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C 2001) Neuropsychology Review, Vol. 11, No. 4, December 2001 (°
Neuropsychological Aspects of Pediatric Sickle Cell Disease Mary C. Kral,1,4 Ronald T. Brown,2 and George W. Hynd3
Sickle cell disease (SCD), a class of genetic disorders characterized by abnormal, sickled red blood cells, is a chronic illness that results in progressive cerebrovascular disease. Neurocognitive sequelae of clinically apparent cerebrovascular accidents in children with SCD are characterized by pervasive impairments, including decrements in general intellectual functioning, language and verbal abilities, visual-motor and visual-spatial processing, memory, academic achievement, and processing of subtle prosodic information. In contrast, subtle neurocognitive deficits in the areas of attention and concentration, executive function, and visual-motor speed and coordination appear to be associated with silent infarcts that are not necessarily detected on physical examination. Investigation of the disease course and associated neurocognitive sequelae suggest a disease-specific model of neuropsychological impairment. Recommendations are made for clinical and research efforts in the field of pediatric neuropsychology. KEY WORDS: sickle cell disease; neuropsychology; pediatric; cerebrovascular.
Sickle cell disease (SCD) provides the neuropsychologist various opportunities to examine brain–behavior relationships in a chronically ill population. As will become evident in our review, a disease-specific model offers the most appropriate means of conceptualizing the neuropsychological sequelae of this devastating illness. It is our contention that the cerebrovasculopathy and associated cognitive deficits described in this paper are unique to children with SCD. Careful neuropsychological assessment provides a means to identify possible markers of central nervous system (CNS) pathology and informs early prevention and intervention for those children at risk. SCD is a group of autosomal recessive disorders, characterized by the production of abnormal hemoglobin, HbS. This group includes sickle cell anemia, sickle betathalassemia, and other hemoglobinopathies involving HbS
(Serjeant, 1992). In the United States, an estimated 1 in 400 African American newborns are diagnosed with SCD annually, and approximately 1 in 12 African Americans carry the sickle cell trait (Charache et al., 1989; Consensus Conference, 1987). SCD is prevalent in African populations, but the disorder also is common in individuals from the Mediterranean Sea area, including southern Italy, northern Greece, southern Turkey, the Eastern Province of Saudi Arabia, and India, at incidence rates equal to or greater than those of African Americans (Nagel, 1994). Among individuals with SCD, the two main causes of mortality are bacterial infection during infancy and early childhood and stroke later in life (Davis et al., 1997). Early diagnosis and prophylactic administration of penicillin prior to age 3 have dramatically decreased the risk of severe complications associated with bacterial infections. Subsequent to these important discoveries in the 1960s, the life expectancy of individuals with SCD has greatly improved (Gaston et al., 1982). In spite of these advances, individuals with SCD continue to experience significantly reduced life expectancy. One recent investigation of sickle cell anemia (HbSS) documented a median age of death at 42 years for males and 48 years for females, ages that are 25–30 years less than expected for the general African American population (Platt et al., 1994).
1 Department
of Pediatrics, Medical University of South Carolina, Charleston, South Carolina. 2 College of Health Professions, Medical University of South Carolina, Charleston, South Carolina. 3 Research Development and Outreach, The University of Georgia, Athens, Georgia. 4 To whom correspondence should be addressed at the Division of Genetics and Developmental Pediatrics, Medical University of South Carolina, 135 Rutledge Avenue, P.O. Box 250561, Charleston, South Carolina 29425; e-mail:
[email protected].
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180 Among children with SCD, neurological complications constitute a significant source of morbidity and mortality. Stroke remains a leading killer of children with SCD. In the Cooperative Study of Sickle Cell Disease (CSSCD; Ohene-Frempong et al., 1998), a longitudinal investigation examining a cohort of over 4,000 children, 6% had cerebrovascular accidents (CVAs). CVA is defined as an acute neurologic event secondary to occlusion of an artery or hemorrhage, with resultant neurological symptoms and signs (e.g., motor weakness or language impairment). Moreover, as many as 17% of the children in the CSSCD cohort evidenced ischemic changes on brain imaging with no apparent neurological symptoms or signs (Kinney et al., 1999). These events have been classified as “silent stroke.” Given the increased potential for direct neurocognitive effects, SCD poses considerable risk for children and adolescents in the areas of academic and social function. Clearly, SCD is a national public health concern and an emerging area of clinical and research interest to the pediatric neuropsychologist. PATHOPHYSIOLOGY AND CLINICAL FEATURES SCD is an autosomal recessive disorder that requires transmission of the HbS gene from both parents to produce HbSS. Sickle cell disorders are classified according to genotype, which is determined by two β-globin genes located on chromosome 11 and four α-globin genes located on chromosome 16. The three predominant forms of sickle cell disorders include sickle cell anemia, sickle beta-thalassemia, and sickle cell hemoglobin C. Sickle cell anemia is the homozygous expression of the sickle β-globin gene (HbSS),characterized by lower hemoglobin levels, an earlier onset, and a higher frequency and severity of symptomatology, compared to the other sickle cell disorders. Sickle beta-thalassemia constitutes a compound heterozygous condition, consisting of one βS gene and one β-thalassemia gene in which no β-globin is produced (HbSβ ◦ ) or some normal β-globin is produced (HbSβ+). The third form of sickle cell disorder, sickle cell hemoglobin C, also is a compound heterozygous condition (HbSC) in which two abnormal β-globin genes are expressed (βS and βC), producing two abnormal hemoglobins, HbS and HbC (Pavlakis et al., 1989; Serjeant, 1992). Sickle cell trait is a heterozygous condition (HbAS) in which one normal β-globin gene (βA) and one abnormal β-globin gene (βS) are inherited. Reportedly, no significant impairment in physical growth, cognitive development (Kramer et al., 1978), or neurological status (Partington et al., 1994) is experienced by individuals with sickle cell trait when no other hemoglobinopathy is present.
Kral, Brown, and Hynd The essential function of hemoglobin is the transport of oxygen to organ systems. When oxygen is released, HbS molecules form long, rigid tubules. The red blood cell membranes containing HbS become rigid and assume a sickle or crescent shape, as opposed to the smooth, doughnut shape of normal red blood cells (Schechter and Noguchi, 1994; Wood, 1978). Their ability to flow through fine capillaries and arterioles is compromised. Sickled red blood cells also stick to one another and become tangled, “sludging” in the microvasculature and leading to vasoocclusion, or deprivation of an adequate blood supply to tissues throughout the body (Serjeant, 1992). The resultant ischemia is experienced as acute painful episodes, sometimes referred to as a “sickle cell crisis.” Although these hypoxic and ischemic events may occur systemwide, the organs at greatest risk are those characterized by slow blood flow and low oxygen tension, which include the major organ systems of the body. Other vulnerable organs are those with a limited arterial blood supply, such as the retina and the head of the femur. Of these clinical complications, sepsis and CVA are the two most common causes of morbidity and mortality (Embury et al., 1994; Partington et al., 1994; Pavlakis et al., 1989; Serjeant, 1992). NEUROLOGICAL COMPLICATIONS Among the most debilitating effects of SCD are neurological complications, which occur in as many as one third of these individuals. As early as 1940, the neurological complications of SCD were well documented, including cerebral microinfarcts and major vessel occlusion (Hughes et al., 1940). Since that time, completed strokes (CVA) in sickle cell patients have traditionally been classified into two types: thrombotic or infarctive strokes, which are blood vessel obstructions within the brain, and hemorrhagic strokes, which are bleeds within the brain as a result of vessel wall weakening (Hariman et al., 1991). Infarctive strokes are the second leading cause of death among children, and hemorrhagic strokes occur more frequently among adults (Ohene-Frempong, 1991). The frequency of CVA is approximately 7% in individuals with HbSS disease, with a typical age of onset in the first decade of life (Balkaran et al., 1992; Earley et al., 1998; Ohene-Frempong et al., 1998). According to these investigations, the risk of stroke is highest among individuals with the HbSS genotype, although stroke also has been reported for the HbSC and thalassemia genotypes (OheneFrempong, 1991; Powars et al., 1978). In contrast to an estimated incidence of 0.0025% in the general pediatric population, these findings purport a relative risk of stroke in children with HbSS that is 250–400 times that of the general childhood population (Ohene-Frempong, 1991).
