Alexandra M. Hogan

Outcome after ischaemic stroke in childhood.

A parental questionnaire was used to investigate the outcome for children who had had ischaemic stroke, who were seen at Great Ormond Street Hospital, London between 1990 and 1996. The results of functional assessments carried out by a physiotherapist and an occupational therapist, and of quantitative evaluations carried out by a neuropsychologist were used for validation where possible. The relationship between clinical and radiological factors and outcome were examined. The children were aged between 3 months and 15 years at the time of stroke (median age 5 years) and the period of follow‐up ranged from 3 months to 13 years (median duration 3 years). Of the 90 children for whom data were obtained, 13 (14%) had no residual impairments. Outcome was good in 37 children (40%) and poor in 53 (60%) (defined according to whether impairments interfered with daily life). Agreement, as measured by Cohens kappa, was good or very good between the parents’responses and the qualitative measures provided by the medical professionals and the therapists, but only fair to moderate for the quantitative measures provided by the neuropsychologists. This may reflect different parental perceptions of the physical and cognitive aspects of outcome. Younger age at time of the stroke was the only significant predictor of adverse outcome.

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 childs 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.

To sleep, perchance to enrich learning?

There is evidence that sleep enhances memory and learning. Childhood is a critical period for neurodevelopment, and minor but persistent disruption of sleep may have long-term implications for cognitive performance. Sleep is critical for health and is undervalued both in our 24 h society and in paediatric clinical practice. Paediatricians need to understand the neurodevelopmental consequences of poor quality sleep in children.

Intelligence After Stroke in Childhood: Review of the Literature and Suggestions for Future Research

Review of published clinical and neuropsychologic outcome studies reveals limited information about intellectual functioning after childhood stroke. The extant data are supplemented here by analysis of intelligence quotient (IQ) results obtained from 38 children in an ongoing study of unilateral middle cerebral artery ischemic stroke. Evidence so far indicates that, after stroke, mean IQ falls significantly below the population mean but remains within the average range. There is no significant difference between hemispheric side of injury; the Verbal and Performance IQ lateralization profile widely recognized in adults with unilateral injury is not apparent in younger children, and there is only a trend toward this profile in older children. The effects of a number of other variables, including sex, site of stroke, and longitudinal assessment, are also considered. Although the generally minor effect of stroke on IQ is encouraging, a number of children do require extra help on return to school. Some suggestions for future research are highlighted in order to encourage further consideration of the issues raised here. (J Child Neurol 2000;15:325-332).

Detecting white matter injury in sickle cell disease using voxel-based morphometry.

Sickle cell disease (SCD) is associated with cerebrovascular disease, cerebral infarction, and cognitive dysfunction. This study aimed to detect the presence and extent of white matter abnormalities in individuals with SCD using voxel‐based morphometry (VBM).

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.

An exploratory study of physiological correlates of neurodevelopmental delay in infants with sickle cell anaemia

This study aimed to investigate whether infants with sickle cell anaemia (SCA) are at risk of neurodevelopmental delay, and whether any delay is associated with SCA pathology. Twenty‐eight infants (14 SCA; 14 age‐ and ethnic‐similar controls) were assessed longitudinally with the Bayley Infant Neurodevelopmental Screener (BINS) at 3, 9 and 12 months. Transcranial Doppler (TCD) and pulse oximetry (SpO2) measures were recorded longitudinally in SCA infants, and a subgroup of controls. Haemoglobin values were obtained from SCA infants. At each age, SCA infants obtained BINS scores indicative of greater risk of neurodevelopmental delay compared with controls. The number of moderate–high BINS risk scores increased significantly between 3 and 9 months. At 9 months BINS raw scores correlated negatively with TCD velocity and positively with haemoglobin. This exploratory study suggests that SCA infants may be at greater risk of neurodevelopmental delay than previously considered, and may provide the impetus for further research into the very early precursors of cognitive impairment.

