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1.  Hypoxic adaptation during development: relation to pattern of neurological presentation and cognitive disability 
Developmental science  2006;9(4):411-427.
Children with acute hypoxic-ischaemic events (e.g. stroke) and chronic neurological conditions associated with hypoxia frequently present to paediatric neurologists. Failure to adapt to hypoxia may be a common pathophysiological pathway linking a number of other conditions of childhood with cognitive deficit. There is evidence that congenital cardiac disease, asthma and sleep disordered breathing, for example, are associated with cognitive deficit, but little is known about the mechanism and whether there is any structural change. This review describes what is known about how the brain reacts and adapts to hypoxia, focusing on epilepsy and sickle cell disease (SCD). We prospectively recorded overnight oxyhaemoglobin saturation (SpO2) in 18 children with intractable epilepsy, six of whom were currently or recently in minor status (MS). Children with MS were more likely to have an abnormal sleep study defined as either mean baseline SpO2 <94% or >4 dips of >4% in SpO2/hour (p = .04). In our series of prospectively followed patients with SCD who subsequently developed acute neurological symptoms and signs, mean overnight SpO2 was lower in those with cerebrovascular disease on magnetic resonance angiography (Mann-Whitney, p = .01). Acute, intermittent and chronic hypoxia may have detrimental effects on the brain, the clinical manifestations perhaps depending on rapidity of presentation and prior exposure.
PMCID: PMC1931424  PMID: 16764614
2.  Fosphenytoin for seizure prevention in childhood coma in Africa: A randomized clinical trial☆☆☆★★★ 
Journal of Critical Care  2013;28(6):1086-1092.
We conducted a double-blind trial to determine whether a single intramuscular injection of fosphenytoin prevents seizures and neurologic sequelae in children with acute coma.
We conducted this study at Kilifi District Hospital in coastal Kenya and Kondele Children's Hospital in western Kenya. We recruited children (age, 9 months to 13 years) with acute nontraumatic coma. We administered fosphenytoin (20 phenytoin equivalents/kg) or placebo and examined the prevalence and frequency of clinical seizures and occurrence of neurocognitive sequelae.
We recruited 173 children (median age, 2.6 [interquartile range, 1.7-3.7] years) into the study; 110 had cerebral malaria, 8 had bacterial meningitis, and 55 had encephalopathies of unknown etiology. Eighty-five children received fosphenytoin and 88 received placebo. Thirty-three (38%) children who received fosphenytoin had at least 1 seizure compared with 32 (36%) who received placebo (P = .733). Eighteen (21%) and 15 (17%) children died in the fosphenytoin and placebo arms, respectively (P = .489). At 3 months after discharge, 6 (10%) children in the fosphenytoin arm had neurologic sequelae compared with 6 (10%) in the placebo arm (P = .952).
A single intramuscular injection of fosphenytoin (20 phenytoin equivalents/kg) does not prevent seizures or neurologic deficits in childhood acute nontraumatic coma.
PMCID: PMC3835934  PMID: 24135012
Coma; Child; Seizure; Prophylaxis; Anticonvulsants
3.  Silent cerebral infarction, income, and grade retention among students with sickle cell anemia 
American journal of hematology  2014;89(10):E188-E192.
Children with sickle cell anemia have a higher-than-expected prevalence of poor educational attainment. We test two key hypotheses about educational attainment among students with sickle cell anemia, as measured by grade retention and use of special education services: (1) lower household per capita income is associated with lower educational attainment; (2) the presence of a silent cerebral infarct is associated with lower educational attainment. We conducted a multicenter, cross-sectional study of cases from 22 U.S. sites included in the Silent Infarct Transfusion Trial. During screening, parents completed a questionnaire that included sociodemographic information and details of their child’s academic status. Of 835 students, 670 were evaluable; 536 had data on all covariates and were used for analysis. The students’ mean age was 9.4 years (range: 5–15) with 52.2% male; 17.5% of students were retained one grade level and 18.3% received special education services. A multiple variable logistic regression model identified that lower household per capita income (odds ratio [OR] of quartile 1 = 6.36, OR of quartile 2 = 4.7, OR of quartile 3 = 3.87; P = 0.001 for linear trend), age (OR = 1.3; P < 0.001), and male gender (OR, 2.2; P = 0.001) were associated with grade retention; silent cerebral infarct (P = 0.31) and painful episodes (P = 0.60) were not. Among students with sickle cell anemia, household per capita income is associated with grade retention, whereas the presence of a silent cerebral infarct is not. Future educational interventions will need to address both the medical and socioeconomic issues that affect students with sickle cell anemia.