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Neuropsychological Aspects of Pediatric Sickle Cell Disease Left untreated, an estimated 47–93% of patients with SCD experience recurrent stroke, usually 12–24 months following the initial CVA (Balkaran et al., 1992; Powars et al., 1978). Chronic transfusion therapy, aimed at reducing the proportion of sickled red blood cells in circulation and increasing oxygen storage, has become the standard of care for prevention of recurrent stroke (Charache et al., 1989). However, the optimal intensity and duration of this therapy remains unclear (Pegelow et al., 1995). Moreover, although transfusion therapy effectively reduces the recurrence of stroke, it does little to remedy the morbidity associated with the first neurologic event (Ohene-Frempong, 1991). In summary, both silent and overt strokes in children with SCD are most commonly ischemic/infarctive in nature, and typically occur during the first decade of life. The reason this age group is particularly prone to these neurologic events is unknown, although cerebral blood flow is relatively greater at this age, possibly rendering the brain more vulnerable to variations in flow (Huttenlocher et al., 1984). Investigations using angiography, histological exam, neuroimaging techniques, and radiographic methods provide further insight into the pathologic process of cerebrovascular disease in children with SCD. Because these imaging and radiographic techniques have particular neuropsychological relevance for children with SCD, from a clinical and theoretical standpoint, these studies are briefly reviewed.
Cerebral Angiography Studies Prior to a seminal investigation by Stockman et al. (1972), cerebral infarction was conceptualized as obstruction of the microvasculature, such as capillaries, arterioles, and venules, by sickled cells. Stockman and associates highlighted the insidious process of chronic injury to the endothelial lining of large vessels by sickled red blood cells, with increasing areas of cellular proliferation in the distal internal carotid artery (ICA), proximal middle cerebral artery (MCA), and proximal anterior cerebral artery (ACA). That is, progressive injury to the vessel wall, particularly the ICA, MCA, and ACA, results in scarring and narrowing of the vessel lumen, which impedes perfusion in the distal distribution of these arteries. Several subsequent angiographic and neuropathologic investigations substantiated the progressive nature of large-vessel disease in SCD (Merkel et al., 1978; Rothman et al., 1986; Russell et al., 1976). Lending further support to these findings, angiography following long-term transfusion therapy revealed improvement of arterial abnormalities (Russell et al., 1976).
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Angiographic and histological investigations suggest that the anterior cerebral circulation supplied by the ACA and MCA is the most common site of cerebrovascular disease. In a review of the angiographic data, Pavlakis et al. (1989) reported that most individuals (86%) in these studies demonstrate some degree of large-vessel disease. Even though occlusion of microvasculature is often associated with cerebral infarction in SCD, the disease process apparently originates and is further exacerbated by largevessel pathology (see Fig. 1). These findings are supported by studies with magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA) of the brain.
Neuroimaging Studies MRI abnormalities (i.e., typically signal intensities) are consistent with the infarct locations described in the neuropathologic and angiographic studies of Merkel et al. (1978), Rothman et al. (1986), and Stockman et al. (1972). Investigations using MRI demonstrate the frequent occurrence of high-signal subcortical lesions associated with either large- or small-vessel disease (Gammal et al., 1986) or lesions associated with the vascular distribution of the MCA, including borderzone or watershed regions (Adams et al., 1988b; Pavlakis et al., 1988) and the deep white matter (Zimmerman et al., 1987). The watershed regions are the brain regions lying between two vascular territories. As such, these brain regions constitute predilection areas for hypoxia and ischemia under conditions of decreased cerebral perfusion. In a more recent series of neuroimaging studies (Glauser et al., 1995; Kugler et al., 1993; Steen et al., 1998; Wang et al., 1998), the progressive nature of cerebrovascular disease in SCD was examined in children with evidence of silent stroke. In an investigation of individuals aged 11– 28 years with HbSS disease, followed for an average period of 3.7 years, individuals with abnormal MRI at study entry showed subcortical white matter lesions, consistent with occlusion of small intracerebral vessels (Kugler et al., 1993). During the course of the study period, MRI lesions were eventually observed among this group in the deep white matter of the frontal lobes and regions adjacent to the lateral ventricles. Consequently, when children with SCD are asymptomatic, evidence of chronic hypoxia in the form of subclinical infarcts may herald clinically observable CVA. Chronic hypoxia results in ischemia which in turn produces clinical signs that are characteristic of a stroke. Similar investigations suggest that over 10% of asymptomatic infants with HbSS disease evidence abnormalities on MRI (Wang et al., 1998). Later in development, the percentage of infarction and ischemia or atrophy on
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Fig. 1. The progressive nature of cerebrovascular disease in sickle cell anemia (HbSS).
MRI was as high as 22–57% (Glauser et al., 1995; Moser et al., 1996). Moreover, 29–50% of these children have no clinical history of stroke. Infarction and ischemia seem to follow a pattern of localization according to clinical symptomatology. That is, lesions localized primarily in the deep white matter of the frontal, parietal, and temporal lobes, corresponding with a borderzone distribution, were characteristic of silent infarct. In contrast, children with a history of CVA more commonly show extensive lesions, which usually involve both cortical and deep white matter tissue, corresponding with the distribution of a major artery. According to neuroimaging investigation, largevessel disease is more likely associated with clinically identifiable CVA, as opposed to small lesions confined to the borderzones, which seem to be characteristic of subclinical strokes. Consistent with these investigations that substantiate the presence of neurological damage in the absence of clinically apparent stroke, lesions may occur even before they are visible with conventional MRI (cMRI). Steen et al.
(1998) used qualitative MRI (qMRI), an imaging technique that detects abnormality or subtle structural changes at the cellular level in the brain that often remain undetected by cMRI techniques. They demonstrated that asymptomatic children with SCD, and otherwise normal MRI, evidenced neurological damage on qMRI, defined by an approximate 4% reduction of T1 cortical gray matter and caudate. Although the mechanisms underlying these findings are unknown, Steen and colleagues postulate that the chronic hypoxia associated with progressive cerebrovascular disease in SCD may lead to small volumes of inadequately perfused tissue in the brain. According to the neuroimaging data, SCD is often associated with a broad spectrum of neurological abnormalities, which are not limited to clinically apparent stroke. An estimated 11–17% of children with HbSS disease evidence silent cerebral infarcts when MRI techniques are employed (Hindmarsh et al., 1987; Moser et al., 1996; Pavlakis et al., 1988). Evidence from neuroimaging studies complements findings reported in angiographic and
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Neuropsychological Aspects of Pediatric Sickle Cell Disease neuropathologic investigations,suggesting that neurologic complications stem from a progressive cerebrovasculopathy, which may be similar in nature to the cerebrovascular disease observed in elderly adults (Steen et al., 1998). The recent application of radiographic techniques offers a promising new method to further characterize the progressive nature of cerebrovascular disease in SCD, along with early identification of those children at greatest risk for neurologic complications.
Ultrasonography Studies With the advent of transcranial Doppler (TCD) ultrasonography, reliable detection of vasculopathy, previously seen only on angiography (e.g., Stockman et al., 1972) or neuropathological examination (e.g., Rothman et al., 1986), may permit identification of asymptomatic children with SCD at highest risk for cerebral infarction (Adams et al., 1992). Likened to a stethoscope that allows clinicians to “listen” to the blood flow changes within the major intracranial vessels (McCartney et al., 1997), TCD ultrasonography is a valid procedure for the detection of cerebrovascular stenosis on the basis of elevated blood flow velocity in the narrowed artery. Children with SCD typically show a 40–50% higher mean velocity (V mean) of flow than do children without anemia (Adams et al., 1988c). Detection of cerebrovasculopathy via TCD has been confirmed with MRI (Adams et al., 1988a) and angiography (Adams et al., 1992) in children with SCD and a history of completed stroke. In a series of investigations, Adams et al. (1990, 1992, 1997) offer evidence for the predictive validity of TCD among children with SCD at risk for stroke. In the first report of TCD detection of vessel stenosis prior to overt stroke in SCD, the researchers (Adams et al., 1990) compared TCD data for a cohort of 115 children with SCD and no history of stroke to 6 children with SCD with known vessel lesions. Velocities at or above the established cutoff of 190 cm/s (representing the 98th percentile for MCA V mean) were attributable to severe stenosis, as distinguished from arterial velocities associated with low hematocrit or young age. In a similar study, Adams et al. (1992) screened a cohort of 190 asymptomatic children with SCD and demonstrated at clinical follow-up that high velocity of cerebral blood flow (i.e., >170 cm/s) was strongly predictive of subsequent stroke. In a follow-up investigation, Adams et al. (1997) monitored the original cohort over a 5-year period. The probability of remaining stroke-free for a 40-month period with a maximum velocity in the range of 170–190 cm/s was 93%. By comparison, if the maximum velocity reached or exceeded 200 cm/s, stroke-free
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survival for this 40-month period declined to 69%. This important series of investigations introduced a possible mechanism for screening children at risk for CVA. Several investigators have confirmed the findings of Adams and colleagues (Kogutt et al., 1994; Seibert et al., 1993, 1998; Siegel et al., 1995; Verlac et al., 1995). The researchers found that screening with TCD effectively detects cerebrovascular disease but does not have as high a specificity as MRI or MRA. However, TCD may depict abnormal flow secondary to small vessel disease that is not detected by MRI or MRA (Siebert et al., 1993). For example, when correlated with angiography, Adams et al. (1992) found that severe stenosis in children with SCD is associated with flow velocities that are 2–3 times normal. Another advantage of TCD is that it is noninvasive and can usually be performed with little discomfort to the child. Taken together with neuroimaging procedures, TCD holds much promise for further characterization of the progressive nature of cerebrovascular disease in pediatric SCD.
