In 1963, Chordokoff and Whitten published a study that compared the intellectual quotient (IQ) of children with sickle cell disease (SCD) with a group of siblings, and concluded that there were no differences Citation[1]. Shortly thereafter in the midst of the civil rights era, assertions were made that IQ testing showed that blacks were intellectually inferior to whites Citation[2]. As a consequence of the significant cultural and civil rights’ implications of this statement, IQ testing of black children in most settings slowed to a halt, and there was no further study of neurocognitive function related to sickle cell anemia for nearly two decades.
In the mid to late 1980s, parents brought concerns about their children’s difficulties in school to the sickle cell centers treating their children. Within this parent advocacy context, several studies began reporting differences in global cognitive function, particularly for children with HbSS or HbSβ0thal, as well as patterns of specific difficulties in processing speed, executive function and academic difficulties in reading and math. At about the same time, the Cooperative Study of Sickle Cell Disease (CSSCD) began examining neurocognitive function and neuroimaging patterns in a large SCD cohort over a 10-year period. The CSSCD found that nearly 22% of children with HbSS experienced a clinical stroke or silent cerebral infarct prior to 15 years of age, and that there were measureable differences in global cognitive function and specific neuropsychological function associated with these events Citation[3]. In addition, the CSSCD found that in children who had no evidence of brain abnormality on MRI over the 10 years of participation, there was still a mean decline of 16 IQ points over time Citation[4]. This strongly suggested that something besides vascular occlusion/infarction placed children with SCD at risk, and mechanisms involving chronic anemia, hypoxia or interference with oxygen perfusion and diffusion have been considered Citation[5].
Recognition that there is high risk of stroke for children with SCD led to an evaluation of stroke prevention strategies that involved screening cerebral vascular flow velocity using transcranial Doppler ultrasonography. After determining that flow velocities greater than 200 cm/s were associated with significant clinical stroke risk, the Stroke Prevention Trial in Sickle Cell Anemia (STOP) and STOP II clinical trials demonstrated that chronic transfusion therapy could prevent stroke in most of these patients Citation[6,7]. Unfortunately, those children with conditional transcranial Doppler flow velocities (170–200 cm/s) who are not transfused also have evidence of mild neurocognitive impairment Citation[8].
Owing to these observations, most recent evaluations of clinical trials to treat children with SCD have included neurocognitive function as a primary or secondary outcome, including those evaluating the effectiveness of hydroxyurea in infants Citation[9] and young children Citation[10], teratogenicity for offspring of adults treated with hydroxyurea Citation[11] and hematopoietic stem cell transplantation. It is clearly a priority of the pediatric SCD community to address concerns and better understand how neurocognitive function is affected and how to prevent this from happening.
It has not been as clear a priority for the adult sickle cell population. Few studies over the last 30 years have included neurocognitive function as an outcome. That is likely to change. The results of a recent cross-sectional study of neurocognitive function and neuroimaging outcomes in neurologically intact adults aged 19–55 years with sickle cell anemia found that 33% had neurocognitive function that was below average, compared with an expected 16% in the general population. The participants were screened in a number of laboratory and clinical measures that might affect neurocognitive function, with the significant clinical inclusion criteria being a hemoglobin level of 10 g/dl or lower. Patients performed significantly worse than matched community controls in measures of nonverbal neurocognitive function. Poorer performance was associated with older age and lower hemoglobin. There were no significant associations between neurocognitive performance and abnormalities on MRI Citation[12]. An editorial accompanying the article suggested that this finding might account for vocational challenges, adherence problems and even pain perception and management for these adults with SCD Citation[13].
It is now very clear that SCD is associated with risk of neurocognitive difficulties from infancy through adulthood. Neurocognitive function is, however, more than performance on a battery of psychological tests. It may be a determining factor for whether a child succeeds in school, has friends and is able to become independent, or whether an adult is able to pursue a career or vocation of choice, be successful in a career, develop long-term and meaningful relationships, or manage a complicated and often debilitating disease.
The consistent data pointing to associations between neurocognitive function and CNS infarction, as well as possible associations with anemia, hypoxia, pulmonary function and nitric oxide availability are intriguing scientific areas of investigation. The observation that these neurocognitive challenges may be evident in infancy, and in nearly one third of the symptomatically healthiest adults with sickle cell anemia, makes this a real and time-sensitive issue. While it is clear that not all individuals with SCD will have neurocognitive difficulties and may, in fact, be incredibly bright and successful, for those who do, this is a potentially debilitating concern. The questions that are unanswered focus on whether this is a life-long risk, increases with age, or results in CNS cognitive difficulties earlier than seen in the general adult population. We also have to address how to treat those who have the neurocognitive difficulties, and, ultimately, how to prevent these from occurring. In the near future, it is almost a certainty that we will discuss expanding the criteria for hematopoetic stem cell transplantation for infants with sickle cell anemia, possibly transfusing children who are asymptomatic except for chronic anemia, exploring more widespread use of hydroxyurea, developing new drugs that target the mechanisms for neurocognitive impairment, examining the safety and efficacy of medications used to treat CNS-related attention and memory difficulties, and evaluating the effectiveness of targeted and intensive cognitive-remediation interventions. These are all promising avenues of investigation.
However, the current challenges for children and adults with sickle cell anemia remain. These are compounded when we consider that, while there have been many positive changes in the social and cultural environment since 1963, concerns about stigmatization related to intellectual function realistically and reasonably still exist for minority individuals. Unfortunately, this social context potentially leads to under-identification of disease-related consequences that affect neurocognitive function. One outcome of this is that cognitive difficulties, poor academic achievement, poor job performance, or difficulty with adherence to treatment become attributed to seemingly unmodifiable factors, such as poverty or social turmoil, or to personal characteristics like laziness or lack of motivation. In this context, there are several critical tasks for the sickle cell community: work to destigmatize these associations, to assure that appropriate evaluation and access to intervention and support are provided, and, ultimately, to continue the drive to find a cure for the underlying disease that causes these problems. As we do this, we have to consider how to address this issue for patients in the global community, where there are many more affected than in the USA, and where resources are substantially fewer.
Sickle cell disease is a horrible disease. We owe our family members, friends, and patients all we can do to understand, support, treat, and prevent the consequences of the disease on neurocognitive function and related quality of life. For too long we have blamed poor school and vocational attainment on poverty and personality – we must do better now that we know better.
Financial & competing interests disclosure
Preparation of this editorial was supported in part by funding from the National Heart, Lung, and Blood Institute (MD, USA; 1U54HL090569), the Administration on Developmental Disabilities (90DD0408) and Health Resources and Services Administration (T73 MC 00013). The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.
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