PMCID: PMC4261188  PMID: 25042018
4.  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.
PMCID: PMC4013758  PMID: 24496173
ASL; arterial spin labeling; brain imaging; cerebral hemodynamics; cerebral blood flow measurement; magnetic resonance; MRI; perfusion weighted MRI
5.  Nocturnal Oxygen Desaturation and Disordered Sleep as a Potential Factor in Executive Dysfunction in Sickle Cell Anemia 
Previous research has identified cognitive impairment in children with sickle cell anemia (SCA, Hemoglobin SS) compared with controls, partly accounted for by overt neuropathology after clinical stroke, “covert” (“silent”) infarction, and severity of anemia. However, cognitive deficits have also been identified in children with SCA with no history of stroke and a normal T2-weighted magnetic resonance imaging (MRI) scan. Our aim was to investigate whether nocturnal hemoglobin oxygen desaturation and sleep fragmentation could be associated with cognitive impairment in children with SCA. We assessed 10 children with SCA (9 with normal MRI) using neuropsychological measures of executive function. Cognitive assessment was immediately followed by overnight polysomnography to record nocturnal hemoglobin oxygen saturation and sleep arousals. Decreases in hemoglobin oxygen saturation and/or increased sleep arousals were associated with reduced performance on cognitive assessment. Nocturnal hemoglobin oxygen desaturation and sleep fragmentation may be a contributing factor to executive dysfunction in SCA.
PMCID: PMC3729265  PMID: 22114954
Anemia; Sickle cell; Intelligence; Neuropsychology; Oximetry; Sleep arousal disorders; Polysomnography
6.  Enuresis Associated with Sleep Disordered Breathing in Children with Sickle Cell Anemia 
The Journal of urology  2012;188(4 0):1572-1576.
Enuresis and sleep disordered breathing are common among children with sickle cell anemia. We evaluated whether enuresis is associated with sleep disordered breathing in children with sickle cell anemia.
Materials and Methods
Baseline data were used from a multicenter prospective cohort study of 221 unselected children with sickle cell anemia. A questionnaire was used to evaluate, by parental report during the previous month, the presence of enuresis and its severity. Overnight polysomnography was used to determine the presence of sleep disordered breathing by the number of obstructive apneas and/or hypopneas per hour of sleep. Logistic and ordinal regression models were used to evaluate the association of sleep disordered breathing and enuresis.
The mean age of participants was 10.1 years (median 10.0, range 4 to 19). Enuresis occurred in 38.9% of participants and was significantly associated with an obstructive apnea-hypopnea index of 2 or more per hour after adjusting for age and gender (OR 2.19; 95% CI 1.09, 4.40; p = 0.03). Enuresis severity was associated with obstructive apneas and hypopneas with 3% or more desaturation 2 or more times per hour with and without habitual snoring (OR 3.23; 95% CI 1.53, 6.81; p = 0.001 and OR 2.07; 95% CI 1.09, 3.92; p = 0.03, respectively).
In this unselected group of children with sickle cell anemia, sleep disordered breathing was associated with enuresis. Results of this study support that children with sickle cell anemia who present with enuresis should be evaluated by a pulmonologist for sleep disordered breathing.
PMCID: PMC3722896  PMID: 22910247
enuresis; sleep; anemia; sickle cell
7.  Role of Reduced ADAMTS13 in Arterial Ischemic Stroke: A Pediatric Cohort Study 
Annals of neurology  2012;73(1):58-64.
Previous studies in adults and mice have implicated ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13), also known as von Willebrand factor (VWF)-cleaving protease, as a protective factor for stroke. Here we investigated ADAMTS13 in 208 pediatric patients with arterial ischemic stroke (AIS) and 125 population-based control children in a frequency-matched case–control study.
