Hydroxyurea for primary stroke prevention in children with sickle cell anaemia in Nigeria (SPRING): a double-blind, multicentre, randomised, phase 3 trial.

BACKGROUND: In high-income countries, standard care for primary stroke prevention in children with sickle cell anaemia and abnormal transcranial Doppler velocities results in a 92% relative risk reduction of strokes but mandates initial monthly blood transfusion. In Africa, where regular blood transfusion is not feasible for most children, we tested the hypothesis that initial moderate-dose compared with low-dose hydroxyurea decreases the incidence of strokes for children with abnormal transcranial Doppler velocities. METHODS: SPRING is a double-blind, parallel-group, randomised, controlled, phase 3 trial of children aged 5-12 years with sickle cell anaemia with abnormal transcranial Doppler velocities conducted at three teaching hospitals in Nigeria. For randomisation, we used a permuted block allocation scheme with block sizes of four, stratified by sex and site. Allocation was concealed from all but the pharmacists and statisticians. Participants were assigned in a 1:1 ratio to low-dose (10 mg/kg per day) or moderate-dose (20 mg/kg per day) oral hydroxyurea taken once daily with monthly clinical evaluation and laboratory monitoring. The primary outcome was initial stroke or transient ischaemic attack, centrally adjudicated. The secondary outcome was all-cause hospitalisation. We used the intention-to-treat population for data analysis. The trial was stopped early for futility after a planned minimum follow-up of 3·0 years to follow-up for participants. This trial was registered with ClinicalTrials.gov, number NCT02560935. FINDINGS: Between Aug 2, 2016, and June 14, 2018, 220 participants (median age 7·2 years [IQR 5·5-8·9]; 114 [52%] female) were randomly allocated and followed for a median of 2·4 years (IQR 2·0-2·8). All participants were Nigerian and were from the following ethnic groups: 179 (82%) people were Hausa, 25 (11%) were Fulani, and 16 (7%) identified as another ethnicity. In the low-dose hydroxyurea group, three (3%) of 109 participants had strokes, with an incidence rate of 1·19 per 100 person-years and in the moderate-dose hydroxyurea group five (5%) of 111 had strokes with an incidence rate of 1·92 per 100 person-years (incidence rate ratio 0·62 [95% CI 0·10-3·20], p=0·77). The incidence rate ratio of hospitalisation for any reason was 1·71 (95% CI 1·15-2·57, p=0·0071), with higher incidence rates per 100 person-years in the low-dose group versus the moderate-dose group (27·43 vs 16·08). No participant had hydroxyurea treatment stopped for myelosuppression. INTERPRETATION: Compared with low-dose hydroxyurea therapy, participants treated with moderate-dose hydroxyurea had no difference in the stroke incidence rate. However, secondary analyses suggest that the moderate-dose group could lower incidence rates for all-cause hospitalisations. These findings provide an evidence-based guideline for the use of low-dose hydroxyurea therapy for children with sickle cell anaemia at risk of stroke. FUNDING: National Institute of Neurological Disorders and Stroke.

Study of montelukast in children with sickle cell disease (SMILES): a study protocol for a randomised controlled trial.