NEUROPSYCHOLOGICAL FINDINGS The application of new technologies, including MRI and TCD, makes possible the comprehensive investigation of neurologic complications associated with pediatric SCD. In addition, these new technologies may serve as validation criteria for the assessment of neuropsychological deficits in children and adolescents with SCD. As will become apparent in the literature review to follow, early investigations of the neurocognitive sequelae of SCD were based on SCD genotype or completed stroke, neither of which affords measurement of the progressive nature of the disease process. According to the neurological literature, cerebrovascular disease in children with SCD likely constitutes a continuum of brain impairment, well before clinical signs and symptoms of cerebral infarction become evident via overt assessment. These methodological issues, along with implications for further research, will be discussed in the following review; these studies were obtained from Psych-Lit and Medline databases (1960– 2001). We have chosen to organize our review of literature according to presentation of symptoms, with data pertaining to overt CVAs presented first (e.g., stroke vs. no stroke) followed by investigations of more subtle impairment (e.g., silent infarcts). The interested reader will find a summary of the literature concerned with the neuropsychological sequelae of pediatric SCD in Table I. One of the first investigations of cognitive impairment in children with SCD was conducted in 1963 by Chodorkoff and Whitten, who reported no differences in intellectual function among children with SCD who had
N = 52 children with SCD ages 6–16 grouped according to CVA and HbSS (n = 21), normal MRI and HbSS (n = 20), and normal MRI and HbSC controls (n = 11); CVA group classified according to lesion location N = 63 children with SCD ages 6–17 grouped by MRI definition: silent infarct (n = 11), CVA (n = 22), normal MRI (n = 30); CVA and silent infarct groups classified according to lesion location
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N = 88 children ages 3–17; children with SCD (n = 70) compared to healthy sibling controls (n = 18)
N = 10 children with HbSS and lateralized CVA; LCI children (n = 4) were compared to those with RCI (n = 6)
Cohen et al., 1994
No significant group differences on measures of behavior; increased ADHD in LCI group
Significant group differences on VIQ, with RCI group outperforming LCI group; LCI group showed global impairment on FSIQ, VIQ, and PIQ compared to focal deficits in nonverbal and construction (PIQ) for RCI group Compared to RCI group, LCI group showed global impairment on academic achievement and memory
Significant group differences in attention and impulsivity; children with SCD had fewer correct items on CPT Significant group differences in academic achievement; children with SCD performed more poorly on K-ABC Reading Decoding Age effect occurred on VMI and MMFT with older children performing more poorly than younger children Hb levels explained 10% of variance in FSIQ, 29% of variance in Bead Memory, and 12% of variance in K-ABC achievement composite
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Children without CNS had significantly higher Hb levels compared to children with silent infarct or CVA Significant group differences for attention and executive function; children without CNS made fewer omission errors on Cancellations of As with trend by CVA group for more commission errors Highest frequency of CNS localized in frontal lobes; children with frontal lobe lesions made significantly more omission and commission errors on Cancellations of A’s
Age and hematocrit significantly associated with neuropsychological function and therefore served as covariates in all analyses Children with history of CVA performed significantly more poorly on intelligence, academic achievement, and motor function Children with silent infarcts performed significantly more poorly compared to children with normal MRIs on vocabulary, arithmetic, and visual motor speed and coordination Children with HbSS and history of CVA made more errors when decoding facial and prosodic emotions Caregiver and child ratings of social or behavioral problems did not differ as function of MRI abnormality No group differences on any measures as function of lesion location
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Intelligence: WISC-III Academic achievement: WJ-R Broad Math and Broad Reading Attention and Executive Function: Cancellation of A’s Trial Making Test, A & B Language: BNT, RAN Visual-motor speed and coordination: Purdue Pegboard Behavioral adjustment: CBCL Adaptive behavior: Vineland Intelligence: K-ABC Expressive language: Expressive One Word Picture Vocabulary Test Receptive language: PPVT-R Visual motor: VMI, Bead Memory subtest of SB-IV Attention and impulsivity: CPT, Kagan MFFT Academic achievement: K-ABC Reading Decoding and Arithmetic, BASIS Reading Comprehension Intelligence: WISC-R Language: PPVT-R, BNT, Wepman Visual-spatial and construction: VMI, TVPS, K-ABC Gestalt Closure Behavioral adjustment: Conners Sensory: Finger Tap, Finger Tip Number Writing Memory: K-ABC Number Recall, Spatial Memory, Hand Movement Academic achievement: WRAT-R, GORT-R
Intelligence: WISC-R Academic Achievement: WJ-R Broad Math and Broad Reading Motor speed and coordination: Purdue Pegboard Behavioral adjustment: CBCL Intelligence: WISC-III Nonverbal emotional decoding: DANVA Social skills: SSRS Children’s Depression Inventory
N = 194 children with SCD ages 6–12 grouped according to normal MRI (n = 161), silent infarct (n = 24), and CVA (n = 9)
Armstrong et al., 1996
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Measures
Participants and methods
Reference
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Table I. Summary of Neuropsychological Findings in Pediatric Sickle Cell Disease
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N = 35 children ages 4–16; SCD and no CVA (n = 24) compared to healthy sibling controls (n = 11) N = 120 adolescents ages 15–18; HbSS (n = 60) compared to HbAA healthy peer controls (n = 60) N = 16 participants ages 11–29 with HbSS in MRI-defined groups: abnormal MIR (n = 10), normal MRI (n = 6)
Goonan et al., 1994
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Memory: Digit Span, Selective Reminding Test, WMS Visual Reproduction Attention: Target Cancellation Test Executive function: Trail Making Test, Odd Man Out, Ravens Progressive Matrices Motor speed: Purdue Pegboard Language: BNT, FAS, WISC-R Animal Naming, Similarities Visual-spatial: WISC-R Digit Symbol and Block Design, Rosen Drawing Test
(Continued )
Significant group-by-age interactions found on measures of sustained attention and inhibitory control; age as covariate contributed greatest significance to predicted variance (older children with SCD showed better sustained attention and less impulsivity) No group differences on parent ratings of behavior Mean VIA, PIQ, and FSIQ HbSS children were at least 5 standard score points lower than HbAA controls (statistically significant) IQ did not correlate with age or gender in either group; in HbSS children, Hb levels not related to intelligence performance No significant differences in any cognitive domains Participants with MRI abnormalities tended toward poorer performance across most measures compared to normal MRI group Most participants in both groups showed defective scores in one or more areas of cognitive function when compared to normative data and adjusted for age and education
No significant group differences for VIQ, PIQ, or FSIQ; both groups had scores on these measures of intelligence in average to low-average range Significant group differences on MFFT; controls outperforming HbSS group Children with SCD performed more poorly than controls on academic achievement Age effect occurred with older children in the HbSS group performing significantly less well on WRAT Reading, Digit, Span, VMI, and latency scores on the MFFT compared to controls
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N = 56 children ages 6–17; children with HbSS and no CVA (n = 28) were compared to healthy peer controls (n = 28) matched for race, age, sex, and SES
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Fowler et al., 1988
TOVA showed lowest number of misclassification errors when sensitivity and specificity ratings were compared for all measures and sensitivity of 95% for detection of silent infarct among children with SCD Sensitivity and specificity indices for other measures not greater than 60%
