Introduction
The most common neurological finding in children and adults with sickle cell disease (SCD) is the presence of silent cerebral infarcts (SCIs). SCIs are, by definition, undetectable by neurologic examination and are recognized on magnetic resonance imaging (MRI) as increased signal intensity in multiple T2-weighted images (1). SCIs are associated with a decline in full-scale IQ (2, 3) and increased risk for future strokes (4). In this paper, we provide an overview of studies that have used magnetic resonance imaging (MRI) to detect SCIs in patients with SCD. We systematically review evidence on SCI prevalence, incidence and associated risk factors.
Methods
A comprehensive systematic search was performed of Embase, MEDLINE, Cochrane, Web of Science and Google Scholar. Publications through June 1st, 2019 were included. Search terms included synonyms for 'SCIs' and 'SCD' in various combinations. All references listed in identified papers, or noted in footnotes of data tables, were reviewed for additional articles missed by computerized database search. After removal of duplicates, 651 studies were screened on potential eligibility. Studies were included if they concerned patients of all ages with either homozygous or compound heterozygous SCD and assessed for and specifically reported MRI-detected SCIs (Figure 1). We present a weighted prevalence by study size. When multiple articles reported on a single or overlapping population sample, prevalence estimates were obtained from the article with the largest sample size to prevent duplications.
Results
We included 61 original papers describing results in a total of 3740 individual SCD patients. Most studies were performed in HbSS or HbSβ0thal SCD patients (n=2122). However, five studies separately reported SCI prevalence in other SCD genotypes i.e. HbSC, HbSβ+thal (n=254) and healthy controls (n=52). The pooled prevalence of SCI among all included patients with SCD (n=3740) was 28.4% (95% CI: 4.0;32.9). Data from included studies showed a statistically significant correlation (P<0.001) between mean SCI prevalence % and increasing mean patient sample age (Figure 2). SCIs were more common in patients with HbSS/HbSβ0thal compared to other SCD genotypes (p<0.001) and healthy controls (P<0.001) (Figure 3). Studies focusing on incidence rates were sparse, with only four identified studies providing estimates ranging from 3.1% to 13.6% per year. The majority of included studies analyzed possible risk- or protective factors for SCI in SCD patients, i.e. hematological parameters, α-thalassemia presence and cerebral blood flow velocity (Table 1). Conflicting results are noted for most risk- and protective factors, with equal numbers of similar studies finding significant versus non-significant associations.
Conclusions
SCIs are common in patients with SCD with a weighted prevalence of 28.4%. Despite advancing neuroimaging technologies and therefore potentially enhanced detection of SCIs, there has been no apparent rise in SCI prevalence over the years. SCIs occur much more frequently in individuals with HbSS or HbSβ0thal than in other SCD genotypes. Analyses of risk- and protective factors showing varying results. The absence of robust findings is probably due to a combination of small sample sizes and weak associations. We believe SCIs are a poorly understood entity in patients with SCD. Despite substantial research efforts into risk- and protective factors, too little attention has been given to underlying pathophysiological mechanisms. Further research should focus on both SCI etiology in SCD as well as on clinical management of patients with evidence of these MRI lesions.
Disclosures
Cnossen: Pfizer: Other: Travel Grants, Research Funding; Bayer: Other: Travel Grants, Research Funding; Novo Nordisk: Research Funding; Nordic Pharma: Research Funding; CSL Behring: Other: Travel Grants, Research Funding; Sobi: Research Funding; Baxter: Other: Travel Grants, Research Funding; Shire: Other: Travel Grants, Research Funding; Takeda: Other: Travel Grants, Research Funding; Roche: Other: Travel Grants; NWO: Other: Governmental grants , ZonMW, Innovation fund and Nationale Wetenschapsagenda 2018.
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