Sickle Cell Disease and the Effect on Neurocognitive Functions
Literature Review from 1993 to 2021 by Lauren Rivera at The Institute for Life Sciences Collaboration
Children with Sickle Cell Disease (SCD) face more developmental delays and cognitive challenges compared to unaffected peers . Neurocognitive deficits in children with SCD are well documented, and include impaired overall intellectual ability, executive functioning, processing speed, attention, memory, language, and academic achievement .
The neurological burden of SCD is severe; the developing brain is especially vulnerable to hypoxemia and ischemia, which children with SCD often experience. In the first decade of life, approximately one-third of children with SCD will have silent cerebral infarction (SCI) , and by 20 years old, 39% of individuals with Sickle Cell Anemia (SCA) will have an overt stroke . An overt stroke causes observable symptoms such as asymmetrical arm weakness or speech impediment, and is defined as neurological deficit lasting for over 24 hours . SCI describes abnormal magnetic resonance imaging (MRI) of the brain, or dead cerebral tissue found by neuroimaging without a history or physical findings of an overt stroke . Overt strokes commonly occur in lesions of the cerebral cortex and deep white matter. SCI occur in various regions of the brain, including the thalamus, temporal lobes, and the deep white matter of the frontal or parietal lobes . The cerebral cortex is responsible for higher-order brain functions such as sensation, perception, working memory, processing speed, verbal comprehension, and visual motor speed coordination .
Silent Cerebral Infarcts
Cerebral injury limits the full potential of a developing child or adult. SCI is the most common neurological disease in children with sickle cell . SCI gained widespread awareness in 1996, when the Cooperative Study of Sickle Cell Disease (CSSCD) standardized MRI radiological parameters to define SCI . The results of an observational study conducted by the CSSCD supported that the presence of SCI, in children with SCD, is a risk factor for additional neurological injury. Notably, a 14-fold increased risk of clinical stroke, and higher risk of progressive silent infarction . Children with SCI exhibit lower cognitive test scores than children with a normal MRI of the brain , . SCI have been associated with neurological deficits in executive functions such as selective attention, working memory, processing speed, visuomotor coordination, vocabulary, visual memory, abstract reasoning, and verbal comprehension , –. Consequentially, SCD greatly impacts academic achievement, with one study finding that 35% of children with SCA and SCI had twice the likelihood of academic difficulties than those without SCI .
Full-Scale IQ (FSIQ) is widely studied and is commonly used as a measure of general cognition for individuals with SCD. Since the 1980s, there have been many studies to show the association between individuals with SCD and lowered global intelligence scores . Researchers from the CSSCD found that school-aged children with SCD (who had experienced overt strokes and silent infarctions) had significantly lower scores for math and reading achievement, FSIQ, Verbal IQ, and Performance IQ, when compared to unaffected peers . Further studies have concluded that the degree of cognitive deficit was associated with the volume or lesion size of SCI . Schatz et al.  found that FSIQ was lowest in SCD children with large tissue loss (>6.8 cm3, IQ = 76) compared to children with smaller tissue loss (<6.8 cm3, IQ = 87). Overall FSIQ scores obtained are lower in children with SCI, and lowest in children with overt stroke, compared to normal children . Given the high risk and occurrence of SCI and overt stroke in children with SCD, it is important to highlight the associated intellectual impairment. However, even SCD children without SCI have shown significantly decreased grade retention and need for special educational services compared to children without SCD . Notably, children with SCD considered neurotypical have an average FSIQ score one standard deviation below the normative mean . Due to HbS, many children with SCD experience chronic insufficient oxygenation of the brain which may play a role in explaining decreased FSIQ, regardless of SCI or ischemia.
Many studies have made comparisons between SCD children with ischemia, SCD children with SCI, and SCD children who are neurotypical. Of these studies, there are only a few that include the use of a control group. Control groups are essential because environmental, ethnic, and socioeconomic factors may contribute to cognitive or behavioral deficits regardless of SCD. Additionally, most pediatric SCD neurological and FSIQ studies have been conducted in the US. Little research exists in the context of other countries. It is important to understand how the degree and type of cognitive deficits may vary throughout the globe in order to adequately and effectively adapt educational interventions for children with SCD. Only a few studies have investigated risk factors for SCI in SCD. Despite it being the most frequent cognitive injury for children and adults with SCD, little is known about the cause and optimal treatment of SCI. Given the association with SCI and poor educational attainment  and future neurological damage , medical interventions are needed. However, there is no standardized treatment for primary or secondary prevention of SCI.
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