The proportion of patients/controls with ADAMTS13 activity levels below and above the 10th percentile was compared. Additionally, in a quintile comparison, the proportion of patients versus controls in the lowest ADAMTS13 quintile was compared to those in the 2nd to 5th quintiles. Adjustment was performed for VWF antigen (VWF:Ag), factor VIII activity (FVIII:C), blood group, and age.
Forty-six of 208 patients (22%) showed ADAMTS13 levels below the 10th percentile, compared with 5 of 125 controls (4%; p < 0.001). Odds ratios/95% confidence intervals were 7.30/2.73–19.50 for the lowest percentile and 2.44/1.15–5.16 in the quintile comparison after adjustment for VWF:Ag, FVIII:C, blood group, and age. Comparing the proportion of patients with ADAMTS13 activity below the 10th percentile within the different stroke subtypes (undetermined, cardioembolic, steno-occlusive arteriopathies), no statistically significant differences were found (undetermined, 16 of 89; cardioembolic, 6 of 40; steno-occlusive arteriopathies, 24 of 79; p = 0.08). ADAMTS13 levels did not significantly differ among stroke subtypes (p = 0.29).
Our findings implicate reduced ADAMTS13 activity as a risk factor for pediatric AIS, and support the concept that ADAMTS13 has a role in the pathogenesis of pediatric AIS.
PMCID: PMC3703929  PMID: 23225307
8.  Acute Silent Cerebral Ischemic Events in Children with Sickle Cell Anemia 
JAMA neurology  2013;70(1):58-65.
Irregular, sporadic episodes of ischemic brain injury are known to occur in sickle cell anemia (SCA), resulting in overt stroke and silent cerebral infarction. Ongoing ischemia in other organs is common in SCA but has never been documented in the brain.
To test the hypothesis that acute silent cerebral ischemic events (ASCIEs) are frequent and potentially transient.
Cross-sectional and cohort study of children with SCA screened by magnetic resonance imaging (MRI) of the brain for a randomized clinical trial.
Clinical trial setting in tertiary care centers.
Asymptomatic children with SCA without known stroke, neurologic injury, or epilepsy not receiving treatment with transfusions or hydroxyurea.
Main Outcome Measure
Incidence of ASCIEs calculated using single diffusion-weighted MRI scans (acute ischemic events that occurred within 10 days of the MRI).
Acute silent cerebral ischemic events were detected on 1.3% of MRIs (10 of 771) in 652 children (mean age, 10.0 years), with an incidence of 47.3 events per 100 patient-years (95% CI, 22.7–87.2). Two of 10 children with ASCIEs had follow-up MRIs of the brain; only 1 had silent cerebral infarction in the same location as the previously detected ASCIE.
Children with SCA experience ongoing (chronic, intermittent) cerebral ischemia, sometimes reversible, far more frequently than previously recognized. The brain in SCA is at constant threat of ischemia.
PMCID: PMC3677221  PMID: 23108767
9.  Hematological and Genetic Predictors of Daytime Hemoglobin Saturation in Tanzanian Children with and without Sickle Cell Anemia 
ISRN Hematology  2013;2013:472909.
Low hemoglobin oxygen saturation (SpO2) is common in Sickle Cell Anemia (SCA) and associated with complications including stroke, although determinants remain unknown. We investigated potential hematological, genetic, and nutritional predictors of daytime SpO2 in Tanzanian children with SCA and compared them with non-SCA controls. Steady-state resting pulse oximetry, full blood count, transferrin saturation, and clinical chemistry were measured. Median daytime SpO2 was 97% (IQ range 94–99%) in SCA (N = 458), lower (P < 0.0001) than non-SCA (median 99%, IQ range 98–100%; N = 394). Within SCA, associations with SpO2 were observed for hematological variables, transferrin saturation, body-mass-index z-score, hemoglobin F (HbF%), genotypes, and hemolytic markers; mean cell hemoglobin (MCH) explained most variability (P < 0.001, Adj r2 = 0.09). In non-SCA only age correlated with SpO2. α-thalassemia 3.7 deletion highly correlated with decreased MCH (Pearson correlation coefficient −0.60, P < 0.0001). In multivariable models, lower SpO2 correlated with higher MCH (β-coefficient −0.32, P < 0.001) or with decreased copies of α-thalassemia 3.7 deletion (β-coefficient 1.1, P < 0.001), and independently in both models with lower HbF% (β-coefficient 0.15, P < 0.001) and Glucose-6-Phosphate Dehydrogenase genotype (β-coefficient −1.12, P = 0.012). This study provides evidence to support the hypothesis that effects on red cell rheology are important in determining SpO2 in children with SCA. Potential mechanisms and implications are discussed.
