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. Author manuscript; available in PMC: 2012 Jan 1.
Published in final edited form as: Stroke. 2010 Nov 18;42(1):81–86. doi: 10.1161/STROKEAHA.110.591818

Sickle cell disease and TCD imaging: inter-hemispheric differences in blood flow Doppler parameters

Jaroslaw Krejza 1,2, Rong Chen 1, Grzegorz Romanowicz 1,2, Janet L Kwiatkowski 3, Rebecca Ichord 4,5, Michal Arkuszewski 1,6, Robert Zimmerman 7, Kwaku Ohene-Frempong 3, Lisa Desiderio 1, Elias R Melhem 1
PMCID: PMC3079337  NIHMSID: NIHMS259886  PMID: 21088242

Abstract

Purpose

To establish reference values of inter-hemispheric differences and ratios of blood flow Doppler parameters in the terminal internal carotid artery (tICA), middle (MCA) and anterior (ACA) cerebral arteries in children with sickle cell anemia.

Subjects and Methods

Fifty seven out of 74 recruited children (mean age 7.8±3.4 years, 3-14 years), who were free of neurological deficits and intracranial narrowings detectable by magnetic resonance angiography (MRA) and had flow velocities below 170 cm/s by conventional transcranial Doppler ultrasound underwent transcranial color-coded duplex ultrasonography. Reference limits of flow parameters corrected and uncorrected for the angle of insonation were estimated using tolerance intervals, within which are included with probability of 0.90 all possible data values from 95% of a population.

Results

Reference limits for left-to-right differences in cm/s in the mean angle-corrected and uncorrected flow velocities were: −56 to 53 and −72 to 75 for MCA; −49 to 57 and −81 to 91 for ACA and −55 to 64 and −73 to 78 for tICA, respectively. Respective reference limits for left-to-right velocity ratios were: 0.31 to 1.84 and 0.38 to 1.75 for MCA; 0.48 to 2.99 and 0.46 to 2.89 for ACA, and 0.61 to 2.56 and 0.56 to 2.23 for tICA.

Conclusions

The study provides reference limits of inter-hemispheric differences and ratios of blood flow Doppler parameters that may be helpful in identification of intracranial arterial narrowings in children with sickle cell disease undergoing ultrasound screening for stroke prevention.

Keywords: sickle cell disease, transcranial Doppler, sonography, blood flow, stroke

Introduction

Children with sickle cell disease (SCD) are at high risk for developing stroke.1-3 The risk is highest in children with elevated blood flow velocity in the distal internal carotid (tICA) or proximal middle cerebral artery (MCA) as measured with transcranial Doppler ultrasonography (TCD).4 Chronic blood transfusions, if implemented in a timely fashion in those with flow velocity over 200 cm/s, can reduce the risk of stroke by as much as 92%.2 The use of a single TCD velocity alone to stratify future risk of stroke is limited, as shown by the fact that 60% of patients with velocities in the high-risk range, who did not receive chronic transfusion therapy, remained stroke-free over the subsequent 40 months.3,5 Also, single flow velocity measurement from an artery cannot differentiate arterial stenosis from hyperemia.6-8 Children with hyperemia may not have the same risk/benefit ratio from indefinite transfusions as those with arterial stenosis.

The STOP investigators suggested that unilateral high flow velocity indicates stenosis, whereas bilateral high velocity represents bilateral stenosis, hyperemia, or both.2,9 Substantial side-to-side differences in flow velocities in individual children without any arterial narrowing,10 however, indicate that extrapolation of average group symmetry in flow velocities to individual children with SCD may not be correct.

There is a potential to improve the ultrasound screening by using reference tolerance limits of inter-hemispheric differences in flow velocities in major brain arteries. These tolerance limits can inform an investigator what side-to-side differences in blood flow Doppler parameters can occur in SCD children without hyperemia or evidence of arterial narrowing. Thus, the goal of our study is to establish such reference tolerance limits for transcranial color-coded duplex ultrasound parameters based on data from children with SCD, who were not on chronic transfusion therapy,who had no history of overt stroke, who were free of signs or symptoms of focal vascular territory ischemic brain injury, and who did not have intracranial arterial narrowing on MRA.

