Risk Of Stroke In Children Research Articles

Does herpes zoster ophthalmicus increase the risk of stroke?

Varicella zoster virus (VZV), a ubiquitous human herpesvirus, causes chicken pox on primary infection and then establishes lifelong latency in all cranial nerve, dorsal root, and autonomic ganglia. When VZV-specific cell-mediated immunity declines, such as in elderly and immunocompromised individuals, virus reactivates in one or more ganglia and typically travels peripherally to cause herpes zoster in the corresponding dermatomes. Herpes zoster can be complicated by stroke and has been described clinically as VZV vasculopathy, granulomatous angiitis, post varicella arteriopathy, and herpes zoster ophthalmicus (HZO) with delayed contralateral hemiparesis. The likely mechanism for stroke caused by VZV is direct viral infection of cerebral arteries. This assertion is supported by animal studies identifying afferent fibers from trigeminal and dorsal root ganglia to both intracranial and extracranial blood vessels, providing an anatomic pathway for spread of the virus,1,2 and observations of viral particles, antigens, and DNA in affected arterial vessels in VZV vasculopathy cases.3,4 Several studies have examined varicella and the risk of stroke in children,5,6 but large studies in the adult population regarding the frequency and risk of …

TCD is Used More to Screen for Stroke Risk in Children with Sickle Cell Disease

TCD is Used More to Screen for Stroke Risk in Children with Sickle Cell Disease

PRIMARY HEMORRHAGIC STROKE IN A 12-YEAR-OLD FEMALE WITH SICKLE CELL DISEASE AND NORMAL TRANSCRANIAL DOPPLER

Stroke is a well-known complication of sickle cell disease (SCD). It is estimated to occur in approximately 11% of patients with SCD by the age of 20. The most frequent cause of cerebrovascular accident (CVA) is blockage of the intracranial internal carotid and middle cerebral arteries. Hemorrhagic stroke is less common, occurring in approximately 3% of children by age 20. Transcranial Doppler (TCD) is the standard test for prediction of stroke risk in children with sickle cell anemia. The authors present a case of a 12-year-old female with SCD transferred to their institution after suffering a catastrophic intracranial hemorrhage. Her most recent TCD was normal 6 months prior to her admission.

Big Strokes in Small Persons

Sickle cell disease (SCD) is understood on a genetic and a molecular level better than most diseases. Young children with SCD are at a very high risk of stroke. The molecular pathologic abnormalities of SCD lead to microvascular occlusion and intravascular hemolytic anemia. Microvascular occlusion is related to painful episodes and probably causes microcirculatory problems in the brain. The most commonly recognized stroke syndrome in children with SCD is large-artery infarction. These "big strokes" are the result of a vascular process involving the large arteries of the circle of Willis leading to territorial infarctions from perfusion failure or possibly artery-to-artery embolism. We can detect children who are developing cerebral vasculopathy using transcranial Doppler ultrasonography (TCD) and can provide effective intervention. Transcranial Doppler ultrasonography measures blood flow velocity in the large arteries of the circle of Willis. Velocity is generally increased by the severe anemia in these patients, and it becomes elevated in a focal manner when stenosis reduces the arterial diameter. Children with SCD who are developing high stroke risk can be detected months to years before the stroke using TCD. Healthy adults have a middle cerebral artery velocity of approximately 60 cm/s, whereas children without anemia have velocities of approximately 90 cm/s. In SCD, the mean is approximately 130 cm/s. Two independent studies have demonstrated that the risk of stroke in children with SCD increases with TCD velocity. The Stroke Prevention Trial in Sickle Cell Anemia (STOP) (1995-2000) was halted prematurely when it became evident that regular blood transfusions produced a marked (90%) reduction in first stroke. Children were selected for STOP if they had 2 TCD studies with velocities of 200 cm/s or greater. Children not undergoing transfusion had a stroke risk of 10% per year, which was reduced to less than 1% per year by regular blood transfusions. Stroke risk in all children with SCD is approximately 0.5% to 1.0% per year. On the basis of STOP, if the patient meets the high-risk TCD criteria, regular blood transfusions are recommended. A second study was performed (2000-2005) to attempt withdrawal of transfusion in selected children in a randomized controlled study. Children with initially abnormal TCD velocities (> or =200 cm/s) treated with regular blood transfusion for 30 months or more, which resulted in reduction of the TCD to less than 170 cm/s, were eligible for randomization into STOP II. Half continued transfusion and half had cessation of transfusion. This trial was halted early for safety reasons. There was an unacceptably high rate of TCD reversion back to high risk (> or =200 cm/s), as well as 2 strokes in children who discontinued transfusion. There are no evidence-based guidelines for the discontinuation of transfusion in children once they have been identified as having high risk based on TCD. The current situation is undesirable because of the long-term effects of transfusion, including iron overload. Iron overload has recently become easier to manage with the introduction of an oral iron chelator. The inflammatory environment known to exist in SCD and the known effect of plasma free hemoglobin, released by hemolysis, of reducing available nitric oxide may contribute to the development of cerebrovascular disease. Further research may lead to more targeted therapies. We can reduce many of the big strokes that occur in these small persons by aggressively screening patients at a young age (and periodically throughout the childhood risk period) and interrupting the process with regular blood transfusions.