PMCID: PMC3649307  PMID: 23691341
10.  Global arginine bioavailability in Tanzanian sickle cell anaemia patients at steady-state: a nested case control study of deaths versus survivors 
British journal of haematology  2011;155(4):522-524.
PMCID: PMC3592384  PMID: 21595648
sickle cell anaemia; arginine; amino acids; Africa; mortality
11.  The tympanic membrane displacement analyser for monitoring intracranial pressure in children 
Child's Nervous System  2013;29(6):927-933.
Raised intracranial pressure (ICP) is a potentially treatable cause of morbidity and mortality but tools for monitoring are invasive. We sought to investigate the utility of the tympanic membrane displacement (TMD) analyser for non-invasive measurement of ICP in children.
We made TMD observations on normal and acutely comatose children presenting to Kilifi District Hospital (KDH) at the rural coast of Kenya and on children on follow-up for idiopathic intracranial hypertension at Evelina Children’s Hospital (ECH), in London, UK.
We recruited 63 patients (median age 3.3 (inter-quartile range (IQR) 2.0–4.3) years) at KDH and 14 children (median age 10 (IQR 5–11) years) at ECH. We observed significantly higher (more negative) TMD measurements in KDH children presenting with coma compared to normal children seen at the hospital’s outpatient department, in both semi-recumbent [mean −61.3 (95 % confidence interval (95 % CI) −93.5 to 29.1) nl versus mean −7.1 (95 % CI −54.0 to 68.3) nl, respectively; P = 0.03] and recumbent postures [mean −61.4 (95 % CI −93.4 to −29.3) nl, n = 59) versus mean −25.9 (95 % CI −71.4 to 123.2) nl, respectively; P = 0.03]. We also observed higher TMD measurements in ECH children with raised ICP measurements, as indicated by lumbar puncture manometry, compared to those with normal ICP, in both semi-recumbent [mean −259.3 (95 % CI −363.8 to −154.8) nl versus mean 26.7 (95 % CI −52.3 to 105.7) nl, respectively; P < 0.01] and recumbent postures [mean −137.5 (95 % CI −260.6 to −14.4) nl versus mean 96.6 (95 % CI 6.5 to 186.6) nl, respectively; P < 0.01].
The TMD analyser has a potential utility in monitoring ICP in a variety of clinical circumstances.
PMCID: PMC3657347  PMID: 23361337
Intracranial pressure; Idiopathic intracranial hypertension; Coma; Child
12.  Seizures in 204 comatose children: incidence and outcome 
Intensive Care Medicine  2012;38(5):853-862.
Seizures are common in comatose children, but may be clinically subtle or only manifest on continuous electroencephalographic monitoring (cEEG); any association with outcome remains uncertain.
cEEG (one to three channels) was performed for a median 42 h (range 2–630 h) in 204 unventilated and ventilated children aged ≤15 years (18 neonates, 61 infants) in coma with different aetiologies. Outcome at 1 month was independently determined and dichotomized for survivors into favourable (normal or moderate neurological handicap) and unfavourable (severe handicap or vegetative state).
Of the 204 patients, 110 had clinical seizures (CS) before cEEG commenced. During cEEG, 74 patients (36 %, 95 % confidence interval, 95 % CI, 32–41 %) had electroencephalographic seizures (ES), the majority without clinical accompaniment (non-convulsive seizures, NCS). CS occurred before NCS in 69 of the 204 patients; 5 ventilated with NCS had no CS observed. Death (93/204; 46 %) was independently predicted by admission Paediatric Index of Mortality (PIM; adjusted odds ratio, aOR, 1.027, 95 % CI 1.012–1.042; p < 0.0005), Adelaide coma score (aOR 0.813, 95 % CI 0.700–0.943; p = 0.006), and EEG grade on admission (excess slow with >3 % fast, aOR 5.43, 95 % CI 1.90–15.6; excess slow with <3 % fast, aOR 8.71, 95 % CI 2.58–29.4; low amplitude, 10th centile <9 µV, aOR 3.78, 95 % CI 1.23–11.7; and burst suppression, aOR 10.68, 95 % CI 2.31–49.4) compared with normal cEEG, as well as absence of CS at any time (aOR 2.38, 95 % CI 1.18–4.81). Unfavourable outcome (29/111 survivors; 26 %) was independently predicted by the presence of ES (aOR 15.4, 95 % CI 4.7–49.7) and PIM (aOR 1.036, 95 % CI 1.013–1.059).
