Children with sickle cell anemia (SCA) are at risk of developing cerebral ischemia, including a high prevalence of silent cerebral infarcts (SCI), which can lead to cognitive impairment and an increased risk of stroke. However, the mechanisms underlying this risk are unclear. In a study published in Blood, researchers tested the hypothesis that SCIs are caused by impaired cerebral oxygen delivery, finding that most SCIs occurred in vulnerable anterior and posterior “border-zone” regions with the lowest cerebral blood flow.
With this information, the authors, led by Andria L. Ford, MD, MSCI, of the Washington University School of Medicine in St. Louis, created an “infarct density map” and were able to identify risk factors – including infarct volume, reticulocyte count, and recurrent headache – associated with a higher three-year risk of overt stroke.
The analysis included 286 children (median age = 9.3 years; range = 5-15 years) with hemoglobin SS or hemoglobin Sβ0 thalassemia who had experienced at least one MRI-identified infarct-like lesion (≥3 mm). All SCIs were centrally adjudicated by a panel of neuroradiologists and neurologists. Children with a history of focal neurologic deficits associated with an MRI-detected infarct, seizure disorder, treatment with hydroxyurea within three months of study entry, or a history of regular transfusion therapy were excluded.
To evaluate the location and frequency of SCIs, the investigators outlined and compared a series of images of each infarct on a brain atlas. Infarct density ranged from 0 to 18 percent, and the map was divided into three infarct-density regions:
- low (1-6%)
- moderate (7-12%)
- high (13-18%)
“Infarct locations with the highest density were found in the white matter of the frontal (n=258; 90%) and parietal lobes (n=152; 53%) above and adjacent to the lateral ventricles,” the authors reported. Additionally, SCI volumes were larger in white matter, compared with gray matter (median size = 278 mm3 vs. 33 mm3; p<0.001).
“A relatively small region, measuring 5.6 percent of total brain volume, encompassed SCIs from 90 percent of children,” they added.
To evaluate whether SCI incidence correlated with areas of low cerebral blood flow, the authors compared cerebral blood flow maps from children enrolled in the present study with an independent cohort of 41 pediatric patients with SCA. Their findings confirmed the hypothesis that SCIs were associated with impaired hemodynamics: Cerebral blood flow was lowest in the region of highest infarct density (p<0.001).
Next, the researchers compared regions commonly affected by SCI with those affected by overt infarct to determine the regions in which SCIs were most likely to develop into strokes.
Using data from 13 children who were originally excluded from the analyses for experiencing an overt stroke, the investigators created a separate infarct density map. “Similar to SCIs, overt infarcts were predominantly located within the border-zone region but were larger in volume when compared with children [who did not develop overt stroke].”
In multivariable analysis of the 286 trial participants, several imaging and clinical factors were associated with a greater likelihood of overt stroke within three years of follow-up:
- baseline infarct volume as a percent of total brain volume (odds ratio [OR] = 9.20; p=0.001)
- steady-state reticulocyte counts (OR=1.10; p=0.008)
- parental report of recurrent headache (OR=4.06; p=0.011)
“Despite a small cohort of [patients having an] overt stroke, we found a strong relationship between low resting cerebral blood flow and increased lesion density,” the study researchers wrote. “These preliminary data suggest that overt infarcts share a similar stroke mechanism to silent infarction with regard to border-zone ischemic vulnerability.”
The authors noted the analysis’ strict inclusion criteria as a limitation. “Our results are specific to children with SCIs and normal or conditional transcranial Doppler velocities (<200 cm/sec), a subgroup that represents the majority of children with SCIs,” they wrote, which potentially limits the generalizability of the findings. The relatively small sample size is an additional limitation of the study.
“The infarct density map provides a template for future studies evaluating novel imaging biomarkers predicting stroke risk in SCA,” the authors concluded.
The authors report no financial conflicts.
Ford AL, Ragan DK, Fellah S, et al. Silent infarcts in sickle cell anemia occur in the borderzone region and are associated with low cerebral blood flow. Blood. 2018 July 30. [Epub ahead of print]
“This observation that the lowest cerebral blood flow region strongly overlapped with the areas of highest infarct (SCI and overt infarct) lesion on density maps suggests a region of vulnerability prior to accumulating SCIs and overt infarcts. Cerebral blood flow analysis in the independent cohort allowed cerebral blood flow measurements to be assessed prior to developing SCI or overt infarcts and therefore is generalizable to the SCA population. The infarct density maps described in this study can be leveraged to include an imaging biomarker to predict stroke risk in SCA. Collectively, this information provides physiological evidence for targeted primary and secondary interventions to improve border-zone cerebral blood flow, which may ultimately reduce the risk of SCI and potentially overt strokes, as well.”
Ify Osunkwo, MD, MPH
Levine Cancer Institute
Carolinas HealthCare System