Transcranial Doppler scanning and the assessment of stroke risk in children with haemoglobin sickle cell disease

Objective: To assess the role of transcranial Doppler (TCD) scanning in assessing the risk of stroke in children with haemoglobin SC (HbSC) disease. TCD scanning has an established role in...

Angle-Corrected Imaging Transcranial Doppler Sonography versus Imaging and Nonimaging Transcranial Doppler Sonography in Children with Sickle Cell Disease

Nonimaging transcranial Doppler sonography (TCD) and imaging TCD (TCDI) are used for determination of the risk of stroke in children with sickle cell disease (SCD). The purpose was to compare angle-corrected, uncorrected TCDI, and TCD blood flow velocities in children with SCD. A total of 37 children (mean age, 7.8 +/- 3.0 years) without intracranial arterial narrowing determined with MR angiography, were studied with use of TCD and TCDI at the same session. Depth of insonation and TCDI mean velocities with and without correction for the angle of insonation in the terminal internal carotid artery (ICA) and middle (MCA), anterior (ACA), and posterior (PCA) cerebral arteries were compared with TCD velocities with use of a paired t test. Two arteries were not found on TCDI compared with 15 not found on TCD. Average angle of insonation in the MCA, ACA, ICA, and PCA was 31 degrees , 44 degrees , 25 degrees , and 29 degrees , respectively. TCDI and TCD mean depth of insonation for all arteries did not differ significantly; however, individual differences varied substantially. TCDI velocities were significantly lower than TCD velocities, respectively, for the right and left sides (mean +/- SD): MCA, 106 +/- 22 cm/s and 111 +/- 33 cm/s versus 130 +/- 19 cm/s and 134 +/- 26 cm/s; ICA, 90 +/- 14 cm/s and 98 +/- 27 cm/s versus 117 +/- 18 cm/s and 119 +/- 23 cm/s; ACA, 74 +/- 24 cm/s and 88 +/- 25 cm/s versus 105 +/- 23 cm/s and 105 +/- 31 cm/s; and PCA, 84 +/- 27 cm/s and 82 +/- 21 cm/s versus 95 +/- 23 cm/s and 94 +/- 20 cm/s. TCD and angle-corrected TCDI velocities were not statistically different except for higher angle-corrected TCDI values in the left ACA and right PCA. TCD velocities are significantly higher than TCDI velocities but are not different from the angle-corrected TCDI velocities. TCDI identifies the major intracranial arteries more effectively than TCD.

Confirmation of an Association Between the TNF(−308) Promoter Polymorphism and Stroke Risk in Children With Sickle Cell Anemia

