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Original Article

The Use of Transcranial Ultrasonography to Predict Stroke in Sickle Cell Disease

List of authors.
  • Robert Adams, M.D.,
  • Virgil McKie, M.D.,
  • Fenwick Nichols,
  • Elizabeth Carl, B.A.,
  • Dao-Long Zhang, M.D.,
  • Kathy McKie,
  • Ramon Figueroa, M.D.,
  • Mark Litaker,
  • William Thompson, Ph.D.,
  • and David Hess, M.D.

Abstract

Background.

Stroke, especially cerebral infarction, is a major cause of morbidity and mortality in children with sickle cell disease. Primary prevention of stroke by transfusion therapy may be feasible if there is a way to identify the patients at greatest risk. Transcranial Doppler ultrasonography can measure flow velocity in the large intracranial arteries. The narrowing of these arteries, which leads to cerebral infarction, is characterized by an increased velocity of flow.

Methods.

Using transcranial Doppler ultrasonography, we prospectively measured the velocity of cerebral blood flow in children and young adults being followed because of sickle cell disease. The results were classified as either normal or abnormal on the basis of the highest velocity of flow in the middle cerebral artery. Abnormal velocity was defined as a flow ≥170 cm per second, a definition determined by post hoc analysis to maximize the predictive success of the test. The end point was a clinically apparent first cerebral infarction.

Results.

Two hundred eighty-three transcranial ultrasound examinations were performed in 190 patients with sickle cell disease (age at entry, 3 to 18 years). After an average follow-up of 29 months, cerebral infarction was diagnosed in seven patients. In 23 patients the results of the ultrasound examinations were abnormal, and in 167 patients they were normal. The clinical and hematologic characteristics of the two groups were similar, but six of the seven strokes occurred among the 23 patients with abnormal ultrasound results (P<0.00001 by Fisher's exact test). In this group, the relative risk of stroke was 44 (95 percent confidence interval, 5.5 to 346).

Conclusions.

Transcranial ultrasonography can identify the children with sickle cell disease who are at highest risk for cerebral infarction. Periodic ultrasound examinations and the selective use of transfusion therapy could make the primary prevention of stroke an achievable goal. (N Engl J Med 1992;326:605–10.)

Introduction

IN sickle cell disease hemoglobin S tends to form intracellular polymers that distort the red cell.1 The disease is characterized clinically by chronic hemolytic anemia, recurrent bouts of pain, and organ infarction, including stroke.1 2 3 4 5 Cerebral infarction in sickle cell disease is associated with an occlusive vasculopathy involving the distal intracranial segments of the internal carotid artery, and the proximal middle and anterior cerebral arteries.6 7 8 9 10 11 12 Stenotic lesions have been demonstrated by cerebral angiography,6 , 9 10 11 and recently by magnetic resonance imaging (MRI)13 , 14 and transcranial Doppler ultrasonography.13 , 15 The narrowing of the vessels results from fibrous proliferation of the intima,3 , 7 , 8 in some cases involving the formation of thrombi.16 , 17 Lesions apparently progress for months or years before cerebral symptoms develop, so there is an opportunity to detect them before infarction. Angiography, however, is invasive and not suitable for screening asymptomatic patients. Transcranial Doppler ultrasonography can detect intracranial arterial stenosis18 19 20 and seems ideally suited to screening for large-vessel disease in patients with sickle cell disease, because it is safe, noninvasive, relatively low in cost, and well tolerated by children.21 , 22

Transcranial Doppler ultrasonography is used to measure flow velocity in the large intracranial vessels of the circle of Willis. Focal stenosis can be identified by the increased velocity that results from reduced arterial diameter. Blood velocity is directly related to cerebral blood flow and inversely related to the diameter of the vessel.23 In sickle cell disease, there is some increase in velocity because of the severe anemia that increases cerebral blood flow.24 , 25 Although children with sickle cell disease have a 40 to 50 percent higher mean velocity of flow than children without anemia,21 , 26 angiographic correlation indicates that severe stenosis is associated with flow velocities that are two to three times normal.15

For transcranial Doppler ultrasonography to be an effective screening tool, it must be demonstrated that abnormal results identify patients with an increased risk of stroke. We undertook a prospective study using transcranial Doppler ultrasonography to screen children who were at risk of stroke because of sickle cell disease.