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Attention and executive function: Test of Variables of Attention WCST, CVLT-C Spatial: DAS Pattern Construction; JLO; WJ-R Position, Visual Form, and Shape Discrimination Language: DAS Word Definition, PPVT-R, WJ-R Word Fluency Picture Vocabulary Memory: CVLT-C Motor: simple and choice RT Family functioning: FACES II, Social Readjustment Scale, Knowledge of SCD Questionnaire Intelligence: WISC-R Visual-motor integration: VMI Visual attention and problem-solving: Kagan MFFT Academic achievement: WRAT Sustained attention: Gordon CPT computerized vigilance task Inhibitory control: Kagan MFFT Behavior rating scales: CBCL Intelligence: WISC-R, WAIS-R
Spatial: Object Assembly and Block Design of WISC-R, Benton Visual Retention Test, Spatial Relations of WJ-R Motor: Finger Tapping Verbal: Vocabulary of WISC-R, Benton Verbal Fluency Test Memory and Attention: CAVL
N = 47 children with SCD ages 5–17, grouped by MRI definition: CVA with anterior lesions (n = 6), CVA with diffuse lesions (n = 11), no CVA and normal MRI (n = 12), age-matched healthy sibling controls (n = 20) N = 28 participants ages 7–21 grouped by MRI definition: silent infarct (n = 7, overt stroke n = 21), healthy sibling controls (n = 17)
Craft et al., 1993
Compared to sibling controls, children with SCD with bifrontal lesions showed atypical pattern for left visual fields suggesting disruption of right-hemisphere attention processes, consisting of abnormally quick disengagement of attention at brief cue intervals and slowed disengagement at lower intervals No lateralized effects in children with diffuse lesions; showed disproportionately greater RTs at brief cue delays SCD children without stroke compared to healthy siblings No significant group differences in verbal, motor, or memory Significant group differences in spatial (silent, diffuse stroke group performed more poorly than anterior stroke group and controls on Object Assembly, Block Design, and Benton Visual Retention) Significant group differences in attention (silent anterior stroke group made more intrusion errors on CAVL compared to diffuse stroke group and controls)
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Sustained visual attention: Covert Orienting Task
N = 48 children ages 5–18 grouped by MRI definition: SCD with no CNS (n = 12), bifrontal lesions (n = 6), diffuse lesions (n = 11) compared to healthy sibling controls (n = 20)
Craft et al., 1994
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Intelligence: WISC-III, WISC-R
N = 102 children ages 4–18; SCD (n = 50) compared to healthy peer controls (n = 52) using quantitative MRI
N = 54 children ages 5–15: SCD with no MRI abnormalities (n = 17) and abnormal MRI (n = 13) compared to healthy peer controls (n = 24); groups also compared using quantitative MRI N = 42 children ages 7–16; HbSS and no CVA (n = 28) compared to healthy sibling controls (n = 21)
N = 73 children ages 8–16; SCD (n = 43) compared to healthy sibling controls (n = 30)
N = 54 children ages 6–17 in MRI-defined groups: SCD and CVA (n = 5), no CVA and silent infarct (n = 4), no CVA and normal MRI (n = 30), healthy sibling controls (n = 15); lesions classified as small, medium, and large
Steen et al., 1999
Steen et al., 1998
Wasserman et al., 1991
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Intelligence: WISC-III Executive function: WCST Memory: WMS Logical Memory, Visual Memory, Paired Association Learning
No significant group differences on WISC-R VIQ but controls outperformed SCD group on FSIQ and PIQ No significant group difference in academic achievement but age effect detected in SCD group with younger children outperforming older children on WRAT Math Younger children in SCD group had significantly higher (abnormal) scores on 7 LNNB-C subtests compared to controls, including measures of visual function, expressive speech, writing, reading, arithmetic, and memory Significant group differences on WISC-III with normal MRI group demonstrating significantly higher FSIQ scores compared to CVA group; trend for normal MRI group to outperform the silent infarct group who outperformed the CVA group on VIQ, PIQ, and FSIQ CVA group had significantly poorer performance on WISC-III compared to SCD and normal MRI and healthy sibling control groups Significant group differences on measures of memory and executive function with significantly more perseverative errors on WCST and poorer performance on WMS from CVA group
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Significant group differences on DTLA-2, WJ Math and Reading, and WISC-R VIQ, PIQ, FSIQ, with controls outperforming HbSS group
No significant group differences In SCD group, hematocrit significantly and positively correlated with FSIQ and the VC, PO, and FFD index scores, accounting for significant difference on FSIQ in children HbSS versus HbSC Low hematocrit correlated with T1 reductions in caudate, putamen, and cortex Significant group differences on mean FSIQ (control group 14 points higher than combined SCD groups); FSIQ of abnormal MRI group 8 points lower than normal MRI group Significant group differences for factor scores on WISC-R with normal MRI group outperforming abnormal MRI group on PO and VC
Significant group differences in the attention and executive function and spatial domains (SCD group performed more poorly on the Tower of Hanoi and TOVA compared to sibling controls, diffuse lesions group had poorer performance on all measures of spatial function compared to anterior lesion group and sibling controls) Lesion volume significantly related to performance in attention and executive function, memory, and language, accounting for 13% of variance in performance on spatial tasks
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Intelligence: WISC-R Memory: DTLA-2 Memory for Designs and Words Visual-motor: VMI Academic achievement: WJ Reading and Math Behavioral adjustment: CBCL Intelligence: WISC-R Academic achievement: WRAT Neuropsychological: Luria-Nebraska Battery for Children
Attention and executive function: TOVA, Tower of Hanoi, WCST Spatial: DAS Position, Visual Form and Shape Discrimination; Pattern Construction; JLO; WJ-R Visual Closure Language: PPVT-R, WJ-R Picture Vocabulary, Word Fluency, DAS Word Definitions Memory: CVLT-C Intelligence: WISC-III
N = 28 participants ages 7–21 grouped by MRI definition: SCD and anterior cerebral infarct (n = 7), diffuse cerebral infarct (n = 18), healthy sibling controls (n = 17); volume of infarcted tissue also considered
Schatz et al., 1999
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Participants and methods
Reference
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Table I. (Continued)
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Neuropsychological Aspects of Pediatric Sickle Cell Disease no known history of neurologic disease and age-matched sibling comparison controls. Probably because of this finding, the next set of studies did not appear in the literature until the following decade. Characterized by such serious methodological flaws as inappropriate grouping of HbSS and HbAS genotypes and use of instruments with suspect psychometric properties (for review, see Brown et al., 1993a), the results of these studies (e.g., Flick and Duncan, 1973; Reing, 1975) remain inconclusive. They did, however, stimulate an intensive program of research related to neurocognitive functioning and SCD. The next set of investigations provided data suggesting that children with SCD were at increased risk for the development of learning disabilities, although the results of these studies were variable and comparisons across investigations were inconsistent, at best. Chapar et al. (1986) reported a higher prevalence of neuropsychological deficits in the areas of fine motor coordination, tactile sensory perception, visual perception, visual-motor integration, and short-term visual memory in a group of adolescents with SCD and no known history of neurologic disease, compared to the performance of healthy adolescent comparison controls. Wasserman et al. (1991) conducted a similar investigation of children with SCD with no known neurologic disease. This study was methodologically superior to the study by Chapar et al. (1986) in that healthy siblings served as the comparison control group, thereby accounting for the effects of socioeconomic status and family experience. In contrast to previous findings, participants in the SCD group in the study by Wasserman and associates had lower general intellectual function. Although there were no group differences in measures of academic achievement, younger children with SCD had poorer performance in the areas of expressive speech, writing, reading, arithmetic, and memory, compared to older children in their cohort and healthy sibling controls. Brown et al. (1993b) investigated cognitive processing and academic achievement in children and adolescents diagnosed with SCD, with no known history of neurologic disease. Performance of children with SCD was compared to that of healthy sibling controls (HbAS or HbAA). Measures of illness severity and variables related to school attendance were included to control the effects of chronic illness on academic and cognitive functioning. Consistent with Chodorkoff and Whitten (1963), no group differences were found for general intellectual functioning. However, specific deficits in sustained attention and concentration were revealed on a continuous performance task, with healthy siblings outperforming the SCD group. Also, an age effect was found for these measures, such that performance among children with SCD declined with age. The SCD group also obtained poorer
