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

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 increas-ing, 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.</p

Cerebral infarcts and cerebrovascular disease in neurologically intact Tanzanian children with sickle cell anaemia

Introduction:Children and adolescents with sickle cell anemia (SCA) without history of neurological manifestations remain at risk of stroke and require cost effective screening as evidence-based stroke prevention interventions are developed. Although there are data on the prevalence of Transcranial Doppler (TCD) abnormality, there are relatively few studies on the prevalence of silent cerebral infarction (SCI) on magnetic resonance imaging (MRI) and vasculopathy on MR angiography (MRA), paricularly in Africa, where the burden of disease is greatest. In this study in Africa, we determined the prevalence of SCI on MRI and cerebral vasculopathy on MRA, and explored associations with age, sex, internal carotid/middle cerebral artery (ICA/MCA) and basilar cerebral blood flow velocities (CBFV) on TCD, and hematological variables.Patients and methods:We prospectively studied children with homozygous SCA (HbSS) without prior clinically overt stroke or TIA or seizures. Clinical information and blood for full blood count was collected for all patients. All were offered TCD using non-imaging equipment (Compumedics) and MRI and MRA of intracranial arteries on a Philips 1.5 Tesla scanner. MRA was graded as 1 Turbulence, 2 Stenosis, 3 Occlusion, 4 Occlusion with collaterals (moyamoya). Imaging was reviewed by 2 neuroradiologists (MJ and DS) and consensus was reached.Results:Within a period of 12 months, 395 children with SCA were recruited. Mean age was 12.7+/-4 (range 5-19 years); 199 (50.4%) were male. Mean hemoglobin was 7.6±1.1 (range 4.1-13.5) g/dl. 381 had TCD, of whom 227 (57%) have had brain MRI and MRA so far.Only 14/395 (3.5%) of patients had abnormal CBFV, 8 (2%) with maximum CBFV 200cm/sec).Prevalence of silent cerebral infarction was 29% (65/227) and was similar in males (30%; 34/114) and females (28%; 31/110) but was lower in children age

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

Transcranial doppler screening in children with Sickle Cell Anemia is feasible in central India and reveals high risk of stroke

Introduction: India has been identified as having the second largest number of births with sickle cell anemia (SCA) in the world after Africa, with estimated 44,400 new-borns affected per year. SCD was previously reported to have a milder course in children from India, with less severe disease among aboriginal tribal populations than in non-tribal populations. Recent reports indicate the occurrence of severe manifestations of SCD in both tribal and non-tribal populations in India. Stroke is one of the serious complications of SCD, but there are no data on transcranial Doppler (TCD) screening for evaluating children with SCD in India who may be at high risk for strokes. The objective of this study was to assess the feasibility of using TCD to measure time averaged maximum of the mean velocities (TAMMV) in the intracranial arteries in children attending a tertiary centre in central India. Methods: STUDY DESIGN: A cross sectional study was conducted in consecutively recruited stable children of either sex with homozygous SCA proven by electrophoresis and high performance liquid chromatography in the age group of 1-26 years. Patients who were febrile, acutely ill, hypoxic or asleep were not included in the study as these conditions can falsely elevate the intracranial blood flow velocities. Patients with hemoglobinopathies other than HbSS or S/b0 Thalassemia and those with a history of congenital neurological illness were excluded. DETERMINATION OF TCD VELOCITY: TCD was performed in a tertiary care center in Nagpur using either an imaging machine (Lasiq s8) in the department of radiology or a portable non-imaging TCD (Compumedics); for both a probe of frequency 2Mhz was used. Maximum values for TAMMV in the Middle (MCA) and Anterior (ACA) cerebral arteries were measured in all; for the non-imaging TCD values for posterior cerebral artery (PCA) and basilar artery were also obtained. The results of the first scan performed on these individuals were included in this study. Using values similar to the STOP trial, TAMMV of each of these vessels were categorized as follows: Normal &lt;= 170cm/s; Conditional - between 170 and 199 cm/s; Abnormal &gt;= 200 cm/s; Low &lt;50 cm/s and unobtainable. MEASUREMENT OF HAEMATOLOGICAL VALUES: Laboratory parameters such as Hemoglobin, white blood cell count (WBC), Mean corpuscular volume (MCV) and hemoglobin F (HbF) levels of the patients in the study were also included if the parameters were available on the day of TCD or within 90 days of TCD study. MEASUREMENT OF HEIGHT, WEIGHT AND BMI: The height and weight of each of the patients on the day of TCD or within a period of 60 days from the TCD were measured and the body mass index (BMI) was calculated. Results One hundred and twenty children and youth aged 1-26 (median 7) years, 67 male (56%), were recruited. Of the 120 patients, 106 (88.5%) belonged to the Scheduled Caste category, 3 (2.5%) to the Scheduled Tribe category and 11 (9.1%) to the Other Classes category. Three (2.5%) had had a clinical stroke and 8 (7%) had had seizures, one of whom also had a stroke. Twenty-seven (23%) children had TAMMV outside the normal range. Five had abnormal TAMMV in the MCA (n=4) and/or ACA (n=1), 8 had conditional TAMMV in the MCA (n=7) and/or ACA (n=1) while 14 patients had low (n=12) or unobtainable (n=2) TAMMV in the MCA. One child with stroke had low TAMMV and one had conditional TAMMV while the third had normal TAMMV. Of the 7 with isolated seizures, one had low TAMMV and one had conditional TAMMV while the remaining 5 were normal. BMI was 8.6-25.3 (median 14.1), height/weight was 3.4-10.3 (median 6.5), hemoglobin was 43-134 (median 81) g/L, oxygen saturation 87-100 (median 99)%, HbF was 1.9-60 (median 21) g/dL, MCV was 59.1-96.7 (median 83.2) fl, WBC was 2.3-35.9 (median 10.1)*109. Those with TAMMV outside the normal range were not different from those with normal TAMMV in terms of age, BMI, Height/weight, or recent hemoglobin, oxygen saturation, HbF, MCV, or WBC