BACKGROUND: Young children with sickle cell anaemia (SCA) often have slowed processing speed associated with reduced brain white matter integrity, low oxygen saturation, and sleep-disordered breathing (SDB), related in part to enlarged adenoids and tonsils. Common treatments for SDB include adenotonsillectomy and nocturnal continuous positive airway pressure (CPAP), but adenotonsillectomy is an invasive surgical procedure, and CPAP is rarely well-tolerated. Further, there is no current consensus on the ability of these treatments to improve cognitive function. Several double-blind, randomised controlled trials (RCTs) have demonstrated the efficacy of montelukast, a safe, well-tolerated anti-inflammatory agent, as a treatment for airway obstruction and reducing adenoid size for children who do not have SCA. However, we do not yet know whether montelukast reduces adenoid size and improves cognition function in young children with SCA. METHODS: The Study of Montelukast In Children with Sickle Cell Disease (SMILES) is a 12-week multicentre, double-blind, RCT. SMILES aims to recruit 200 paediatric patients with SCA and SDB aged 3-7.99 years to assess the extent to which montelukast can improve cognitive function (i.e. processing speed) and sleep and reduce adenoidal size and white matter damage compared to placebo. Patients will be randomised to either montelukast or placebo for 12 weeks. The primary objective of the SMILES trial is to assess the effect of montelukast on processing speed in young children with SCA. At baseline and post-treatment, we will administer a cognitive evaluation; caregivers will complete questionnaires (e.g. sleep, pain) and measures of demographics. Laboratory values will be obtained from medical records collected as part of standard care. If a family agrees, patients will undergo brain MRIs for adenoid size and other structural and haemodynamic quantitative measures at baseline and post-treatment, and we will obtain overnight oximetry. DISCUSSION: Findings from this study will increase our understanding of whether montelukast is an effective treatment for young children with SCA. Using cognitive testing and MRI, the SMILES trial hopes to gain critical knowledge to help develop targeted interventions to improve the outcomes of young children with SCA. TRIAL REGISTRATION: ClinicalTrials.gov NCT04351698 . Registered on April 17, 2020. European Clinical Trials Database (EudraCT No. 2017-004539-36). Registered on May 19, 2020.

Fetal stroke and cerebrovascular disease: Advances in understanding from lenticulostriate and venous imaging, alloimmune thrombocytopaenia and monochorionic twins.

Fetal stroke is an important cause of cerebral palsy but is difficult to diagnose unless imaging is undertaken in pregnancies at risk because of known maternal or fetal disorders. Fetal ultrasound or magnetic resonance imaging may show haemorrhage or ischaemic lesions including multicystic encephalomalacia and focal porencephaly. Serial imaging has shown the development of malformations including schizencephaly and polymicrogyra after ischaemic and haemorrhagic stroke. Recognised causes of haemorrhagic fetal stroke include alloimmune and autoimmune thrombocytopaenia, maternal and fetal clotting disorders and trauma but these are relatively rare. It is likely that a significant proportion of periventricular and intraventricular haemorrhages are of venous origin. Recent evidence highlights the importance of arterial endothelial dysfunction, rather than thrombocytopaenia, in the intraparenchymal haemorrhage of alloimmune thrombocytopaenia. In the context of placental anastomoses, monochorionic diamniotic twins are at risk of twin twin transfusion syndrome (TTTS), or partial forms including Twin Oligohydramnios Polyhydramnios Sequence (TOPS), differences in estimated weight (selective Intrauterine growth Retardation; sIUGR), or in fetal haemoglobin (Twin Anaemia Polycythaemia Sequence; TAPS). There is a very wide range of ischaemic and haemorrhagic injury in a focal as well as a global distribution. Acute twin twin transfusion may account for intraventricular haemorrhage in recipients and periventricular leukomalacia in donors but there are additional risk factors for focal embolism and cerebrovascular disease. The recipient has circulatory overload, with effects on systemic and pulmonary circulations which probably lead to systemic and pulmonary hypertension and even right ventricular outflow tract obstruction as well as the polycythaemia which is a risk factor for thrombosis and vasculopathy. The donor is hypovolaemic and has a reticulocytosis in response to the anaemia while maternal hypertension and diabetes may influence stroke risk. Understanding of the mechanisms, including the role of vasculopathy, in well studied conditions such as alloimmune thrombocytopaenia and monochorionic diamniotic twinning may lead to reduction of the burden of antenatally sustained cerebral palsy.

Cerebral perfusion characteristics show differences in younger versus older children with sickle cell anaemia: Results from a multiple-inflow-time arterial spin labelling study.