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scores on a measure of reading decoding, compared to their healthy siblings. Children in the SCD group met discrepancy-based criteria for learning disabilities across all academic categories at a rate twice that expected of the normal population. Additionally, hemoglobin levels accounted for a significant proportion of the variance on measures of intelligence, fine-motor skills, and overall academic achievement, even when controlling the effects of socioeconomic status. Brown and colleagues attributed their findings to the compromised oxygen delivery associated with SCD, particularly for functions subserved by the frontal lobes. In a follow-up of the Brown et al. (1993b) investigation, Goonan et al. (1994) studied neurocognitive performance related specifically to attention and concentration among children with SCD, compared to their healthy siblings, on measures of sustained attention, inhibitory control, and parental ratings of attention and impulsivity. In addition, the effects on attention of socioeconomic status, gender, and disease severity (i.e., hemoglobin levels, frequency of hospitalizations, and emergency room visits) were examined. No differences were found between children with SCD and healthy sibling controls in their capacity to sustain attention and inhibit impulsive responding. These neuropsychological findings were corroborated by parent ratings of behavior and attention. Failing to support the results reported by Brown et al. (1993b), the authors concluded that the development of attention and inhibitory control for children with SCD, with no known neurologic disease, is comparable to that of normally developing children. Although the data provided by Goonan et al. (1994) were inconsistent, some have attributed these equivocal findings to problems with classification (White and DeBaun, 1998). For example, none of the studies controlled for the effect of SCD genotype. Children with HbSS disease manifest greater disease severity (e.g., increased frequency and severity of painful crises and increased incidence of cerebral infarction) compared to other hemoglobinopathies (e.g., HbSC). Therefore, a diseasespecific model of neurocognitive impairment would require group comparisons by genotype. Thus, the results of the Brown et al. (1993b) study may be accounted for, in part, by this misclassification bias, as hemoglobin levels were found to be significantly predictive of neurocognitive and academic performance, even when controlling for the effects of socioeconomic status. A number of investigators, in fact, have controlled for the effect of SCD genotype. In one study, Fowler et al. (1988) compared children with SCD (HbSS) with no known history of stroke to a group of healthy children, matched for gender, race, socioeconomic status, and age,
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188 on measures of fine-motor coordination, visual attention and problem-solving, and academic achievement. They also included indicators of illness severity, such as number of days hospitalized, hemoglobin data, school absences, and acute painful episodes, to examine the contribution of illness-related factors on academic and cognitive functioning. No group differences were reported for general intellectual ability; both groups demonstrated average to low average abilities. However, group differences were reported for measures of visual attention, reading, and spelling, with the comparison control group outperforming the SCD group. Interestingly, illness severity did not predict cognitive functioning. Consistent with the findings by Brown et al. (1993b), an age effect was identified, such that older children with SCD performed significantly less well than the younger members of their cohort on measures of reading, auditory attention, sustained attention, and visual-motor integration. Swift et al. (1989) compared the performance of a group of children with SCD (HbSS) with no known history of major neurologic disease to that of age-matched healthy sibling controls (HbAS or HbAA). These researchers suggested some degree of cognitive impairment associated with HbSS, even in the absence of observed neurologic complications. The group with SCD generally scored one standard deviation below their healthy siblings on measures of intellectual functioning, perceptual organization, attention and distractibility, memory, and academic achievement. No age or gender effects were found. Similarly, Knight et al. (1995) examined intellectual functioning in a representative sample of Jamaican adolescents with SCD (HbSS) who were compared to a group of ageand gender-matched healthy adolescents. A significant 5-point difference between groups on full-scale intelligence quotients (FSIQ), verbal intelligence quotients (VIQ), and performance intelligence quotients (PIQ) was found, with healthy adolescents performing better than the SCD group. IQ was not significantly associated with illness severity variables, such as hemoglobin levels. Comparisons of the investigations reviewed were limited by a number of methodological and psychometric shortcomings. The effect of SCD genotype was controlled, often by sampling HbSS only, but the studies were limited because they failed to account for the possibility of silent cerebral infarcts (White and DeBaun, 1998). The neurological status of participants in the studies was not verified via neuroimaging techniques, and so it is possible that children with silent infarct were erroneously classified as free of CNS pathology. Further, many of these studies used measures of intellectual functioning and academic achievement that may mask or underestimate subtle
Kral, Brown, and Hynd neurocognitive deficits, making their contribution to the literature suspect. The finding of age effects in several of these investigations also implicates the progressive and possible cumulative effects of cerebrovascular disease associated with SCD (Brown et al., 1993a). Neurocognitive Correlates of SCD and Stroke We turn next in our review to those studies that have examined neurocognitive functioning in children and adolescents with overt evidence of CVAs. In this body of literature, the misclassification biases highlighted earlier are controlled in comparisons of stroke versus no-stroke groups. In an investigation of the nature and degree of functional recovery following completed stroke, Hariman et al. (1991) compared children with SCD and history of CVA to a group of children with SCD and no known history of CVA, matched for age and gender, on measures of intellectual and motoric functioning. The CVA group included HbSS, HbS-thalassemia, and HbSC genotypes. Additionally, individuals in the stroke group had experienced one to three strokes, with a mean age of onset at 6 years 1 month. As expected, results were indicative of relatively intact overall motor performance in both groups, compared with significantly higher IQ scores in the no-CVA group (mean FSIQ = 91.4 ± 13.1) versus the positive CVA group (mean FSIQ = 68.4 ± 17.8). The CVA group also demonstrated language function in the below average range. Cohen et al. (1994) investigated the neuropsychological functioning of children with SCD (HbSS) with lateralized stroke. Four children with left hemisphere cerebral infarct (LCI) were compared to six children with right hemisphere cerebral infarct (RCI) on measures of intelligence, language, visual-spatial and constructional ability, sensory perceptual function, memory, and academic achievement. Children with SCD again experienced significant impairment of cognitive function following stroke. Moreover, children with LCI demonstrated pervasive impairment in intellectual functioning (PIQ > VIQ by 4 points) versus a relative decline in PIQ for the RCI group (VIQ > PIQ by 13 points). The LCI group also demonstrated deficits in linguistic ability (receptive and expressive), auditory and verbal memory, and visualmotor and constructional functioning. In contrast, RCI deficits were more focal, characterized by impairments in visual-motor and constructional praxis and visual-spatial memory. Both groups demonstrated deficits in visual and spatial memory. The LCI group showed generalized deficits in academic achievement, but RCI group deficits were limited to the area of arithmetic.