Materials and methods

Study group

Institutional Review Board of the Children’s Hospital of Philadelphia (CHOP) approved the protocol of this prospective cross-sectional study that was also compliant with Health Insurance Portability and Accountability Act (HIPAA). Our cohort was recruited within the frame of SCD Children Ongoing Radiological Evaluation (SCORE) Study sponsored by National Institute of Health. Written informed consent was obtained from parents (with assent for subjects seven years and older). The study group was drawn from the Comprehensive Sickle Cell Center (CSCC) at CHOP using the following inclusion criteria: 1) homozygous for the sickle cell gene (SS), confirmed by DNA-based mutational analysis, 2) ages 2–14 years, 3) absence of localizing abnormalities on neurologic exam indicating prior vascular-territory ischemic injury, and 4) no history of stroke. Exclusion criteria were: 1) history of major head injury, 2) history of seizure disorder requiring anticonvulsant therapy, 3) active chronic transfusion or hydroxyurea therapy, 4) occurrence of acute chest syndrome or other significant acute illness in the period between laboratory blood and sonographic testing, 5) history of prenatal or perinatal hypoxic-ischemic brain injury, 6) evidence of human immunodeficiency virus infection, 7) pregnancy, 8) mean flow velocity 170 cm/s or higher in any intracranial artery on a screening routine TCD examination at the time of study entry.

Study procedures

A pediatric neurologist performed a baseline neurological examination on each child who fulfilled inclusion and exclusion criteria. The examination included language, cranial nerves, sensorimotor ability and coordination and the PANESS (Physical and Neurological Examination of Soft Signs). All children were subsequently scheduled for TCD and MRA examinations. Hemoglobin (Hb) concentration and hematocrit (Hct) level were obtained during well-visits close in time to ultrasound studies.

Magnetic resonance angiography

To exclude children with intracranial arterial narrowing we performed time-of-flight (TOF) 3-dimensional gradient-echo sequence (TR/TE=28/3.28ms, flip angle 25° matrix 512×448) imaging on a 3-Tesla scanner (Siemens Trio, Erlangen, Germany) covering the extracranial and intracranial arteries in the axial plane. Raw data from TOF MRA were transferred to an on-line workstation for the generation of segmented 2-dimensional arterial re-projections using a commercially available maximum intensity projection ray-trace and multi-planar reconstruction algorithms. The segmented 2-dimensional re-projections and raw data were displayed on a 1024×1024 pixel workstation and arteries were evaluated independently by two pediatric neuroradiologists - ERM with 15 and RZ with 25 years of experience in angiography - unaware of the ultrasound findings. Each evaluated all studies, and discrepancies were resolved by consensus. No extracranial arterial narrowing was identified in any of patients. The neuroradiologists excluded seven children with intracranial arterial narrowing and four with degraded MRAs due to motions artifacts. An additional six children did not complete MRA examinations.

Imaging ultrasound studies

Transcranial color-coded duplex sonography (TCCS) (sonographic scanner HDI 5000, Philips, Eindhoven, Netherlands, with 1.8-3.6 MHz probe) studies were performed by one of three sonographers, each with over three years of experience. Children were not permitted to sleep during examinations and were not sedated. The tICA, M-1 MCA and A1 segment of the anterior cerebral artery (ACA) were identified via temporal acoustic windows using published standards.11 The mean-time-averaged-maximum (VMN) called thereafter mean flow velocity, peak-systolic (VPS), and end-diastolic (VED) velocities were calculated by automatic tracing the Doppler waveform. Pulsatility (PI) and Resistivity (RI) indexes were calculated as follow: PI= (VPS - VED)/VMN; RI= (VPS - VED)/VPS.

Statistical analysis

We used statistical software SYSTAT 12 (SPSS Science, Chicago, IL), GraphPad free software [(GraphPad software, La Jolla, CA), http://www.graphpad.com], and R statistical computing software (http://www.r-project.org/) to analyze data. Flow velocities were treated for outliers using Grubb’s T-statistics at α level less than 0.05.12 Outliers, if present, were not considered while checking for normality using Lilliefors test, provided by SYSTAT. As data were normally distributed, the values from hemispheres were first compared using paired two-sided t-test. We used Pearson correlation coefficient (r) to quantify bilateral relationships between Doppler parameters, and non-paired two-sided t-test to compare Doppler values between genders. To obtain TCCS velocities that are closer to velocities obtained with conventional TCD, we multiplied the angle corrected velocities by cosine of the angle of insonation. The resulted velocity values are called further here as “uncorrected” velocities.