Seizures are common in comatose children, and are associated with an unfavourable outcome in survivors. cEEG allows the detection of subtle CS and NCS and is a prognostic tool.
PMCID: PMC3338329  PMID: 22491938
Seizures; Status epilepticus; Coma; Child; Outcome; Medicine & Public Health; Pain Medicine; Emergency Medicine; Intensive / Critical Care Medicine; Pneumology/Respiratory System; Pediatrics; Anesthesiology
13.  Mortality in Sickle Cell Anemia in Africa: A Prospective Cohort Study in Tanzania 
PLoS ONE  2011;6(2):e14699.
The World Health Organization has declared Sickle Cell Anemia (SCA) a public health priority. There are 300,000 births/year, over 75% in Africa, with estimates suggesting that 6 million Africans will be living with SCA if average survival reaches half the African norm. Countries such as United States of America and United Kingdom have reduced SCA mortality from 3 to 0.13 per 100 person years of observation (PYO), with interventions such as newborn screening, prevention of infections and comprehensive care, but implementation of interventions in African countries has been hindered by lack of locally appropriate information. The objective of this study was to determine the incidence and factors associated with death from SCA in Dar-es-Salaam.
Methods and Findings
A hospital-based cohort study was conducted, with prospective surveillance of 1,725 SCA patients recruited from 2004 to 2009, with 209 (12%) lost to follow up, while 86 died. The mortality rate was 1.9 (95%CI 1.5, 2.9) per 100 PYO, highest under 5-years old [7.3 (4.8–11.0)], adjusting for dates of birth and study enrollment. Independent risk factors, at enrollment to the cohort, predicting death were low hemoglobin (<5 g/dL) [3.8 (1.8–8.2); p = 0.001] and high total bilirubin (≥102 µmol/L) [1.7 (1.0–2.9); p = 0.044] as determined by logistic regression.
Mortality in SCA in Africa is high, with the most vulnerable period being under 5-years old. This is most likely an underestimate, as this was a hospital cohort and may not have captured SCA individuals with severe disease who died in early childhood, those with mild disease who are undiagnosed or do not utilize services at health facilities. Prompt and effective treatment for anemia in SCA is recommended as it is likely to improve survival. Further research is required to determine the etiology, pathophysiology and the most appropriate strategies for management of anemia in SCA.
PMCID: PMC3040170  PMID: 21358818
14.  Cerebral Venous Sinus (Sinovenous) Thrombosis in Children 
Cerebral venous sinus (sinovenous) thrombosis (CSVT) in childhood is a rare, but underrecognized, disorder, typically of multifactorial etiology, with neurologic sequelae apparent in up to 40% of survivors and mortality approaching 10%. There is an expanding spectrum of perinatal brain injury associated with neonatal CSVT. Although there is considerable overlap in risk factors for CSVT in neonates and older infants and children, specific differences exist between the groups. Clinical symptoms are frequently nonspecific, which may obscure the diagnosis and delay treatment. While morbidity and mortality are significant, CSVT recurs less commonly than arterial ischemic stroke in children. Appropriate management may reduce the risk of recurrence and improve outcome, however there are no randomized controlled trials to support the use of anticoagulation in children. Although commonly employed in many centers, this practice remains controversial, highlighting the continued need for high-quality studies. This article reviews the literature pertaining to pediatric venous sinus thrombosis.
PMCID: PMC2892748  PMID: 20561500
Cerebral sinovenous thrombosis; CSVT; Pediatric; Neonatal; Stroke
15.  Increased Cerebral Blood Flow Velocity in Children with Mild Sleep-Disordered Breathing 
Pediatrics  2006;118(4):e1100-e1108.
