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A Marriage of Hematology and Neurology: Studying Sickle Cell Disease in the Pediatric Brain

By Daniel J. Bonthius, MD, PhD | Summer 2023

As we all learned in medical school, sickle cell disease is an inherited hemoglobinopathy, caused by a single base pair mutation in the beta-globin gene. Although sickle cell disease was one of the first genetic diseases discovered, research into its clinical manifestations has lagged behind many other more recently discovered disorders. As a result, the neurological and developmental consequences of sickle cell disease and the optimal ways of preventing and treating them remain largely unknown. Dr. Eboni Lance (Figure 1) aims to fill that void.

Figure 1. Dr. Eboni Lance explains her research findings regarding neurodevelopmental disabilities in children with sickle cell disease.

Dr. Lance is a physician at Kennedy Krieger Institute and an Associate Professor at Johns Hopkins University School of Medicine. She first became interested in sickle cell disease as a medical student when she evaluated a home sleep study monitoring device as part of a summer research project. While fascinated by the field of hematology, she was especially captivated by her experience in neurology, and she struggled to decide which field to enter. Her problem was solved by wise mentors who guided her to the realization that she could pursue both fields by specializing in the neurology of sickle cell disease.

As a fellow in neurodevelopmental disorders (NDD), she founded the Kennedy Krieger Institute Sickle Cell Disease Neurodevelopmental Clinic, a multidisciplinary clinic that has grown to prominence and she continues to lead. In this clinic, she has observed the many ways in which sickle cell disease adversely impacts the neurodevelopment of children. These effects include not only stroke – a well known complication of sickle cell disease – but also silent cerebral infarction and a host of neurodevelopmental deficits, including ADHD, cognitive impairment, language disorders, and executive function impairment.

Dr. Lance encountered many patients with neurodevelopmental disorders and sickle cell disease during her NDD fellowship period. However, she discovered that there was a gap in knowledge regarding the mechanisms underlying these disorders as well as diagnosis and treatment. She decided that, if she wanted to provide optimal clinical care for these patients, she would have to conduct research herself. Therefore, she enrolled in a Clinical Investigation graduate program and received her PhD four years later.

Armed with a passion to understand the neurology of sickle cell disease and the skills to conduct research, Dr. Lance launched a clinical research program, The Sickle Cell Disease and Neurodevelopment Clinic and Research Center. She leverages a variety of techniques and collaborators to study multiple facets of sickle cell neurology, including its molecular underpinnings, physiology, neuroimaging, and behavioral manifestations.

Dr. Lance has studied the co-occurrence rates and clinical phenotypes of various neurodevelopmental disorders in pediatric sickle cell disease (figure 2). She found that 24% of children with sickle cell disease have neurodevelopmental disorders. Further, even when patients with stroke are excluded, the rate is still high at 19%. Dr. Lance found that silent cerebral infarctions underlie the deficits in some of these cases, but that no evidence of stroke can be found in others. This suggests that sickle cell disease disrupts brain activity in ways other than stroke. Indeed, her physiologic studies have revealed evidence for alterations in cerebral blood flow, oxygen extraction fraction, and cerebral metabolic rate of oxygen.

Figure 2. Bar graph showing the co-occurrence of specific neurodevelopmental disorders in four pediatric populations: pediatric patients with sickle cell disease, the general US pediatric population, Black children in the general US population, and Hispanic children in the general US population. Different neurodevelopmental disorders occur at markedly different rates in all four populations, including those with sickle cell disease. (Lance EI, et al. J Dev Behav Pediatr 42:463-471, 2021)

Dr. Lance’s molecular studies have shown that patients with sickle cell disease have elevated circulating levels of certain brain-derived proteins, including brain-derived neurotrophic factor (BDNF) and neurogranin. Elevated plasma levels of these proteins likely represent biochemical evidence of neurological injury.

The over-riding goal of Dr. Lance’s research is to improve neurodevelopmental outcomes in children with sickle cell disease. The undaunted way in which she addresses complex research issues makes it highly likely that she will accomplish this ambitious goal.