Methods

Patients

The study patients were drawn from those attending the Medical College of Georgia Pediatric Sickle Cell Disease Clinic, which consists of two facilities in Augusta and six satellite clinics in southeastern Georgia. Children were referred to the clinic primarily through a voluntary statewide program of screening cord blood and by local physicians and county health departments. Two pediatricians began providing care at these clinics four years before the study began and continued to do so throughout the study. The children were brought to the Medical College of Georgia Hospital for specialized diagnostic testing and the treatment of serious illness, including stroke.

Most patients were enrolled in this study during routine visits to the clinic. Initially, no efforts were made to alter the clinic roster for research purposes. Beginning in January 1990, the families of patients who had not been enrolled in the study were offered the opportunity to participate in screening. Enrollment required informed consent. Each of these patients underwent an ultrasound examination, and the parent or care giver answered questions from a standard form about developmental and neurologic history. Transcranial Doppler ultrasonography was repeated in previously screened patients if feasible, but a second examination was not required.

Exclusion criteria included the following: an acute illness that might alter the ultrasound findings, such as fever or central nervous system infection, or a history of stroke of any type. Headache was not grounds for exclusion unless associated with a loss of consciousness or focal neurologic symptoms. Patients with stroke that preceded ultrasound screening became part of a parallel study comparing transcranial Doppler ultrasonography with cerebral angiography and MRI and CT imaging of the brain. Children younger than three years at the time of ultrasonography were excluded for two reasons: ultrasonography requires a cooperative subject, and previous experience had shown that cooperation was unpredictable in young subjects; and the risk of stroke is low in children under three.5 Patients with related hemoglobinopathies other than sickle cell anemia, such as hemoglobin SC disease or hemoglobin S—β-thalassemia, were excluded because the risk of stroke is low in persons with these conditions.27

Transcranial Doppler Ultrasonography

Studies were performed with a TC2–64 (1986) or TC2–64b (1987 to 1991) ultrasound device (Eden Medical Electronics, Uberlingen, Germany), with the results printed on paper. From 1988 to 1991 approximately 30 percent of the studies were performed on a TC-2000 device (Eden) and recorded on diskette. The method of examination was similar to that previously described for adults28 and children.22 The instrument used pulsed ultrasound at a frequency of 2 MHz. A small (2 by 5 cm) cylindrical transducer was held against the temporal portion of the scalp. By manipulating probe angulation, probe position, and the depth setting of the instrument, the ultrasound sample volume was placed on major arterial segments of the circle of Willis.

The middle cerebral, distal internal carotid, anterior cerebral, and posterior cerebral arteries were studied with the transtemporal approach, and the basilar artery with the suboccipital approach. In selected patients who were enrolled later in the study, the distal internal carotid artery was assessed by transorbital ultrasonography. In each patient, velocity was recorded in the middle cerebral artery at three or four depth settings ranging from 40 to 60 mm. One recording each was attempted in the anterior cerebral, posterior cerebral, and basilar arteries. In 98 percent of the examinations, velocities were recorded from the middle cerebral arteries, and in approximately 75 percent from the anterior cerebral, posterior cerebral, and basilar arteries. Most studies were performed by one of two examiners and were completed in 30 to 40 minutes.

Velocity was recorded as a spectrum, with time as the x axis and velocity (in centimeters per second) as the y axis. The direction of flow (away from or toward the probe) was encoded on the display. Velocity could have been underestimated if the angle of the ultrasound beam was significantly greater than zero. However, velocity cannot be overestimated or artificially elevated because of operator technique or equipment setting. Although peak systolic, end-diastolic, and time-averaged mean velocities were read from the spectrum, the time-averaged mean is considered the most accurate in transcranial Doppler ultrasonography23 and is used in this report.

