Abnormal Transcranial Doppler Research Articles

Cerebrovascular reactivity and vasospasm after subarachnoid hemorrhage: A pilot study

The authors performed serial transcranial Doppler (TCD) and carbon dioxide reactivity (CO2R) testing in 20 aneurysmal subarachnoid hemorrhage patients to determine whether impaired cerebrovascular reactivity was associated with symptomatic vasospasm. Symptomatic vasospasm occurred in 9 of 14 patients with abnormal CO2R and in none of 6 patients with preserved reactivity (p = 0.011). Abnormal CO2R preceded the onset of vasospasm in 7 of 9 patients. Abnormal standard TCD testing was not associated with vasospasm.

Long Term Follow-Up of Pediatric Sickle Cell Disease Patients with Conditional Velocities on Transcranial Doppler (TCD).

Abnormal TCD defined as high mean maximum velocities > 200 cm/sec are highly predictive of stroke risk and justify long term transfusion program. Outcome and risk factors of conditional TCD defined as velocities 170–200 cm/sec remains to be described. Patients and methods Since 1992, 371 pediatric SCD patients (303 SS, 44 SC, 18 Sß+, 6 Sß0) were systematically explored once a year by TCD. The newborn screened cohort (n=174) had the first TCD exploration between 12 and 18 months of age. TCD was performed with a real-time imaging unit, using a 2 MHz sector transducer with color Doppler capabilities. Biological data were assessed at baseline, after the age of 1.5 years and remotely of transfusion or VOC. We report the characteristics and the outcome in patients (n=43) with an history of conditional TCD defined by mean maximum velocities ranging between 170 and 200 cm/s in the ACM, the ACA or the ICA.Results: The mean follow-up of TCD monitoring was 5,5 years (0 – 11,8 y). All patients with an history of conditional doppler were SS/Sb0 (n=43). Mean (SD) age of patients at the time of their first conditional TCD was 4.3 years (2.2) whereas in our series the mean age at abnormal TCD (> 200 cm/sec) occurrence was 6.6 years (3.2). Comparison of basal parameters showed highly significant differences between patients with conditional TCD and those with normal TCD: Hb 7g4 vs 8g5 (p<0.001), MCV 82.8 vs 79 (p=0.047). We also had found such differences between patients with normal and those with abnormal TCD (Hb and MCV p< 0.001). Two patients were lost of follow-up. Two patients died during a trip to Africa. Conditional TCD became abnormal in 11/43 patients and justified transfusion program. Mean (SD) conversion delay was 1.8 (2.0) years (range 0.5–7y). No stroke occurred. 16 patients required a treatment intensification for other indications (frequent VOC/ACS, splenic sequestrations): 6 were transplanted and 10 received HU or TP. Significant risk factors (Pearson) of conversion to abnormal were the age at time of conditional TCD occurrence < 3 y (p<0.001), baseline Hb < 7g/dl (p=0.02) and MCV > 80 (p=0.04). MRI/MRA was performed in 31/43 patients and showed ischemic lesions in 5 of them at the mean (SD) age of 7.1 y (1.8) (range 4.5–8.9): no significant difference was observed in the occurrence of lesions between the 2 groups. Conclusions This study confirms the importance of age as predictive factor of conditional to abnormal TCD conversion with a risk of 64% when first conditional TCD occured before the age of 3 years. TCD has to be frequently controled during the 5 first years of life.

Cerebral Blood Flow Velocities Measured by Transcranial Doppler Ultrasonography in Children with Sickle Cell Disease in Africa.

