECLS) for cardiac indications. METHODS: A retrospective single centre consecutive cohort study was conducted in children who received ECLS for cardiac indications between January 1990 and June 2000. Health records and neuroimaging films were assessed, and long-term outcomes were obtained by standardized telephone follow-up or by assessments performed in outpatient clinic. Clinical, neuroimaging and surgical predictors of outcome were tested. RESULTS: Of 90 children studied, short-term clinical neurological events (during hospitalization) occurred in 20 children (22%) during or following ECLS. Long-term neurological sequelae were present in 11 of 31 children discharged alive, after a mean follow-up interval of 4.5 years (range 4 months to 9 years). Death occurred in 59 children (66%) during hospitalisation, and in 3 following discharge. Of the 28 long-term survivors, only 15 children (17%) survived without neurological sequelae. Abnormal neuroimaging was associated with short-term neurological events (P = 0.03, OR 10.5), and the use of CPR prior to ECLS (P = 0.02, OR 2.9) was the only significant predictor of death. There were no significant predictors of long-term neurological sequelae. CONCLUSIONS: More than two-thirds of the children receiving ECLS died, and 39% (11/28) of long-term survivors had neurological deficits. Although mortality is close to 100% without this type of support, there is still a significantly high morbidity and mortality with this type of support.

Trend to efficacy and safety using antithrombin concentrate in prevention of thrombosis in children receiving l-asparaginase for acute lymphoblastic leukemia. Results of the PAARKA study.

An association has been reported between thrombotic events and the use of L-asparaginase (ASP) in children with acute lymphoblastic leukaemia (ALL). The mechanism for thrombosis is likely related to an acquired antithrombin deficiency. Since a primary prophylaxis using antithrombin concentrates may prevent thrombosis, the PARKAA (Prophylactic Antithrombin replacement in kids with ALL treated with L-asparaginase) study was performed. The objectives of PARKAA were to determine if there was a trend to efficacy and safety of antithrombin treatment as assessed by 1) incidence of thrombosis 2) incidence of bleeding and 3) plasma markers of endogenous thrombin generation as surrogate outcomes for thrombosis. The study was not powered to answer the question of efficacy and safety, but rather to detect a trend. PARKAA was an open, randomised, controlled study in children with ALL being treated with ASP. Children were randomised to receive antithrombin infusions or no antithrombin treatment. All thrombotic events were confirmed using bilateral venography, ultrasound, echocardiography and MRI. The incidence of thrombosis in patients treated with antithrombin was 28% (95% CI 10-46%), compared to 37% (95% CI 24-49%) in the non treated arm. Two minor bleeds occurred in patients in the treated arm, but were not considered to be related to antithrombin. No significant differences were seen in plasma markers by the treatment group. In conclusion, treatment with antithrombin concentrate shows a trend to efficacy and safety. In contrast, there was no difference in surrogate markers for thrombosis. Carefully designed clinical trials are needed to test the efficacy and safety of antithrombin in this population.

A prospective cohort study determining the prevalence of thrombotic events in children with acute lymphoblastic leukemia and a central venous line who are treated with L-asparaginase: results of the Prophylactic Antithrombin Replacement in Kids with Acute Lymphoblastic Leukemia Treated with Asparaginase (PARKAA) Study.

BACKGROUND: Thrombotic events (TEs) are serious secondary complications in children with acute lymphoblastic leukemia (ALL) who receive L-asparaginase (ASP) therapy; however, the prevalence of TEs has not been established. The primary objective of the Prophylactic Antithrombin Replacement in Kids with Acute Lymphoblastic Leukemia Treated with Asparaginase (PARKAA) Study was to determine the prevalence of TEs. The secondary objective was to detect any association of TEs with the presence of congenital or acquired prothrombotic disorders. METHODS: Children with ALL were screened for TEs at the end of ASP treatment using bilateral venograms, ultrasound, magnetic resonance imaging, and echocardiography. Symptomatic TEs were confirmed by appropriate radiographic tests. All tests were read by a blinded central adjudication committee. RESULTS: Twenty-two of 60 children had TEs, a prevalence of 36.7% (95% confidence interval, 24.4-48.8%). TEs were located in the sinovenous system of the brain in 1 patient, the right atrium in 3 patients, and the upper central venous system in 19 patients. TEs detected by venography resulted in 1) 25-100% occlusion, with 1 in 3 patients showing occlusion of > 75% of the greatest vessel dimension, and 2) the presence of collaterals in 60% of patients, with 40% categorized as major. No children with TEs were positive for factor V Leiden or prothrombin gene 20201A, and four of eight children with antiphospholipid antibodies had a TE. CONCLUSIONS: The prevalence of TEs is exceedingly high in this population, and it is likely that the extent of occlusion is likely clinically significant. No trend was seen toward an association between TEs and the presence of congenital prothrombotic disorders. A trend was seen toward an association between TEs and antiphospholipid antibodies. Carefully designed clinical trials of primary prophylaxis for the prevention of TEs are required in this patient population.