Sickle cell anaemia (SCA) is associated with chronic anaemia and oxygen desaturation, which elevate cerebral blood flow (CBF) and increase the risk of neurocognitive complications. Arterial spin labelling (ASL) provides a methodology for measuring CBF non-invasively; however, ASL techniques using only a single inflow time are not sufficient to fully characterize abnormal haemodynamic behaviour in SCA. This study investigated haemodynamic parameters from a multi-inflow-time ASL acquisition in younger (8-12 years) and older (13-18 years) children with SCA with and without silent cerebral infarction (SCI+/-) (n = 20 and 19 respectively, 6 and 4 SCI+ respectively) and healthy controls (n = 9 and 7 respectively). Compared with controls, CBF was elevated globally in both groups of patients. In the younger SCA patients, blood oxygen content was negatively correlated with CBF in the middle and posterior cerebral artery territories and significantly positively correlated with bolus arrival time (BAT) in the anterior and middle cerebral artery territories. In older children, SCA patients had significantly shorter BAT than healthy controls and there was a significant negative correlation between CBF and oxygen content only in the territory of the posterior cerebral artery, with a trend for a correlation in the anterior cerebral artery but no relationship for the middle cerebral artery territory. In the younger group, SCI+ patients had significantly higher CBF in the posterior cerebral artery territory (SCI+ mean = 92.78 ml/100 g/min; SCI- mean = 72.71 ml/100 g/min; F = 4.28, p = 0.04), but this no longer reached significance when two children with abnormal transcranial Doppler and one with haemoglobin SC disease were excluded, and there were no significant differences between patients with and without SCI in the older children. With age, there appears to be increasing disparity between patients and controls in terms of the relationship between CBF and oxygen content in the anterior circulation, potentially predicting the risk of acute and chronic compromise of brain tissue.

Parent reported sleep problems in preschool children with sickle cell anemia and controls in East London.

Snoring and poor sleep may affect cognition, particularly in young children with chronic conditions. Parents of London preschoolers with sickle cell anemia (SCA; n = 22), matched controls (n = 24), and unselected typically developing (n = 142) preschoolers completed sleep questionnaires. Preschoolers with SCA had significantly more sleep problems when compared to matched controls and the larger population. Snoring occurred at least one to two nights a week for 79% of the SCA group. This is compared with 25% of matched controls and 33% of larger population. Randomized controlled trials to improve sleep in young children with SCA already at-risk for cognitive dysfunction should be considered.

Arterial spin labeling characterization of cerebral perfusion during normal maturation from late childhood into adulthood: normal 'reference range' values and their use in clinical studies.

The human brain changes structurally and functionally during adolescence, with associated alterations in cerebral perfusion. We performed dynamic arterial spin labeling (ASL) magnetic resonance imaging in healthy subjects between 8 and 32 years of age, to investigate changes in cerebral hemodynamics during normal development. In addition, an inversion recovery sequence allowed quantification of changes in longitudinal relaxation time (T1) and equilibrium longitudinal magnetization (M0). We present mean and reference ranges for normal values of T1, M0, cerebral blood flow (CBF), bolus arrival time, and bolus duration in cortical gray matter, to provide a tool for identifying age-matched perfusion abnormalities in this age range in clinical studies. Cerebral blood flow and T1 relaxation times were negatively correlated with age, without gender or hemisphere differences. The same was true for M0 anteriorly, but posteriorly, males but not females showed a significant decline in M0 with increasing age. Two examples of the clinical utility of these data in identifying age-matched perfusion abnormalities, in Sturge-Weber syndrome and sickle cell anemia, are illustrated.

Environmental tobacco smoke and airway obstruction in children with sickle cell anemia.

