Retinal Optical Coherence Tomography as a Noninvasive Biomarker of Silent Cerebral Infarcts in Pediatric Sickle Cell Disease

Background

Stroke is one of the most devastating complications of sickle cell disease (SCD). Silent cerebral infarcts (SCI) occur even more frequently than overt stroke, affecting nearly 40% of children with HbSS or HbSβ0 thalassemia (SS/Sβ0) by 18 years of age. Early detection of SCI is critical, as chronic transfusion therapy can halt lesion progression, mitigate cognitive decline, and reduce the risk of overt stroke. Brain MRI is currently the only modality capable of detecting SCI; however, routine MRI screening is limited by cost, accessibility, and sedation risks in children. No reliable prescreening strategy exists to identify children at the highest risk. Examining brain pathology may be enhanced by insights gained through examination of the retina. The retina and brain share embryologic origin, microvascular architecture, and susceptibility to ischemic injury. In SCD, both organs are vulnerable to subclinical vascular damage that usually first appears in the watershed border zones between vascular territories. Optical coherence tomography (OCT) provides high-resolution, in vivo visualization of retinal microstructure and can detect ischemic injury such as selective retinal thinning. OCT is widely available, rapid, noninvasive, and well-tolerated in young children, making it an attractive option for prescreening Since 2015, we have incorporated retinal OCT into the SCD screening for children aged ≥ 5 years. This study investigated the correlation between SCI and retinal injury detected by OCT. Associations of brain and retina findings with SCD clinical markers and hematologic values were also analyzed.

Methods

In this prospective case series, 269 children and young adults with SCD (128 male; age range 4.4–21.9 years) were enrolled at Nemours Delaware Comprehensive Sickle Cell Research Center. All participants underwent comprehensive ophthalmic examinations, including dilated fundoscopy and retinal OCT. Retinal ischemic injury was defined as loss of the inner retinal layer definition and focal or regional thinning on cross-sectional OCT images. Among the cohort, 158 patients had SS/Sβ0 genotypes, and 111 of these patients (56 male) underwent brain MRI/MRA as part of clinical care. Hematologic laboratory values obtained within one year of retinal and brain imaging were extracted from the medical record. Categorical variables were analyzed using chi-square tests, and continuous variables were analyzed using nonparametric methods. Diagnostic performance of OCT for detecting SCI was assessed using sensitivity, specificity, and diagnostic odds ratio.

Results

Funduscopic examination identified retinopathy in 14 of 158 SS/Sβ0 patients (8.9%), whereas retinal OCT detected ischemic thinning in 106 patients (67.1 %, age at detection range 5.35 – 21.88 years). Among the 111 patients with brain MRI, 40 (36.0%, age at detection range 1.95 – 18.18 years) demonstrated MRI abnormalities consistent with SCI. Of these, 37 patients (92.5%) also had abnormal OCT findings, compared with 33 of 71 patients (46.5%) with normal MRI who did not show OCT abnormalities (χ², p < 0.001). Using OCT as a prescreening tool for SCI, sensitivity was 0.93 (95% CI: 0.84–1.00), specificity was 0.47 (95% CI: 0.35–0.58), and the diagnostic odds ratio was 10.7. Patients with MRI abnormalities had a significantly higher rate of bilateral OCT involvement (p < 0.001), a greater extent of retinal thinning, and extension into the foveal region (p < 0.001). MRI abnormalities were also associated with male sex, older age, history of acute chest syndrome, markers of hemolysis, and lower fetal hemoglobin levels.

Conclusions

Retinal OCT demonstrated substantially higher sensitivity than conventional funduscopic examination for detecting subclinical retinal injury in children with SCD. The strong association between OCT abnormalities and silent cerebral infarcts suggests that OCT may serve as a feasible, noninvasive prescreening tool to identify children at high risk for SCI who may benefit from targeted brain MRI. Early identification could expand the therapeutic window for stroke prevention. Additionally, retinal OCT may function as an accessible biomarker of cerebrovascular injury for monitoring disease progression and evaluating emerging disease-modifying and curative therapies. These findings warrant validation in larger, multicenter prospective studies.

Brain MRA and the right eye retinal OCT