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Neuropsychological Aspects of Pediatric Sickle Cell Disease Craft et al. (1993) examined the effects of lesion location on specific neurocognitive functions in children with SCD. Four MRI-defined groups were formed, including an anterior-stroke group (n = 6), defined by lesions in the anterior regions of the watershed areas, centrum semiovale, MCA distribution, or basal ganglia; a diffuse-stroke group (n = 11), defined by lesions localized throughout the brain, but not exclusively in the anterior regions; a nostroke group (n = 12), defined by no history of neurological pathology or MRI abnormality; and a healthy sibling comparison control group (n = 20). Group performance was compared across the neuropsychological domains of visual-spatial perception, motor function, verbal ability, memory, and attention. The pattern of stroke influenced the pattern of neurocognitive impairment. Children with injury in the anterior portion of the brain had poorer performance on measures of attention, compared to profound deficits in complex spatial ability in children with anterior plus posterior (diffuse) cortical injury. Children with SCD with no neurologic disease (i.e., no MRI abnormality) performed similarly to healthy sibling comparison controls. The investigators appropriately concluded that SCD, in the absence of MRI abnormality, has no significant effects on cognitive development, which supported our previous speculation that cognitive deficits found in children with SCD without overt stroke may be due to the inadvertent inclusion of children with silent stroke in the asymptomatic groups. To extend their previous investigation, Craft et al. (1994) examined the effects of early brain injury on attention by using a covert visual orienting task, which is comparable to a computerized continuous performance task. Comparison groups were formed according to the MRI guidelines established in an earlier study by Craft et al. (1993), including a bifrontal-stroke group, a diffuse-stroke group, a no-stroke group, and a healthy-sibling control group. Significantly, greater reaction times for distracting stimuli within both visual fields were found for the diffuse-lesion group, compared to the no-stroke group and sibling controls. In comparison, children with bifrontal lesions had lateralized effects. They exhibited faster reaction time commission errors when the cue was brief, and slow disengagement times for commission errors when the cue duration was lengthened. These results were evident for stimuli presented to the left visual field. The investigators contrast these patterns of performance with those following adult-onset lesions. Anterior brain regions in study children seemed to mediate the initial stages of visual attention, which are typically mediated by posterior regions in adults. Bilateral lesions found among study children seemed to produce lateralized effects on visual
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attention, effects typically observed in adults with lateralized lesions. Schatz et al. (1999) further extended the work of Craft et al. (1993) by examining the effects of lesion location and volume on subsequent neurocognitive function in children with SCD and history of cerebral infarct. Comparison groups were formed according to the MRI guidelines established in the Craft study, including an anterior-lesion group, diffuse-cortical-injury group, and healthy-sibling control group. Neuropsychological performance was assessed in the domains of attention and executive function, spatial skills, language, and memory. Greater neuropsychological impairment occurred across each domain in children with diffuse cortical injury, with more pronounced deficits in attention, executive function, and spatial skills. When lesion volume was considered along with lesion location, lesion location uniquely accounted for 2% of the variance in performance on spatial tasks, whereas lesion volume uniquely accounted for 13% of the variance in performance on these tasks. In contrast, the anterior lesion group demonstrated more focal deficits in the attention and executive function domain, compared to the performance of the comparison control group. Moreover, children with small volume lesions located in the frontal lobes showed a similar level of impairment on attention and executive function tasks compared to those with large-volume diffuse lesions. It seems, then, that the pattern of neurocognitive deficits following cerebral infarct among children with SCD is dependent on the location of CNS injury and especially on the total volume of cerebral injury. In a recent investigation of CVA location and social information processing, Boni et al. (2001) compared the performance of a group of children with HbSS disease with MRI-evident CVA to two groups of children, one with HbSS disease but no CNS pathology (as confirmed by MRI) and one with HbSC disease but no CNS pathology, on measures of nonverbal decoding of emotions. Children with HbSS disease and a history of CVA showed deficits in facial and vocal decoding of emotions. Interestingly, lesion location (e.g., right vs. left hemisphere) did not differentiate the performance of children with MRI abnormality, possibly because of low power that may have mitigated differences. Nonetheless, children in the MRIpathology group demonstrated deficits in the processing of low-intensity (i.e., subtle) adult facial affect and low intensity prosodic expressions in both adults and children. The authors suggest that these findings provide evidence for deficits in social information processing among children with HbSS disease and CNS pathology. The investigation is one of the first to link social and emotional
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190 functioning in these children to known structural impairments in the CNS. Cautious interpretation of each of the aforementioned studies (Boni et al., 2001; Cohen et al., 1994; Craft et al., 1993, 1994; Schatz et al., 1999) is warranted for a number of reasons. First, it is well recognized that localization of function is a complex developmental phenomenon (Spreen et al., 1995). We believe that the use of adult models to interpret localization of function in pediatric populations is suspect. Moreover, the small sample sizes of the studies reviewed, together with the wide range in chronological ages (including young children, adolescents, and adults) preempts interpretation of data from a developmental perspective. By failing to consider onset of injury, consideration of such developmental issues as plasticity of function in young children is confounded. Further, it will be the role of future research to examine the contribution of lesion location and lesion volume to patterns of cognitive functioning across age groups of children. This will require large-scale multisite investigation. Neurocognitive Correlates of Subclinical Neurological Disease Given the pervasiveness of silent CVAs that are not necessarily identifiable by overt physical examination, there is significant interest in identifying silent infarcts and their sequelae. A series of investigations addressed the neurocognitive sequelae of silent cerebral infarcts in children with SCD. In one such study, Kugler et al. (1993) investigated differences among children with SCD (HbSS) based on findings of normal versus abnormal MRI. Group differences in performance were examined for the neuropsychological domains of memory, attention, executive function, motor speed, language, and visual-spatial function. Although no significant group differences were found, the group with MRI abnormalities performed more poorly on most measures. The researchers suggested that this trend may reflect that the majority of MRI abnormalities were rather small subcortical lesions and, as such, may not have manifested as significant deficits in neurocognitive performance. A global performance rating (GPR) also was derived, based on measures of memory, visualspatial function, attention, language, intelligence, and executive function. Both groups had generally lower GPRs, compared with normative data. These findings were interpreted by Kugler and associates to suggest that the disease process associated with SCD may produce neurocognitive deficits, even in the absence of stroke. Steen et al. (1998) compared children with SCD who had normal versus abnormal MRIs to healthy African American peers on a measure of general intellectual
Kral, Brown, and Hynd functioning. In contrast to the Kugler et al. (1993) study findings, healthy peers in this study had higher intellectual functioning (mean FSIQ = 88.0 ± 16.1) compared to all children with SCD (mean FSIQ = 74.9 ± 10.9). Also, the SCD group with MRI abnormalities demonstrated a significantly lower FSIQ (mean = 70.6) compared with the SCD group with normal MRI results (mean = 78.9). Given the growing body of evidence implicating the frontal lobes as a site commonly affected by cerebrovascular disease in sickle cell anemia, DeBaun et al. (1998) tested the hypothesis that measures of attention and executive function would prove to be the most sensitive and specific for detection of silent cerebral infarct. Also tested were the domains of motor functioning, language, visual memory, and visual-spatial skills. Children with SCD (HbSS) were grouped according to the results of MRI as silent versus overt stroke and were then compared to healthy sibling controls. Of the neuropsychological domains tested, only the attention and executive function domain had sensitivity above 60% for the detection of silent infarct. And of these measures, the Test of Variables of Attention (TOVA) was the only measure administered that accurately identified 6 of 7 children with silent cerebral infarcts (sensitivity, 86%) and 13 of 16 healthy controls without overt stroke (specificity, 81%). In the National Institutes of Health natural history study, Armstrong et al. (1996) recruited children who were MRI-defined, such that children with normal MRI, children with abnormal MRI but no history of stroke (silent infarct), and children with overt stroke were compared to determine whether neuroimaging evidence of infarct might be associated with impairment in cognitive and academic functioning. Groups included HbSS and HbSC genotypes, except the stroke group, which consisted entirely of children with HbSS disease. The test battery consisted of measures of general intellectual functioning, academic achievement, and fine motor speed and coordination. Consistent with the literature, children with MRI abnormalities were mostly those with the HbSS genotype; 22% of the HbSS group had abnormal MRI, and 15.6% had silent infarct. All children with a clinical history of stroke were characterized by the HbSS genotype, and children with HbSS disease had significantly lower hematocrit levels compared to these with the HbSC genotype. Neuropsychological deficits were associated with the presence of CVA in children with HbSS disease, with pervasive deficits evidenced in the areas of intellectual functioning, language and verbal abilities, visual-motor and visual-spatial processing and performance, sequential memory, and academic achievement. A less severe pattern of impairment characterized the HbSS group with silent infarct, although performance in the areas of arithmetic,