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.
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.
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.
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.
PMCID: PMC1995426  PMID: 17015501
sleep disordered breathing; cerebral blood flow; transcranial Doppler; executive function; neuropsychological function
17.  Risk factors for high cerebral blood flow velocity and death in Kenyan children with Sickle Cell Anaemia: role of haemoglobin oxygen saturation and febrile illness 
British Journal of Haematology  2009;145(4):529-532.
High cerebral blood flow velocity (CBFv) and low haemoglobin oxygen saturation (SpO2) predict neurological complications in sickle cell anaemia (SCA) but any association is unclear. In a cross-sectional study of 105 Kenyan children, mean CBFv was 120 ± 34·9 cm/s; 3 had conditional CBFv (170–199 cm/s) but none had abnormal CBFv (>200 cm/s). After adjustment for age and haematocrit, CBFv ≥150 cm/s was predicted by SpO2 ≤ 95% and history of fever. Four years later, 10 children were lost to follow-up, none had suffered neurological events and 11/95 (12%) had died, predicted by history of fever but not low SpO2. Natural history of SCA in Africa may be different from North America and Europe.
PMCID: PMC3001030  PMID: 19344425
Sickle Cell Anaemia; Africa; transcranial Doppler ultrasound; mortality; cerebrovascular accidents
18.  Continuous EEG monitoring in Kenyan children with non-traumatic coma 
Archives of Disease in Childhood  2012;97(4):343-349.
The aim of this study was to describe the EEG and clinical profile of seizures in children with non-traumatic coma, compare seizure detection by clinical observations with that by continuous EEG, and relate EEG features to outcome.
This prospective observational study was conducted at the paediatric high dependency unit of Kilifi District Hospital, Kenya. Children aged 9 months to 13 years presenting with acute coma were monitored by EEG for 72 h or until they regained consciousness or died. Poor outcome was defined as death or gross motor deficits at discharge.
82 children (median age 2.8 (IQR 2.0–3.9) years) were recruited. An initial medium EEG amplitude (100–300 mV) was associated with less risk of poor outcome compared to low amplitude (≤100 mV) (OR 0.2, 95% CI 0.1 to 0.7; p<0.01). 363 seizures in 28 (34%) children were observed: 240 (66%) were electrographic and 112 (31%) electroclinical. In 16 (20%) children, electrographic seizures were the only seizure types detected. The majority (63%) of electroclinical seizures had focal clinical features but appeared as generalised (79%) or focal with secondary generalisation (14%) on EEG. Occurrence of any seizure or status epilepticus during monitoring was associated with poor outcome (OR 3.2, 95% CI 1.2 to 8.7; p=0.02 and OR 4.5, 95% CI 1.3 to 15.3; p<0.01, respectively).
Initial EEG background amplitude is prognostic in paediatric non-traumatic coma. Clinical observations do not detect two out of three seizures. Seizures and status epilepticus after admission are associated with poor outcome.
PMCID: PMC3329232  PMID: 22328741
19.  The Young Everest Study: preliminary report of changes in sleep and cerebral blood flow velocity during slow ascent to altitude in unacclimatised children 
Archives of Disease in Childhood  2013;98(5):356-362.
Cerebral blood flow velocity (CBFV) and sleep physiology in healthy children exposed to hypoxia and hypocarbia are under-researched.
To investigate associations between sleep variables, daytime end-tidal carbon dioxide (EtCO2) and CBFV in children during high-altitude ascent.
Vital signs, overnight cardiorespiratory sleep studies and transcranial Doppler were undertaken in nine children (aged 6–13 years) at low altitude (130 m), and then at moderate (1300 m) and high (3500 m) altitude during a 5-day ascent.
