Decline in Processing Speed Tells Only Half the Story: Developmental Delay in Children Living with Sickle Cell Disease.

Children with sickle cell disease (SCD) may experience cognitive difficulties, including slowed processing speed. Thus, we investigated if processing speed changes over time. From 1992-2001, 103 participants with SCD aged 3-16 years (n ≤ 8.99 = 45; n ≥ 9.00 = 58) completed cognitive assessments. MRI was available for 54 participants. Between 1992-2002, 58 participants consented to one or two further assessments. A repeated measures regression using linear mixed-effects modelling determined longitudinal changes in processing speed index (PSI), examining the interaction between age (continuous variable) and timepoint (i.e., assessment 1 or 3) and controlling for MRI infarct status (i.e., no infarct, silent infarct, or stroke). Those aged ≤8.99 and ≥9.00 at first assessment experienced PSI decline. Declines were most prominent for the processing speed coding subtest, with a significant interaction between timepoint and age, t(31) = 2.64, p = 0.01. This decline may reflect a developmental delay, likely due to disease progression, with slower improvements in processing speed. Although there have been significant improvements in SCD treatments, mostly in high-income countries, processing speed still remains a target; thus, incorporating clinical monitoring of processing speed may help identify delay and allow for early intervention.

Effects of regional brain volumes on cognition in sickle cell anemia: A developmental perspective.

Background and objectives: Cognitive difficulties in people with sickle cell anemia (SCA) are related to lower processing speed index (PSI) and working memory index (WMI). However, risk factors are poorly understood so preventative strategies have not been explored. Brain volumes, specifically white matter volumes (WMV) which increases through early adulthood, have been associated with better cognition in healthy typically developing individuals. In patients with SCA, the reduced WMV and total subcortical volumes noted could explain cognitive deficits. We therefore examined developmental trajectories for regional brain volumes and cognitive endpoints in patients with SCA. Methods: Data from two cohorts, the Sleep and Asthma Cohort and Prevention of Morbidity in SCA, were available. MRI data included T1-weighted axial images, pre-processed before regional volumes were extracted using Free-surfer. PSI and WMI from the Weschler scales of intelligence were used to test neurocognitive performance. Hemoglobin, oxygen saturation, hydroxyurea treatment and socioeconomic status from education deciles were available. Results: One hundred and twenty nine patients (66 male) and 50 controls (21 male) aged 8-64 years were included. Brain volumes did not significantly differ between patients and controls. Compared with controls, PSI and WMI were significantly lower in patients with SCA, predicted by increasing age and male sex, with lower hemoglobin in the model for PSI but no effect of hydroxyurea treatment. In male patients with SCA only, WMV, age and socioeconomic status predicted PSI, while total subcortical volumes predicted WMI. Age positively and significantly predicted WMV in the whole group (patients + controls). There was a trend for age to negatively predict PSI in the whole group. For total subcortical volume and WMI, age predicted decrease only in the patient group. Developmental trajectory analysis revealed that PSI only was significantly delayed in patients at 8 years of age; the rate of development for the cognitive and brain volume data did not differ significantly from controls. Discussion: Increasing age and male sex negatively impact cognition in SCA, with processing speed, also predicted by hemoglobin, delayed by mid childhood. Associations with brain volumes were seen in males with SCA. Brain endpoints, calibrated against large control datasets, should be considered for randomized treatment trials.

Epidemiology of Stroke in Sickle Cell Disease.

Sickle cell disease is the most common cause of stroke in childhood, both ischaemic and haemorrhagic, and it also affects adults with the condition. Without any screening or preventative treatment, the incidence appears to fall within the range 0.5 to 0.9 per 100 patient years of observation. Newborn screening with Penicillin prophylaxis and vaccination leading to reduced bacterial infection may have reduced the incidence, alongside increasing hydroxyurea prescription. Transcranial Doppler screening and prophylactic chronic transfusion for at least an initial year has reduced the incidence of stroke by up to 10-fold in children with time averaged mean of the maximum velocity >200 cm/s. Hydroxyurea also appears to reduce the incidence of first stroke to a similar extent in the same group but the optimal dose remains controversial. The prevention of haemorrhagic stroke at all ages and ischaemic stroke in adults has not yet received the same degree of attention. Although there are fewer studies, silent cerebral infarction on magnetic resonance imaging (MRI), and other neurological conditions, including headache, epilepsy and cognitive dysfunction, are also more prevalent in sickle cell disease compared with age matched controls. Clinical, neuropsychological and quantitative MRI screening may prove useful for understanding epidemiology and aetiology.

MRI detection of brain abnormality in sickle cell disease.

