Lesion burden and cognitive morbidity in children with sickle cell disease

The effect of increased tissue injury in children with sickle cell disease and silent cerebral infarcts is not known. We determined the relationship between the extent of injury and IQ scores in children with silent cerebral infarcts. Participants were 27 children with sickle cell disease who had received magnetic resonance imaging (MRI). Children were divided into three groups: group 1, small lesion volume (n = 9, < 6.8 cm3); group 2, large lesion volume (n = 9; > 6.8 cm3); and group 3, no cerebral infarcts (n = 9). The Wechsler Full-Scale IQ was significantly lower for group 2 (mean = 76.1) when compared with group 1 (mean = 87.7) or group 3 (mean = 89.9). In children with silent cerebral infarcts, large tissue loss is associated with lower Wechsler Full-Scale IQ and small tissue loss is associated with no apparent change in IQ compared with children with no cerebral infarcts. The progressive accumulation of silent infarcts may lead to poorer intellectual functioning.     

A pilot randomized education rehabilitation trial is feasible in sickle cell and strokes

A randomized trial was completed to assess the feasibility of a 2-year education rehabilitation program for students with sickle cell disease and memory deficits. Eleven students were assigned to tutoring with or without memory training for 2 years. Eighty-two percent completed the program. Evidence of improvement in memory and academic achievement existed. Educational rehabilitation is a feasible strategy, but further investigation is needed to assess the benefit in a multi center trial.     

Cognitive deficits in children with sickle cell disease

We tested a hypothesis that children with sickle cell disease who are completely normal by magnetic resonance imaging can still be cognitively impaired, as predicted by a model of diffuse brain injury. Fifty-four patients with hemoglobin SS (average age 10.9 years +/- 2.9 years SD) were examined with the Wechsler Intelligence Scale for Children-III (WISC-III) and were randomly matched by age, race, and gender with healthy children from the Wechsler normative database. Patients were also imaged at 1.5 Tesla with standard imaging sequences. Among 30 patients who were normal by magnetic resonance imaging, there were substantial deficits in Wechsler Full-Scale IQ, Verbal IQ, and Performance IQ (all P < .01) compared with African-American controls. The patient Wechsler Full-Scale IQ was 12.9 points lower than that of controls and decreased as a function of age (probability = .014). The findings suggest that there is diffuse brain injury in patients and that patient deficits increase with age.     

Anxiety and depression in children and adolescents with sickle cell disease

A growing body of evidence suggests that depressive disorders and anxiety disorders are much more prevalent among medically ill children and adolescents when compared with the general population, and that the presence of comorbidity may adversely affect medical outcomes and quality of life. Whereas the prevalence and impact of anxiety and depressive disorders have been described in chronic conditions such as asthma, diabetes, and epilepsy, much less is known about sickle cell disease (SCD), a disorder that affects more than 70,000 Americans, primarily those of African and Mediterranean descent. A hallmark of this disorder is recurrent, acute, and chronic pain that often requires emergency management and hospitalization. Medical advances in the treatment of this illness have transformed SCD from a condition associated with very early morbidity and mortality into a chronic condition of adulthood. This article reviews the evidence describing our knowledge of anxiety and depression in children and adolescents with SCD, its clinical impact, and effectiveness of interventions.     

Poor school and cognitive functioning with silent cerebral infarcts and sickle cell disease

The authors evaluated education attainment and neuropsychological deficits in children with sickle cell disease (SCD) and silent cerebral infarcts. Children with silent infarcts had twice the rate of school difficulties as children without infarcts. Eighty percent of silent infarct cases had clinically significant cognitive deficits, whereas 35% had deficits in academic skills. Children with silent cerebral infarcts show high rates of poor educational attainment, cognitive deficits, and frontal lobe injury. Poor school performance in SCD is one indicator of silent infarcts.     