Background: Sickle cell anemia (SCA) is one of the commonest monogenic disorders, with 90% of the world's population living in sub-Saharan Africa. Cerebrovascular accident (CVA) is a major cause of morbidity, but its clinical prediction in resource rich countries has allowed effective primary and secondary prevention. Measurements of time-averaged maximum of the mean (TAMM) cerebral blood flow velocity (CBFv) in the internal carotid/middle cerebral (ICA/MCA) arteries by Transcranial Doppler (TCD) ultrasonography and of mean overnight oxyhemoglobin saturation (SpO2) have been useful in predicting CVA. The criteria used in Western populations may not be appropriate to children living in Africa.Aims: The aims of this study were to evaluate the TAMM CBFv in patients with SCA in Kilifi district hospital, Kenya, to assess risk factors associated with high ICA/MCA TAMM CBFv and to examine any association with neurological complications.Study design: This was a cross sectional descriptive study, where TCD ultrasonography was performed on all SCA patients attending the outpatient clinic at CGMR-C, Kilifi, Kenya in 2002. Previous data from 1990 and follow-up data from 2004 were included.Results: In 140 patients with SCA, aged 3 months to 16 years, the median ICA/MCA TAMM CBFv was 116cm/sec (SD 38, range 0–219 cms/s) compared with 97 (SD 24, range 46–190) cm/sec in 142 controls aged 2 months to 14 years (p=0.0001). 28 SCA patients (20%) had TAMM CBFv greater than and 16 (11%) had TAMM CBFv less than 2 standard deviations from the mean for controls in one or both ICA/MCA's, but only seven (5%) had a velocity above 170 cm/sec (one >200cm/sec), with the highest proportion of patients aged between 5–9 years (p=0.02). In only two of the patients with low velocities, both with previous CVA, was there no ultrasound signal from either side. 45 (32%) SCA patients had a second TCD after 2 years (two after 14 years). Of the 21 restudied who had high TAMM CBFv at baseline, 14 remained high and 2 became low. Of the 15 restudied who had low TAMM CBFv at baseline, 14 remained low and none became high. Patients with abnormal TCD had lower daytime SpO2 oxygen saturation (p=0.01) and hematocrit (p=0.05). Abnormal TCD was also associated with lower haemoglobin level, red blood cell count and higher white cell count, but not significantly. Neurological abnormalities included history of convulsions in 25 (18%) and history of CVA in 5 (4%). Of those with CVA, maximum TAMM CBFv on either side were 157, 156, 108, 0 and 0; the last patient subsequently died. Three patients who had convulsions in the interim attended for follow-up TCD; compared with those without seizures there was a trend for a greater increase in TAMM CBFv in these patients (p=0.06).Conclusion: Compared with the developed world, in Africa a smaller proportion of patients with SCA have conditional or abnormal TCDs or CVA, although convulsions are common. The proportion of those with low velocities, perhaps due to ICA/MCA occlusion with moyamoya, may increase with time. Further population-based studies in a birth cohort will determine whether cerebrovascular disease is rare or lethal and, together with imaging and neuropsychology, will establish whether abnormal TCD predicts neurological events in Africa.

Change over Time of Transcranial Doppler Cerebral Blood Flow Velocity and the Relationship with Turbulence on Magnetic Resonance Angiography in Patients with Sickle Cell Anemia.

Cerebrovascular disease (CVD) involving the circle of Willis and documented using time-averaged maximum velocity (TAMM) on transcranial Doppler (TCD) and on magnetic resonance angiography (MRA), is common in sickle cell anemia (SCA). Few studies have examined the natural history of CVD. The relationship between TAMM and MRA turbulence is also unclear. We aimed to examine time trends in TAMM and any relationship with clinical stroke and silent infarction (SI) on MRI. We also wanted to determine (a) the degree of MRA turbulence associated with TCD V>200 cm/sec (b) the TCD signature of MRA occlusion and (c) the proportion of patients with no TCD signal who did not have MRA occlusion. TCD was performed in a cohort of 169 patients with highest TAMM measured in either internal carotid/middle cerebral artery recorded (time point 1). Studies were categorised as follows: 0=normal TAMM, 1=170–200cm/sec (conditional TAMM), 2=>200cm/sec, 3=<50cm/sec. The median age was 8 (range 1–25) years. Six (4%) patients had an abnormal scan with TAMM>200cm/sec; 3 had not been screened for SCD neonatally. 11 (7%) patients had abnormally low TAMM <50cm/sec. In the neonatally screened cohort, the median for the highest TAMM ever recorded was 124 (range 33–258 cm/s) at a median age of 9 (1–25 years). 91 patients had repeat TCD at time point 2 (median 5 years later). 63 patients remained normal throughout and 16 with initially normal TAMM changed to TAMM<50cm/s at time point 2. 3/5 patients with TAMM>200cm/s at time point 1 had TAMM<50cm/s at time point 2 and 3/5 patients with TAMM<50cm/s at time point 1 remained low at time point 2. Patients with abnormally high or low TAMM at time point 1 were more likely to have abnormally low TAMM at time point 2 (x2, p= 0.001). Although clinical stroke (x2, p=0.001)and SI were commoner in those with abnormal TCD, the latter relationship was not significant (x2, p=0.94). 92 patients had both TCD and MRA within 1 month. The results were analysed for symptomatic (n=63) and asymptomatic (n=29) groups. There was no difference between groups for age (median 13; range 0–27 years). MRAs were examined for evidence of MCA turbulence graded as none, mild, moderate, severe or occlusion. There was a significant association between TAMM and MRA turbulence for the whole (ANOVA, right p=0.0001, left p=0.001), and symptomatic groups (ANOVA, right p=0.01, left p=0.025). All patients with TAMM>200 cm/sec had severe MCA turbulence but 2/3 with TAMM>170<200 cm/sec had normal MRA. The highest TAMM seen in a patient with occlusion was 80 cm/sec. Eighteen patients had no TCD signal, of whom 11 had abnormal MRA (3 occlusion). There is progressive CVD in children with SCD over time as evidenced by an increase in the number of children with abnormally low TCD. Patients with low TAMM or no signal may require MRA to document the severity of their CVD. Patients with TAMM>80 cm/sec are unlikely to have occlusion. As silent infarction is not predicted by TCD, MRA has a role as an additional tool to identify high risk patients, particularly in those with low TAMM. TAMM>200cm/sec appears to be a screen for severe turbulence, although this condition may represent specific pathophysiology rather than part of a spectrum.