Introduction: Over the past decades, neuroimaging studies have clarified that a significant proportion of patients with sickle cell disease (SCD) have functionally significant brain abnormalities. Clinically, structural magnetic resonance imaging (MRI) sequences (T2, FLAIR, diffusion-weighted imaging) have been used by radiologists to diagnose chronic and acute cerebral infarction (both overt and clinically silent), while magnetic resonance angiography and venography have been used to diagnose arteriopathy and venous thrombosis. In research settings, imaging scientists are increasingly applying quantitative techniques to shine further light on underlying mechanisms.Areas covered: From a June 2020 PubMed search of 'magnetic' or 'MRI' and 'sickle' over the previous 5 years, we selected manuscripts on T1-based morphometric analysis, diffusion tensor imaging, arterial spin labeling, T2-oximetry, quantitative susceptibility, and connectivity.Expert Opinion: Quantitative MRI techniques are identifying structural and hemodynamic biomarkers associated with risk of neurological and neurocognitive complications. A growing body of evidence suggests that these biomarkers are sensitive to change with treatments, such as blood transfusion and hydroxyurea, indicating that they may hold promise as endpoints in future randomized clinical trials of novel approaches including hemoglobin F upregulation, reduction of polymerization, and gene therapy. With further validation, such techniques may eventually also improve neurological and neurocognitive risk stratification in this vulnerable population.

Sleep-disordered breathing and comorbidities: role of the upper airway and craniofacial skeleton.

Obstructive sleep-disordered breathing (SDB), which includes primary snoring through to obstructive sleep apnea syndrome (OSAS), may cause compromise of respiratory gas exchange during sleep, related to transient upper airway narrowing disrupting ventilation, and causing oxyhemoglobin desaturation and poor sleep quality. SDB is common in chronic disorders and has significant implications for health. With prevalence rates globally increasing, this condition is causing a substantial burden on health care costs. Certain populations, including people with sickle cell disease (SCD), exhibit a greater prevalence of OSAS. A review of the literature provides the available normal polysomnography and oximetry data for reference and documents the structural upper airway differences between those with and without OSAS, as well as between ethnicities and disease states. There may be differences in craniofacial development due to atypical growth trajectories or extramedullary hematopoiesis in anemias such as SCD. Studies involving MRI of the upper airway illustrated that OSAS populations tend to have a greater amount of lymphoid tissue, smaller airways, and smaller lower facial skeletons from measurements of the mandible and linear mental spine to clivus. Understanding the potential relationship between these anatomical landmarks and OSAS could help to stratify treatments, guiding choice towards those which most effectively resolve the obstruction. OSAS is relatively common in SCD populations, with hypoxia as a key manifestation, and sequelae including increased risk of stroke. Combatting any structural defects with appropriate interventions could reduce hypoxic exposure and consequently reduce the risk of comorbidities in those with SDB, warranting early treatment interventions.

Indications for the performance of neuroimaging in children.

Pediatric neurology relies on ultrasound, computed tomography (CT), and magnetic resonance (MR) imaging. CT prevails in acute neurologic presentations, including traumatic brain injury (TBI), nontraumatic coma, stroke, and status epilepticus, because of easy availability, with images of diagnostic quality, e.g., to exclude hemorrhage, usually completed quickly enough to avoid sedation. Concerns over the risks of ionizing radiation mean re-imaging and higher-dose procedures, e.g., arteriography and venography, require justification. T1/T2-weighted imaging (T1/T2-WI) MR with additional sequences (arteriography, venography, T2*, spectroscopy, diffusion tensor, perfusion, diffusion- (DWI) and susceptibility-weighted imaging (SWI)) often clarifies the diagnosis, which may alter management in acute settings, as well as chronic conditions, e.g., epilepsy. Clinical acumen remains essential to avoid imaging, e.g., in genetic epilepsies or migrainous headaches responding to treatment, or to target sequences to specific diagnosis, e.g., T1/T2-WI for shunt dysfunction (with SWI for TBI); DWI, arteriography including neck vessels, and venography for acute hemiplegia or coma; coronal temporal cuts for partial epilepsy; or muscle imaging for motor delay. The risk of general anesthesia is low; "head-only" scanners may allow rapid MRI without sedation. Timely and accurate reporting, with discrepancy discussion between expert neuroradiologists, is important for management of the child and the family's expectations.

Pattern of Lung Function Is Not Associated with Prior or Future Morbidity in Children with Sickle Cell Anemia.

