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AJR 2004; 183:1117-1122
© American Roentgen Ray Society


Neuroimaging

Comparison of Transcranial Doppler Sonography With and Without Imaging in the Evaluation of Children With Sickle Cell Anemia

M. Beth McCarville1,2, Chenghong Li3, Xiaoping Xiong3 and Winfred Wang4,5

1 Department of Radiological Sciences, Division of Diagnostic Imaging, St. Jude Children's Research Hospital, 332 N Lauderdale St., Memphis, TN 38015-2794.
2 Department of Radiology, University of Tennessee, School of Medicine, Memphis, TN 38163.
3 Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, TN 38015-2794.
4 Department of Hematology-Oncology, St. Jude Children's Research Hospital, Memphis, TN 38015-2794.
5 Department of Pediatrics, University of Tennessee, School of Medicine, Memphis, TN 38163.

Received December 29, 2003; accepted after revision March 23, 2004.

 
Supported in part by the American Lebanese Syrian Associated Charities.

Address correspondence to M. B. McCarville (beth.mccarville{at}stjude.org).


Abstract
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
 
OBJECTIVE. High blood flow velocity in the middle cerebral artery or distal internal carotid artery, as measured by nonduplex transcranial Doppler sonography, predicts stroke in children with sickle cell anemia. However, velocities measured using the more widely available duplex transcranial Doppler imaging equipment may not be comparable. We sought to determine the magnitude and significance of the potential differences.

SUBJECTS AND METHODS. We performed 55 paired examinations with duplex imaging and nonduplex nonimaging sonography machines on 53 children with sickle cell anemia. Examinations were performed consecutively by three sonographers blinded to the results of the opposing study. Velocities were measured in five clinically relevant vessels.

RESULTS. Time-averaged mean maximum (TAMx) velocity measurements obtained with the duplex equipment were significantly lower than those made with the nonduplex equipment for all vessels except the posterior cerebral artery. The mean differences were 10.9% (p < 0.0001) in the middle cerebral artery, 12.7% (p = 0.002) in the anterior cerebral artery, 2.2% (p = 0.69) in the posterior cerebral artery, 21.0% (p < 0.0001) in the distal internal carotid artery, and 15.3% (p < 0.0001) at the bifurcation of the distal internal carotid artery.

CONCLUSION. If TAMx velocities measured with duplex equipment are used to assign stroke risk in children with sickle cell anemia, we suggest that 180 cm/sec or more should be considered abnormal, and 153–179 cm/sec, as conditional. These values are 10% lower than those obtained from the nonduplex equipment used in the Stroke Prevention Trial in Sickle Cell Anemia study.


Introduction
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
 
Sickle cell disease is a genetic disorder of hemoglobin synthesis that results in chronic hemolytic anemia, recurrent episodes of pain, and organ infarction [1, 2]. The most common and devastating cerebrovascular complication of sickle cell anemia in children is stroke, which occurs in approximately 11% of patients by the time they are 20 years old and is most common between the ages of 4 and 15 years [35]. Strokes in children with sickle cell anemia usually result from an occlusive vasculopathy of the distal internal carotid artery or the proximal portions of the middle cerebral artery and anterior cerebral artery or both [3, 68].

The risk of stroke in children with sickle cell anemia is accurately predicted by the intracranial arterial blood velocity as measured by nonduplex transcranial Doppler (TCD) sonography: stroke risk increases with increasing blood velocity [9, 10]. In children with abnormal velocities, first stroke can be prevented by prophylactic treatment with frequent RBC transfusions [7, 1012]. However, TCD screening has not become the standard of care, except in large sickle cell centers, primarily because the necessary equipment and trained personnel are not available. Although most centers in the United States have sonography equipment, they may not possess the appropriate transducer needed to perform duplex TCD with imaging (TCDI). Because the cost of the imaging transducer is considerably less than that of a nonduplex TCD machine, many centers are likely to use duplex imaging equipment. More important, those performing and interpreting these studies require specific training in TCD sonography techniques, regardless of the equipment used, because these examinations are technically challenging and optimization of velocity measurements requires careful attention to the audible signal, the velocity readouts, and the probe position [1317].