The etiology of stroke in children with sickle cell anemia (SCA) is complex and poorly understood. Growing evidence suggests that genetic factors beyond the sickle cell mutation influence stroke risk in SCA. We previously reported risk associations with polymorphisms in several proinflammatory genes in SCA children with ischemic stroke. The aim of this replication study was to confirm our previous findings of associations between the TNF(-308) G/A, IL4R 503 S/P, and ADRB2 27 Q/E polymorphisms and large vessel stroke risk. Using previously collected MRA data, we assessed an independent population of SCA children from the multicenter Stroke Prevention Trial in Sickle Cell Anemia (STOP) for the presence or absence of large vessel stenosis. Samples were genotyped for 104 polymorphisms among 65 candidate vascular disease genes. Genotypic associations with risk of large vessel stroke were screened using univariable analysis and compared with results from our original study. Joint analysis of the 2 study populations combined was performed using multivariable logistic regression. A total of 96 children (49 MRA-positive, 47 MRA-negative) were included in this study. Of the SNP associations previously identified in the original study, the TNF(-308) G/A association with large vessel stroke remained significant and the IL4R 503 S/P variant approached significance in the joint analysis of the combined study populations. Consistent with our original findings, the TNF(-308) GG genotype was associated with a >3-fold increased risk of large vessel disease (OR=3.27; 95% CI=1.6, 6.9; P=0.006). Unadjusted analyses also revealed a previously unidentified association between the LTC4S(-444) A/C variant and large vessel stroke risk. Similar findings in 2 independent study populations strongly suggest that the TNF(-308) G/A promoter polymorphism is a clinically important risk factor for large vessel stroke in children with SCA. The previously observed association with the IL4R 503 S/P variant and the novel association with the LTC4S(-444) A/C variant suggest that these loci may also contribute to large vessel stroke risk in children with SCA.

Elevated blood flow velocity in the anterior cerebral artery and stroke risk in sickle cell disease: extended analysis from the STOP trial

Elevated velocity in the internal carotid artery (ICA) or middle cerebral artery (MCA), detected by transcranial Doppler (TCD) ultrasonography, predicts an increased risk of stroke in children with sickle cell disease (SCD). Although strokes also occur in an anterior cerebral artery (ACA) distribution, the significance of elevated velocity in this vessel has not been determined previously. We assessed the effect of elevated ACA velocity on stroke risk using the results of the first adequate TCD study performed on 1975 children as part of The Stroke Prevention Trial in Sickle Cell Anemia (STOP). Elevated ACA velocity (> or =170 cm/s) was associated with an increased risk of stroke (P = 0.0013) after adjusting for the ICA/MCA classification. Among subjects with normal ICA/MCA velocity, the risk of stroke was more than 10-fold greater in those with elevated compared with normal ACA velocity (2.13 and 0.20 per 100 patient-years, respectively, P < 0.001); risk more than doubled with elevated compared with normal ACA velocity in those already at high risk due to abnormal ICA/MCA findings (7.56 vs. 3.22 per 100 patient-years, P = 0.042). Few of the strokes in those with elevated ACA velocity occurred in an ACA distribution, suggesting changes in blood flow velocity in anterior vessels may be associated with diffuse arterial disease or, alternatively, manifest collateral flow from compromised middle cerebral vessels.

