{'fraction_non_alphanumeric': 0.032241685707032244, 'fraction_numerical': 0.01574003554201574, 'mean_word_length': 4.811209439528024, 'pattern_counts': {'":': 0, '<': 0, '<?xml version=': 0, '>': 0, 'https://': 0, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 0, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
MRI abnormalities in infants with sickle cell anemia—indication for preemptive therapy?

P rogress in the management of sickle cell anemia (SCA) has improved life expectancy, leading to greater efforts to preserve long-term quality of life. Central nervous system (CNS) involvement in children with SS is gaining importance as we deal more efficiently with other complications of the disease. Stroke remains a major source of disability in children with SCA, occurring in 11% of the patients by the age of 20 years [1]. The routine use of transcranial Doppler (TCD) to identify patients with SS and at high risk for cerebral infarction [2] had a major impact in implementing preemptive maintenance transfusions, resulting in prevention of clinically evident strokes by 90% [3]. TCD is a noninvasive and reproducible tool to detect narrowing of the large vessels such as the internal carotid or the middle cerebral arteries which are particularly prone to stenosis [4]. With the availability of magnetic resonance imaging (MRI), it became clear that neurological abnormalities were not limited only to those clinically symptomatic SS children, but were detected also in neurologically normal patients. These lesions, called ‘‘silent infarcts,’’ appear especially in the deep white matter, sparing the cortex and in contrast to those patients with overt stroke [5]. The ‘‘silent infarcts’’ occur in about 20% of children with SCA [6–8]. As for those patients with high TCD velocities, there is an increased risk for stroke in patients with silent infarcts, with the risk being even higher for those with both [9]. The HUSOFT extension trial observed the long-term administration of HU to children who were between 6 and 24 months of age at the moment of enrolment in the initial study. These patients, followed for a mean period of 4.9 1.3 years (range 2.1–6.0 years), benefited from HU in terms of preservation of splenic function, acute chest syndrome events, and higher HbF levels [10]. However, prevalence of silent infarcts were 21% at a median age of 5 years, making it unclear whether HU prevented development of cerebrovascular disease in SCA. Wang et al. report on the initial CNS evaluation findings of the infants enrolled in the BABY HUG trial which compares HU versus placebo for splenic and renal functions as primary endpoints, and the effects on the brain as secondary endpoints. CNS imaging by MRI and MRA (magnetic resonance angiography), developmental testing, TCD and neurological examinations were the study tests required for eligibility. Twenty-three infants with SS at a mean age of 13.7 months (10–18 months) were enrolled in the study. Three patients had MRI abnormalities in the form of small right frontal infarcts (13%). Low HbF levels and high TCD velocities seemed to be associated with MRI lesions. Wang et al. previously reported on their 2-year pilot trial of HU on 39 very young children, of whom 4 (10%) had silent infarcts. This and the study presented in this issue of Pediatric Blood & Cancer encompass 7/62 patients with cerebral infarcts (12%) detected at an average age of 16–17 months [11], and in agreement with each other in terms of prevalence of asymptomatic CNS disease in very young children with SS. We have learned from the STOP I and STOP II trials that chronic transfusion can reduce the incidence of stroke [12,13]. Furthermore the benefits of transfusion were reversed once stopped. However, recommendations for management of children with silent infarcts are lacking. With the known risks of chronic transfusions, preemptive HU therapy started at a very young age may be an attractive alternative. Still, caution is required as to the risks of long-term exposure, especially in this age group. The report by Wang et al. points to the urgent need to develop a randomized clinical trial on the role of preemptive use of HU to prevent or delay CNS disease in very young children with SCA.