If stroke risk is to be assigned from measurements obtained by using duplex equipment on the basis of criteria established with nonduplex equipment, it is necessary to consider how velocity measurements obtained with these types of equipment might differ. Previous investigators have found that imaging Doppler sonography equipment produces lower velocity measurements than nonimaging equipment [1315]. To further validate these findings, we sought to compare velocity measurements obtained by the duplex imaging technique using a Sequoia (Acuson) sonography machine with those obtained by the nonduplex method using a Pioneer TCD (Nicolet Biomedical) sonography machine.


Subjects and Methods
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
 
This prospective study was approved by our institutional review board. Patients from 2 to 20 years old with sickle cell anemia were eligible. Informed consent was obtained from patients 18 years old or older and from the legal guardians of those younger than 18 years. Assent was obtained from patients between 14 and 18 years old. Patients were not allowed to sleep or be sedated during the examinations because sleep or sedation raises arterial PCO2 and increases intracranial blood flow velocities [18]. They were allowed to watch television during the TCDI examinations. Patients had to be afebrile at the time of examination because fever increases cardiac output and results in elevated intracranial arterial velocity [18].

Of 56 patients enrolled, three could not be evaluated because of inadequate temporal bone windows. The 53 patients who could be evaluated included 28 boys and 25 girls, 2–17 years old (median age, 10.0 years). Two patients were enrolled twice; therefore, 55 pairs of TCD and TCDI examinations were performed on 53 patients. All pairs of examinations were performed consecutively but in random order (with regard to which examination was performed first) by two of three sonographers who were blinded to the results of the opposing study. Two sonographers had attended a TCD training course offered by the Medical College of Georgia, and the third performed TCDI examinations under the supervision of the principal investigator. Two sonographers were registered by the American Registry of Diagnostic Medical Songraphers as vascular sonographers, and the third was a pediatric radiologist with 9 years' experience in sonography. The TCDI examinations were performed on an Acuson Sequoia sonography machine with a 3V2 cardiac transducer set at 2.5 MHz. The TCD examinations were performed on a Nicolet Pioneer TCD machine with a 2-MHz transducer. For both types of examination, we used a transtemporal window setting and a 6-mm gate in most cases and obtained measurements at 2-mm increments along the entire length of the middle cerebral artery, beginning at the most superficial depth that allowed an accurate tracing. We obtained measurements at two depths from the distal internal carotid artery and its bifurcation, the anterior cerebral artery, and the posterior cerebral artery. When possible, we obtained two measurements at each depth in all vessels to determine their reproducibility.

We recorded the time-averaged mean maximum (TAMx) velocity, peak systolic velocity (Vs), and end diastolic velocity (Vd) and calculated the resistive index (RI) as follows:

We made every effort to standardize our technique for the two types of equipment so that they would be as similar as possible. We sought to obtain maximal velocity readings from each depth by using the audible signals for both TCD and TCDI, which guided probe positioning and the angle of insonation. During TCDI examinations, we also used the visual image to guide cursor placement. We adjusted the Doppler gain so that a well-defined waveform was displayed and there was a tight envelope tracing around the waveform. All TCDI measurements were obtained using the Auto-Measure function on the Acuson Sequoia machine, which automatically encases the entire Doppler waveform in an envelope. This function also automatically calculates velocity measurements from envelope tracings taken over two cardiac cycles and displays these measurements on the machine's monitor and on the recorded images (Fig. 1). The measurements that were recorded were selected by scrolling through the entire wavestrip to identify the highest velocity that was obtained during interrogation of that vessel segment.



