Prevalence of Extracranial Internal Carotid Arteriopathy in Stroke-Free SCA-Children: A New Risk Factor for Silent Strokes

Strokes are a well-known complication of sickle-cell anemia (SCA), and are largely due to intracranial arteriopathy, detected by routine transcranial Doppler (TCD). Adams et al. showed in the STOP I trial (N Engl J Med, 1998) the efficiency of transfusion programs for primary stroke prevention in patients identified by TCD as being at risk of stroke. We recently reported in the CHIC newborn cohort (Bernaudin et al., Blood, 2011) that early TCD imaging (TCDI) screening significantly reduces the risk of stroke by age 18 from the previously reported 11% to only 1.9%, but has not allowed adequate prevention of silent infarcts, with a risk of 37.1% by age 14, suggesting that TCDI does not distinguish all SCA-patients at risk of silent infarcts. Extracranial internal carotid artery (eICA) vasculopathy is considered rare and has not been routinely assessed; however, several recent cases of stroke with extracranial arteriopathy prompted the inclusion of eICA evaluation in routine screening. The aim of the study was to establish the ranges of eICA velocities in SCA-patients, to determine the cut-off limits of velocities predictive of eICA stenoses by extracranial MRA, to evaluate the prevalence of abnormal eICA velocities and to determine their association with intracranial stenoses and/or silent infarcts by MRI.

Since June-2011, all stroke-free SCA patients from the CHIC and Debre cohorts who had routine yearly TCDI for intracranial arteries were also systematically assessed for eICA using submandibular windows (Gorman et al., Neurology 2009) and the same 2Mhz TCDI transducer probe. Time-averaged mean of maximum velocities (TAMMV) were obtained for intra and extracranial cerebral arteries. By color Doppler mapping, the course of eICA was considered as straight, or as tortuous if the artery changed direction with an angle > 120° between adjacent segments. Extracranial cervical MRA was added to routine intracranial MRI/MRA, performed every 2 years or as soon as abnormal velocities were found.

Between June 2011 and January 2012, 435 consecutive SCA-children from the two cohorts (202M, 233F) were assessed by Doppler at the median age of 8.5 years (range: 1.3–18.7). MRI/intra and extracranial MRA was performed in 104 patients. At time of Doppler assessment, mean±SD hemoglobin was 9.1±1.6 g/dl. eICA velocities were significantly correlated with middle cerebral arteries (MCA) velocities (r=0.234, p<0.001), and were about 25–30% lower than MCA velocities (mean:95±38 vs 127±32 cm/sec). As for MCA, eICA velocities were maxima between 3–7 years of age. eICA tortuosities were echo-detected in 25% cases (107/435), and were more frequent in boys (65/202; 32%) than in girls (42/233; 18%), p<0.001. Regression logistic analysis showed that tortuosities were not associated with age, but significantly associated with males (OR:2.2, 95%CI:1.4–3.4, p=0.001). Cervical MRA found stenoses in 40/104 patients. ROC curve showed that eICA velocities ≥ 160 cm/sec were highly predictive of stenoses on eMRA (100% specificity, 80% sensitivity). The prevalence of eICA velocities ≥ 160 cm/sec was 10.3% (45/435), and was significantly higher in males (14.9% vs 6.4%; p=0.004). Low hemoglobin (OR:2.6/1g/dl decrease, 95%CI:1.4–4.6; p=0.002) and tortuosities (OR:14.5, 95%CI:4.1–50; p<0.001) were significant and independent risk factors for eICA velocities ≥ 160cm/sec. Intracranial stenoses were detected in 29/104 patients, while 40/104 patients had extracranial stenoses with 31/40 showing no intracranial stenoses. Silent infarcts were detected in 35/104 patients, and were highly associated with the presence of intra and/or extracranial stenoses (30/35: 86%, p<0.001). Intra (OR:5.1,95% CI:1.9–13.8, p=0.002) and extracranial (OR:4.5, 95% CI:1.7–11.6; p=0.002) stenoses were significant and independent risk factors for silent infarcts.

This study shows for the first time that in cohorts previously assessed early by TCDI for intracranial arteries, about 10% stroke-free patients have eICA vasculopathy. Moreover, we show that intra and/or extracranial stenoses are significant risk factors for silent infarcts. These data may explain why silent infarcts still occurred in patients early assessed by TCDI exploring only intracranial arteries. Thus, extracranial Doppler assessment should be routinely done with TCD to evaluate the full extent of cerebral vasculopathy in SCA.

No relevant conflicts of interest to declare.