Feasibility and Characteristics of Systematic Transcranial Doppler in Adults With Sickle Cell Disease: A Cross‐Sectional Single Center Study

Transcranial Doppler (TCD) is a widely used, non-invasive screening method recommended in children with SCD [1] to effectively identify those at highest risk of stroke [2]. Unfortunately, the well-defined data in pediatric care cannot be generalized to adults. First, the feasibility of systematic TCD in adults with SCD is still unclear, including a long-standing notion that TCD becomes technically more challenging past a certain age due to disease-related bone structure changes, leading to higher transtemporal bone thickness and poorer TCD feasibility [3]. Second, pediatric velocity thresholds are not valid in adults [4], as TCD velocities tend to decline with age [5, 6]. Thus, data is insufficient to recommend regular TCD screening in adults with SCD [1], which is then usually stopped past late adolescence. Nevertheless, TCD as an adult screening tool for SCD vasculopathy could have multiple advantages, especially in resource-limited settings, where most adults with SCD live, due to its low cost, non-invasiveness, dynamic parameters assessment, and easy availability. Additionally, TCD is already commonly used in adults for other indications, such as vasospasm detection in neurocritical patients after subarachnoid hemorrhage [7]. Thus, all adults with SCD followed at our institution receive routine multidisciplinary neuro-hematology care, including routine TCD examination for neurosurveillance purposes, independent of their genotype, neurologic history, or vascular risk. The objectives of this study are to evaluate the feasibility of TCD in unselected adults with SCD, to describe the mean flow velocities (MFV) in that population, and to correlate them with routinely available, patient-specific factors. We conducted a retrospective analysis of all patients ≥ 18 years with SCD in which TCD examination was attempted between September 2021 and June 2024. Baseline TCD is performed systematically with the SONARA Doppler (Natus Medical Incorporated) by one of two vascular neurologists with expertise in TCD. Examinations are performed in an outpatient setting, and care is taken to avoid performing TCD examination during an acute disease. Bilateral temporal and sub-occipital regions are insonated to track the proximal segment of intracranial arteries on their longest possible length. When measurable, the highest detectable mean flow velocity (MFV) was recorded in middle (MCA), anterior (ACA), posterior (PCA), and basilar (BasA) cerebral arteries. Although time-averaged maximum mean velocities (TAMMs) are the usually reported velocity measures in pediatric studies, we used MFVs as primary velocity measures, consistent with routine ultrasound practice in adults. Additionally, a prior history of symptomatic stroke was defined as any cerebral infarction or intracranial hemorrhage on brain imaging with a corresponding focal neurological deficit or other related symptoms. The primary outcome was the overall feasibility of systematic TCD. A “standard” Doppler examination was defined as successful insonation of at least the bilateral MCA. This definition reflects the primary vessels assessed in landmark pediatric TCD-SCD trials. The Doppler study was deemed “complete” if all arteries (bilateral ACA, MCA, and PCA, and BasA) were successfully insonated. We assessed differences in age, sex, phenotypic category, body mass index (BMI), and hemoglobin (Hb) level between patients in whom “standard” or “complete” examination was feasible and those in whom it was not. Secondly, MFV was reported for each artery. A priori selected covariates were: age, sex, phenotypic category, Hb, BMI, mean arterial blood pressure (MAP), chronic transfusions and prior stroke. Interhemispheric MFV asymmetry was also correlated to history of stroke, using a 40 cm/s difference threshold between both sides of the same vessel based on previously published data [4, 8]. Of the consecutive 233 patients (Table 1) with a documented TCD attempt, 214 (92%) reached a “standard” level of completeness. Of the 19 unfeasible examinations, MCA was measurable only unilaterally 11 (58%), and was not measurable at all in 8 (42%), in whom only the basilar artery was measurable. No patient had a completely undoable TCD. Furthermore, 176 (76%) TCD examinations were “complete”. Of the 57 patients with unfeasible examinations, 29 had all but one vessel available for insonation. Overall, TCD had the poorest feasibility rate in ACA (not measurable on at least one side in 54), followed by PCA (not measurable on at least one side in 45) and BasA (not measurable in 15). MCA had the best feasibility (not measurable on at least one side in 26). No significant differences in age, sex, phenotype, Hb, or BMI were found between feasible and non-feasible TCD groups (Table S1). MFVs in each single artery are shown in Figure S1. At univariate level (Table 2), MFVs tended to be higher in women compared to men, which was statistically significant in MCA and PCA. MFVs were significantly higher in all vascular territories in patients of HbSS/HbSβ0 compared to HbSC/HbSβ+ phenotype. Statistically significant negative correlations between MFV and age, as well as MFV