Objective:
The Evolving Treatment of Hemophilia’s Impact on Neurodevelopment, Intelligence and Other Cognitive Functions (eTHINK) study aims to evaluate the impact of hemophilia on neurodevelopment and cognitive function through the use of validated instruments and to identify covariates that drive differences in neuropsychological performance.
Methods:
A sample of at least 510 males aged 1-21 years (~25 per age) with hemophilia A or B (any severity, with or without inhibitors) will be enrolled in a cross-sectional, non-interventional study. Following ethics review and informed consent, data collected will include a structured developmental and hemophilia history interview, a standardized neurologic examination, and a comprehensive neuropsychological assessment of cognitive/motor development (Bayley-III), intelligence (WPPSI-IV/WASI-II), attention/processing speed (CogState™), executive function (BRIEF-P/BRIEF2/BRIEF-A), mood and behavior (BASC-3), and adaptive behavior (ABAS-3). Assessments will include objective tests as well as parent and patient self-report rating scales. Z scores will be derived from published general population norms for each instrument and analyzed to develop hemophilia population specific norms. Secondary analysis for predictors of outcome will include regression modeling and chi-square tests of top vs bottom quartile responses.
Summary:
Initiated in the early 1990s under Centers for Disease Control, Maternal and Child Health Bureau, and National Institutes of Health, the Hemophilia Growth and Development Study (HGDS) evaluated the impact of hemophilia on neurodevelopment, executive function, and intelligence. The 4-year observational study enrolled 333 patients from 14 US centers, aged 6-18 years at baseline (62% HIV+), who underwent annual/semi-annual comprehensive assessments including neurologic examination, neuroimaging (MRI), and neuropsychological assessment. Results suggested that hemophilia and HIV had independent effects at baseline and follow-up. Baseline neurologic examination findings were common, as were progressive abnormalities of gait/coordination. Imaging showed baseline CNS bleeds in 12% of patients and new CNS bleeds (2% per year), which often occurred in the absence of reported head trauma. HIV+ children were more likely to show lower scores on neuropsychological assessments. Academic/adaptive skills were lower than expected based on mean IQ, and more behavioral/emotional problems were seen, including attention abnormalities related to known/silent CNS bleeds. There was a large shift in mean scores in IQ and achievement for the children with more severe hemophilia. Six small studies published between 1996 and 2009 reported impacts on academic achievement, attention, and behavior.
Conclusions:
HGDS established 25 years ago that hemophilia and HIV have independent effects on cognitive and behavioral function in children with hemophilia. Since then, standards of care in hemophilia treatment have changed significantly, but no follow-up studies have investigated whether these changes have affected the profile of neurocognitive outcomes in hemophilia. We therefore designed the eTHINK study to provide valuable insights into whether subgroups of children and young adults with hemophilia remain at risk for impaired neuropsychological outcomes.