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Fig. 1. Typical transcranial Doppler with imaging scan and recording from middle cerebral artery (MCA). Waveform is enclosed in envelope, and measurements are made over two cardiac cycles. Image is frozen to allow user to scroll along waveform and identify highest velocity. Doppler image shows circle of Willis. A = anterior cerebral artery, M = middle cerebral artery, P = posterior cerebral artery, RI = resistive index, TAMx = time-averaged mean-maximum.

 

The TCD measurements were obtained by using the envelope tracing on the Nicolet Pioneer machine, which automatically encased the waveform over the entire strip (Fig. 2). We postprocessed the TCD recordings by adjusting the gain to maximize the velocity readings while maintaining a tight envelope around the waveform. Because it was not possible to perform angle correction with the TCD equipment, we did not do so for the TCDI measurements.



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Fig. 2. Typical transcranial Doppler sonographic recording from middle cerebral artery. Waveform is enclosed by envelope, and mean velocity measurement for entire strip (mean, 118 cm/sec) is instantaneously displayed on side panel. SYS = peak systolic velocity.

 

We used the Stroke Prevention Trial in Sickle Cell Anemia Study (STOP) criteria [11], which are based on the velocity (TAMx) measured in the middle cerebral artery and distal internal carotid artery, by the nonduplex (TCD) method, to assign stroke risk as normal (TAMx < 170 cm/sec), conditional (TAMx < 170 cm/sec but < 200 cm/sec), or abnormal (TAMx < 200 cm/sec). To ensure the equivalence of these categories for the duplex (TCDI) method, we adjusted these ranges to appropriate values by performing a regression analysis and determining kappa coefficients for the comparison.

Because multiple measurements were obtained at various depths along each vessel, the maximum values were used as the primary statistics for analysis. The relationship between TCD and TCDI is best represented as a relative (or percentage) difference expressed by

The mean of this difference was estimated for each vessel separately. The TAMx, peak systolic velocity, and end diastolic velocity for vessels on both sides of the brain were pooled for analysis because we found no significant differences between the left and right sides in most instances, except for the TAMx and peak systolic velocity from the distal internal carotid artery (p = 0.03) and posterior cerebral artery (p = 0.02) for TCD. The correlation between age and TAMx, peak systolic velocity, or end diastolic velocity was determined by using the Pearson's correlation coefficient with all vessels combined. Agreement between TCD-based and TCDI-based stroke risk assignments was evaluated using the kappa statistic, which ranges from 0 to 1 [19]. In general, a kappa value of 0.4 or greater indicates moderate agreement, and a kappa value of 0.8 or greater indicates excellent agreement [20]. A regression analysis without intercept was performed to determine which ranges of TAMx measurements taken from the middle cerebral artery by TCDI correlated best with the STOP-established TCD ranges. We investigated five possible cut points by determining the kappa coefficient for each possibility. The reproducibility of TCD and TCDI measurements was determined by taking the SDs of the two measurements obtained at each depth and averaging them for the entire vessel. This analysis was performed by combining the data obtained by all three sonographers. All p values of less than 0.05 were considered significant. Because of time constraints, we could not determine inter- or intraobserver variability because this would have required each patient to undergo at least four examinations: two TCDs and two TCDIs. Furthermore, the sonographers could not have remained blinded to the results of the opposing study because only three sonographers participated in this study.


Results
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
 
In general, TAMx measurements were successfully obtained more often by TCD than by TCDI, especially from the distal internal carotid artery and the anterior cerebral artery (Table 1). Obtaining a good signal from these vessels was more challenging with the imaging equipment, possibly because of limitations in acquiring an adequate angle of insonation with the bulkier TCDI transducer. Consistent with previous reports, we found a negative correlation between age and TAMx velocities obtained by both TCD and TCDI: younger patients had higher velocities [10, 18] (Fig. 3). This correlation was statistically significant for TCD measurements (p = 0.02) but not for TCDI measurements (p = 0.08). For all vessels except the posterior cerebral artery, TAMx measurements obtained with the TCD machine were significantly higher (p < 0.01) than those obtained with the TCDI machine (Table 2).