BACKGROUND: The contribution of environmental tobacco smoke (ETS) exposure to pulmonary morbidity in children with sickle cell anemia (SCA) is poorly understood. We tested the hypothesis that children with SCA and ETS exposure would have an increased prevalence of obstructive lung disease and respiratory symptoms compared with children with SCA and no ETS exposure. METHODS: Parent reports of ETS and respiratory symptom frequency were obtained for 245 children with SCA as part of a multicenter prospective cohort study. One hundred ninety-six children completed pulmonary function testing. Multivariable regression models were used to evaluate the associations between ETS exposure at different time points (prenatal, infant [birth to 2 years], preschool [2 years to first grade], and current) and lung function and respiratory symptoms. RESULTS: Among the 245 participants, a high prevalence of prior (44%) and current (29%) ETS exposure was reported. Of the 196 children who completed pulmonary function testing, those with parent-reported infant and current ETS exposure were more likely to have airway obstruction (defined as an FEV1/FVC ratio below the lower limit normal) compared with unexposed children (22.0% vs 3.1%, P < .001). Those with ETS exposure also had a lower forced expiratory flow, midexpiratory phase/FVC ratio (0.82 vs 0.97, P = .001) and were more likely to have evidence of bronchodilator responsiveness (23% vs 11%, P = .03). Current and prior ETS exposure and in utero smoke exposure were associated with increased frequency of respiratory symptoms. CONCLUSIONS: ETS exposure is associated with evidence of lower airway obstruction and increased respiratory symptoms in SCA.

Stability of polysomnography for one year and longer in children with sickle cell disease.

STUDY OBJECTIVES: Serious morbidity may be linked to sleep disordered breathing (SDB) among children with sickle cell disease (SCD). We investigated the stability of polysomnography (PSG) results among children not having acute complications of SCD. METHODS: Two PSGs were performed on a subsample of 63 children 4 to 18 years of age from the Sleep and Asthma Cohort Study. All had Hb SS or HbSß(0) disease. Two PSGs were compared for 45 subjects. Excluded from comparison were 18 children who had begun transfusions or hydroxyurea, had an adenotonsillectomy between the PSGs, or had a pain crisis or the acute chest syndrome within 3 months of the second PSG. Sleep disordered breathing was identified using 2 thresholds for the apnea hypopnea index (AHI): ≥ 2 or ≥ 5 respiratory events per hour. RESULTS: Ages were 12.3 yrs ± 4.0, BMI, 18.2 ± 3.2. Interval between PSGs was 581 ± 119 days (19.1 ± 3.9 months). Ten of 45 changed from ≥ 2 events per hour to < 2; 3 of 45 from < 2 to ≥ 2; 7 of 45 had ≥ 2 on both nights. Six of 45 changed from ≥ 5 to < 5, 2 of 45 from < 5 to ≥ 5, and 1 had ≥ 5 on both nights (McNemar χ(2), p = 0.09, and p = 0.29). CONCLUSIONS: In the absence of acute SCD complications, overnight PSG usually remains stable or improves over a 12- to 30-month period. Only 6.7% subjects, or fewer, had AHI on a subsequent PSG that would re-classify the child as having SDB not identified in the earlier PSG.

Sickle cell anemia: iron availability and nocturnal oximetry.

STUDY OBJECTIVE: To test the hypothesis that low iron availability, measured as transferrin saturation, is associated with low nocturnal hemoglobin oxygen saturation (SpO(2)) in children with homozygous sickle cell anemia (SCA; hemoglobin SS). METHODS: This was a cross-sectional study of Tanzanian children with SCA who were not receiving regular blood transfusions. Thirty-two children (16 boys) with SCA (mean age 8.0, range 3.6-15.3 years) underwent motion-resistant nocturnal oximetry (Masimo Radical) and had steady state serum transferrin saturation and hematological indices assessed. RESULTS: Higher transferrin saturation, adjusted for age and α-thalassemia deletion, was associated with lower nocturnal mean SpO(2) (p = 0.013, r(2) = 0.41), number of SpO(2) dips/h > 3% from baseline (p = 0.008, r(2) = 0.19) and with min/h with SpO(2) < 90% (p = 0.026 r(2) = 0.16). Transferrin saturation < 16% (indicative of iron deficiency) was associated with a 2.2% higher nocturnal mean SpO(2). CONCLUSIONS: Contrary to our hypothesis, higher iron availability, assessed by transferrin saturation, is associated with nocturnal chronic and intermittent hemoglobin oxygen desaturation in SCA. Whether these associations are causal and are driven by hypoxia-inducible factor and hepcidin-mediated upregulation of demand for iron warrants further investigation.

