Sickle cell disease (SCD) is a genetic disorder caused by a single-point mutation in the 6th position of the hemoglobin beta chain gene, which leads to abnormal hemoglobin, that polymerizes when exposed to low oxygen tension, with subsequent deformity of the erythrocytes which aggregate and cause sluggishness in the microcirculation resulting in local hypoxia, ischemia and tissue damage. SCD complications are frequent; they include bone disease, splenic dysfunction, pulmonary complications, skin ulceration, depression or behavioral disorders, neurologic, and cognitive deficits .
Cognitive deficits may include impairment in general cognitive functions as well as deficits in specific areas of cognition including language, short term memory, speed of processing, and working memory . Little information is available on the frequency and risk factors of cognitive impairment in Egyptian children with SCD.
In our study, we assessed the IQ by the Standford Binet test fourth edition . The mean cognitive IQ score among our patients was 75.6 which was significantly lower than that of control (IQ was 102 with P value of 0.01). This score was in close approximation to that reported in previous studies [15, 16], while Noll et al. reported higher IQ scores in their study where the IQ score reached up to 101.4 . This variation in the reported scores might be related to the presence of silent neurological insults in neurologically free SCD patients; which may affect their intellectual abilities. The frequency of impaired IQ in our studied patients was 65.5%, with most of them categorized as slow learners or having mild mental retardation, these findings were on line with previous reports [10, 18].
The cognitive deficits in SCD patients might be multifactorial and the exact risk factors are still not completely clarified. In our studied cases, we found that patients with abnormal IQ were mostly females and were older than those with normal IQ. Age correlated negatively with IQ, which was in agreement with several previous reports stating that IQ decreased with increasing age [10, 19, 20], while contradicted by other studies, which found that age showed no significant difference between SCD patients with normal IQ and those with abnormal score [17, 21]. Moreover, we found that the age of first blood transfusion correlated negatively with the IQ score. A possible explanation is that scheduled blood transfusion early in life improves growth, prevents VOC, limits school absences and hence improves cognition .Blood transfusion also increases the total hemoglobin and abates the anemia severity, thus improving the neurocognitive abilities by improving oxygenation and cerebral blood flow [23, 24].
In our studied cases, we found no difference in disease severity between group with abnormal IQ and the group with normal IQ. This has been previously reported [18, 25], however, contradicts have been reported as well, where disease severity was a contributing factor of school absence, leading to poor performance on IQ tests and low verbal abilities [26, 27].
In the current study, the group with abnormal IQ had insignificantly lower hemoglobin than the group with normal IQ. The same findings were detected by other authors [20, 28]. On the other hand, others found moderate to strong correlation between anemia severity and neurocognitive impairment, where hemoglobin was a strong marker for neurocognitive dysfunction [10, 14, 19, 24, 29].
Other laboratory variables including alanine transaminase (ALT), lactate dehydrogenase (LDH) and serum ferritin showed no significant differences between both groups. A higher total and direct bilirubin were found in patients with abnormal IQ, and negative correlations were found between IQ and both; AST and total bilirubin. These were in agreement with Weiskopf RB and colleague who reported that SCD patients with cognitive impairment had increased bilirubin .
In our study, we found no significant association between sickle genotype and IQ score. This was in line with previous studies reporting abnormal IQ equally in all SCD genotypes (Hb-SS, Hb-SC, Hb-SB)0 [31, 32]. A finding that was contradicted by others [29, 33] who found that SS genotype patients were more vulnerable to disease related complications, due to lack of fetal hemoglobin which ensures better oxygenation of the brain.
In our studied cases, hydroxyurea dose and duration of therapy were not proved to affect the degree of IQ impairment. Our results mismatch the results of a previous study reporting that neurologically intact SCD children who received regular hydroxyurea scored significantly higher IQ than patients without hydroxyurea .
Sickle cell patients are chronically anemic so increase in the cardiac output is required to maintain proper tissue oxygenation; this produces a mildly hyper-catabolic state, increasing resting energy expenditure, and chronic oxidative stress . Antioxidant capacity is an important protector against tissue injury, especially in patients with increased oxidant stress. Our patients showed significantly lower levels of the tested antioxidant compared to matching healthy controls. This is in agreement with previous study conducted on Egyptian children  while most of the other previous studies concerned with the oxidative stress in chronic hemoglobinopathies were carried out on adults [5,6,7,8].
Several authors reported alteration in the lipid soluble vitamins level as vitamin E in SCD patients [5, 9, 36]. The observed depletion of serum levels of vitamin E can be explained by impairment of liver function due to chronic hepatic iron overload, in addition to increased oxidative processes which cause substantial reduction of serum lipids with a concurrent reduction of serum vitamin E [37, 38].
We observed that SCD patients possess an extremely altered pattern of the tested serum antioxidants namely vitamin E and selenium. All SCD cases had below normal vitamin E and selenium levels versus none of the control group. This observation is consistent with other authors [5, 9, 36, 39, 40], and could be explained by the state of chronic oxidative stress with subsequent depletion of all antioxidants . However, the depleted antioxidants were not proved to be related to IQ scores among the studied population, this could be attributed to the fact that all the patients we studied were deficient in both vitamin E and selenium.
One of the limitations of our study is that we tested for individual antioxidants like vitamin E and selenium which may be less informative than other tests like total antioxidant capacity which reflects the collective contribution to the reducing property of non-protein individual antioxidant or electron donating components. Another limiting factor is the lake of magnetic resonance image (MRI) to exclude underling brain disorders that may affect cognition which were not done due to limited financial resources. And lastly the small sample size which might affect our conclusions.