We used estimates of tolerance interval, which have probability of 0.90 of containing 95% of the population, to determine reference ranges of inter-hemispheric differences and ratios in Doppler parameters.13 Inter-hemispheric differences in Doppler parameters followed Gaussian distribution, thus we calculated Gaussian tolerance interval. If L1 and L2 are the lower and upper limits of the interval then L1=μ-ks, L2= μ+ks, where values of k were taken from paper by Weissberg-Beatty,14 μ=mean, s=standard deviation. For inter-hemispheric ratios in Doppler parameters, we calculated nonparametric tolerance intervals based on the Wilks method.15

Multivariable linear regression analysis was used to determine associations, if any, of inter-hemispheric differences or ratios in blood flow Doppler parameters with age and gender after adjustment for Hb or Hct. Probability less than 0.05 was considered significant.

Results

There were 57 children (mean age 7.7±3.4 years, range 3-14 years; 32 females, 25 males) with complete evaluable data. Measurements of Hct level and Hb concentrations were taken on average 21±16 days (range 0-62 days) from the sonographic study. For eight children without recent laboratory values, we used the average Hb and Hct from the previous three visits (mean 140±70 days, range 73-386 days).

Values of angle corrected blood flow Doppler parameters were on average 20% higher than uncorrected values, and differences were significant (Table 1). No outliers were found in values of blood flow velocities. Variability of angle corrected velocity values was lower than variability of uncorrected velocities. The variability of impedance indexes was lower than variability of velocity values and subsequently tolerance intervals were narrower, especially for the values calculated based on angle corrected velocities (Table 1).

Table 1.

Blood flow Doppler parameters and their Gaussian tolerance intervals (in parentheses) in middle cerebral (MCA), anterior (ACA) and terminal internal carotid (tICA) arteries obtained with transcranial color-coded duplex sonography (TCCS) with and without correction for the angle of insonation in 57 children with sickle cell disease

Parameters Artery
MCA (value±SD) ACA (value±SD) tICA (value±SD)
LEFT RIGHT LEFT RIGHT LEFT RIGHT
Uncorrected, VPS
cm/s		 153±39
(64;242)		 157±34
(81;233)		 111±37
(26;195)		 104±38
(19;189)		 133±34
(55;210)		 129±28
(64;193)
VMN
cm/s		 108±29
(45;171)		 110±24
(55;164)		 78±25
(23;134)		 74±25
(17;131)		 93±25
(38;149 )		 89±21
(43;135)
VED
cm/s		 73±21
(24;121)		 70±21
(23;117)		 52±16
(15;88)		 49±16
(12;85)		 63±18
(22;104)		 58±16
(22;94)
RI 0.44±0.09
(0.24;0.65)		 0.46±0.09
(0.25;0.66)		 0.39±0.12
(0.13;0.66)		 0.38±0.11
(0.14;0.64)		 0.47±0.11
(0.21;0.72)		 0.49±0.12
(0.21;0.76)
PI 0.63±0.16
(0.28;0.99)		 0.67±0.17
(0.29;1.04)		 0.56±0.21
(0.10;1.03)		 0.55±0.18
(0.15;0.96)		 0.68±0.21
(0.21;1.15)		 0.72±0.22
(0.22;1.22)
Angle corrected, VPS
cm/s		 185±47
(80;291)		 186±41
(93;278)		 156±52
(39;274)		 150±61
(12;287)		 158±50
(45;270)		 156±50
(43;268)
VMN
cm/s		 130±33
(56;204)		 129±28
(66;192)		 111±38
(26;196)		 106±41
(13;199)		 111±34
(33;188)		 108±35
(28;188)
VED
cm/s		 87±24
(33;142)		 82±24
(28;137)		 73±25
(17;129)		 69±28
(7;132)		 74±24
(20;129)		 70±24
(16;124)
RI 0.53±0.07
(0.36;0.69)		 0.54±0.08
(0.37;0.71)		 0.53±0.08
(0.35;0.71)		 0.53±0.08
(0.36;0.71)		 0.53±0.08
(0.36;0.71)		 0.56±0.08
(0.38;0.74)
PI 0.76±0.16
(0.40;1.11)		 0.78±0.16
(0.41;1.14)		 0.76±0.18
(0.36;1.17)		 0.76±0.17
(0.38;1.14)		 0.77±0.18
(0.37;1.17)		 0.83±0.18
(0.43;1.23)
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VPS,VMN, VED – peak systolic, mean and end-diastolic blood flow velocities respectively, RI – resistivity index, PI – pulsatility index, SD – standard deviation.