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TABLE 1 Number of Cases with Successful Time-Averaged Mean Maximum Velocity Measurements on Transcranial Doppler (TCD) Sonography and TCD Sonography with Imaging (TCDI)

 


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Fig. 3. Graph shows age-related changes in time-averaged mean-maximum velocity measurements obtained with transcranial Doppler (TCD) sonography (solid line) and TCD sonography with imaging (TCDI) (dotted line). This correlation was significant for TCD (p = 0.02) but not for TCDI (p = 0.08).

 

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TABLE 2 Mean Difference in Time-Averaged Mean Maximum Velocity Measurements Between Transcranial Doppler Sonography and Transcranial Doppler Sonography with Imaging

 

In Table 2 and in the data analysis, we included not only patients who had both left and right vessels measured but also those who had only one vessel (left or right) measured. Also, the data set included a few measurements for which the side was not specified. Cases in which the side was unknown were excluded when calculating the numbers presented in Table 1, but all measurements were included in the analysis presented in Table 2, even when the side was unknown. The TCD-based peak systolic velocity and end diastolic velocity measurements were also significantly higher (p < 0.05) than the corresponding TCDI measurements from all vessels except the posterior cerebral artery. We obtained significantly different RI values for the distal internal carotid artery (TCDI value higher by 6.8%; p = 0.002) and the posterior cerebral artery (TCDI value higher by 3.8%; p = 0.05).

On the basis of the STOP criteria, TCD examinations placed 41 patients in the normal risk category, 12 in the conditional category, and two in the abnormal category. By the same (unadjusted) criteria, TCDI examinations placed 52 patients in the normal, two in the conditional, and one in the abnormal category. This poor agreement in stroke risk assignment between the two techniques was reflected in a low kappa value (0.24), and the difference between the two sets of results was statistically significant (p = 0.01). The regression analysis of TAMx values obtained from the middle cerebral artery showed that the TCDI values were (mean ± SD) 12.1% ± 1.2% lower than the TCD values (p < 0.0001). We then determined the kappa coefficients for agreement between the established TCD cut points and five proposed TCDI cut points at values centered around a 12.1% reduction (Table 3). A reduction of the TCDI cut points by 10% resulted in the best agreement (highest kappa value) between our data sets for the two techniques ({kappa} = 0.68, p < 0.0001) (Table 3). The adjusted categories of velocity measured by the TCDI method were therefore normal for TAMx less than 153 cm/sec, conditional for TAMx of 153 cm/sec or greater but less than 180 cm/sec, and abnormal for TAMx of 180 cm/sec or greater.


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TABLE 3 Kappa Statistics for Determination of Appropriate Velocity Cut Points as Measured by Transcranial Doppler Sonography with Imaging (TCDI)

 

TAMx measurements obtained by TCD sonography had significantly smaller SDs than did those obtained by TCDI in the middle cerebral artery (p = 0.0001) and bifurcation of the distal internal carotid artery (p = 0.01), but SDs of TAMx measurements were similar from the distal internal carotid artery (p = 0.11), the anterior cerebral artery (p = 0.72), and the posterior cerebral artery (p = 0.44) regardless of the machine used. For all vessels combined, the SDs of TAMx measurements made by TCD sonography were significantly smaller than those of measurements obtained by TCDI (p = 0.0004).


