In this largest prospective study to date in SCA, to our knowledge, we have provided evidence that clinically silent cerebral ischemia can be detected acutely, and that ASCIEs occur in asymptomatic children without concurrent or antecedent illness. Only 1 case of an ASCIE was documented in association with an acute illness (following acute chest syndrome). Moreover, ASCIEs appear to be 4 times more frequent than progressive SCI. Along with limited follow-up imaging data, this suggests, but does not confirm, that a fraction of ASCIEs may be transient lesions. We provide evidence that some ASCIEs are either radiographically reversible, as has been reported in transient ischemic attacks in the general population,16
or produce permanent infarction that is smaller than the limits of detection by MRI of the brain.
Two previous single-center studies provided the proof of principle that acute ischemic lesions occur in children with SCA who have nonfocal neurologic examinations. Dowling et al8
published a case series of children with SCA who had clinically silent acute cerebral ischemia detected by MRI with DWI sequences. These events were termed acute SCI because 4 of 7 cases had SCI on follow-up MRI that corresponded to the location of the previously detected DWI signal abnormality. Enninful-Eghan et al1
also reported 5 cases of acute SCI in children with SCA. In both studies, acute SCI was found mainly in the context of acute anemic or febrile illnesses. We prefer the designation ASCIE to acute SCI because it appears, based on our data and that of Dowling et al,8
that not all ASCIEs progress to radiographically detectable, permanent infarction that would later be classified as SCI. To our knowledge, we are the first to calculate the incidence of ASCIEs. Moreover, we show that ASCIEs occur in asymptomatic children without antecedent or concurrent acute medical illnesses.
We also find that SCI is a frequently progressive lesion in children with SCA. The incidence of progressive SCI, both new and enlarging lesions, is 10.7 events per 100 patient-years in a population of children with a mean age of 9.5 years (range, 5–15 years). The incidence of progressive SCI in 229 children aged 6 to 19 years in the Cooperative Study of Sickle Cell Disease was 7.1 per 100 patient-years (95% CI, 4.2 –11.8).9
Our similar findings (10.7 per 100 patient-years; 95% CI, 4.6–21.0, vs 7.1 per 100 patient-years; 95% CI, 4.2–11.8; P
= .35) provide strong evidence that the true incidence of progressive SCI is near these estimates. To our knowledge, there are no other reports of the incidence of SCI in SCA for comparison.
In summary, we found evidence to support our hypothesis that ongoing (chronic, intermittent) ischemia occurs in the brain, just as it occurs in other organ systems in SCA. The clinical implications of our findings are that children who have SCA with no history of overt stroke experience spontaneous cerebral ischemic events far more frequently than previously recognized, and that most of this cerebral ischemia is clinically silent. We postulate that small foci of acute cerebral ischemia (ASCIEs), potentially leading to infarction of brain tissue, may occur repeatedly in asymptomatic children with SCA, but the affected tissue is potentially salvageable. As such, the ASCIE may represent a lesion analogous to the concept of the ischemic penumbra in other forms of acute ischemic stroke,17,18
except that the entire ASCIE lesion can be considered the penumbra. Like other ischemic processes, reperfusion of ASCIE lesions may bring oxidative and inflammatory injury.19
We propose that ASCIEs are a paradigm of ischemia-reperfusion injury, occurring in the brain just as it is thought to occur in other tissues and organs in SCA.20–22
Additionally, supporting this concept is the preliminary observation that the plasma concentration of glial fibrillary acidic protein, a known plasma biomarker of acute stroke and brain trauma, is increased in patients with SCA compared with individuals without SCA.23
The optimal management of patients with ASCIEs has not been established. Children with SCA and ASCIEs will need to be studied systematically to determine what treatment, if any, is warranted.
This study has several limitations. First, we did not study a random sample of children with SCA. The prevalence of SCI in the ASCIE incidence population was more than 40% compared with 20% to 37% in prior studies of SCI.2,9,24,25
Therefore, we may have studied a population enriched with children at risk for SCI and ASCIEs; however, our estimate of prevalence approximates that of Bernaudin et al (37% by 14 years of age).2
Nevertheless, this was a generally healthy population of children with SCA, without known stroke, neurologic injury, or epilepsy, and not receiving treatment with transfusion or hydroxyurea for severe SCA. Also, our estimate of the incidence of progressive SCI agrees with Pegelow et al.9
There are no reports of the incidence of ASCIEs for comparison, but the ratio of ASCIEs to SCI indicates that ASCIEs occur more frequently (4-fold) than SCI. Second, because of the SIT Trial design, we did not have follow-up MRIs on most cases of ASCIEs, thus we cannot confirm how many cases of ASCIEs progressed to SCI. Nevertheless, the disparate incidence rates (ASCIEs much higher than SCI), our limited follow-up imaging data, and the follow-up imaging data from Dowling et al8
together suggest that ASCIEs occur more frequently than SCI. Third, antecedent and concurrent medical events associated with ASCIEs were captured using a retrospective tool, thus mis-classification of silent status was possible. Nevertheless, all ASCIEs were discovered incidentally and only 1 case had new issues prompting medical attention. Fourth, because DWI and apparent diffusivity coefficient signal abnormalities can persist for 7 to 14 days after the onset of acute cerebral ischemia, choosing different time intervals will affect the calculated incidence rate of ASCIEs. For example, if we consider that diffusion-weighted scans provide only 7 patient-days of observation, the calculated incidence of ASCIEs would be approximately 7 times higher than SCI. We chose to be conservative in this analysis by using 10 days, which available evidence suggests is the reasonable upper limit.12–14
Fifth, we calculated the incidence of ASCIEs using a novel method that uses the temporal information contained within the DWI signal of a single MRI, rather than the classic method of using paired MRIs. Each DWI scan provides 10 continuous days of observation for acute ischemia; thus, it is a valid method for construction of an incidence. Finally, the different MRI methods used to calculate the incidence of ASCIEs and SCI may have different sensitivities for the lesion in question, thus this might limit precise comparisons of rates.
We conclude that asymptomatic children with SCA experience cerebral ischemia far more frequently than previously recognized. By considering only discrete, easily visualized, and permanent brain lesions (stroke and SCI), one underestimates the true frequency of all ischemic insults to the brain in SCA. We propose that the brain in SCA is at constant threat of ischemic injury. Further research is needed to better understand the causes, consequences, and treatment options of ASCIEs in SCA.