Comparative Effects of Transfusion Program, Hydroxyurea or Stem Cell Transplant on Frequency of Hospitalisations in Pediatric Sickle Cell Patients.

Frequent vaso-occlusive crisis (VOC) and acute chest syndromes (ACS) cause high morbidity and early death and justify intensification of treatment. We report the comparative effects of Hydroxyurea (HU), Transfusion program (TP) or Stem Cell Transplant (SCT) on VOC and/or ACS occurrence in 76 SS/Sb0 patients.Patients and Methods: This study only concerned the patients always followed and hospitalized in our pediatric center in Creteil, from 1979 to June 2004: among this cohort of 256 SS/Sb0 patients, 76 received a treatment intensification justified by a high frequency of hospitalizations (3 3 VOC/y or 2 ACS/y). For this indication, HU was proposed since 1992 in 53 patients older than 3 years of age without abnormal cerebral velocities on Trans-cranial Doppler (TCD), TP in 42 patients younger than 3 years of age or having abnormal TCD (> 200 cm/sec) or HU failure in VOC/ACS frequency reducing, and SCT was performed in 15 patients with an available HLA identical sibling donor (14/15 successful). Several patients successively received different treatments: HU-TP (n=19), HU-TP-SCT (n=5), TP-SCT (n=6) and one patient who rejected the graft was treated with HU. We compared (student t-test) the causes, the frequency and duration of hospitalizations occurred during the year preceding the treatment intensification with those observed after the intensification program. For transplanted patients, we distinguishly considered the events having occurred during the first year post-transplant and those having occurred after.Results: Mean (± SD) follow-up before intensification was 8.1 years (± 4.5) with 2.3 hospitalizations/year (± 2.2) occured since birth. During the year preceding the treatment intensification, an higher number of hospitalizations (3.9 ± 2.1) occurred with 24.3 days of hosp (± 19.1) and the mean number of VOC was 2.3 (± 2) and ACS was 0.5 (± 0.8). After intensification, number of hospitalizations and VOC and ACS, duration of hosp significantly (p<0.001)decreased. On HU, with a mean follow-up of 4.7 years (± 3) in 53 patients, 1.7 (± 1.5) hosp/year, with 8.8 days/year (± 9.3), 1 VOC/year (± 1) and 0.2 ACS/year (± 0.4) occurred. On TP, with a mean follow-up of 2.6 years (± 2.5) in 35 patients, 1.2 hosp/year (± 1.2) with 5.5 days/y (± 6.2), 0.4 VOC/y (± 0.6) and 0.04 ACS/year (± 0.1) were observed. SCT was performed in 15 patients frequently experiencing VOC/ACS: during the first year post-transplant, the mean (± SD) number of hosp. was 3.1 (± 2.1) with 60.1 (± 26.1) days of hosp. related to the procedure and infectious complications. With a mean (± SD) follow-up of 4.1 years (± 3.8), after exlusion of the first year post-transplant, the number of hosp, days of hosp/year were respectively 0.3 (± 0.5) and 1.3 (2.1) and 0.01 (± 0.04) VOC or ACS/y. Number of hosp, days of hosp, VOC, ACS were highly significantly (p=0.001) lower after SCT than on HU therapy and the prevention of VOC (p<0.001) and ACS (p=0.04) was better on TP than with HU.Conclusion: Intensive treatments were significantly efficient to decrease the number and the duration of hospitalizations and the number of VOC and ACS. TP maintening HbS level < 40% was significantly more efficient than HU to prevent VOC (p<0.001) and ACS (p=0.03). SCT, after the 1 year post-transplant was the most efficient (p<0.001) to reduce the number and duration of hospitalizations and VOC/ACS rate occurrence. However, benefits/risks and costs of each treatment have to be prospectively assessed.