and Hb, were observed in all territories (Table 2, Figure 1). MFV tended to decrease with MAP; this was only statistically significant in the posterior circulation (PCA and BasA). Chronic transfusions were not associated with significantly different MFVs, nor was a history of stroke. On multivariate analysis, age and hemoglobin were the only covariables significantly associated with MFV in all vascular territories, with the exception of BasA, in which HbSS/HbSß0 genotype was associated with higher velocities (Table S2). History of stroke correlated with interhemispheric MFV discrepancy of 40 cm/s; 3/13 (23%) of those with MFV discrepancy of 40 cm/s had suffered a stroke, compared to 6/200 (3%) in those with documented absence of MFV discrepancy (p = 0.017, Fisher's exact test). For all patients with a history of stroke and interhemispheric asymmetry, the stroke had occurred ipsilaterally. Our findings challenge the prevailing notion that TCD becomes impractical beyond adolescence in SCD and are in line with reported adult TCD feasibility rates in other clinical contexts, which spread around 81%–98%, both in healthy subjects [9] and neurocritical patients [10]. Our study also offers uniform reference values for cerebral blood flow velocity in adults with SCD, for whom previously reported values were limited to small-sized highly selected cohorts. In our cohort, TCD velocities in adult SCD patients were significantly lower compared to previously reported values in children [4, 11], but higher than healthy adult controls [4, 11, 12]. We confirm negative correlations between TCD velocities and age, which was already described elsewhere [13]. The negative correlation with Hb was also expected [4, 11, 12, 14, 15]. The difference in MFVs between phenotypes was most probably influenced by differences in Hb levels. No significant differences in MFV between patients with or without prior stroke were observed. Previously, higher velocities had been reported to correlate with stroke history [16]. Our findings do not seem to be confounded by the high transfusion rate and high mean Hb level of our population, as no correlation was found at the multivariate level in any vessel. We hypothesize that MFV itself might not be a sensitive measure to correlate with retrospective neurovascular events in adults with SCD. Other TCD-derived measures, like interhemispheric velocity asymmetry and abnormally low values, might correlate better with neurovascular events [8]. Future studies are needed to evaluate whether incorporating asymmetry and low-flow states into risk models improves prediction of neurovascular events. We demonstrate 92% feasibility of systematic TCD screening in adults with SCD. TCD represents a low-cost and relatively accessible neuroimaging modality that is already used in multiple conditions in adults to assess cerebral vascular hemodynamics. While brain magnetic angiography can detect SCD-related cerebral vasculopathy, this modality is costly and not widely accessible. The inexpensive and non-invasive nature of TCD could make it a practical neurosurveillance tool for the majority of adults with SCD living in resource-constrained settings [17]. We acknowledge our study's limitations. First, velocities were measured as MFVs, which are more commonly used in adult ultrasound practice. Comparability of our findings with studies using TAMM could be impaired. However, the correlation between peak systolic velocity and end diastolic velocity (both used to compute MFV [18]) and TAMM velocities has been previously established using the STOP trial's TCD and stroke outcome data [19]. Secondly, as each patient only had one TCD, we could not examine inter-examiner and inter-examination variability, which could be an issue given the operator-dependent nature of echographic imaging. Thirdly, the retrospective nature of this analysis impedes correlations with long-term neurological outcomes. Further studies are needed to explore the prospective neurosurveillance value of TCD in adults with SCD. We thank the patients, their families, and all members of the clinical team. This study was supported by the R.K. Smiley Award from the Canadian Hematology Society. This is a retrospective analysis of data collected in a prospective registry, which has been approved by the local ethics committee (IRB no. 21.335). All patients consented to research prior to inclusion. S.F. has received consulting fees from Bristol Myers Squibb, Pfizer, NovoNordisk, and Vertex. The data that support the findings of this study are available from the corresponding author upon reasonable request. Table S1: Data of Influence Factors Subanalysis for “Standard” and “Complete” Feasibilities. Figure S1: MFV of the Different Cerebral arteries. Mean MFVs of left (dark gray) and right (light gray) sides are shown with standard deviation for each vessel. Basilar artery is represented by a single deep gray bar, as it is a unilateral vessel. MFV: mean flow velocity, MCA: middle cerebral artery, ACA: anterior cerebral artery, PCA: posterior cerebral artery, BasA: basilar artery. Table S2: Unstandardized Coefficients of the Multiple Regression Model for all Covariates Studied (as Applied on MCA, ACA, PCA and BasA Territories). Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.