Nocturnal oxygen saturation and painful sickle cell crises in children

The pathogenesis of acute painful crisis in children with sickle cell disease is poorly understood; suggested risk factors include sickle cell type, severity of anemia, fetal hemoglobin concentration, and hypoxemia from upper airway obstruction. In a cohort study of 95 patients the relationship between clinical, laboratory, and sleep study data and frequency of painful crisis was investigated. Both univariate and multiple regression modeling showed that low nocturnal oxygen saturation was highly significantly associated with a higher rate of painful crisis in childhood (P &lt; .0001). Screening and treatment for hypoxemia may reduce the frequency of this and other complications of the disease.</p

Expression of interleukin 3 and granulocyte-macrophage colony-stimulating factor receptor common chain βc, β_IT in normal haematopoiesis: lineage specificity and proliferation-independent induction

Interleukin 3 (IL-3), granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin 5 (IL-5) exert their biological activities through interaction with cell-surface receptors that consist of two subunits, a specific α subunit and a common β transducing subunit (βc). We have evaluated the expression of βc on purified haematopoietic progenitor cells (HPCs) induced to unilineage differentiation/maturation through the erythroid (E), granulocytic (G), megakaryocytic (Mk) or monocytic (Mo) lineage, HPCs displayed low βc expression, which increased during the initial stages of HPC differentiation along the E, G, Mo or Mk lineages. At later stages of differentiation, βc chain expression increased in both G and Mo lineages, was expressed at low levels in the Mk lineage and declined to undetectable levels in the E lineage. Analysis of the full-length βc and intracytoplasmically truncated βc (βIT) mRNAs showed that the former was predominant in the G and Mo lineages, whereas the latter was prevalent in the E and Mk lineages. The βc induction takes place even in the absence of cell cycling. Thus, incubation of HPCs with graded amounts of IL-3 showed that the initial induction of βc expression is unrelated to cell proliferation. Furthermore, circulating monocytes and granulocytes exhibit a low level of βc expression that is greatly stimulated following incubation with either IL-3 or GM-CSF.</p

Age is a predictor of a small decrease in lung function in children with sickle cell anemia

The longitudinal pattern of lung function in children with sickle cell anemia (SCA) has shown a decrease in FEV1 % predicted, a risk factor for death in adults with SCA, but predictors for this decline are poorly characterized. In a prospective longitudinal multi-center cohort of children with SCA, we tested the hypotheses that: (1) FEV1 % predicted declines over time; and (2) SCA-specific characteristics and therapy predict this decline. At three clinical centers, children with SCA (HbSS or HbSβ0 thalassemia), unselected for respiratory disease, were enrolled in the Sleep and Asthma Cohort (SAC) study. Study-certified pulmonary function technicians performed spirometry and lung volumes. Each assessment was reviewed centrally. Predicted values were determined for TLC, FEV1 , FVC, and FEV1 /FVC ratio. A total of 197 participants, mean age 11.0 years at first testing (range 4-19.3 years), had a minimum of three spirometry measurements, over an average of 4.4 years (range 1.1-6.5 years) from baseline to endpoint. In a multivariable model, FEV1 % predicted declines by 0.3% for every additional year of age (95% CI -0.56 to -0.05, P = .020). Sex, asthma history, hemoglobin, reticulocyte count, white blood cell count, incidence rate of severe acute pain and acute chest syndrome episodes, and hydroxyurea therapy were not associated with a decline in FEV1 % predicted. In a large, rigorously evaluated, prospective cohort of an unselected group of children with SCA, FEV1 % predicted declines minimally over an average of 4 years, and none of the examined disease features predict the decline.</p

Cervical carotid artery disease in sickle cell anemia: Clinical and radiological features

Cervical internal carotid artery (cICA) occlusion is a recognized cause of acute ischemic stroke (AIS) in sickle cell disease (SCD), but the associated clinical and radiologic features are not well described. We reviewed data on cervical magnetic resonance angiography (cMRA) performed prospectively in 67 patients (55 children) for indications including transcranial Doppler (TCD) abnormalities, AIS, or previous AIS. cICA lesions were seen in 10 (15%) patients, including 4 of 7 patients presenting with AIS, and appear to have been missed on first presentation in 4 of 10 patients with previous AIS. Radiologic features in 7 patients were consistent with dissection. In 2 patients, there was strong clinical and radiologic evidence for thromboembolic AIS, and this was also considered possible in 4 other patients. Three of the 4 AIS patients were anticoagulated acutely, and the nontreated patient had recurrent, probably thromboembolic, AIS. TCD findings were variable, but in 4 patients there were high velocities in the cerebral vessels contralateral to the cICA stenosis. We suggest that all patients with AIS should have cMRA during acute evaluation to identify cICA occlusions that may require anticoagulation. Routine screening of children with SCD should also include evaluation of neck vessels by carotid Doppler followed by cMRA if a cervical vascular lesion is suspected.</p