Correlation coefficients for Doppler parameters between sides were statistically significant for both angle-corrected and uncorrected values (Table 2). For uncorrected values r varied from 0.30 to 0.59, while for angle corrected values r ranged from 0.33 to 0.68 (Table 2).

Table 2.

Pearson correlations coefficients (r) for ultrasound Doppler parameters from right sided arteries with corresponding parameters from left sided arteries in 57 children with sickle cell disease

Artery Parameter Blood flow Doppler
parameters uncorrected
for the angle of insonation		 Blood flow Doppler
parameters corrected for
the angle of insonation
Correlation
coefficient		 p Correlation
coefficient		 p
MCA VPS 0.43 0.001 0.58 0.000
VED 0.30 0.022 0.39 0.003
VMN 0.44 0.001 0.58 0.000
RI 0.68 0.000 0.40 0.003
PI 0.65 0.000 0.53 0.000
ACA VPS 0.54 0.000 0.55 0.000
VED 0.59 0.000 0.56 0.000
VMN 0.54 0.000 0.55 0.000
RI 0.52 0.000 0.66 0.000
PI 0.57 0.000 0.64 0.000
tICA VPS 0.57 0.000 0.33 0.013
VED 0.59 0.000 0.34 0.011
VMN 0.54 0.000 0.33 0.014
RI 0.43 0.001 0.67 0.000
PI 0.50 0.000 0.65 0.000
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VPS,VMN, VED – peak systolic, mean and end-diastolic blood flow velocities respectively; RI – resistance index; PI – pulsatility index; MCA – middle cerebral artery, ACA – anterior cerebral artery; tICA – terminal portion of internal carotid artery, ICA – extracranial portion of internal carotid artery, p – probability.

No statistically significant side-to-side differences were found in any Doppler parameter in any artery. Average differences for the mean flow velocities were close to zero for both corrected and uncorrected values in all arteries, though in general, left sided velocities were usually slightly higher than right sided ones (Table 3). Also the interhemispheric differences in impedance indexes were close to zero for the respective arteries (Table 3). Slightly lower impedance indexes were found in the left MCA and tICA (Table 3). The tolerance interval for absolute differences between sides in the mean flow velocities in the MCA varied from 72 cm/s to 75 cm/s for uncorrected values and 53 cm/s to 56 cm/s for angle corrected values, respectively (Table 3). For other arteries, the width of the tolerance limits was greater for uncorrected values of the velocity differences, 81 cm/s to 91 cm/s for the ACA and 73 cm/s to 78 cm/s for the tICA (Table 3). Tolerance limits tend to be asymmetric, for instance in the tICA the limit of the mean velocity on the right side is 64 cm/s - the difference still considered “normal” compared to respective velocity on the left side, whereas the velocity on the left side compared to the velocity on the right side is considered “normal” if the difference is not higher than 55 cm/s (Table 3). Tolerance limits for impedance indexes showed the same asymmetric pattern - tolerance limits for PIs and RIs on the right side were smaller compared to the limits on the left side (Table 3).

Table 3.

Mean values of interhemispheric differences [left (L) values minus right (R) values] and ratios (L values divided by R values) of peak-systolic, mean and end-diastolic velocities, with their Gaussian tolerance intervals (in parentheses), in the middle cerebral (MCA), anterior cerebral (ACA) and terminal segments of internal carotid (tICA) arteries obtained with imaging transcranial color-coded duplex sonography (TCCS) with and without correction of angle of insonation in 57 children with sickle cell disease