STOP 2 Makes the Case for NOT Stopping Transfusions

Hematology-Oncology| May 01 2006 STOP 2 Makes the Case for NOT Stopping Transfusions AAP Grand Rounds (2006) 15 (5): 54–55. https://doi.org/10.1542/gr.15-5-54 Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share Twitter LinkedIn Tools Icon Tools Get Permissions Cite Icon Cite Search Site Citation STOP 2 Makes the Case for NOT Stopping Transfusions. AAP Grand Rounds May 2006; 15 (5): 54–55. https://doi.org/10.1542/gr.15-5-54 Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search toolbar search search input Search input auto suggest filter your search All PublicationsAll JournalsAAP Grand RoundsPediatricsHospital PediatricsPediatrics In ReviewNeoReviewsAAP NewsAll AAP Sites Search Advanced Search Topics: blood transfusion, transfusion, cerebrovascular accident Source: Adams RJ, Brambilla D; Optimizing Primary Stroke Prevention in Sickle Cell Anemia (STOP 2) Trial Investigators. Discontinuing prophylactic transfusions used to prevent stroke in sickle cell disease. N Engl J Med. 2005;353:2769–2778. Children with sickle cell disease (SCD) are at increased risk for stroke. The results of the Stroke Prevention Trial in Sickle Cell Anemia (STOP), a multi-center, NIH-supported clinical trial, indicated that prophylactic blood transfusions reduced the risk of stroke in children with abnormal transcranial Doppler (TCD) studies by 92%.1 This important finding, published in 1998, has led to the nearly universal practice of routine TCD screening and primary stroke prevention with chronic transfusion therapy. In a follow-up to the 1998 study, the STOP investigators report the results of Optimizing Primary Stroke Prevention in Sickle Cell Anemia (STOP 2). In this study, children with SCD receiving chronic transfusion therapy for primary stroke prevention because of abnormal TCD studies were randomly assigned to a group that continued transfusion therapy (n=38) or a group that stopped transfusion therapy after 30 months of participation in STOP (n=41). Patients aged 5 to 20 years were eligible for the study if they had received at least 24 transfusions in 30 months, had sickle hemoglobin (Hb S) levels below 30% in at least 20 of those months, and had 2 normal TCD examinations within the previous 4 months. As in STOP 1, children in the transfusion group were transfused to keep the Hb S level less than 30%. Outcome measures were any neurologic event, defined as either TCD findings of reversion to abnormal blood flow or stroke. The investigators also tracked patients who started hydroxyurea therapy or crossed over to reinstitute or halt transfusion therapy. The study was stopped early after TCD examination showed that 14 of the 41 children in the transfusion-halted group reverted back to high-risk blood flow velocities, and 2 of those 14 patients developed overt stroke. Strokes occurred at 21 weeks and 42 weeks following the cessation of transfusions. No events occurred in the 38 children selected to continue receiving transfusions. There was a decrease in iron overload in the non-transfusion group after 12 months in the study. The investigators concluded that discontinuation of transfusion therapy in children with SCD results in a high rate of TCD findings of reversion to abnormal blood flow velocities and stroke. Dr. Villella has disclosed no financial relationship relevant to this commentary. This commentary does not contain a discussion of a commercial product/device. This commentary does not contain a discussion of an unapproved/investigative use of a commercial product/device. The STOP investigators hoped that stroke could be prevented in patients discontinuing transfusion therapy after 30 months by close monitoring of blood flow velocities with TCD and reinstitution of transfusion therapy if reversion to abnormal studies occurred. This approach would reduce the number of patients requiring indefinite transfusion therapy, thus limiting the harmful effects of transfusions, namely iron overload. Unfortunately, despite close surveillance, 2 patients developed stroke, both within... You do not currently have access to this content.

Stroke may appear to be rare in Saudi‐Arabian and Nigerian children with sickle cell disease, but not in Cameroonian sickle cell patients

We read with much interest the excellent review entitled ‘Defining stroke risk in children with sickle cell anaemia’ (Hoppe, 2005), but felt the necessity to clarify two issues. In reviewing the epidemiology of stroke in sickle cell disease (SCD), Dr Hoppe stated that, ‘Stroke appears to be rare in SaudiArabian and Nigerian children with SCD’ and cited among other studies Izuora et al (1989) and Obama et al (1994). Concerning the incidence rates of stroke in SCD in Nigeria, Izuora et al (1989) did report a relative incidence of associated neurological disorders of 1AE3% and that cerebrovascular accidents were responsible for 57AE5% of that number. It should be noted that the study by Obama et al (1994) was not done in Nigeria. This study was done in Yaounde, Cameroon: a neighbouring country to Nigeria. In this study of paediatric stroke in general, the average annual stroke incidence was 1AE85 per 1000 (18AE5%) paediatric hospitalisations in Yaounde and the main aetiological factor was homozygous SCD, accounting for nearly a third of stroke cases (31AE4%). We have recently studied a sample of 120 homozygous sickle cell patients in Yaounde, Cameroon. Clinical examinations and computerised tomography scans identified a stroke prevalence of 6AE7% with an annual recurrence rate of 25% (Njamnshi et al, 2005). This prevalence rate in our study might be an underestimation, given that we did not use more sensitive procedures that detect silent infarcts like magnetic resonance imaging and neuropsychological testing. Moreover, recent genetic studies indicated that the Cameroon and atypical haplotypes were more prevalent than reported in patients with homozygous (SS) sickle cell disease in general (Sarnaik & Ballas, 2001). In one report on 80 beta S chromosomes studied in Cameroonians, 13 exhibited the Cameroon haplotype (Lapoumeroulie et al, 1992). Furthermore, neonates with four or more alpha-genes whose beta(S) haplotype was Ben/CAR, Cameroon or CAR/CAR seemed to be at a higher risk for cerebrovascular accidents than other patients (Sarnaik & Ballas, 2001; Lyra et al, 2005). This may explain why stroke does not appear to be rare in Cameroonian sickle cell patients. In conclusion, we believe that stroke is not so rare in SCD, as reported in African patients and, for Cameroon in particular, stroke risk in these patients may be even higher because of the presence of atypical beta(S) haplotypes. It is therefore important not to minimise the magnitude of this problem, which has far reaching consequences. Alfred Kongnyu Njamnshi Ambroise Wonkam Vincent de Paul Djientcheu Pierre Ongolo-Zogo Marie-Therese Obama Wali F. T. Muna Roman Sztajzel Faculty of Medicine and Biomedical Sciences, University of Yaounde 1, Yaounde, Cameroon, Africa, Department of Neurology, and Department of Genetic Medicine and Development, University Hospitals of Geneva, Geneva, Switzerland E-mail: aknjamnshi@yahoo.co.uk