Sickle cell disease: Ischemia and seizures

Although the prevalence of seizures in children with sickle cell disease (SCD) is 10 times that of the general population, there are few prospectively collected data on mechanism. With transcranial Doppler and magnetic resonance imaging (MRI) and angiography, we evaluated 76 patients with sickle cell disease, 29 asymptomatic and 47 with neurological complications (seizures, stroke, transient ischemic attack, learning difficulty, headaches, or abnormal transcranial Doppler), who also underwent bolus-tracking perfusion MRI. The six patients with recent seizures also had electroencephalography. Group comparisons (seizure, nonseizure, and asymptomatic) indicated that abnormal transcranial Doppler was more common in the seizure (4/6; 67%) and nonseizure (26/41; 63%) groups than in the asymptomatic (10/29; 34%) group (chi2; p = 0.045), but abnormal structural MRI (chi2; p = 0.7) or magnetic resonance angiography (chi2; p = 0.2) were not. Relative decreased cerebral perfusion was found in all seizure patients and in 16 of 32 of the remaining patients with successful perfusion MRI (p = 0.03). In the seizure patients, the perfusion abnormalities in five were ipsilateral to electroencephalographic abnormalities; one had normal electroencephalogram results. These findings suggest that vasculopathy and focal hypoperfusion may be factors in the development of sickle cell disease-associated seizures.

Long-term follow-up of pediatric sickle cell disease patients with abnormal high velocities on transcranial Doppler

Cerebral arteriopathy can be detected in children with sickle cell disease (SCD) by transcranial Doppler (TCD). Abnormally high velocities are predictive of high stroke risk, which can be reduced by transfusion therapy. We report the results of the screening of 291 SCD children followed in our center, including the clinical and imaging follow-up of 35 children with abnormal TCDs who were placed on transfusion therapy. We postulated that patients with normal MRA findings and abnormal TCD velocities that normalized on a transfusion program could be safely treated with hydroxyurea (HU). We report their outcome (median follow-up of 4.4 years). Of 13 patients with normalized velocities on transfusion, 10 had normal MRAs, and transfusion therapy was stopped and HU begun. Four of these ten patients redeveloped high velocities off transfusion, so currently only six remain transfusion-free. Six other transplanted patients remain transfusion-free. Abnormal TCD velocities detect a high-risk group, justifying the research for suitable transplant donors. Multicenter studies comparing HU therapy to long-term transfusion might help identify which patients can avoid transfusion and its complications while avoiding vasculopathy.

TCD in sickle cell disease: an important and useful test

Sickle cell disease is associated with a high risk of stroke in the early years of childhood. The risk of a secondary stroke can be significantly reduced through chronic blood transfusions. Prevention of the first stroke (primary prevention) was made possible through the use of transcranial Doppler (TCD) US and demonstrated in a randomized clinical trial called the stroke prevention trial in sickle cell anemia (STOP). TCD results were classified as normal, conditional, abnormal or inadequate based on velocity readings in specific arterial segments. The MCA and ICA were carefully searched to find the highest velocity, and this was used to stratify patients as to stroke risk. Those with abnormal or high-risk TCD received either monthly blood transfusions or no transfusions, and those randomized to transfusion had a much better outcome in terms of stroke (one stroke, versus ten in the control group) and also fewer other medical problems while transfused. TCD screening is recommended for SCD patients to begin at 24 months of age and should be repeated every 6-12 months during early childhood. Transcranial Doppler imaging (TCDI) can be easier to use and learn and with a few adjustments can provide equivalent predictive power. Currently, TCD is the only recommended method for treatment selection for primary-stroke prevention. MRI and MRA can provide important information on the status of the brain and the blood vessels and, when abnormal, indicate greater risk. Although TCD cannot predict all strokes, TCD and TCDI offer an opportunity to apply an effective therapy for patients in this risk group and reduce many first-time strokes.

Sickle cell diseases: current therapeutic options and potential pitfalls in preventive therapy for transcranial Doppler abnormalities

Sickle cell disease is an important and common hemoglobinopathy that is highly prevalent worldwide. Recent clinical research has clarified the natural history, and newer, exciting therapeutic maneuvers have been developed, including stem cell transplantation, a curative, albeit toxic strategy. There is a need for early identification of a severe disease profile so that these newer therapeutic interventions can be offered before severe organ damage occurs. Investigative methodologic research by radiologists to discover early organ damage can be important to successful planning of treatment protocols. Stroke is one complication, which, if diagnosed early, can be satisfactorily managed with more aggressive therapy. The advent of transcranial Doppler and MRI have greatly increased the ability to detect early CNS disease.