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Neuropsychological Aspects of Pediatric Sickle Cell Disease vocabulary, and visual-motor speed and coordination was significantly lower compared to the HbSS group with no MRI abnormalities. The authors interpreted these findings as evidence for disruption of myelinization in the frontal cortex or calcification in the frontal cortex and basal ganglia. More important, the study by Armstrong and colleagues supported the utility of cognitive measures in screening for either silent or overt infarct in children and adolescents with SCD. In a similar study with MRI-defined groups, Watkins et al. (1998) examined neurocognitive function among children with SCD (HbSS, HbSC, HbS) on measures of intellectual functioning,executive functioning,and memory. The groups were MRI-defined as follows: symptomatic included children with SCD and a history of stroke, evidenced by large areas of infarction on MRI; asymptomatic included children with SCD and no history of stroke, although small areas of infarction were evident on MRI; children with SCD and normal MRI; and healthy sibling controls. Interestingly, and consistent with the frontal lobe deficit hypothesis posited for children with SCD, many of the lesions seen on MRI were located in the frontal cortex. Consistent with the findings in the Cohen et al. (1994) and Armstrong et al. (1996) research group studies, performance of the symptomatic group was impaired in the areas of intellectual functioning, learning, memory, and executive function, relative to children with SCD and normal MRI and healthy sibling controls. The asymptomatic group also demonstrated a trend toward lower scores. Although perhaps because of the small sample size of this group (n = 4), the only difference that reached statistical significance was obtained on a measure of arithmetic. The asymptomatic group had poorer performance compared to children with SCD with normal MRI and healthy sibling controls. Increasingly, researchers find children with SCD who are free of neurological symptoms may still be at risk for disease-related damage to the brain. Steen et al. (1999) used qMRI to reveal a pattern of subtle T1 reduction in children with SCD, with T1 abnormality limited to gray matter. In addition, an age effect was found; T1 was significantly lower than normal by age 4 in the head of the caudate, nucleus pulvinares, and cortical gray matter. Abnormality was present even in children who appeared normal by cMRI. Significant differences also were found between genotypes for FSIQ, with higher scores obtained by children with the HbSC genotype, compared to the HbSS cohort. Hematocrit explained a significant amount of variance in FSIQ (as much as 56%), and low hematocrit was associated with T1 reduction in the caudate, putamen, and cortical gray matter. Steen and colleagues hypothesized from these results that the T1 reduction in gray matter
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and the deficits in FSIQ resulted from chronic hypoxia associated with low hematocrit. Our review of the literature thus far reveals several important findings. Defined as ischemic changes seen on MRI in the absence of clinically evident neurological signs and symptoms, children with silent infarct show subtle neurocognitive deficits compared to children with SCD and normal MRI. These neurocognitive deficits seem to be less severe than those manifested by children with overt stroke. In addition, measures of attention and executive function seem to be more sensitive in the detection of silent cerebral infarct. As suggested by Schatz et al. (2001), this emerging pattern of neurocognitive decline calls into question the veracity of the descriptor silent when characterizing the symptomatic nature of cerebral infarcts in this population. However, methodological limitations, such as small samples of children with silent cerebral infarct and the failure to control for lesion location, limit the conclusions that may be drawn from these data regarding the direct effects of silent cerebral infarct on neurocognitive function. Neurocognitive Correlates of Localized Silent Stroke We found only one investigation in which groups of children with SCD and abnormalities visualized on MRI were defined by lesion location sites. In this investigation, Brown et al. (2000) examined neurocognitive functioning in children with SCD grouped according to MRI findings, including an overt-stroke group, a silentcerebral infarct group, and a normal-MRI group. Lesions visualized on MRI were further classified as cerebral infarct, atrophy, or cerebral infarct and atrophy. This study was an extension of the investigation by Armstrong et al. (1996) because it provided a comprehensive assessment of neurocognitive functioning, to include assessment of language processing, executive function, and visual-motor skills. Group differences were found only in the areas of attention and executive function, including tasks that require sustained attention and frontal lobe functioning. Children with silent cerebral infarct demonstrated similar attentional impairments compared to children with a history of overt CVA. Children with overt or silent strokes were further classified and compared according to infarct location, which included lesions localized in the frontal lobe, temporal lobe, parietal lobe, occipital lobe, thalamus, putamen, globus pallidus, caudate nucleus, and internal capsule. For the entire sample, the highest frequency of damage was overwhelmingly localized in the frontal lobe, present in 93% of children in the overt stroke and silent cerebral infarct groups. Although multiple lesion locations also were noted, of interest here is that the majority of
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192 children sustained frontal lobe impairments. It is unclear as to why the frontal lobes are most vulnerable to insult. However, these findings were consistent with evidence suggestive of altered metabolism on positron emission tomography (PET) scans in the frontal lobe area of adult patients with SCD (Rodgers et al., 1988). The data also are consistent with the finding of pervasive frontal cortex cerebral blood flow dysfunction in adults with HbSS disease, despite structurally normal tissue on MRI (Prohovnik et al., 1995). Once again, the findings support the hypothesis that measures of attention and concentration may be the most useful indices of neurological pathology among children with SCD. SUMMARY, CONCLUSIONS, AND DIRECTIONS FOR FUTURE RESEARCH Sickle cell disease consists of a group of genetic disorders, characterized by the production of abnormal hemoglobin that causes red blood cells to assume a rigid, sickled shape upon release of oxygen, thereby reducing the viability of red blood cells in circulation. Consequently, chronic anemia and systemwide ischemia result in acute painful episodes, organ system failure, and neurological complications (Embury et al., 1994; Kaul et al., 1989; Serjeant, 1992). One of the most devastating outcomes of SCD is neurological complications. Cerebrovascular accidents (CVA) constitute a leading cause of morbidity and mortality, occurring most frequently among children with the HbSS genotype at an estimated incidence of 4–8% (Ohene-Frempong et al., 1998; Powars et al., 1978). According to angiographic and neuropathologic studies, overt stroke appears to be the outcome of progressive cerebrovascular disease that involves vascular lesions in the major cerebral arteries (Merkel et al., 1978; Rothman et al., 1986; Stockman et al., 1972). Investigations involving neuroimaging, primarily including MRI, confirm this disease course by frequently localizing cerebral infarction in the cortex and deep white matter associated with the distribution of a major artery, such as the middle cerebral artery or the internal carotid (Moser et al., 1996). Neurocognitive sequelae of CVA in children with SCD are characterized by pervasive impairments, including decrements in general intellectual functioning, language and verbal abilities, visual-motor and visual-spatial processing, memory, academic achievement (Armstrong et al., 1996), and processing of subtle prosodic information (Boni et al., 2001). In addition, neuropsychological deficits follow a pattern that is associated with lesion location and lesion volume. Lesions localized in the right hemisphere generally result in visual-spatial deficits and constructional apraxia, whereas lesions localized in the
Kral, Brown, and Hynd left hemisphere produce relatively greater decrements in language (Cohen et al., 1994). In contrast, deficits in attention and executive function are associated with anterior focal lesions, compared to profound deficits in complex spatial ability in children with anterior plus posterior (diffuse) cortical injury (Craft et al., 1993, 1994; Schatz et al., 1999). Children with HbSS disease also may evidence neurologic pathology and associated neurocognitive deficits prior to the presentation of clinically apparent signs and symptoms. As many as 11–17% of children with HbSS disease show silent cerebral infarcts, lesions of infarction and ischemia identified on brain MRI images in otherwise asymptomatic children (Hindmarsh et al., 1987; Moser et al., 1996; Pavlakis et al., 1988). Silent cerebral infarct is likely accounted for by chronic hypoxia in the microvasculature. This distal insufficiency syndrome results in microinfarcts in the deep white matter, basal ganglia, or anterior watershed regions, which constitute the borderzones between two arterial distributions (Kugler et al., 1993; Moser et al., 1996; Pavlakis et al., 1989; Wang et al., 1998). For example, the anterior-middle cerebral artery borderzone is a common location for cerebral infarction in children with HbSS disease (Pavlakis et al., 1988). This type of cerebral injury is often sustained at a very early age, before age 6 for example (Wang et al., 1998), and is characterized by proliferation and enlargement of lesions as age increases (Kugler et al., 1993; Moser et al., 1996). The neuropsychological deficits associated with silent infarct are typically less severe compared to overt CVA (Armstrong et al., 1996). Subtle neurocognitive deficits following silent cerebral infarct are described in a few studies, but there also is growing evidence indicating impairment in sustained attention and concentration, executive function, and visual-motor speed and coordination (Brown et al., 2000; DeBaun et al., 1998; Steen et al., 1999; Watkins et al., 1998). These subtle neuropsychological deficits documented in children with HbSS disease who do not manifest signs and symptoms of CVA suggest that this population may be at increased risk for learning difficulties, as suggested by below-gradelevel performance in the academic areas of reading and mathematics (Armstrong et al., 1996) and an increased incidence of special education placements (Bonner et al., 1999; Schatz et al., 2001). Given the strength of evidence suggesting frontal lobe impairments in these children (Brown et al., 2000), the neuropsychologist is well advised to incorporate measures that assess functions purportedly subserved by the frontal lobes (e.g., measures of attention/concentration and executive function). A disease-specific model of neurocognitive decline in children with HbSS disease was found in the neurological