RATIONALE: Patient factors associated with development of abnormal lung function in children with sickle cell anemia (SCA) have not been fully characterized. OBJECTIVES: To characterize lung function abnormalities among children with SCA and to determine whether these steady-state lung function results were associated with morbidity before or after testing among children with SCA. METHODS: This study was part of the prospective National Institutes of Health-funded Sleep and Asthma Cohort Study. Children with HbSS or Hb Sß(o) (SCA) were enrolled without regard for sickle cell-related comorbidities or diagnosis of asthma. Lung function was measured by spirometry and plethysmography on the same day, when free of acute disease. Standardized asthma symptom questionnaires and review of the medical records were also performed. MEASUREMENTS AND MAIN RESULTS: A total of 149 children aged 6 to 19 years completed lung function testing, of whom 139 participants had retrospective morbidity data from birth to the test date, and 136 participants were followed prospectively for a median of 4.3 years from the test date. At baseline, percentages with normal, obstructive, restrictive, nonspecific, and mixed lung function patterns were 70, 16, 7, 6, and 1, respectively. Neither retrospective rates of pain nor acute chest syndrome was associated with lung function patterns. Furthermore, baseline lung function pattern was not predictive of future pain or acute chest syndrome episodes. CONCLUSIONS: The majority of children with SCA have lung function that is within the normal range. Abnormal lung function patterns were not associated with prior vasoocclusive pain or acute chest syndrome episodes, and baseline lung function patterns did not predict future vasoocclusive pain or chest syndrome episodes.

Adaptation to Life in the High Andes: Nocturnal Oxyhemoglobin Saturation in Early Development.

STUDY OBJECTIVES: Physiological adaptation to high altitude hypoxia may be impaired in Andeans with significant European ancestry. The respiratory 'burden' of sleep may challenge adaptation, leading to relative nocturnal hypoxia. Developmental aspects of sleep-related breathing in high-altitude native children have not previously been reported. We aimed to determine the influence of development on diurnal-nocturnal oxyhemoglobin differences in children living at high altitude. METHODS: This was a cross-sectional, observational study. Seventy-five healthy Bolivian children aged 6 mo to 17 y, native to low altitude (500 m), moderate high altitude (2,500 m), and high altitude (3,700 m) were recruited. Daytime resting pulse oximetry was compared to overnight recordings using Masimo radical oximeters. Genetic ancestry was determined from DNA samples. RESULTS: Children had mixed European/Amerindian ancestry, with no significant differences between altitudes. Sixty-two participants had ≥ 5 h of nocturnal, artifact-free data. As predicted, diurnal mean oxyhemoglobin saturation decreased across altitudes (infants and children, both P < 0.001), with lowest diurnal values at high altitude in infants. At high altitude, there was a greater drop in nocturnal mean oxyhemoglobin saturation (infants, P < 0.001; children, P = 0.039) and an increase in variability (all P ≤ 0.001) compared to low altitude. Importantly, diurnal to nocturnal altitude differences diminished (P = 0.036), from infancy to childhood, with no further change during adolescence. CONCLUSIONS: Physiological adaptation to high-altitude living in native Andeans is unlikely to compensate for the significant differences we observed between diurnal and nocturnal oxyhemoglobin saturation, most marked in infancy. This vulnerability to sleep-related hypoxia in early childhood has potential lifespan implications. Future studies should characterize the sleep- related respiratory physiology underpinning our observations.

Pituitary function at long-term follow-up of childhood traumatic brain injury.

Pituitary dysfunction is a recognized sequela of traumatic brain injury (TBI), occurring in 10-83% of adult patients, but there are few data on the prevalence or natural history in childhood. Our objective was to determine pituitary function in children and young adults at least 4 years after TBI requiring pediatric intensive care unit (PICU) admission. The effects of TBI and hypopituitarism on height, adiposity, and quality of life (QOL) were also evaluated. Unselected patients discharged from the regional PICU with TBI (age < 18 years at injury) from 1999-2004 were recruited. Blood and urine samples were collected for baseline pituitary function testing. Height and weight were measured. Adiposity was assessed by mid-upper arm and waist circumferences, and body fat percentage estimation using four-site skinfold thickness and bioelectrical impedance. Auxology and adiposity data were compared to local age- and sex-matched healthy control data. QOL questionnaires (PedsQL 4.0 and QOL-AGHDA) were completed. Twenty subjects (median age 16.7 years, range 9.2-23.3 years, 13 male) of 127 who were eligible agreed to participate at a median of 6.8 years (range 4.2-10.3 years) since TBI. Markers of injury were higher in those recruited than those who were not. Biochemical evidence of hypopituitarism was identified in only one case, possibly related to comorbid pre-existing attention deficit-hyperactivity disorder. Height, weight, and adiposity were similar to healthy controls. Poor QOL was seen in patients with chronic functional deficits or comorbidities. Overall, pituitary dysfunction was less prevalent than in previous studies in adults and children. The results of this study do not support the use of routine endocrine evaluation of children following TBI.