Multigenic Dissection and Prognostic Modeling of Overt Stroke in Sickle Cell Anemia.

Stroke is a major vascular complication of sickle cell anemia, more frequent in patients under the age of 20 years. Transcranial Doppler (TCD) flow studies can predict the likelihood of stroke in children with sickle cell anemia, but only 10% of individuals with abnormal TCD values will have stroke, and stroke will occur in some individuals with normal TCD. Therefore, more precise means of prognosis would be welcome so that prophylactic treatments like transfusions or hydroxyurea can be targeted to individuals at highest risk. Using Bayesian networks (BNs), we analyzed 235 single nucleotide polymorphisms (SNPs) in 80 candidate genes in 1398 unrelated subjects with sickle cell anemia enrolled in the Cooperative Study of Sickle Cell Disease. Bayesian networks are a novel generation of multivariate models that represent the complex structure of interactions between many variables by a network of interrelated modules. These modules can be learned from data and then can be used to describe how changes in some variables affect other variables and ultimately the risk for the phenotype of interest. Bayesian networks provide a coherent framework within which genotypes, phenotypes and environmental factors can be seamlessly integrated into a comprehensive genomic landscape. We found that 25 SNPs on 11 genes and 4 clinical variables - including α thalassemia and fetal hemoglobin - interact in a complex network of dependency to modulate the risk of stroke. This network of interactions includes three genes (TGFBR2, TGFBR3, BMP6) with a functional role in the TGF-beta pathway and one gene (SELP) already associated with stroke in the general population. We validated our results in a different population by predicting the occurrence of stroke in a set of 114 subjects not included in the original study: 7 stroke patients and 107 control patients, a proportion consistent with the phenotype distribution in the original cohort study. Our model predicted the correct outcome for all 7 stroke patients, and for 105 of 107 non-stroke patients, with 100% true positive rate and 98.14% true negative rate, and an overall predictive accuracy of 98.2%. Our results support the hypothesis that stroke in sickle cell anemia patients is a complex trait caused by the interaction of multiple genes, and the predictive accuracy of our model is a step toward the development of additional prognostic tests to allow us to more precisely identify sickle cell anemia patients at risk for stroke. The presence in our model of genes already associated with stroke, such as SELP, suggests that some genetic factors predisposing to stroke are shared by both sickle cell anemia patients and stroke victims in the general population, and that our model may offer some insights into the genetic basis of the third leading cause of death in the United States.

Can peak systolic velocities be used for prediction of stroke in sickle cell anemia?

Ischemic stroke occurs in at least 11% of patients with homozygous sickle cell anemia (SCD) by the time they turn 20 years old. High risk associated with distal intracranial internal carotid (ICA) and proximal middle cerebral artery (MCA) stenosis can be detected by transcranial Doppler (TCD). TCD screening offers the possibility of reducing the risk of first stroke significantly based on a paradigm tested and proven to be effective in a stroke prevention trial in sickle cell anemia (STOP). Children with high flow velocity in the ICA and MCA of 200 cm/s time average mean of the maximum (TAMM) or higher had a 10% per year risk of first stroke that was reduced to <1% with regular red cell transfusion (reduction of hemoglobin S <30%). The clinical application of the STOP results could be enhanced if criteria for treatment could be found that are based on peak systolic velocity (PSV), the measure more commonly used in vascular ultrasound practice. To compare PSV and end diastolic velocity (EDV) with TAMM for prediction of stroke and to derive PSV cutpoints for STOP protocol definitions of conditional and abnormal TCD. Using the STOP TCD and stroke outcome data to compare PSV and TAMM in terms of stroke prediction, PSV cutpoints comparable to those based on TAMM and used in STOP were derived. Because of their familiarity to the vascular ultrasound community, PSV cutpoints should be an important alternative to TAMM and may increase availability of screening and risk stratification for children with this disease. Data from 1,937 baseline TCD studies from STOP were correlated with stroke outcome in those not treated with transfusion. Stroke prediction was assessed with survival analysis using TAMM, PSV and EDV as continuous variables individually and then pair-wise in the same model, which contained 53 stroke events. PSV and EDV were highly correlated to the TAMM velocity (r=0.94). The multivariate model for prediction indicated that TAMM velocity was a better predictor than EDV, and PSV and TAMM were approximately equivalent. PSV cutpoints defining the two relevant STOP risk categories--"conditional," which should lead to increased TCD surveillance, and "abnormal," which should lead to strong consideration for treatment according to STOP--were derived taking into consideration known differences in measurements between the dedicated Doppler systems (TCD) used in STOP and the transcranial Doppler imaging (TCDI) systems commonly used in clinical practice. The recommended PSV cutpoint for conditional TCD is 200 cm/s, and for abnormal TCD triggering consideration for treatment is 250 cm/s. Assuming TCDI equipment is used and the STOP protocol is applied, a PSV cutpoint of 200 cm/s is recommended as the threshold for increased TCD surveillance (comparable to a TCD TAMM of 170 cm/s in STOP); a PSV of 250 cm/s is recommended as the cutpoint at which, if confirmed in a second examination, chronic transfusion should be considered. Assuming the STOP scanning protocol is used, PSV is at least as good as TAMM and can be used to select children with SCD for treatment or increased surveillance to prevent first stroke.