Autonomic reactivity and clinical severity in children with sickle cell disease

Abstract Individual differences in autonomic nervous system reactivity have been studied in relation to physical and mental health outcomes, but rarely among children with chronic disease. The purpose of this study was to examine the associations among autonomic reactivity, clinical severity, family stressors, and mental health symptoms in children with homozygous sickle cell disease. Nineteen children with homozygous sickle cell disease participated in a cross-sectional study involving parent-completed measures, medical record reviews and laboratory-based measures of autonomic nervous system responses to social, cognitive, physical and emotional challenges. Autonomic reactivity was significantly associated with both clinical severity and externalizing behavior symptoms. Children with greater parasympathetic withdrawal during challenges compared to rest had significantly more severe disease (r=–0.45, p<0.05); greater sympathetic activation during challenges compared to rest was associated with more externalizing behavior symptoms (r=0.44, p<0.05). Children experiencing major family stressors had internalizing behavior symptoms but no difference in autonomic reactivity or clinical severity compared to children experiencing fewer family stressors. Individual differences in autonomic reactivity may offer a new, biologically plausible account for observed variation in painful episodes, other physical complications and behavioral symptoms among children with sickle cell disease.     

Electroencephalography hyperventilation and stroke in children with sickle cell disease.

A recent study and report in which hyperventilation was used during electroencephalography (EEG) in 6 children with sickle cell disease (SCD) and seizures, without serious complication, prompted a cautionary response regarding the potential risks attending the practice of EEG hyperventilation in SCD patients. Earlier reports of neurological impairment and stroke precipitated by the routine use of hyperventilation in children with SCD are reviewed, the mechanism and management of vascular infarction following hyperventilation are discussed, and readers are reminded of the AEEGS guidelines and contraindications to routine hyperventilation, which include SCD and trait and cerebrovascular disorders. The frequent nonobservance of these guideline recommendations among neurologists, and the need to more widely inform practitioners of the risks of hyperventilation in SCD are discussed.     

Brain injury in children with sickle cell disease: prevalence and etiology

Our objective was to evaluate the relationship between brain injury by magnetic resonance imaging (MRI) and vasculopathy by magnetic resonance angiography (MRA) in children with hemoglobin SS, the most serious form of sickle cell disease. We reviewed imaging for all 146 SS patients imaged at St. Jude Children's Research Hospital since 1993. Standard MRI criteria were used to identify cystic infarction, leukoencephalopathy, encephalomalacia, or atrophy. Standard MRA criteria were used to identify arterial tortuousity (limited vasculopathy), and stenosis or occlusion (extensive vasculopathy). At an average age of 10 years, the estimated prevalence of infarction, ischemic damage, or atrophy in SS patients was 46%, and of vasculopathy was 64%. Only 28% of patients were normal by both modalities, and patients abnormal by MRA often were abnormal by MRI (p < 0.00001). Patients with cystic infarction had limited vasculopathy, whereas patients with encephalomalacia had stenosis or occlusion (p < 0.0001). Large arteries were affected in 31% of brain injury patients, whereas small arteries are inferred to be abnormal in up to 69% of patients with brain injury. The degree of vasculopathy is closely related to the degree of brain injury, implying that vasculopathy is prodromal to most forms of brain injury in hemoglobin SS.     

Cognitive deficits associated with frontal-lobe infarction in children with sickle cell disease

This study examined the cognitive manifestations of frontal-lobe infarction in a population of children with sickle cell disease (SCD). Forty-one patients with SCD underwent MRI. Five patients with stroke symptoms had large infarcts encroaching on the tissue of the frontal lobes. Four patients without symptoms had smaller frontal-lobe infarcts. The patients with stroke were significantly impaired on measures of intelligence, memory, and frontal-lobe function (Wisconsin Card Sorting Test, WCST) compared with both the patients with normal MRI scans ( N = 30) and a group of sibling controls ( N = 15), who did not differ from each other. Patients with covert infarction obtained scores on the intelligence tests and the WCST that fell in between those of the stroke patients and the other two groups. This trend toward impairment suggests that patients with covert infarction are at similar risk for cognitive deficits to those with stroke.     