Very good inter-rater reliability of Engel and ILAE epilepsy surgery outcome classifications in a series of 76 patients.

The inter-rater reliability, expressed as kappa score, k, of the Engel and International League Against Epilepsy (ILAE) classifications of epilepsy surgery seizure outcome has not previously been evaluated. In a consecutive series of 76 patients (40 male; 25 children), 75 undergoing resective and 1 disconnective surgery at a mean age of 27.5 years (13 months-62 years), one observer classified 88% (n=67) and a second observer classified 87% (n=66) of patients as either Engel I or II (free from or rare disabling seizures) after a median follow up of 36 months (range 12-92 months); comparably, both observers classified 84% (n=64) as ILAE 1-3. Correlation for Engel versus ILAE for observer 1 was 0.933 (p<.0005) and for observer 2 was 0.931 (p<.0005). Both ILAE (k 0.81, 95% confidence intervals 0.69, 0.91) and Engel (k 0.77, 95% CI 0.65, 0.87) classifications have very acceptable inter-rater reliability as well as significant correlation.

Outcome following decompressive craniectomy for malignant middle cerebral artery infarction in children.

AIM: Mortality from malignant middle cerebral artery infarction (MMCAI) approaches 80% in adult series. Although decompressive craniectomy decreases mortality and leads to an acceptable outcome in selected adult patients, there are few data on MMCAI in children with stroke. This study evaluated the frequency of MMCAI and the use of decompressive craniectomy in children. METHOD: We retrospectively reviewed cases of MMCAI from five pediatric tertiary care centers. RESULTS: Ten children (two females, eight males; median age 9y 10mo, range 22mo-14y) had MMCAI, with a median Glasgow Coma Scale score of 6 (range 3-9). MMCAI represented fewer than 2% of cases of pediatric arterial ischemic stroke. Three patients who did not undergo decompression, all of whom had monitoring of intracranial pressure, developed intractable intracranial hypertension, and fulfilled criteria for brain death. In contrast, seven patients underwent decompressive craniectomy and survived, with rapid improvement in their level of consciousness postoperatively. All seven survivors now walk independently with mild to moderate residual hemiparesis and speak fluently, even though four had left-sided infarcts. INTERPRETATION: Decompressive craniectomy can lead to a moderately good outcome for children with MMCAI and should be considered, even with symptomatic stroke and deep coma. Monitoring of intracranial pressure may delay life-saving treatment.

Stroke and cerebrovascular disorders.

PURPOSE OF REVIEW: Stroke and cerebrovascular disorders in childhood are a cause for significant morbidity in childhood. There is growing emphasis on understanding the mechanisms of stroke so as to inform developments in investigation and management. RECENT FINDINGS: Advances have been made in the classification of pediatric stroke, aided by clinical and radiological recognition of patterns of injury and differential outcomes dependent on timing of stroke occurrence. Risk factors are multifactorial, with evidence of geographical and national variation. Causality, however, remains difficult to prove. Recent studies highlight a significant association between stroke recurrence and outcome and the presence of steno-occlusive arterial disease, Moyamoya disease and progressive arteriopathy. Focal arteriopathy of childhood is a new term proposed to refine the nomenclature of childhood arteriopathy. The association between infection and childhood stroke is increasingly recognized, with associations with sinovenous thrombosis and childhood arteriopathy. The recommendation to screen for arteriopathy in genetic conditions such as sickle cell disease is now extended to include children with neurofibromatosis type 1. Perfusion and magnetic resonance wall imaging have helped in the determination of the cause of stroke with impact on management in adults. Two new treatment guidelines have been published (American Heart Association and Chest), but barriers remain to the use of thrombolysis in childhood stroke. SUMMARY: Continued developments in understanding and practice in childhood stroke are encouraging. However, the absence of clinical trials and evidence-based guidelines is limiting. The conduct of such trials is a goal towards which the International Pediatric Stroke Study is moving.

Cerebral blood flow velocity and cognition in children before and after adenotonsillectomy.