Hydroxyurea for the Prevention of Stroke and Other Vasoocclusive Complications in Children with Sickle Cell Disease.

Due to the immigration of families of Mediterranean, Asian and African origins to Switzerland an increasing number of children with Sickle Cell Disease (SCD) are being followed in our centers. The Swiss Pediatric Sickle Cell Disease Registry is aimed to study prognostic aspects and the outcome of different therapeutic approaches. Particularly, indications for hydroxyurea treatment and the effects of its long-term use are assessed.The risk of stroke in children with sickle cell disease (SCD) is approximately 200–300-fold greater compared to healthy children. 10% of children with SCD have a specially high risk for stroke with an incidence of 1 in 100 children per year. The US stroke prevention (STOP) trial has demonstrated the benefit of regular red cell transfusions for stroke prevention; however hemochromatosis is frequent and blood-borne infections can occur. Hydroxyurea (HU) can be a therapeutic alternative for the prevention of stroke in children with SCD and other severe vasoocclusive complications (VOC).From 52 children in our centers with SCD or with compound hemoglobinopathies 27 (median age 10.5, range 3.8–19 y) are treated with HU and were followed for 9–101 (mean 47) months. 16 received HU for recurrent VOC, including 4 children with chest syndrome. Two children recieved HU for silent cerebral infarctions and after stroke, respectively (Jehovas Witness). In 9 children HU was commenced for pathological transcranial dopppler ultrasonography (TCD) results according to the STOP trial criteria. TCDs were performed in all SCD patients once a year, in children with conditional TCDs every 6 months, and every 3 months in patients with pathological TCD results. Upon observation of two pathological TCDs at 2–3 months interval, HU was initiated with 10 to maximally 30 mg/kg/day.HU was well tolerated in all patients and no leuko- or neutropenia was observed. No stroke, stroke recurrence, chest syndrome or splenic sequestration was observed during HU treatment and the average number of hospital days/y before (9d) and after 12 months of HU (3d) were reduced significantly (P=0.002). However after 12–24 months, abnormal lung function and growth retardation did not improve significantly. Laboratory studies documented a significant increase in total Hb (mean 79 to 93 g/l; P=0.03), HbF (9 to 23%; P=0.0001) and MCV (83 to 94 fl; P=0.001) and a significant decrease of HbS (86 to 71%; P<0.0001), WBC (7,8 to 5.4; P<0.05) and bilirubin (54 to 36 umol/l; P<0.05) after 12 months of HU. In children that had received HU for pathological TCDs the increase of HbF resulted in a reduction of the middle cerebral arteries blood flow velocities as soon as after 5–7 months.We conclude that HU is a promising therapeutic alternative for the prevention of stroke and other VOC in SCD. Safety and efficacy of this treatment in children has to be assessed by further long-term studies.

The TNF-a Gene Modifies Stroke Risk in Children with Sickle Cell Anemia: Results from the STOP Trial.