Daytime (130 m: 98%; 3500 m: 90%, p=0.004) and mean (130 m: 97%, 1300 m: 94%, 3500: 87%, p=0.0005) and minimum (130 m: 92%, 1300 m: 84%, 3500 m: 79%, p=0.0005) overnight pulse oximetry oxyhaemoglobin saturation decreased, and the number of central apnoeas increased at altitude (130 m: 0.2/h, 1300 m: 1.2/h, 3500 m: 3.5/h, p=0.2), correlating inversely with EtCO2 (R2 130 m: 0.78; 3500 m: 0.45). Periodic breathing occurred for median (IQR) 0.0 (0; 0.3)% (130 m) and 0.2 (0; 1.2)% (3500 m) of total sleep time. At 3500 m compared with 130 m, there were increases in middle (MCA) (mean (SD) left 29.2 (42.3)%, p=0.053; right 9.9 (12)%, p=0.037) and anterior cerebral (ACA) (left 65.2 (69)%, p=0.024; right 109 (179)%; p=0.025) but not posterior or basilar CBFV. The right MCA CBFV increase at 3500 m was predicted by baseline CBFV and change in daytime SpO2 and EtCO2 at 3500 m (R2 0.92); these associations were not seen on the left.
This preliminary report suggests that sleep physiology is disturbed in children even with slow ascent to altitude. The regional variations in CBFV and their association with hypoxia and hypocapnia require further investigation.
PMCID: PMC3625826  PMID: 23471157
Transcranial Doppler; hypoxia; acute mountain sickness; altitude; Sleep
20.  Precursors of Executive Function in Infants With Sickle Cell Anemia 
Journal of Child Neurology  2013;28(10):1197-1202.
Executive dysfunction occurs in sickle cell anemia, but there are few early data. Infants with sickle cell anemia (n = 14) and controls (n = 14) performed the “A-not-B” and Object Retrieval search tasks, measuring precursors of executive function at 9 and 12 months. Significant group differences were not found. However, for the A-not-B task, 7 of 11 sickle cell anemia infants scored in the lower 2 performance categories at 9 months, but only 1 at 12 months (P = .024); controls obtained scores at 12 months that were statistically comparable to the scores they had already obtained at 9 months. On the Object Retrieval task, 9- and 12-month controls showed comparable scores, whereas infants with sickle cell anemia continued to improve (P = .027); at 9 months, those with lower hemoglobin oxygen saturation passed fewer trials (R s = 0.670, P = .024) and took longer to obtain the toy (R s = –0.664, P = .013). Subtle delays in acquiring developmental skills may underlie abnormal executive function in childhood.
PMCID: PMC3807734  PMID: 22859700
anemia; sickle cell; cognition; neuropsychology; executive; dysfunction; function
21.  Haptoglobin, alpha‐thalassaemia and glucose‐6‐phosphate dehydrogenase polymorphisms and risk of abnormal transcranial Doppler among patients with sickle cell anaemia in Tanzania 
British Journal of Haematology  2014;165(5):699-706.
Transcranial Doppler ultrasonography measures cerebral blood flow velocity (CBFv) of basal intracranial vessels and is used clinically to detect stroke risk in children with sickle cell anaemia (SCA). Co‐inheritance in SCA of alpha‐thalassaemia and glucose‐6‐phosphate dehydrogenase (G6PD) polymorphisms is reported to associate with high CBFv and/or risk of stroke. The effect of a common functional polymorphism of haptoglobin (HP) is unknown. We investigated the effect of co‐inheritance of these polymorphisms on CBFv in 601 stroke‐free Tanzanian SCA patients aged <24 years. Homozygosity for alpha‐thalassaemia 3·7 deletion was significantly associated with reduced mean CBFv compared to wild‐type (β‐coefficient −16·1 cm/s, P = 0·002) adjusted for age and survey year. Inheritance of 1 or 2 alpha‐thalassaemia deletions was associated with decreased risk of abnormally high CBFv, compared to published data from Kenyan healthy control children (Relative risk ratio [RRR] = 0·53 [95% confidence interval (CI):0·35–0·8] & RRR = 0·43 [95% CI:0·23–0·78]), and reduced risk of abnormally low CBFv for 1 deletion only (RRR = 0·38 [95% CI:0·17–0·83]). No effects were observed for G6PD or HP polymorphisms. This is the first report of the effects of co‐inheritance of common polymorphisms, including the HP polymorphism, on CBFv in SCA patients resident in Africa and confirms the importance of alpha‐thalassaemia in reducing risk of abnormal CBFv.
PMCID: PMC4154124  PMID: 24666344
sickle cell disease; Africa; children; cerebral blood flow velocity

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