Identifying Clinical and Socioeconomic Factors Associated with Neuropsychological Impairment in Pediatric Patients with Sickle Cell Disease

Background: Children with sickle cell disease (SCD) are at high risk of neuropsychological impairment (NPI), which can impact their performance in school, future employment, social interactions, and overall quality of life. Overt strokes, silent cerebral infarcts, cerebral hypoxia from chronic anemia, and vaso-occlusion are all thought to contribute to NPI. The 2021 ASH Guideline for the prevention and management of cerebrovascular disease in SCD recommends basic screening surveillance questions asked of parents and caregivers to identify concerns for neurocognitive abnormalities. However, there is insufficient evidence to recommend a specific assessment tool. The gold standard, a complete neuropsychological assessment, includes 4-6 hours of testing by a qualified neuropsychologist or neurologist and is not feasible for every patient. In this study, we sought to retrospectively identify demographic and clinical factors that are associated with the presence of NPI. This work lays the foundation for developing a tool to identify patients most at risk for NPI and most likely to need priority referral for complete neuropsychological assessment.

Methods: We reviewed electronic medical records for all children with SCD who underwent complete neuropsychological assessment between 2014-2023 at our institution. Neuropsychological assessment involved a variety of tests evaluating multiple cognitive domains, but always included the evaluation of seven core domains: visual/spatial reasoning, attention/working memory, processing speed, executive function, fine motor skills, memory, and reading. We selected a strict definition of NPI, defined as having three or more domains with a test score more than 1.5 standard deviations below the mean value in healthy children. Using historical data from the electronic medical record, we evaluated which demographic data, clinical history data, lab/clinical metrics, and socioeconomic data associated with NPI. Individuals were compared by the Chi-squared or Fisher's exact tests for categorical variables and Kruskal-Wallis test for continuous variables based on NPI status. Multivariable logistic regression was used to identify factors associated with increased probability of NPI status. All analyses were performed using R software version 4.3.0 (R Core Team, Vienna, Austria). P-value <0.05 was considered statistically significant.

Results: We identified 114 children who underwent neuropsychological assessment during the period of review. Among those, 36 patients met criteria for NPI. Within the entire cohort, 64 (56.1%) had an MRI prior to neuropsychological evaluation. There was 1 (1.6% of MRIs) documented overt stroke, which occurred in a child with NPI. No patients had documented silent stroke. Of the clinical history parameters investigated, history of acute chest syndrome (ACS) was significantly correlated with presence of NPI (OR 3.96, 95% CI: 1.36-13.2, p = 0.02). Other clinical factors, including number of prior hospitalizations, an obstructive sleep apnea diagnosis, and the use of hydroxyurea, were not significantly different between patients with or without NPI. Reported medical provider or caregiver concern about school, behavior, or development was also not significantly different between the two groups. Of the socioeconomic factors we investigated, we found that patients with NPI were more likely to have a caregiver without a high-school degree (7.7% vs 22.2%, p = 0.04). Other socioeconomic factors, including type of insurance coverage or whether the child lives in a single-caregiver household, were not significantly different between the groups.

Conclusions: Given our finding that simple surveillance questions may not be predictive of NPI and given the limitations of comprehensive neuropsychological testing for every SCD patient, larger prospective studies should be done to determine how to use the factors identified in this study and others to assess risk of NPI and which patients need to undergo comprehensive neuropsychological assessment. In addition, identifying an abbreviated set of neuropsychological tests most appropriate for SCD patients could make universal testing more accessible.

Tubman:Global Blood Therapeutics: Research Funding; Novartis Pharmaceuticals: Consultancy, Research Funding; Agios Pharmaceuticals: Research Funding.