Interpretation of Ultrasonographic Results

One or more spectra of velocity were recorded for each artery. The highest recorded velocity for each artery was assumed to be the most representative. Because it is difficult to distinguish the distal internal carotid artery from the proximal middle cerebral artery, the highest velocity flowing toward the probe between 50 and 60 mm deep (the midline is at approximately 65 to 70 mm) was arbitrarily coded as the speed in the middle cerebral artery. Stenotic lesions in the distal internal carotid artery and proximal middle cerebral artery were assumed to have the same clinical importance in this setting.

Criteria for the detection of stenosis by transcranial ultrasonography in patients with sickle cell disease were developed during the study period by comparison with the results of cerebral angiography in patients with sickle cell disease and stroke.15 A simple criterion classifying a patient as positive on ultrasonography if the mean velocity in the middle cerebral artery reached or exceeded 170 cm per second was chosen retrospectively on the basis of the following considerations. Blood velocity is significantly and inversely related to hematocrit but not to age, height, or weight in children with sickle cell disease26; 170 cm per second represented approximately the 95th percentile of velocity at the average hematocrit. Previous studies in patients with sickle cell disease suggested that velocities of more than 190 cm per second were seen only with marked arterial stenosis, whereas velocities of less than 140 cm per second were due to increased cerebral blood flow, not the narrowing of vessels.15 Assuming that the patient's hematocrit was in the usual range of 19 to 27 percent, the velocity that marked the first clear evidence of stenosis was expected to be between 140 and 190 cm per second. This threshold maximized the predictive success of transcranial Doppler ultrasonography in this cohort (see the Statistical Analysis section).

Hematologic Studies

Venous blood was drawn by venipuncture into tubes containing EDTA. Hematologic studies (measuring the hemoglobin level, hematocrit, reticulocyte count, mean corpuscular volume, mean corpuscular hemoglobin concentration, mean corpuscular hemoglobin, and red-cell count) were performed with a Sysmex K-1000 (TOA Medical Electronics, Kobe, Japan). The reticulocyte count (expressed as a percentage of the total red-cell count) was estimated manually from a peripheral-blood smear stained with methylene blue. Hemoglobins F and S were measured as percentages of total hemoglobin with ion-exchange Chromatographic methods.29 , 30

Definition of End Points

The patients were examined clinically an average of twice a year throughout the study period or until they reached the age of 21, died, or moved from the area. Focal neurologic symptoms that were associated with CT or MRI evidence of brain infarction were considered clinical end points. Transient neurologic symptoms were not considered to be strokes unless associated with infarction on CT or MRI. Intracranial hemorrhage that was not associated with infarction was not a primary end point.

Statistical Analysis

A logistic regression with the higher of the velocities in the left and right middle cerebral arteries as a continuous variable and stroke as the outcome was first used to demonstrate an overall association. In patients with multiple studies, left and right measurements were averaged across studies. The predictive power of velocity was further tested by adjusting for age, hematocrit, levels of hemoglobins F and S, and sex, including these variables in the logistic model. Next, the most discriminating cutoff point for velocity was determined by comparing the effect of using cutoff points that increased from 140 to 190 cm per second in increments of 10 cm per second. For each cutoff velocity, we computed the sensitivity, specificity, stroke rate, and relative risk.