Long-term stroke risk in children with sickle cell disease screened with transcranial doppler

Stroke is an important complication of sickle cell disease. Stroke prediction is clinically important because it offers the possibility of primary prevention. In 1992, transcranial Doppler (TCD) evidence of elevated intracranial internal carotid or middle cerebral artery velocity was demonstrated to be associated strongly with an increased risk of ischemic stroke. This study extends the original study and includes 125 more children, longer follow-up, and intracranial hemorrhage in the stroke-risk model. Elevated time averaged mean maximum blood flow velocity, especially when velocity is 200 cm/sec or greater by TCD, was associated strongly with stroke risk. The cases not predicted by TCD point to the need for more information on the optimal timing of TCD surveillance for stroke risk.     

Multicenter prospective study of children with sickle cell disease: radiographic and psychometric correlation

After obtaining familial informed consent, between January 1996 and July 1997, 173 children (5 to 15 years old) with sickle cell disease were enrolled in a prospective multicenter study using blood screening, transcranial Doppler ultrasonography (n = 143), cerebral magnetic resonance imaging (n = 144), and neuropsychologic performance evaluation (n = 156) (Wechsler Intelligence tests WISC-III, WIPPSI-R), which were also performed in 76 sibling controls (5 to 15 years old). Among the 173 patients with sickle cell disease (155 homozygous for hemoglobin SS, 8 sickle cell beta0 thalassemia, 3 sickle cell beta+ thalassemia, 7 sickle cell hemoglobin C disease SC), 12 (6.9%) had a history of overt stroke, and the incidence of abnormal transcranial Doppler ultrasonography (defined as mean middle cerebral artery velocity > 200 cm/sec or absent) was 8.4% in the overall study population and 9.6% in patients with homozygous sickle cell anemia The silent stroke rate was 15%. Significantly impaired cognitive functioning was observed in sickle cell disease patients with a history of stroke (Performance IQ and Full Scale IQ), but also in patients with silent strokes (Similarities, Vocabulary, and Verbal Comprehension). However, infarcts on magnetic resonance imaging were not the only factors of cognitive deficit: Verbal IQ, Performance IQ, and Full Scale IQ were strongly impaired in patients with severe chronic anemia (hematocrit < or = 20%) and in those with thrombocytosis (platelets > 500 x 10(9)/L). Multivariate logistic regression analysis showed that abnormal magnetic resonance imaging (odds ratio [OR] = 2.76) (P = .047), hematocrit < or =20% (OR = 5.85) (P = .005), and platelets > 500 x 10(9)/L (OR = 3.99) (P = .004) were independent factors of cognitive deficiency (Full Scale IQ < 75) in sickle cell disease patients. The unfavorable effect of low hematocrit has already been suggested, but this is the first report concerning an effect of thrombocytosis and showing that silent stroke alone is not a factor of cognitive deficit when not associated with low hematocrit or thrombocytosis. The effect of hydroxyurea, which is known to increase hematocrit and decrease platelet count, on cognitive functioning of sickle cell patients should be evaluated prospectively.     

