Interventions to Prevent Silent Cerebral Infarcts in Sickle Cell Disease

Background Silent cerebral infarcts (SCI) are a significant neurological complication of sickle cell disease (SCD), affecting both adult and pediatric populations. These lesions are associated with cognitive impairment, reduced quality of life, and is associated with higher risk of overt strokes. Despite their prevalence and impact, a comprehensive synthesis of the evidence on effective interventions for SCI is lacking. This systematic review aims to evaluate the current literature on a range of therapeutic strategies for improving outcomes and preventing the progression or recurrence of SCI in patients with SCD. Methods We conducted a systematic review following a pre‐established protocol. A comprehensive search of electronic databases including PubMed and Google Scholar was performed, yielding a total of 189 records. After removing 73 duplicates, 116 records were screened for eligibility. We included 43 studies in the final review, comprising randomized controlled trials, observational studies, case series, and case reports. Data on a range of outcomes were extracted, with the most frequently reported outcome serving as the primary endpoint. The interventions of interest included, but not limited to, those aimed at: 1) preventing the progression or enlargement of existing SCI, 2) preventing new/recurrent SCI 3) improving cognitive outcomes. Data on a range of outcomes were extracted, with the most frequently reported outcome serving as the primary endpoint. Results We found 43 studies that explored interventions for MRI‐defined silent cerebral infarcts (SCI) in patients of all ages with sickle cell disease. This includes randomized trials, observational cohorts, and post hoc analyses from major trials. Regular blood transfusions significantly lower the chance of new/progressive SCI. The STOP II trial showed that stopping prophylactic transfusions increased SCI occurrences (27.5% vs 8.1%, p=0.03). The SIT trial pointed towards more transfusion associated with better cognitive outcomes. Keeping HbS below 50% (compared to the usual 30%) further decreases sickling and cerebrovascular risk while minimizing complications related to transfusions. Hydroxyurea, studied in TWiTCH (n=121) and several observational cohorts, was linked to low rates of new or worsening MRI lesions over time. Hematopoietic stem cell transplantation (HSCT), including matched sibling donor transplants, were associated with a low new SCI rate (2.2 per 100 person‐years), based on stable/improved MRI results, further supported by a normalized transcranial Doppler velocities. Factors like hypertension, parvovirus B19 infection, anemia, and/or impaired red‐cell function were shown to be major risk factors for SCI and their management could be effective strategies for future trials aimed at preventing them. Conclusion Overall, different interventions show varying levels of evidence. Chronic blood transfusion and hematopoietic stem cell transplantation demonstrate the strongest evidence for preventing new silent cerebral infarcts and/or their progression in sickle cell disease. While other therapies like hydroxyurea show promise, high‐quality prospective studies with well‐defined MRI endpoints are required to confirm their efficacy. Future interventions should also focus on key modifiable risk factors such as blood pressure control and anemia management to prevent SCI.