Background: The etiology of stroke in sickle cell anemia (SCA) is complex and multiple genetic factors outside of the sickle gene undoubtedly contribute to stroke risk in SCA. Simultaneous analyses of multiple genetic variants may therefore be more informative than evaluation of individual candidate genes. Moreover, stroke in SCA is phenotypically heterogeneous, varying from large cortical vessel (LV) distribution infarcts to milder lacunar infarcts due to small vessel disease, suggesting distinct pathogenetic mechanisms for stroke in SCA.We previously reported risk associations with particular TNFA, IL4R and ADRB2 polymorphisms in children enrolled in the CSSCD.Methods: To confirm our previous findings from the CSSCD and identify other potential “susceptibility” loci that may influence the development of LV stroke, we extended our investigations to SCA children who participated in the Stroke Prevention Trial in Sickle Cell Anemia (STOP). Children with MRA evidence of obstruction or stenosis of one or more large vessels (LV disease) were compared with untransfused children with a normal MRA. Ninety-seven patients were included in this study. Of the 119 patients originally enrolled in STOP, 77 (30 MRA+, 47 MRA−) were eligible for this study and were analyzed together with a local sample of 20 MRA(+)patients. Genotyping for 110 polymorphisms among 65 candidate cardiovascular and proinflammatory genes was performed using multiplex linear array methods. Of the 110 variant sites examined, 95 were sufficiently polymorphic to permit statistical testing, using 2 x 2 exact tests.Results: When comparing MRA(+) patients with MRA(−) patients, 9 of the polymorphic loci revealed nominally significant differences (P<0.10): TNF(−308), IL4(−589), ADRB2 16, ICAM1 56, APOC3(−482), LPL 93, AGT 235, and MMP3(−1171). For TNF G(−308)A, the frequency of the G allele was 80%, consistent with allele frequency data in African-Americans. In the current study, there was a relative excess of children with the GG genotype in the MRA(+) group compared to the MRA(−) group (OR= 2.48; p = 0.037). These results, showing the TNF(−308) locus to be predictive of LV vasculopathy, are virtually identical to our previous findings in the CSSCD population and confirm that the TNF gene plays a significant role in stroke risk. The TNF gene lies within the HLA region, making this finding particularly intriguing in light of our previous data indicating HLA associations with stroke risk. Detailed studies of this region are now necessary to determine if it is indeed the TNF locus or other genes in linkage disequilibrium that are responsible for this association.

Transcranial Doppler in Systemic Conditions and Stroke

Transcranial Doppler (TCD) is currently used in monitoring subarachnoid hemorrhage, acute stroke, and carotid endarterectomy and in diagnosing intracranial vascular disease. In this article we review other uses of TCD, in systemic conditions related to ischemic stroke. Transcranial Doppler, in fact, can identify right-to-left shunts (RLS), usually due to patent foramen ovale (PFO), a risk factor for cryptogenic stroke in the young. Recently an association between RLS and migraine with aura has been reported; migraine is a risk factor for stroke, for silent brain infarctions, and for silent white matter disease, but there are no data yet on a similar risk for the association of migraine plus PFO. TCD can also be used to stratify the risk of stroke in children with sickle cell disease, to better identify subjects to be transfused to prevent strokes.

Defining stroke risk in children with sickle cell anaemia

Sickle cell anaemia (SCA) is the most common cause of childhood stroke, occurring with the highest frequency before the age of 6 years. Despite the relative frequency of stroke in SCA, few predictors of risk exist. Anaemia, leucocytosis, hypertension, silent infarction, and history of acute chest syndrome are well-documented risk factors for ischaemic stroke in SCA. Recent data suggest that other environmental and genetic factors, many unrelated to SCA, influence the development of cerebrovascular disease. Non-invasive assessment of individual stroke risk using transcranial Doppler ultrasonography has provided a means of selecting and prophylactically treating SCA children at highest risk. With the ultimate goal of preventing stroke, the information gained from the studies reviewed here may lead to improved prediction of stroke so that clinical trials to assess risk-based therapy may be carried out on selected children with SCA.

Predicting stroke risk in pediatric moyamoya disease with xenon-enhanced computed tomography.