Selecting 170 cm per second as the best cutoff point, we compared the following variables between the group with positive results and the group with negative results using t-tests: age at entry, red-cell count, total hemoglobin level, hematocrit, levels of hemoglobins F and S, reticulocyte count, and mean and median ages at entry. Time in the study, defined as the number of months from entry through September 1991 or until the patient was lost to follow-up, died, or reached a primary end point, was compared between the two groups with the Wilcoxon rank-sum test. The distribution according to sex was compared by chi-square analysis. The distribution between groups of strokes, patients lost to follow-up, and deaths was compared by Fisher's exact test. We computed the relative risk of stroke using the cutoff point of ≥170 cm per second to represent positive ultrasonographic results. All analyses were performed with the SAS statistical package.31

Results

Characteristics of the Study Patients

Between October 1986 and January 1991, 190 children with sickle cell disease were enrolled and had at least one transcranial Doppler ultrasound examination. Enrollment proceeded unevenly but steadily; 50 percent of the patients had been enrolled by May 1989, and 80 percent by September 1990. The mean (±SD) time in the study was 29±17 months (range, 4 to 58). Total follow-up was 5463 months. Five subjects were lost to the study. One died of sepsis and one of myocarditis. Three others moved out of the area. None of them had stroke. The average age at entry was 8.9±4.2 years. However, 75 percent of the study group was enrolled before the age of 12, and 50 percent before the age of 8.

Prediction of Infarction

Table 1. Table 1. Comparison of Cutoff Velocities.*

Seven patients had cerebral infarction during the observation period. High velocity of cerebral blood flow was strongly associated with stroke. The higher of the velocities in the left and right middle cerebral arteries predicted cerebral infarction, both as a single variable (P = 0.0011) and after we included age, hematocrit, levels of hemoglobins F and S, and sex in the logistic model (P = 0.0046). The optimal cutoff point for velocity was determined post hoc by an inspection of the data in Table 1, which shows the effects of choosing different cutoff velocities from 140 to 190 cm per second. Using a higher velocity as the cutoff point decreased the sensitivity but greatly reduced the number of false positive results (the finding of increased cerebral blood flow in a patient who did not have a stroke), so there was a significant distribution difference in the rate of stroke regardless of the point chosen. At 170 cm per second, statistical significance and relative risk were greatest and the lower limit of the confidence interval was highest.

Classification According to Ultrasonographic Results

Table 2. Table 2. Characteristics of the Study Patients, According to Ultrasonographic Classification.*

A patient was classified as positive on ultrasonography if the mean velocity in the middle cerebral artery reached 170 cm per second. On this basis, 167 of the 190 patients were classified as negative and 23 as positive on ultrasonography. The clinical and hematologic characteristics of the two groups were similar (Table 2), except that the patients who were positive on ultrasonography were younger at entry. There were no significant differences in the hematocrit, levels of hemoglobin F or S, or length of observation. The highest velocities in the patients who were positive on ultrasonography ranged from 172 to 280 cm per second (mean [±SD], 201±31), as compared with a mean of 129±22 cm per second in the negative group (P = 0.0001). Nineteen of the 23 patients who were positive on ultrasonography were positive at entry, and 4 who were intially negative were positive at the time of a second ultrasound examination (performed 6, 6, 9, and 40 months after entry). Twenty-one of the 23 had a single velocity that exceeded 170 cm per second, and 2 had high velocities on both sides. A comparison of outcome according to ultrasound results (Table 2) demonstrated that a positive examination was associated with a greatly increased risk of cerebral infarction (P = 0.00001; relative risk, 44; 95 percent confidence interval, 5.5 to 346).

Strokes

Table 3. Table 3. Characteristics of the Patients with Stroke.*

The characteristics of the seven patients with stroke are shown in Table 3. The single ischemic stroke not predicted by transcranial Doppler ultrasonography occurred three years after the patient's only previous ultrasound examination. The mean age at the time of stroke was 9.0±2.6 years. Six of the seven patients were boys. The time from study entry to the occurrence of stroke ranged from 4 to 51 months. Two other patients were evaluated for possible infarction. One had headache with evidence of subarachnoid blood on CT, but negative results on MRI and normal cerebral angiographic findings. The other had a possible transient ischemic attack not witnessed by medical personnel. She had negative MRI results and normal cerebral angiographic findings. Both these patients were classified as normal on ultrasonography.