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Neuropsychological Aspects of Pediatric Sickle Cell Disease and neuropsychological literatures. Given the extremely rare incidence of CVA in the general pediatric population, the neurological and neuropsychological complications associated with this illness appear to be unique to pediatric SCD. In addition, just as the neurological literature documents the progressive nature of neurological complications in this population (e.g., Steen et al., 1999), researchers are fairly consistent in suggesting age-related decrements in neuropsychological functions across a number of domains (e.g., Brown et al., 1993b; Fowler et al., 1988). Clearly, the interface between the developing brain and the progressive nature of this chronic illness pose a number of challenges, both clinical and empirical, in the realm of developmental neuropsychology. In this regard, Bonner et al. (1999) astutely underscore the issue of timing and neurological insult; the onset of neuropsychological sequelae and consequences for the developmental trajectory in this population are not yet clear. Given the growing body of evidence suggestive of impairment in functions subserved by the frontal lobe, children may in fact “grow into” their CNS insults. As technology improves, detection of subclinical neurological complications will increase. In this regard, it is likely that the percentage of children who had been previously described as free of cerebrovascular pathology may in fact decrease. Longitudinal investigations that track development in these neuropsychological domains are needed to explore the cumulative effects of this devastating illness. Given the progressive nature of cerebrovascular disease in this population and corresponding severity of neurocognitive deficits, the economic and social priority of early intervention and stroke prevention is clearly evident. In this regard, the identification of risk factors that serve as reliable predictors of silent and overt stroke has historically proven unreliable (Ohene-Frempong, 1991; Pavlakis et al., 1989; Powars et al., 1978). The recent application of TCD as a screening technique offers much promise for reliable, noninvasive, early prediction of the neurological complications associated with pediatric SCD. Moreover, TCD may offer an index of disease progression, which will be critical in future longitudinal investigations. Although the neuropsychological correlates of abnormal blood flow velocity, as determined by TCD, have yet to be investigated, TCD presents a method of exploring the continuum of disease severity and its direct neurocognitive effects. Related to prevention and early intervention, little research has been conducted with preschool children with SCD. Thompson and colleagues (cited in Bonner et al., 1999) are currently following a cohort of infants with SCD through early childhood. According to these researchers, preliminary data reveal normative cognitive functioning for infants in this cohort. However, longitudinal
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investigation will reveal neurocognitive outcomes for these children as they develop into early childhood. Related to the notion of risk, systematic efforts will need to identify preschool children at risk for CVA and measure the effects of early intervention programs in mitigating the effects of the disease on those children who are designated at greatest risk. Further investigation will provide needed data regarding the sensitivity and specificity of those neuropsychological screening instruments (e.g., measures of academic readiness) with children identified as at-risk by neurological methods, such as radiography and ultrasonography. Neuropsychology may make clinical and empirical contributions to an evolving understanding of SCD that promise to be both multiple and diverse. For example, the confounding role of chronic transfusion therapy in research paradigms to date remains unclear. Alternatively, numerous clinical trials are underway to assess the efficacy of hydroxyurea, a chemotherapy agent designed to stimulate the production of fetal hemoglobin in an effort to reduce acute painful episodes associated with intravascular sickling, and, consequently, the need for transfusions (Ohene-Frempong and Smith-Whitley, 1997). Given the iatrogenic effects of chemotherapeutic agents for children with cancer (for review, see Brown et al., in press), the effects of these agents on the developing CNS in children with SCD will need to be carefully evaluated in future neuropsychological investigations. In addition, bone marrow transplantation has been the only curative procedure for pediatric SCD. As such, neurocognitive outcome following transplantation warrants careful empirical investigation over the next decade. Given the demonstrated association between neurocognitive functioning and social and emotional functioning (Boni et al., 2001), more systematic investigation of issues related to peer sociometry, social competence, and the role of peer supports in adaptation to SCD is needed, particularly as these variables may be mediated and moderated by cognitive dysfunction. A number of deficits have been identified from this review of literature that suggest appropriate intervention targets. We are increasingly cognizant of the frontal lobe as a region of vulnerability in pediatric SCD. Children with acquired frontal injuries frequently benefit from peer social skills groups, stimulant medication designed to improve attention and concentration, and cognitive remediation targeting poor impulse control and executive dysfunction. Whether these therapies will prove viable for children with SCD will require careful investigation over the next decade. It is hoped that clinical trials that incorporate the rigors of experimental design will offer further substantiation for the correlational findings that have been reported thus far. This
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194 program of intervention research will constitute the tertiary stage of research in the area of pediatric SCD, namely the experimental validation of correlational findings. It is hoped and anticipated that such research programs will enhance the quality of life for these children and their families. REFERENCES Adams, R. J., Aaslid, R., Gammal, T. E., Nichols, F. T., and McKie, V. (1988a). Detection of cerebral vasculopathy in sickle cell disease using transcranial doppler ultrasonography and magnetic resonance imaging: Case report. Stroke 19: 518–520. Adams, R. J., McKie, V. C., Carl, E. M., Nichols, F. T., Perry, R., Brock, K., McKie, K., Figueroa, R., Litaker, M., Weiner, S., and Brambilla, D. (1997). Long-term stroke risk in children with sickle cell disease screened with transcranial Doppler. Annals of Neurology 42: 699–704. Adams, R. J., McKie, V. C., Hsu, L., Files, B., Vichinsky, E., Pegelow, C., Abboud, M., Gallagher, D., Kutler, A., Nichols, F. T., Bonds, D. R., and Brambilla, D. (1998). Prevention of a first stroke by transfusions in children with sickle cell anemia and abnormal results on transcranial Doppler ultrasonography. New England Journal of Medicine 339: 5–11. Adams, R., McKie, V., Nichols, F., Carl, E., Zhang, D.-L., McKie, K., Figueroa, R., Litaker, M., Thompson, W., and Hess, D. (1992). The use of transcranial ultrasonography to predict stroke in sickle cell disease. New England Journal of Medicine 326: 605–610. Adams, R. J., Nichols, F. T., Aaslid, R., McKie, V. C., McKie, K., Carl, E., Stephens, S., Thompson, W. O., Milner, P., and Figueroa, R. (1990). Cerebral vessel stenosis in sickle cell disease: Criteria for detection by transcranial Doppler. American Journal of Pediatric Hematology/Oncology 12: 277–282. Adams, R. J., Nichols, F. T., Figueroa, R., McKie, V., and Lott, T. (1992). Transcranial doppler correlation with cerebral angiography in sickle cell disease. Stroke 23: 1073–1077. Adams, R. J., Nichols, F. T., McKie, V., McKie, K., Milner, P., and Gammal, T. E. (1988b). Cerebral infarction in sickle cell anemia: Mechanisms based on CT and MRI. Neurology 38: 1012– 1017. Adams, R. J., Nichols, F. T., Stephens, S., Carl, E. M., McKie, V., Fischer, C., and Thompson, W. O. (1988c). Transcranial Doppler: The influence of age and hematocrit in normal children. Journal of Cardiovascular Ultrasound 7: 201–205. Armstrong, F. D., Thompson, R. J., Wang, W., Zimmerman, R., Pegelow, C. H., Miller, S., Moser, F., Bello, J., Hurtig, A., and Vass, K. (1996). Cognitive functioning and brain magnetic resonance imaging in children with sickle cell disease. Pediatrics 97: 864–870. Balkaran, B., Char, G., Morris, J. S., Thomas, P. W., Serjeant, B. E., and Serjeant, G. R. (1992). Stroke in a cohort of patients with homozygous sickle cell disease. Journal of Pediatrics 120: 360–366. Boni, L. A., Brown, R. T., Davis, P. C., Hsu, L., and Hopkins, K. (2001). Social information processing and magnetic resonance imaging in children with sickle cell disease. Journal of Pediatric Psychology 26: 309–319. Bonner, M. J., Gustafson, K. E., Schumacher, E., and Thompson, R. J. (1999). The impact of sickle cell disease on cognitive functioning and learning. School Psychology Review 28: 182–193. Brown, R. T., Armstrong, F. D., and Eckman, J. R. (1993a). Neurocognitive aspects of pediatric sickle cell disease. Journal of Learning Disabilities 26: 33–45. Brown, R. T., Buchanan, I., Doepke, K., Eckman, J. R., Baldwin, K., Goonan, B., and Schoenherr, S. (1993b). Cognitive and academic functioning in children with sickle-cell disease. Journal of Clinical Child Psychology 22: 207–218.
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