The accuracy of transcranial Doppler in the diagnosis of stenosis or occlusion of the terminal internal carotid artery.

Transcranial Doppler (TCD) can detect intracranial stenoses and occlusions that can help in the diagnosis and management of ischemic stroke. The accuracy parameters for lesions located in the terminal internal carotid artery (TICA) are less known, unlike other basal cerebral vessels. The authors studied consecutive patients referred for TCD who underwent contrast angiography or magnetic resonance angiography. They calculated the sensitivity, specificity, positive and negative predictive values (PPV and NPV), and likelihood ratios. Forty-three patients had TCD and angiography: mean age was 57 +/- 20 years, and 65% were men. Twenty-two patients were diagnosed with TICA stenosis or occlusion on TCD underwent angiography. Four patients had abnormal TCD findings that were not confirmed by angiography. Two of 21 patients with normal TCD showed moderate (< 50%) stenosis of the TICA and cavernous segment of the internal carotid artery at angiography. Accuracy parameters for TCD were as follows: sensitivity = 90% (confidence interval [CI], 63%-96%), specificity = 83% (CI, 61%-94%), PPV = 82%, NPV = 86%, positive likelihood ratio = 5, and negative likelihood ratio = 0.17. TCD is a sensitive screening tool for the lesions in the TICA. Specificity is likely affected by a wide spectrum of the stenosis severity shown at angiography and time lags between the studies.

Transcranial Doppler Changes in Children With Sickle Cell Disease on Transfusion Therapy.

Transcranial Doppler (TCD) is an effective method for screening patients with sickle cell disease (SCD) at risk for first stroke. Its usefulness in monitoring children with SCD receiving transfusions has not been established. The authors studied 17 children with SCD evaluated with TCDs and magnetic resonance angiograms (MRAs) while receiving transfusion therapy. Patients with normalized TCDs had normal MRAs that remained normal on transfusions. Patients with persistently abnormal TCDs had abnormal MRAs. In these children, TCD velocities decreased but rarely reverted to normal. Patients with low TCD velocities (<70 cm/s) had corresponding vasculopathy on MRA. Low velocities may be a risk factor for stroke and should be followed. Overall, there was good correlation between TCD velocity changes and MRA analysis.

The Accuracy of Transcranial Doppler in the Diagnosis of Stenosis or Occlusion of the Terminal Internal Carotid Artery

ABSTRACT Background and Purpose. Transcranial Doppler (TCD) can detect intracranial stenoses and occlusions that can help in the diagnosis and management of ischemic stroke. The accuracy parameters for lesions located in the terminal internal carotid artery (TICA) are less known, unlike other basal cerebral vessels. Patients and Methods. The authors studied consecutive patients referred for TCD who underwent contrast angiography or magnetic resonance angiography. They calculated the sensi tivity, specificity, positive and negative predictive values (PPV and NPV), and likelihood ratios. Results. Forty‐three patients had TCD and angiography: mean age was 57 ± 20 years, and 65% were men. Twenty‐two patients were diagnosed with TICA stenosis or occlusion on TCD underwent angiography. Four patients had abnormal TCD findings that were not confirmed by angiography. Two of 21 patients with normal TCD showed mod erate (&lt; 50%) stenosis of the TICA and cavernous segment of the internal carotid artery at angiography. Accuracy parameters for TCD were as follows: sensitivity = 90% (confidence interval [CI], 63%‐96%), specificity = 83% (CI, 61%‐94%), PPV = 82%, NPV = 86%, positive likelihood ratio = 5, and negative likelihood ratio = 0.17. Conclusions. TCD is a sensitive screening tool for the lesions in the TICA. Specificity is likely affected by a wide spectrum of the stenosis severity shown at angiography and time lags between the studies.