All the patients with infarction underwent CT within three days of the development of symptoms, followed by MRI six days to eight months after stroke (Table 3). All were initially treated with intravenous hydration and transfusion and then with regular exchange transfusions. Six patients underwent cerebral angiography, which was performed without complication after hemoglobin S had been reduced to less than 30 percent of the total hemoglobin level. Angiography revealed large-artery disease ranging from moderate stenosis (50 percent of the luminal diameter of the internal carotid artery, in Patient 3) to occlusion of the distal internal carotid artery (Patient 7).

Hemiparesis was the presenting symptom in all cases. Arm weakness usually exceeded facial or leg weakness. Residual arm weakness and spasticity of the arm and leg were present in four of the seven patients when they were examined at intervals ranging from 1 to 24 months after the stroke. Three patients had no residual hemiparesis, including two in whom weakness resolved within three months of the stroke. None have had recurrent stroke.

Increases in the velocity of blood flow were recorded in the three patients studied in the four months before they became symptomatic. In two patients the velocities increased from 171 to 230 cm per second and from 154 to 215 cm per second over a 30-month period. Stroke occurred 1 and 11 months, respectively, after their second ultrasound studies.

Discussion

The findings of our study of children with sickle cell disease indicate that increased velocity of flow, as assessed by transcranial Doppler ultrasonography, can identify the children at highest risk of stroke. These results are consistent with other observations that ultrasonography can detect intracranial arterial stenosis and that most cerebral infarctions in sickle cell disease are associated with large-artery disease.32 33 34 Our study, however, provides prospective data not available from angiographic correlation, indicating the predictive possibilities of a test performed months before the development of symptoms.

Our study suggests that primary stroke prevention may be feasible in children with sickle cell disease. Long-term transfusion therapy appears to prevent the progression of lesions on angiography and reduce the risk of recurrent cerebral infarction.1 , 5 , 11 , 34 35 36 Although there are no data on primary stroke prevention with transfusion or any other therapy, it is reasonable to propose that transfusion might be as effective in preventing a first stroke as it is in preventing recurrence. If so, transcranial Doppler ultrasonography could identify the subgroup of asymptomatic children in whom long-term transfusion therapy is justified. The efficacy of this approach, along with its risks and benefits, has not yet been established.

There are methodologic limitations to our study. When it began, there was insufficient experience with transcranial Doppler ultrasonography in children to define criteria for abnormality or to estimate the minimal frequency of testing needed to ensure detection. Repeated examinations were not mandated, which accounts for the fact that Patient 6 was not restudied for nearly three years. On the basis of this study, twice-yearly examinations would probably ensure the identification of most, if not all, children who are at risk.

Our retrospective analysis of the data on velocity did not lead to classification bias. Velocity spectra provide quantitative estimates and do not require subjective interpretation. Operator technique is important, however, in ensuring the optimal recording of flow velocities. Although there is generous ultrasound access in children through their thin temporal bones, their arteries are close together and high blood-flow velocities are routinely encountered because of anemia. Specialized training and experience with children who have anemia are recommended before screening.

Transcranial Doppler ultrasonography has several advantages. Because it is without risk and is well tolerated without sedation, it can be repeated at short intervals, reducing reliance on a single examination or cutoff velocity. Patients with velocities near a threshold value can be restudied to optimize measurements and determine trends. Although the cost may vary with the setting, the relatively low price of the equipment ($20,000 to $70,000), its portability, and the short study time make ultrasonography attractive as a screening test. A disadvantage is that current equipment does not allow intracranial visualization, but relies on operator technique to identify the arteries. There is now substantial experience with transcranial Doppler ultrasonography, however. With training, interobserver reliability is high, especially for the middle cerebral artery.37 A comparison of transcranial Doppler ultrasonography with cerebral angiography in 25 patients with sickle cell disease showed a sensitivity of 91 percent and a specificity of 100 percent in determining which patients had arterial narrowing that exceeded 50 percent of the luminal diameter (unpublished data). These results are comparable to those reported for the detection of intracranial atherosclerosis by transcranial Doppler ultrasonography in adults.20

The post hoc analysis we used maximized the success of ultrasonography in this sample. The optimal cutoff velocity may not be the same for a different cohort. However, velocity as a continuous variable was strongly related to the risk of stroke and remained so after adjustment for age, hematocrit, sex, and hemoglobin F and S levels by logistic regression. For this reason, our overall positive results were not greatly affected by choosing different cutoff values between 140 and 190 cm per second.