OBJECTIVE: The goal was to determine whether amelioration of sleep-disordered breathing through adenotonsillectomy would reduce middle cerebral artery velocity in parallel with improvements in cognition and behavior. METHODS: For 19 children (mean age: 6 years) with mild sleep-disordered breathing, and 14 healthy, ethnically similar and age-similar, control subjects, parents repeated the Pediatric Sleep Questionnaire an average of 12 months after adenotonsillectomy. Children with sleep-disordered breathing underwent repeated overnight measurement of mean oxyhemoglobin saturation. Neurobehavioral tests that yielded significant group differences preoperatively were readministered. Middle cerebral artery velocity measurements were repeated with blinding to sleep study and neuropsychological results, and mixed-design analyses of variance were performed. RESULTS: The median Pediatric Sleep Questionnaire score significantly improved postoperatively, and there was a significant increase in mean overnight oxyhemoglobin saturation. The middle cerebral artery velocity decreased in the sleep-disordered breathing group postoperatively, whereas control subjects showed a slight increase. A preoperative group difference was reduced by the postoperative assessment, which suggests normalization of middle cerebral artery velocity in those with sleep-disordered breathing. The increase in mean overnight oxyhemoglobin saturation postoperatively was associated with a reduction in middle cerebral artery velocity in a subgroup of children. A preoperative group difference in processing speed was reduced postoperatively. Similarly, a trend for a preoperative group difference in visual attention was reduced postoperatively. Executive function remained significantly worse for the children with sleep-disordered breathing, compared with control subjects, although mean postoperative scores were lower than preoperative scores. CONCLUSIONS: Otherwise-healthy young children with apparently mild sleep-disordered breathing have potentially reversible cerebral hemodynamic and neurobehavioral changes.

Hemolytic anemia presenting with idiopathic intracranial hypertension.

We report on an 8-year-old girl with hemolytic anemia because of infection with parvovirus B19 and increased intracranial pressure. She presented acutely with headache, vomiting, and mild scleral and mucosal icterus. Upon evaluation, the patient exhibited profound hemolytic anemia, papilledema, and increased intracranial pressure. The patient was treated with intravenous immunoglobulin, prednisone, and packed red blood cells. Concurrent with an improvement of her anemia, she experienced a gradual resolution of her headache, vomiting, and optic-disc swelling. Signs of idiopathic intracranial hypertension may occur as a consequence of severe anemia, and are reversible upon correction of the underlying hematologic disorder.

Increased cerebral blood flow velocity in children with mild sleep-disordered breathing: a possible association with abnormal neuropsychological function.