Stroke and conversion to high risk in children screened with transcranial Doppler ultrasound during the STOP study

AbstractThe Stroke Prevention Trial in Sickle Cell Anemia (STOP) was a randomized multicenter controlled trial comparing prophylactic blood transfusion with standard care in sickle cell anemia (SCA) children aged 2 to 16 years selected for high stroke risk by transcranial Doppler (TCD). More than 2000 children were screened with TCD to identify the 130 high-risk children who entered the randomized trial. A total of 5613 TCD studies from 2324 children were evaluated. We also collected information on stroke. We describe the changes in TCD with repeated testing and report the outcome without transfusion in the STOP screened cohort. Risk of stroke was higher with abnormal TCD than with normal or conditional TCD (P < .001) or inadequate TCD (P = .002), and risk with conditional TCD was higher than with normal TCD (P < .001). Repeated TCD in 1215 children showed that the condition of 9.4% of children became abnormal during observation. Younger patients and those with higher initial flow velocities were most likely to convert to abnormal TCDs. Screening in STOP confirmed the predictive value of TCD for stroke. Substantial differences in the probability of conversion to abnormal TCD were observed, with younger children and those with higher velocity more likely to have an abnormal TCD with rescreening.

Transcranial Doppler ultrasonography and executive dysfunction in children with sickle cell disease.

To identify behavioral manifestations of executive dysfunction that are associated with cerebrovasculopathy, as measured by transcranial Doppler (TCD) ultrasonography, in children with sickle cell disease (HbSS). Participants were 62 children and adolescents with HbSS disease who had no documented history of cerebrovascular accident. Children were classified according to the National Institutes of Health Stroke Prevention Trial in Sickle Cell Anemia (STOP) criteria (i.e., normal, conditional, and abnormal). Although children with abnormal TCD values were rated by their parents as exhibiting greater executive dysfunction in the areas of inhibitory control, problem-solving flexibility, and modulation of emotional responses compared with children in the conditional group, these differences were not clinically significant. In contrast, teachers rated children in the abnormal TCD group as having clinically significant executive dysfunction as manifested in their ability to solve problems in working memory, plan and organize, and self-monitor. Our findings lend preliminary support for the utility of teacher-completed screening instruments designed to assess everyday behaviors associated with executive dysfunction in children with HbSS disease, especially among those children at greatest risk for neurological impairment as identified by TCD ultrasonography.

Is Chlamydia pneumoniae infection associated with stroke in children with sickle cell disease?

Stroke is often a devastating complication of sickle cell disease (SCD). Most children with SCD-related stroke have stenotic and occlusive disease of cerebral blood vessels due to intimal hyperplasia. This hyperplasia is hypothesized to result from an inflammatory response similar to that in atherosclerosis and has been attributed to infection by Chlamydia pneumoniae. To determine whether C pneumoniae infection is associated with stroke and cerebrovascular disease, including transient ischemic attacks and abnormal transcranial Doppler examinations, in children with SCD. Children with SCD on chronic transfusion due to a history of stroke, transient ischemic attack, or abnormal transcranial Doppler; children with SCD without stroke; healthy controls; and children being transfused for other reasons were enrolled. Peripheral blood and nasopharyngeal (NP) swab specimens were collected from all patients. In patients on transfusion, pretransfusion specimens and samples from the unit of packed red blood cells being transfused were obtained. Peripheral blood monocytic cells (PBMCs) and NP swab specimens were cultured for C pneumoniae in HEp-2 cells. C pneumoniae polymerase chain reaction was performed on PBMCs with a nested touch-down method with primers from the omp-1gene (in duplicate) and a second real-time polymerase chain reaction by using 16S ribosomal RNA primers. C pneumoniae DNA was detected in the PBMCs of 1 of 14 (7.1%) children with SCD on chronic transfusion, 1 of 10 (10%) sickle cell controls, 1 of 10 (10%) healthy controls, and none of the 5 children receiving chronic transfusion for other reasons. It was not detected in specimens from transfusion units. One child with SCD and stroke, 1 sickle cell control, and 1 transfusion control had positive NP cultures for C pneumoniae. C pneumoniae DNA was not detected in their PBMCs, and all 3 children were asymptomatic. C pneumoniae was not detected by culture of PBMCs from any of the patients after 7 passages. Stroke in children with SCD does not seem to be associated with C pneumoniae infection in our population.