Velocities of more than 200 cm per second may indicate more proximate risk. In general, higher velocities are associated with more severe arterial narrowing, but criteria for precisely estimating intracranial stenosis from any cause on the basis of transcranial Doppler ultrasonography have not been published. We analyzed measurements made months before stroke, which made correlation with later angiographic findings difficult. Stenosis may not be the only factor involved, since symptoms may be caused by artery-to-artery embolism as well as perfusion failure. The exact relation between the risk of stroke and reduction in arterial diameter is unknown and may be complex. A sharp increase in velocity was observed in two patients in the months immediately before infarction, suggesting that trends in velocity may eventually be used to identify those at imminent risk.

Our analysis was restricted to clinically evident cerebral infarctions, because these clearly affect morbidity and because treatment decisions are based on symptomatic stroke. Subclinical brain abnormalities in patients with sickle cell disease are not uncommon on MRI,38 but the relation of small, primarily subcortical lesions, presumably ischemic in nature, to the likelihood of symptomatic infarction is unclear. We have performed MRI in 12 of the 17 patients in this cohort who were positive on ultrasonography but who did not have symptoms during observation. One internal-carotid-artery occlusion with stroke and two others with small subcortical lesions were found. Of the 12 patients from the negative group studied so far, 1 had a small lesion on MRI. Preliminary data suggest that a positive ultrasound examination increases the likelihood of subclinical stroke,39 but further study is required.

The appropriate therapeutic response in asymptomatic patients with sickle cell disease who are found to have arterial stenosis is not known. Because noninvasive detection was previously not feasible, the incidence of intracranial arterial lesions in patients with sickle cell disease and the risk directly attributable to these lesions are unclear. The arterial occlusive process may not progress in all patients, even without treatment, and because of collateral circulation, the internal carotid artery can occlude without infarction. This study establishes that children with high flow velocity on transcranial Doppler ultrasonography are at higher risk, but they may not all have symptoms. Screening with transcranial Doppler ultrasonography makes treatment of a high-risk group an option before brain injury occurs. However, the opportunity to prevent disabling stroke must be weighed against the risks of long-term transfusion, bone marrow transplantation, or any other therapy.

Funding and Disclosures

Supported in part by a grant (1PO1 HL 41544) from the National Institutes of Health to the Medical College of Georgia (Titus H.J. Huisman, Principal Investigator) and by the Medical College of Georgia Research Institute.

We are indebted to Ms. Pamela Lewis for assistance in the preparation of the manuscript, to Dr. Thomas R. Swift for support and helpful comments, to Dr. Rune Aaslid for technical consultation and support, and to the patients and their families for their cooperation.

Author Affiliations

From the Departments of Neurology (R.A., F.N., E.C., D.-L.Z., D.H.), Pediatrics (V.M., K.M.), Radiology (R.F.), and Biostatistics (M.L., W.T.), Medical College of Georgia, Augusta. Address reprint requests to Dr. Adams at the Department of Neurology, HB-2060, Medical College of Georgia, Augusta, GA 30912.

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Citing Articles (417)

    Figures/Media

    1. Table 1. Comparison of Cutoff Velocities.*
      Table 1. Comparison of Cutoff Velocities.*
    2. Table 2. Characteristics of the Study Patients, According to Ultrasonographic Classification.*
      Table 2. Characteristics of the Study Patients, According to Ultrasonographic Classification.*
    3. Table 3. Characteristics of the Patients with Stroke.*
      Table 3. Characteristics of the Patients with Stroke.*

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