To determine whether estimates of regional cerebral blood flow (rCBF) using xenon computed tomography (XeCT) in children with moyamoya disease can predict stroke risk before and after treatment. Seven patients with moyamoya disease underwent 22 serial Xe computed tomographic scans. Estimates of rCBF were obtained at three computed tomographic levels by use of a 5-minute inhalation of 28% Xe. Acetazolamide challenge was performed in eight scans. For comparison of abnormal vessel distribution and areas of infarction, 17 intra-arterial digital subtraction angiograms, 47 computed tomographic scans, and 15 magnetic resonance imaging scans were available. Follow-up exceeded 36 months in all patients. Mean follow-up for the interventional group was 65.2 months (n = 5; range, 37-109 mo) and 38 months for the nonoperative patients (n = 2; 36 and 40 mo). Of six Xe computed tomographic scans obtained at diagnosis, four revealed regions of oligemia, augmented vertebrobasilar flow, and regions of carotid steal after acetazolamide. In the delay between diagnosis and treatment, three patients had strokes in ischemic areas identified by XeCT. Of the 10 posttreatment scans obtained from 4 patients, 2 revealed improved tissue perfusion with angiography confirming successful encephaloduroangiomyosynangiosis. In 2 others, XeCT performed 6 months posttreatment revealed improved perfusion without angiographic change, and angiography at 1 year revealed failed encephaloduroangiomyosynangiosis and new native collaterals. None of the patients with improved rCBF had new strokes. Eleven of 14 Xe computed tomographic scans were obtained within 30 days of angiography. Comparison of these studies demonstrates that regions of oligemia were confined to areas associated with vessel stenosis and little neovascularity or collateral pathways. XeCT, particularly with acetazolamide challenge, objectively quantifies rCBF. Our preliminary data suggest that it may permit assessment of stroke risk in children with moyamoya disease and may predict surgical outcome earlier than angiography.

Gene interactions and stroke risk in children with sickle cell anemia

AbstractStroke is a devastating complication of sickle cell anemia (SCA), affecting up to 30% of children with the disease. Despite the relative frequency of stroke in SCA, few predictors of risk exist. Because stroke in SCA is likely a multifactorial disease, analysis of the combined effect of multiple genetic variants may prove more successful than evaluation of individual candidate genes. We genotyped 230 children with SCA for 104 polymorphisms among 65 candidate vascular genes to identify risk associations with stroke. Patients were phenotyped based on magnetic resonance imaging/angiography (MRI/MRA) findings into large-vessel (LV) versus small-vessel (SV) disease stroke subgroups. Specific polymorphisms in the IL4R 503, TNF (-308), and ADRB2 27 genes were independently associated with stroke susceptibility in the LV stroke subgroup, while variants in the VCAM1 (-1594) and LDLR NcoI genes were associated with SV stroke risk. The combination of TNF (-308)GG homozygosity and the IL4R 503P variant carrier status was associated with a particularly strong predisposition to LV stroke (odds ratio [OR] = 5.5; 95% confidence interval [CI] = 2.3-13.1). We show that several candidate genes may play a role in predisposition to specific stroke subtypes in children with SCA. If confirmed, these results provide a basis for population screening and targeted intervention to prevent stroke in SCA.

Risk of stroke in children: ethnic and gender disparities.

Using a California-wide hospital discharge database, the authors analyzed all first admissions for stroke in children 1 month through 19 years of age from 1991 through 2000. Incidence rates were estimated as the number of first hospitalizations divided by the person-years at risk; case fatality rates were based on in-hospital deaths. The authors identified 2,278 first admissions for childhood stroke, yielding an annual incidence rate of 2.3 per 100,000 children (1.2 for ischemic stroke, 1.1 for hemorrhagic stroke). Compared with whites, black children were at higher risk of stroke (for ischemic stroke, relative risk [RR] 2.59, 95% CI 2.17 to 3.09, p < 0.0001; subarachnoid hemorrhage [SAH], RR 1.59, CI 1.06 to 2.33, p = 0.02; intracerebral hemorrhage [ICH], RR 1.66, CI 1.23 to 2.13, p = 0.0001). Hispanics, however, had a lower risk of ischemic stroke (RR 0.70, CI 0.60 to 0.82, p < 0.0001) and ICH (RR 0.77, CI 0.64 to 0.93, p = 0.0004), whereas Asians had similar risks as whites. Boys were at higher risk for all stroke types than girls (ischemic stroke, RR 1.25, CI 1.11 to 1.40, p = 0.0002; SAH, RR 1.24, CI 1.00 to 1.53, p = 0.047; ICH, RR 1.34, CI 1.16 to 1.56, p = 0.0001). After eliminating cases with coexisting sickle cell disease, excess stroke risk persisted in blacks; after elimination of trauma, excess stroke risk persisted in boys. Case fatality rates were similar among different ethnic groups. Compared with girls, boys had a higher case fatality rate for ischemic stroke (17 vs 12%; p = 0.002) but not for ICH or SAH. Rates of hospitalization for stroke are higher among black children and boys; sickle cell disease and trauma do not fully account for these findings.