OBJECTIVE: Sleep-disordered breathing describes a spectrum of upper airway obstruction in sleep from simple primary snoring, estimated to affect 10% of preschool children, to the syndrome of obstructive sleep apnea. Emerging evidence has challenged previous assumptions that primary snoring is benign. A recent report identified reduced attention and higher levels of social problems and anxiety/depressive symptoms in snoring children compared with controls. Uncertainty persists regarding clinical thresholds for medical or surgical intervention in sleep-disordered breathing, underlining the need to better understand the pathophysiology of this condition. Adults with sleep-disordered breathing have an increased risk of cerebrovascular disease independent of atherosclerotic risk factors. There has been little focus on cerebrovascular function in children with sleep-disordered breathing, although this would seem an important line of investigation, because studies have identified abnormalities of the systemic vasculature. Raised cerebral blood flow velocities on transcranial Doppler, compatible with raised blood flow and/or vascular narrowing, are associated with neuropsychological deficits in children with sickle cell disease, a condition in which sleep-disordered breathing is common. We hypothesized that there would be cerebral blood flow velocity differences in sleep-disordered breathing children without sickle cell disease that might contribute to the association with neuropsychological deficits. DESIGN: Thirty-one snoring children aged 3 to 7 years were recruited from adenotonsillectomy waiting lists, and 17 control children were identified through a local Sunday school or as siblings of cases. Children with craniofacial abnormalities, neuromuscular disorders, moderate or severe learning disabilities, chronic respiratory/cardiac conditions, or allergic rhinitis were excluded. Severity of sleep-disordered breathing in snoring children was categorized by attended polysomnography. Weight, height, and head circumference were measured in all of the children. BMI and occipitofrontal circumference z scores were computed. Resting systolic and diastolic blood pressure were obtained. Both sleep-disordered breathing children and the age- and BMI-similar controls were assessed using the Behavior Rating Inventory of Executive Function (BRIEF), Neuropsychological Test Battery for Children (NEPSY) visual attention and visuomotor integration, and IQ assessment (Wechsler Preschool and Primary Scale of Intelligence Version III). Transcranial Doppler was performed using a TL2-64b 2-MHz pulsed Doppler device between 2 pm and 7 pm in all of the patients and the majority of controls while awake. Time-averaged mean of the maximal cerebral blood flow velocities was measured in the left and right middle cerebral artery and the higher used for analysis. RESULTS: Twenty-one snoring children had an apnea/hypopnea index <5, consistent with mild sleep-disordered breathing below the conventional threshold for surgical intervention. Compared with 17 nonsnoring controls, these children had significantly raised middle cerebral artery blood flow velocities. There was no correlation between cerebral blood flow velocities and BMI or systolic or diastolic blood pressure indices. Exploratory analyses did not reveal any significant associations with apnea/hypopnea index, apnea index, hypopnea index, mean pulse oxygen saturation, lowest pulse oxygen saturation, accumulated time at pulse oxygen saturation <90%, or respiratory arousals when examined in separate bivariate correlations or in aggregate when entered simultaneously. Similarly, there was no significant association between cerebral blood flow velocities and parental estimation of child's exposure to sleep-disordered breathing. However, it is important to note that whereas the sleep-disordered breathing group did not exhibit significant hypoxia at the time of study, it was unclear to what extent this may have been a feature of their sleep-disordered breathing in the past. IQ measures were in the average range and comparable between groups. Measures of processing speed and visual attention were significantly lower in sleep-disordered breathing children compared with controls, although within the average range. There were similar group differences in parental-reported executive function behavior. Although there were no direct correlations, adjusting for cerebral blood flow velocities eliminated significant group differences between processing speed and visual attention and decreased the significance of differences in Behavior Rating Inventory of Executive Function scores, suggesting that cerebral hemodynamic factors contribute to the relationship between mild sleep-disordered breathing and these outcome measures. CONCLUSIONS: Cerebral blood flow velocities measured by noninvasive transcranial Doppler provide evidence for increased cerebral blood flow and/or vascular narrowing in childhood sleep-disordered breathing; the relationship with neuropsychological deficits requires further exploration. A number of physiologic changes might alter cerebral blood flow and/or vessel diameter and, therefore, affect cerebral blood flow velocities. We were able to explore potential confounding influences of obesity and hypertension, neither of which explained our findings. Second, although cerebral blood flow velocities increase with increasing partial pressure of carbon dioxide and hypoxia, it is unlikely that the observed differences could be accounted for by arterial blood gas tensions, because all of the children in the study were healthy, with no cardiorespiratory disease, other than sleep-disordered breathing in the snoring group. Although arterial partial pressure of oxygen and partial pressure of carbon dioxide were not monitored during cerebral blood flow velocity measurement, assessment was undertaken during the afternoon/early evening when the child was awake, and all of the sleep-disordered breathing children had normal resting oxyhemoglobin saturation at the outset of their subsequent sleep studies that day. Finally, there is an inverse linear relationship between cerebral blood flow and hematocrit in adults, and it is known that iron-deficient erythropoiesis is associated with chronic infection, such as recurrent tonsillitis, a clinical feature of many of the snoring children in the study. Preoperative full blood counts were not performed routinely in these children, and, therefore, it was not possible to exclude anemia as a cause of increased cerebral blood flow velocity in the sleep-disordered breathing group. However, hemoglobin levels were obtained in 4 children, 2 of whom had borderline low levels (10.9 and 10.2 g/dL). Although there was no apparent relationship with cerebral blood flow velocity in these children (cerebral blood flow velocity values of 131 and 130 cm/second compared with 130 and 137 cm/second in the 2 children with normal hemoglobin levels), this requires verification. It is of particular interest that our data suggest a relationship among snoring, increased cerebral blood flow velocities and indices of cognition (processing speed and visual attention) and perhaps behavioral (Behavior Rating Inventory of Executive Function) function. This finding is preliminary: a causal relationship is not established, and the physiologic mechanisms underlying such a relationship are not clear. Prospective studies that quantify cumulative exposure to the physiologic consequences of sleep-disordered breathing, such as hypoxia, would be informative.