Variables Artery
MCA ACA tICA
L-R L/R L-R L/R L-R L/R
uncorrected VPS 0±47
(−106;106)		 1.02±0.27
(0.36;1.98)		 7±55
(−118;130)		 1.15±0.46
(0.41;2.81)		 2±46
(−103;107)		 1.06±0.36
(0.63;2.21)
VMN 1±33
(−72;75)		 1.03±0.26
(0.38;1.75)		 5±38
(−81;91)		 1.14±0.45
(0.46;2.89)		 3±33
(−73;78)		 1.08±0.36
(0.56;2.23)
VED 5±29
(−59;69)		 1.6±0.6
(0.3;2.1)		 4±24
(−50;58)		 1.15±0.48
(0.43;3.34)		 5±22
(−44;54)		 1.12±0.38
(0.60;2.43)
RI −0.01±0.02
(−0.14;0.13)		 0.99±0.11
(0.68;1.31)		 0.00±0.08
(−0.17;0.17)		 1.01±0.15
(0.66;1.43)		 −0.03±0.08
(−0.22;0.16)		 0.96±0.16
(0.66;1.55)
PI −0.02±0.13
(−0.32;0.28)		 0.99±0.17
(0.52;1.44)		 0.00±0.16
(−0.36;0.37)		 1.02±0.22
(0.60;1.78)		 −0.05±0.18
(−0.45;0.35)		 0.96±0.24
(0.50;1.88)
angle corrected VPS −4±34
(−80;73)		 0.99±0.22
(0.29;1.69)		 6±36
(−74;87)		 1.15±0.45
(0.42;2.92)		 4±37
(−79;87)		 1.07±0.37
(0.63;2.64)
VMN −2±24
(−56;53)		 1.0±0.23
(0.31;1.84)		 4±24
(−49;57)		 1.14±0.43
(0.48;2.99)		 5±26
(−55;64)		 1.1±0.38
(0.61;2.56)
VED 3±23
(−50;55)		 1.2±0.79
(0.28;5.51)		 3±15
(−31;38)		 1.15±0.46
(0.54;3.46)		 5±23
(−40;50)		 1.16±0.45
(0.54;2.66)
RI −0.01±0.10
(−0.24;0.21)		 0.99±0.23
(0.54;1.62)		 0.00±0.09
(−0.21;0.22)		 1.03±0.26
(0.49;1.74)		 −0.02±0.10
(−0.24;0.20)		 0.99±0.26
(0.52;2.27)
PI −0.02±0.16
(−0.39;0.32)		 0.98±0.24
(0.53;1.68)		 0.01±0.16
(−0.36;0.38)		 1.05±0.32
(0.43;2.04)		 −0.04±0.18
(−0.45;0.36)		 0.99±0.33
(0.44;2.60)
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VPS, VMN, VED – peak systolic, mean and end-diastolic blood flow velocities respectively (differences given in cm/s, otherwise no units), PI – pulsatility index, SD – standard deviation.

The average inter-hemispheric index calculated on the basis of uncorrected velocity values for the MCA was 1.03, while left-right limits of tolerance interval were 0.38 - 1.75 (Table 3). For instance mean velocity on the left side as high as 75% of the velocity on the right side is considered “normal”, while on the right side velocity as high as 62% of the velocity on the left side is still “normal”. The respective values for angle corrected velocity values were similar (Table 3). The tolerance intervals for other arteries were wider, in particular for the angle corrected velocities.

The average left/right inter-hemispheric ratios in impedance indexes were close to value “1.0” for both uncorrected and angle corrected values (Table 3). However, the width of the tolerance interval for the left/right ratios in the RIs in the MCA varied from 0.68 to 1.31 for uncorrected values and from 0.54 to 1.62 for angle corrected values, respectively (Table 3). For other arteries, the tolerance was in general much wider, and also was wider for angle corrected RIs and PIs values.

No significant association of between-sides differences or ratios and Doppler parameter with age and gender after adjustment for Hct level and Hb concentration was found for any artery.

Discussion

Our study provides tolerance limits for inter-hemispheric differences in TCCS parameters for children with SCD without arterial stenosis. We believe that interhemispheric differences within these limits in a child in whom TCD velocities are below 170 cm/s likely do not represent arterial stenosis, while the differences over the tolerance limits may indicate the presence of stenosis. The latter suggestion needs to be verified in a separate study in a group of children with and without stenosis. These limits also may help distinguish stenosis from hyperemia in children with TCD velocities over 170 cm/s, a concept that deserves further study. Tolerance limits, therefore, may allow more reliable selection of children who would most benefit from close TCD or MRA surveillance and treatment.16,17