Discussion
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Abstract
Introduction
Subjects and Methods
Results
Discussion
References
 
Our results agree with those of others who found that measurements obtained with TCDI are significantly lower than those obtained with TCD sonography. For example, Bulas et al. [13] compared results from the duplex HDI 5000 (ATL) sonography machine with those from the nonduplex EME TC 2000 (Nicolet Biomedical) TCD machine and found that TAMx velocities determined manually from the duplex machine were 9.0% lower in the middle cerebral artery, 16.3% lower in the bifurcation of the distal internal carotid artery, and 10.8% lower in the distal internal carotid artery, although p values were not reported. Jones et al. [14] compared measurements obtained by using the Auto-Measure function of the duplex Acuson Aspen sonography machine with those obtained from the nonduplex Nicolet TC 2000 machine with a TCDI scanning technique closely simulating the STOP scanning protocol. They reported that TCDI-based TAMx measurements from the middle cerebral artery were 13% lower on the right (p < 0.001) and 16% lower on the left (p < 0.02) than were the TCD-based values. Similarly, our TCDI-based TAMx measurements obtained by using the Auto-Measure function of the Acuson Sequoia machine were significantly lower in the middle cerebral artery, the bifurcation of the distal internal carotid artery, and the distal internal carotid artery than were the TCD-based measurements in these arteries (all, p < 0.0001). A less clear differential was reported by Neish et al. [15], who used the combined imaging results from two TCDI machines (Acuson Sequoia; Logics, GE Healthcare) in comparison with a Nicolet Companion TCD machine to measure TAMx and peak systolic velocity. They reported similar TAMx and peak systolic velocity values in the middle cerebral artery, anterior cerebral artery, and distal internal carotid artery but significantly different values in the posterior cerebral artery (p < 0.0001) and the bifurcation of the distal internal carotid artery (p < 0.0001). In that study, TAMx measurements obtained from the bifurcation of the distal internal carotid artery were lower from the duplex machines (GE Healthcare, 18.6% lower; Acuson, 14.1% lower) than from the nonduplex Nicolet Companion (no p values reported) [18].

Because of the Doppler shift effect, velocity measurements are most accurate when the angle of insonation between the transducer and the vessel being interrogated is less than 15° [16, 17, 21]. Therefore, a more desirable angle of insonation can be obtained for the middle cerebral artery or posterior cerebral artery than for the other intracranial arteries because the aforementioned vessels tend to course directly toward the transducer when a transtemporal window setting is used.

Because angle correction is not possible with nonduplex equipment and we wished to replicate the STOP scanning protocol, we did not use angle correction in our TCDI measurements. During examination of the distal internal carotid artery and anterior cerebral artery, a necessarily large angle of insonation results in less accurate measurements. This loss of accuracy may explain why we found greater differences between TCD- and TCDI-based measurements in the distal internal carotid artery and anterior cerebral artery than we did between TCD- and TCDI-based measurements in the middle cerebral artery, the bifurcation of the distal internal carotid artery, and the posterior cerebral artery. In addition, the SDs in our TAMx measurements from the middle cerebral artery tended to be smaller than those from most other vessels regardless of the machine used. Others have found that the most reliable velocity measurements are provided by the middle cerebral artery and the least reliable, by the anterior cerebral artery [2225]. We also found that for all vessels combined, TCD-based measurements have a significantly lower SD than do TCDI-based measurements (p = 0.0004), suggesting that TCD-based results are more reproducible. This result may be at least partially explained by the fact that TCD TAMx measurements are obtained from numerous cardiac cycles, whereas the TCDI measurements are obtained over only two cycles. The greater number of raw data points obtained by TCD would be expected to result in less variability.

Several factors may partially explain why significant differences exist between TCD- and TCDI-based velocity measurements. The transducer used for TCD examinations has a smaller "footprint" and is lighter and easier to manipulate than the TCDI probe. These features are advantageous, especially when the temporal bone window setting is small because very small differences in probe position and angle can result in significant differences in velocity measurements. Also, the TCD machine is equipped with a small hand-held remote control pad that can be easily managed to record velocity measurements with one hand while the other hand manipulates the Doppler probe. This feature allows the TCD examiner to sit comfortably throughout the examination. In contrast, the TCDI examiner must be able to reach the keyboard with one hand while holding the probe in the other. This may require the examiner to stretch across the patient, if standing at the bedside, or to twist toward the keyboard, if sitting at the head of the table. In addition, when acquiring measurements with the Acuson Sequoia, the examiner must freeze the image and then scroll along the entire wavestrip to identify the highest velocity before recording the measurements. The Nicolet TCD machine provides a continuous readout of velocity measurements and allows instantaneous storage of measurements without a delay in the study. These factors may result in examiner fatigue during TCDI that could affect the accuracy of the TCDI examination. Not surprisingly, considering these factors, Neish et al. [15] found that TCD examinations were performed more quickly than TCDI examinations: the average TCD examination took 29 min and the average TCDI, 43 min.