Magnetic resonance angiography in children with sickle cell disease and abnormal transcranial Doppler ultrasonography findings enrolled in the STOP study

AbstractThe stroke prevention study in sickle cell disease (STOP) demonstrated a 90% reduction in stroke risk with transfusion among patients with time-averaged mean cerebral blood velocity (TAMV) of 200 cm/s or more as measured by transcranial Doppler (TCD). In STOP, 232 brain magnetic resonance angiograms (MRAs) were performed on 100 patients, 47 in the transfusion arm and 53 in the standard care arm. Baseline MRA findings were interpreted as normal in 75 patients and as indicating mild stenosis in 4 patients and severe stenosis in 21 patients. Among 35 patients who underwent magnetic resonance angiography within 30 days of random assignment, the TAMV was significantly higher in 7 patients with severe stenosis compared with 28 patients with normal MRA findings or mild stenosis (276.7 ± 34 vs 215 ± 15.6 cm/s;P< .001). In the standard care arm, 4 of 13 patients with abnormal MRA findings had strokes compared with 5 of 40 patients with normal MRA findings (P= .03). In this arm, TAMV became normal (less than 170 cm/s) or conditional (170-199 cm/s) in 26 of 38 patients with normal or mildly abnormal baseline MRA but remained abnormal in 8 of 10 patients with severely abnormal baseline MRA. These results suggest that TCD often detects flow abnormalities indicative of stroke risk before MRA lesions become evident. Furthermore, patients with abnormal MRA findings and higher TCD velocities are at higher risk for stroke, and their cerebral TAMVs are unlikely to decrease without transfusion. (Blood. 2004;103:2822-2826)

Transcranial Doppler ultrasonography and neurocognitive functioning in children with sickle cell disease.

We examined the relationship between cerebral blood flow velocity, measured by transcranial Doppler (TCD) ultrasonography, and neurocognitive functioning. Participants were 60 children who had sickle cell disease (HbSS) and had no documented history of stroke. Children were classified according to Stroke Prevention Trial in Sickle Cell Anemia criteria (normal, conditional, and abnormal), and their performance was compared on measures of intellectual abilities, academic achievement, sustained attention/concentration, executive function, and parent and teacher ratings of executive function. Children with abnormal TCD values performed more poorly than children with conditional TCD values on measures of verbal intelligence and executive function. Children with conditional TCD values performed more poorly than children with normal TCD values on measures of sustained attention/concentration and executive function. TCD values also were a significant predictor of auditory working memory in exploratory analyses. Our findings support the hypothesis that neurocognitive functions subserved by the frontal systems (eg, sustained attention/concentration and executive function) seem to be the most useful indices of progressive cerebrovasculopathy in children with HbSS disease.

Alpha Thalassemia is associated with decreased risk of abnormal transcranial Doppler ultrasonography in children with sickle cell anemia.

Cerebrovascular complications of sickle cell disease (SCD) are common, but the risk factors remain unclear. The multicenter Stroke Prevention Trial in Sickle Cell Anemia (STOP) provided an opportunity to examine alpha thalassemia-2 as a modifying risk factor, using abnormal transcranial Doppler ultrasonography (TCD) as a surrogate marker for cerebrovascular disease. The authors hypothesized that children with abnormal TCD are less likely to have alpha thalassemia-2, and an increased hemoglobin level accounts for this protective effect. A retrospective study was conducted of children with SCD who had both alpha gene and TCD data from STOP: 128 with TCD of at least 200 cm/s (abnormal TCD) and 172 with TCD less than 170 cm/s (normal TCD). Alpha thalassemia-2 was more frequent in the normal TCD group compared with the abnormal TCD group. The odds ratio for normal TCD and alpha thalassemia-2 was 4.1. Adjusting for either hemoglobin level or red cell size (mean corpuscular volume) reduced the odds ratio only slightly. Age, normal TCD, and alpha thalassemia-2 had significant statistical interaction, so that alpha thalassemia-2 was not related to TCD for age 10 years or older. The frequency of alpha thalassemia-2 was significantly higher in children with normal TCD. Speculation on mechanisms of effect includes improved erythrocyte deformability, reduced red cell adhesion, and reduced nitric oxide scavenging in alpha thalassemia-2. The association of alpha thalassemia-2 and normal TCD adds to the evidence on the protective effects of alpha thalassemia-2 in SCD and highlights the contribution of epistatic factors.