Average side-to-side differences in hemodynamic parameters in adults were reported to be negligible, thus substantial inter-hemispheric asymmetry is commonly interpreted as a sign of arterial narrowing.2,9,18-20 The statistical average group difference cannot be applied to an individual, in whom the exact configuration of the circle of Willis,21 including presence, caliber and course of each artery,22,23 as well as the degree of inter-hemispheric anatomical,24-26 physiological27-29 and pathophysiological differences is a priori unknown.18,23,30,31 Large variability in side-to-sides impedance indexes and modest correlation coefficients for vessels that supposedly have no stenosis, and hemispheres that are seeing the same circulating oxygen content and hemoglobin, indicate that there is not such a tight agreement between sides in blood flow redistributions in response to chronic oxygen deficit.6-8,30

Also a minor arterial narrowing, which could have remained undetected on MRA, potentially contributed to the variability in our study as analysis of the Hagen-Poiseuille equation indicates that even small changes in artery radius may result in extremely drastic changes in flow velocity. Assuming that 140 cm/s is an average MCA velocity in asymptomatic children with SCD, a “small” 10% of 1.5 mm radius reduction should increase the velocity to 343 cm/s to maintain the same blood flow, while the 25% reduction should increase the velocity to 442 cm/s. In the STOP II trial children with TCD velocity over 200 cm/s but without moderate MRA narrowing, defined as over 25% diameter reduction, were classified as those with hyperemia.2 Such minor to moderate narrowing, however, may have important significance in children with SCD in whom adaptation to altered blood rheology may not be well balanced. Hence, the diagnostic importance of the reference tolerance limits of interhemispheric differences of those blood flow Doppler parameters that are commonly used in screening children with SCD.

The use of side-to-side indices to detect stenosis can be beneficial because they are supposed to be resistant to bilateral physiological changes.32 The use of inter-hemispheric indices improves inter-observer and intra-observer reproducibility of Doppler parameters by approximately 50%.32 A strong association between asymmetric MCA velocity pattern, taken as 15% side-to-side variations in healthy adults,19,20 and hemodynamically significant carotid disease or presence of underlying ischemic stroke was reported.18 Higher flow velocity asymmetry was reported in healthy white children, almost similar to asymmetry observed in our group.10 The threshold of 15% of inter-hemispheric differences as a reference tolerance limit, therefore, should no longer be applied to the individual child with SCD for differentiation of hyperemia from arterial stenosis.

We believe that uncorrected TCCS velocities can be useful for interpretation of conventional TCD data with some minor reservations, however, because they are not necessarily the same.33,34 We applied our tolerance limit 75 cm/s for interhemispheric differences in uncorrected mean MCA velocities to TCD data published by Adams et al.,9 on TCD detection of arterial stenoses in patients with SCD. Twelve out of 13 stenoses could have detected using the limit, which itself can be a sensitive marker to discriminate hyperemia from stenosis. This hypothesis, however, needs to be verified in future studies.

A commonly used term “hyperemia” needs a remark in respect to children with SCD, in whom hyperemic blood flow velocity and hence shear rate is an adaptation to increased blood viscosity. Differentiation of such hyperemic flow from pathologic hyperemia is a matter of arbitrary judgment. We propose to define the latter when blood flow velocity in a particular artery exceeds 170 cm/s without presence of narrowing.

Our number of subjects is relatively small compared to studied groups of healthy children. The National Committee for Clinical Laboratory Standards recommends that the sample size should consists of al least 120 values.35,36 The Committee recognizes, however, that in special category of individuals 39 observations is the required minimum to compute a 95% reference interval at 2.5% and 97.5% points of the distribution.

Figure.

Figure

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Color images of the middle cerebral artery in red with corresponding velocity waveforms from left (A) and right (B) sides obtained with imaging transcranial Doppler ultrasonography from 11 year-old boy with sickle cell anemia, who had no any intracranial arterial narrowing on magnetic resonance angiography. Note that the differences in the time average mean flow velocity is 48 cm/s, the velocity on the right side is almost 47% higher than on the left side. The angle of insonation on the right side is 48 degrees, while on the left 38 degrees – far more than the assumption of zero angle in the conventional TCD.

Acknowledgments

Acknowledgments and Funding:

This research was supported by the National Institutes of Health (grant 5-R01 NS-046717, PI-Elias Melhem)

Footnotes

Disclosures:

Nothing to disclose.

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