Auto-adjusting positive airway pressure in children with sickle cell anemia: results of a phase I randomized controlled trial

Sleep related breathing disorders and especially low nocturnal oxygen saturation may favor complications of sickle cell disease (SCD) In this phase I trial, autoadjusting continuous positive airway pressure (CPAP) was shown to be a feasible and safe therapy for SCD children. Sleep breathing disorders were improved, and there was evidence of a trend towards reduction of diurnal pain. Low nocturnal oxygen saturation (SpO2) is implicated in complications of Sickle Cell Anemia (SCA). Twenty-four children with SCA were randomized to receive overnight auto-adjusting continuous positive airway pressure (auto-CPAP) with supplemental oxygen, if required, to maintain SpO2 ≥94% or as controls. We assessed adherence, safety, sleep parameters, cognition and pain. Twelve participants randomized to auto-CPAP (3 with oxygen) showed improvement in Apnea/Hypopnea Index (p<0.001), average desaturation events >3%/hour (p=0.02), mean nocturnal SpO2 (p=0.02) and cognition. Primary efficacy endpoint (Processing Speed Index) showed no group differences (p=0.67), but a second measure of processing speed and attention (Cancellation) improved in those receiving treatment (p=0.01). No bone marrow suppression, rebound pain or serious adverse event resulting from auto-CPAP use was observed. Six weeks of auto-CPAP therapy is feasible and safe in children with SCA, significantly improving sleep-related breathing disorders and at least one aspect of cognition.

Development of aptitude at altitude

Millions of people currently live at altitudes in excess of 2500 metres, where oxygen supply is limited, but very little is known about the development of brain and behavioural function under such hypoxic conditions. We describe the physiological, cognitive and behavioural profile of a large cohort of infants (6-12 months), children (6-10 years) and adolescents (13-16 years) who were born and are living at three altitude locations in Bolivia ( approximately 500 m, approximately 2500 m and approximately 3700 m). Level of haemoglobin oxygen saturation and end-tidal carbon dioxide were significantly lower in all age groups living above 2500 metres, confirming the presence of hypoxia and hypocapnia, but without any detectable detriment to health. Infant measures of neurodevelopment and behaviour yielded comparable results across altitude groups. Neuropsychological assessment in children and adolescent groups indicated a minor reduction in psychomotor speed with increasing altitude, with no effect of age. This may result from slowing of underlying brain activity in parallel with reduced cerebral metabolism and blood flow, evidenced here by reduced cerebral blood flow velocity, particularly in the basilar artery, in children and adolescents. The proportion of European, Native American and African genetic admixture was comparable across altitude groups, suggesting that adaptation to high altitude in these children occurred in response to chronic hypoxic exposure irrespective of ethnic origin. Thus, psychomotor slowing is proposed to be an adaptive rather than a deficient trait, perhaps enabling accuracy of mental activity in hypoxic conditions.

Intellectual decline in children with moyamoya and sickle cell anaemia

Intelligence is reported to decline after onset of moyamoya in Japanese populations, but there is less evidence for this in Western populations where the condition may be secondary to stroke and sickle cell anaemia (SCA). Preoperative longitudinal IQ data were obtained from 15 children (seven males, eight females) who developed moyamoya syndrome (MMS) following a stroke (six with SCA, nine without SCA), and 19 controls (10 males, nine females; nine healthy control participants, 10 with SCA). At baseline assessment (Time 1) median age of patients was 7 years 6 months (range 3y 7mo to 12y 5mo); median age of controls was 6 years 3 months (range 4y to 11y 6mo). At follow-up (Time 2), ages were 11 years 8 months (range 3y 7mo to 12y 5mo) and 12 years 8 months (range 6y 4mo to 16y 8mo) in patients and controls respectively. Median duration of follow-up for the patient group was 3 years (range 7 to 10y) and in controls, 4 years 1 month (range 1 to 10y). In children with SCA, Verbal and Performance IQs (VIQ and PIQ) were significantly lower than in controls at Time 1; there was an additional independent statistically significant reduction in PIQ associated with MMS (p=0.004). Although there were further significant reductions in IQ by the second assessment for patients with MMS compared with controls, IQ did not differ significantly between groups with and without SCA. While the reduction in IQ attributed to SCA does not appear to become more marked with increasing age, the difference between those with and without MMS is associated with increasing effect over time.