Transcranial Doppler ultrasonography in siblings with sickle cell disease.

The risk of stroke in sickle cell disease (SCD) may be influenced by either genetic or environmental factors. Elevated blood flow velocity in the large cerebral arteries, detected by transcranial Doppler (TCD) ultrasonography, predicts an increased stroke risk in children with SCD. We undertook this study to investigate the possibility of a familial predisposition to elevated cerebral blood flow velocity, a surrogate marker for stroke risk. We analysed the results of TCD studies performed on 63 children from 29 families that had more than one child with SCD. We assessed the association of elevated cerebral blood flow velocity with sibling TCD results as well as age and haemoglobin level, which are factors known to affect cerebral blood flow velocity. Positive or negative TCD results were highly correlated between family members (r = 0.61). The presence of a sibling with a positive TCD result was significantly associated with an elevated cerebral blood flow velocity in other siblings with SCD (odds ratio = 50.7, 95% confidence interval 10.1-253.7, P < 0.001). Furthermore, children who had a sibling with a positive TCD result had a significantly higher TCD velocity than children with SCD but without a sibling who were matched for age, sex, genotype and haemoglobin level. Our results are consistent with a familial predisposition to cerebral vasculopathy in SCD.

Transcranial Doppler ultrasonography in siblings with sickle cell disease

Summary. The risk of stroke in sickle cell disease (SCD) may be influenced by either genetic or environmental factors. Elevated blood flow velocity in the large cerebral arteries, detected by transcranial Doppler (TCD) ultrasonography, predicts an increased stroke risk in children with SCD. We undertook this study to investigate the possibility of a familial predisposition to elevated cerebral blood flow velocity, a surrogate marker for stroke risk. We analysed the results of TCD studies performed on 63 children from 29 families that had more than one child with SCD. We assessed the association of elevated cerebral blood flow velocity with sibling TCD results as well as age and haemoglobin level, which are factors known to affect cerebral blood flow velocity. Positive or negative TCD results were highly correlated between family members (r = 0·61). The presence of a sibling with a positive TCD result was significantly associated with an elevated cerebral blood flow velocity in other siblings with SCD (odds ratio = 41·9, 95% confidence interval 8·2–214·7, P &lt; 0·001). Furthermore, children who had a sibling with a positive TCD result had a significantly higher TCD velocity than children with SCD but without a sibling who were matched for age, sex, genotype and haemoglobin level. Our results are consistent with a familial predisposition to cerebral vasculopathy in SCD.

Impact of chronic transfusion on incidence of pain and acute chest syndrome during the Stroke Prevention Trial (STOP) in sickle-cell anemia

Objective: The Stroke Prevention Trial (STOP) demonstrated that chronic transfusion is highly effective in reducing the risk of stroke in children with sickle-cell disease and an abnormal transcranial Doppler ultrasonography examination result. Our objective was to determine whether chronic transfusion therapy reduces the incidence of pain and acute chest syndrome. Methods: During STOP, 130 children with sickle-cell anemia or sickle β 0-thalassemia and abnormal transcranial Doppler ultrasonography examination result were randomly assigned to chronic transfusion (n = 63) or observation (n = 67). In addition to monitoring for stroke, nonneurologic sickle-cell complications were identified and recorded. Results: Mean age at STOP study entry was 8.3 ± 3.3 years, and mean follow-up was 19.6 ± 6.5 months. Hospitalization rates (based on intent-to-treat analysis) for acute chest syndrome were 4.8 and 15.3 per 100 patient-years ( P = .0027) and for pain were 16.2 and 27.6 per 100 patient-years ( P = .13) in the chronic transfusion and observed groups, respectively. If analyzed according to treatment actually received, the difference in pain rate becomes significant (9.7 vs 27.1 events per 100 patient-years, P = .014), and transfusion remains protective from acute chest syndrome (2.2 vs 15.7 events per 100 patient-years, P = .0001). Conclusions: Compliance with aggressive chronic transfusion reduces the frequency of acute chest syndrome and pain episodes. (J Pediatr 2001;139:785–9)