Stroke and sickle cell disease

Sickle cell disease has evolved from an illness of abnormal red blood cells to a multisystemic molecular disease. It attacks at an early age, with stroke being one of the most feared complications. Sickle hemoglobinopathy is inherited in a Mendelian fashion, with a 25% chance of inheriting the disease if both parents are heterozygous. The polymerization of red blood cells in harsher environments, such as hypoxia, acidosis, or dehydration, is the basic change that can promote subsequent systemic diseased states. Stroke in sickle cell patients is fairly common, with an incidence ranging between 4% and 8%. The most common stroke is ischemic, but hemorrhagic stroke can be seen in up to 2% of patients, particularly in early adulthood. Several risk factors increase the likelihood for stroke. Evaluating the middle cerebral and internal carotid arteries with transcranial Doppler has emerged as a very accessible marker of stroke risk (using time-averaged mean velocities above 200 cm/sec). Stroke presentation follows usual clinical patterns, but it can be confused in the presence of other illnesses such as pain crises or pain treatments. Clinical diagnosis relies on many of the usual modalities used in stroke evaluation, with particular importance for those that allow full-vessel visualization (magnetic resonance angiography, angiography). The pathophysiology of endothelial proliferation manifests itself in both small and large vessels. Other hematologic abnormalities, perhaps with hypercoagulable states, might compound the risk of stroke. Intracranial hemorrhage etiology may occur, especially in older patients. The landmark STOP trial has established periodic transfusion as a clear primary prevention method to reduce the incidence of stroke in patients at risk. There are still many unanswered questions, but this first century of sickle cell disease knowledge has brought hope for a long-term cure of this life-threatening disease.     

Current concepts in the management of stroke in children with sickle cell disease

Stroke is the most significant complication of sickle cell disease (SCD) in children with the potential for major morbidity and mortality. The recent two decades have witnessed tremendous advancements in understanding the pathophysiology of stroke, risk stratification of children and the role of timely preventative interventions. The aetiopathogenesis, types of stroke and specific risk factors are reviewed here with special emphasis on the role of transcranial Doppler ultrasonogram in the early identification of at-risk children. Published studies on primary and secondary prevention of stroke in children with SCD are analysed with respect to the levels of evidence, in favour of preventative and therapeutic strategies. The roles of the neurologist and the neurosurgeon are highlighted.     

Markers of endothelial dysfunction differ between subphenotypes in children with sickle cell disease

In adult patients with sickle cell disease two distinct subphenotypes have previously been defined: patients with the viscosity-vaso-occlusion subphenotype (VVO) suffer mainly from vaso-occlusive pain crises and have a relatively high hemoglobin concentration. Patients classified as the hemolysis-endothelial dysfunction subphenotype (HED) suffer from stroke and pulmonary hypertension and have an elevated concentration of lactate dehydrogenase. However, this classification is not possible in children due to low rates of complications. We used laboratory markers to classify children into the two subphenotypes, and measured vWF and vWF propeptide as markers of endothelial dysfunction. We included 106 children with sickle cell disease (mean age 8.7 years), 74 (70%) with HbSS/HbSβ° genotype and 32 (30%) with HbSC/HbSβ⁺ genotype. vWF and vWF propeptide were significantly elevated in patients with sickle cell disease; this was more pronounced in patients with the HbSS/HbSβ° genotype. Patients with the HED subphenotype had higher levels of vWF propeptide, and a trend towards higher levels of vWF compared to those with the VVO subphenotype. We demonstrated that even young children in a stable clinical condition show signs of persistent endothelial dysfunction. A prospective study should demonstrate whether elevated levels of vWF and its propeptide are associated with an increased risk of complications specific for the HED subphenotype.     

Decreased corpus callosum size in sickle cell disease: relationship with cerebral infarcts and cognitive functioning.

We assessed midsagittal corpus callosum size in sickle cell disease (SCD) and its relationship to lesion volume, lesion location, and cognitive functioning. Twenty-eight children with SCD and 16 demographic controls completed magnetic resonance imaging (MRI) and neuropsychological testing. Corpus callosum (CC) size was smaller for children with silent infarcts (n = 8) or overt stroke (n = 8) than for those without visible infarcts (n = 12) or control participants. Lesion volume was a robust predictor of IQ and other cognitive scores; total CC size did not typically add explanatory power for these measures. The size of the rostral body of the CC, however, independently predicted measures of distractibility, speeded production, and working memory. Posterior CC size was also decreased among many of the children with SCD, even in the absence of visible infarcts in this region. Brain morphology appears to provide additional information about SCD-related effects on the brain above and beyond visible infarcts.