Celiac disease and childhood stroke.

Celiac disease is associated with a diversity of central nervous system manifestations although an association with stroke has not been documented. This case report describes a child who presented with a recurrent transient hemiplegia. Magnetic resonance imaging of the brain confirmed infarction; transcranial Doppler studies and magnetic resonance angiography were abnormal. Although there were virtually no gastrointestinal symptoms and the child was thriving, celiac disease serology was strongly positive and a duodenal biopsy confirmed the disease. Tissue transglutaminase is the major autoantigen in celiac disease and is thought to maintain vascular endothelial integrity. Antiendomysial immunoglobulin A antibodies, demonstrated to be the same autoantibody as antitransglutaminase, react with cerebral vasculature, suggesting an autoimmune mechanism for celiac disease associated vasculopathy. Because celiac disease is a potentially treatable cause of cerebral vasculopathy, serology-specifically antitissue transglutaminase antibodies-should be included in the evaluation for cryptogenic stroke in childhood, even in the absence of typical gut symptoms.

Risk factors for arterial ischemic stroke in childhood.

Stroke affects up to 13 of 100,000 children, is more common in boys and African Americans, and is associated with considerable cognitive and psychiatric morbidity, as well as motor disability. Around half are hemorrhagic and half are ischemic. Underlying conditions include sickle cell disease, cardiac abnormalities, chromosomal abnormalities (eg, Down syndrome), and neurocutaneous conditions (eg, neurofibromatosis), but up to half the patients with ischemic stroke have no previously diagnosed condition. Although there is almost certainly an important genetic component to stroke risk, head trauma, infections, drugs and radiation appear to play an etiological role in some patients. The majority of the patients with infarction in an arterial distribution have associated cerebrovascular disease. Vascular pathologies include carotid or vertebrobasilar dissection, intracranial vasculopathy affecting the middle and anterior cerebral arteries, which is often transient, and moyamoya. Intermediate risk factors may include hypertension, hypoxia, and poor nutrition leading, for example, to iron deficiency and hyperhomocysteinemia. Some chronic conditions may directly influence the child's behavior and stroke recurrence risk, although large cohorts and randomized controlled trials will be needed before strategies for modification can be evidence-based.

Is there a genetic basis for pediatric stroke?

UNLABELLED: PURPOSE OF REVIEW Childhood: stroke is more common than brain tumor, but because there is a wide spectrum in terms of etiology and most centers see only a few cases every year, there have been few large studies of genetic and environmental risk factors until recently. This review focuses on the clinical and radiologic methodology required to distinguish phenotypes in patients, and it focuses on the available data on genetic predisposition. RECENT FINDINGS: A number of conditions with Mendelian inheritance (eg, sickle cell disease) predispose to childhood stroke, but the search for epistatic polymorphisms that explain why some but not all of these patients are affected has been hampered by our poor understanding of the pathophysiology. Emergency vascular imaging, including arteriography and venography, will almost certainly assist with the description of stroke subtypes with different genetic predisposition in these patients and in the important group of children who were completely healthy before their stroke. Environmental exposure (eg, to infection, hypoxemia, and vitamins) may play a crucial role in modifying genetic expression and must be described carefully in prospective studies. SUMMARY: Now that much of the work on classifying stroke subtypes in children has been undertaken, international collaboration is likely to lead to identification of the genetic and environmental risk factors, and thus to primary and secondary prevention.