Inherent differences in signal processing between these two types of equipment may also account for the differences we found. In the future, comparative studies using phantoms may improve our understanding of differences between imaging and nonimaging Doppler sonography.

Nevertheless, TCDI does offer several advantages. The equipment is readily available, although a probe capable of performing transcranial Doppler sonography is also required. Imaging offers enhanced operator confidence because one can visualize the vessel being examined and know with certainty from which vessel measurements are obtained. Consequently, TCDI may require a shorter learning period. In addition, TCDI may reveal unexpected vascular findings such as an aneurysm or vascular malformation [25].

In applying the STOP criteria for stroke risk to our TCD- and TCDI-based measurements, we found 12 cases (22%) of discordance between the two sets of values. In every case, the TCDI result placed the patient in a lower stroke risk category than did the TCD result (11 patients classified as conditional using TCD examination were classified as normal using TCDI, and one patient whose TCD result was abnormal was classified as conditional by TCDI). Because middle cerebral artery measurements are probably the most accurate, as discussed previously, and because the STOP study found that the highest velocity measurement was obtained from the middle cerebral artery in more than 90% of cases (Adams R, personal communication), it is appropriate to determine stroke risk on the basis of velocity measurements from the middle cerebral artery. We found that a reduction of 10% in the cut points of the middle cerebral artery TAMx values measured by TCDI resulted in the best agreement between TCD-based and TCDI-based stroke risk assignments for our cohort. Therefore, on the basis of our results and those of others, we recommend that when assigning stroke risk on the basis of blood velocity in the middle cerebral artery (but not other vessels) measured by TCDI, a TAMx of 153 cm/sec or greater should be considered conditional and a TAMx of 180 cm/sec or greater, abnormal. Jones et al. [14] similarly recommended that a TCDI-based TAMx of 180 cm/sec or more be considered abnormal. Applying these adjusted values to our study cohort results in six (11%) rather than 12 discordant cases (22%) and an improvement in agreement between data sets from low ({kappa} = 0.24) to moderate ({kappa} = 0.68).

Stroke risk is a continuum. Patients with conditional results should have a repeat TCD or TCDI examination within 6 months, and those with abnormal results should be reevaluated within 1 week for confirmation [911, 14]. Those with values just below the abnormal cut point also deserve close and early follow-up examinations. Patients with conditional or abnormal TCD or TCDI results should be evaluated with MRI and MR angiography, which can reveal ischemic brain injury or arterial stenoses and occlusions [7, 9, 10, 2629]. These imaging studies provide a baseline assessment that may prove to be particularly valuable for comparison purposes if the patient subsequently experiences an overt or suspected clinical central nervous system event. Patients with two abnormal TCD or TCDI results are candidates for chronic RBC transfusion, but the decision to begin transfusion therapy should be made only after careful consideration of the associated risks and benefits. Problems with venous access, compliance, cost, and complications of transfusions must be weighed against the risk of irreversible brain damage secondary to stroke [10].


Acknowledgments
 
We thank Robert Adams for reviewing this manuscript and sonographers April Chapman and Stacey Glass for technical assistance.


References
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
 

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Angle-Corrected Imaging Transcranial Doppler Sonography versus Imaging and Nonimaging Transcranial Doppler Sonography in Children with Sickle Cell Disease
AJNR Am. J. Neuroradiol., September 1, 2007; 28(8): 1613 - 1618.
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