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In order to prevent stroke, screening for disease-related intracranial vasculopathy using Doppler ultrasound is recommended in sickle-cell disease (SCD) children. How to screen such vasculopathy in adults remains largely unknown. The objective of this study was to assess whether transcranial color-coded duplex sonography (TCCD) is sensitive and specific enough to identify SCD adult patients with vasculopathy, compared with magnetic resonance angiography (MRA). Sickle cell disease adults followed in referral centers at high risk of vasculopathy were included in this study. Transcranial color-coded duplex sonography examination and 3-D time-of-flight MRA were performed on the same day. On MRA, vasculopathy was defined by the presence of at least one ≥50% arterial stenosis. On TCCD, vasculopathy was defined by a time-averaged mean of the maximum velocity (TAMx) stenotic/prestenotic ratio ≥ 3, an occlusion, or a Moyamoya pattern. Vasculopathy was also considered as present when TAMx ratio could not be calculated because of the presence of severe cervical lesions. Among 80 included patients, quality of MRA was insufficient in three patients. Among the 38 patients with vasculopathy on MRA, 37 had a vasculopathy according to TCCD criteria: TAMx ratio ≥ 3 or intracranial occlusion in 33 patients and cervical lesion in four patients. A Moyamoya pattern was identified with TCCD in all 17 patients with Moyamoya on MRA. Sensitivity and specificity of TCCD to identify patients with ≥50% vasculopathy on MRA were (n = 37/38) 97% and (n = 28/34) 82%, respectively. Positive and negative predictive values were (n = 37/43) 86% and (n = 28/29) 97%, respectively. Note, TCCD may be used to identify SCD adult patients with vasculopathy., (© 2021 Wiley Periodicals LLC.)

Cerebral vasculopathy is the most severe complication affecting children with sickle cell anemia. Significant progress has been made in the management of sickle cell anemia cerebral vasculopathy, including early transcranial Doppler screening, chronic transfusion, andhydroxyurea. Nevertheless, for patients with a potential matched-sibling donor (MSD), stem cell transplantation (SCT) is now the treatment offering the best cerebral vasculopathy outcome. In the absence of MSD,alternative SCT should be recommended only in those with worsening cerebral vasculopathy despite standard treatments, and should be limited to related haplo-identical SCT undertaken in controlled studies., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 King Faisal Specialist Hospital & Research Centre. Published by Elsevier Ltd. All rights reserved.)

Sickle cell disease (SCD) is a common cause of cerebrovascular disease in childhood. Primary stroke prevention is effective using transcranial Doppler (TCD) scans to measure intracranial blood velocities, and regular blood transfusions or hydroxycarbamide when these are abnormal. Inadequate TCD scans occur when it is not possible to measure velocities in all the main arteries. We have investigated the prevalence and significance of this in a retrospective audit of 3915 TCD scans in 1191 children, performed between 2008 and 2015. 79% scans were normal, 6.4% conditional, 2.8% abnormal and 12% inadequate. 21.6% of 1191 patients had an inadequate scan at least once. The median age of first inadequate scan was 3.3 years (0.7-19.4), with a U-shaped frequency distribution with age: 28% aged 2-3 years, 3.5% age 10 years, 25% age 16 years. In young children reduced compliance was the main reason for inadequate TCDs, whereas in older children it was due to a poor temporal ultrasound window. The prevalence of inadequate TCD was 8% in the main Vascular Laboratory at King's College Hospital and significantly higher at 16% in the outreach clinics (P<0.0001), probably due to the use of a portable ultrasound machine. Inadequate TCD scans were not associated with underlying cerebrovascular disease.

Objectives: Cerebrovascular reactivity (CVR) measures the ability of cerebral blood vessels to change their diameter and, hence, their capacity to regulate regional blood flow in the brain. High resolution quantitative maps of CVR can be produced using blood-oxygen level-dependent (BOLD) magnetic resonance imaging (MRI) in combination with a carbon dioxide stimulus, and these maps have become a useful tool in the clinical evaluation of cerebrovascular disorders. However, conventional CVR analysis does not fully characterize the BOLD response to a stimulus as certain regions of the brain are slower to react to the stimulus than others, especially in disease. Transfer function analysis (TFA) is an alternative technique that can account for dynamic temporal relations between signals and has recently been adapted for CVR computation. We investigated the application of TFA in data on children with sickle cell disease (SCD) and healthy controls, and compared them to results derived from conventional CVR analysis., Materials and Methods: Data from 62 pediatric patients with SCD and 34 age-matched healthy controls were processed using conventional CVR analysis and TFA. BOLD data were acquired on a 3 Tesla MRI scanner while a carbon dioxide stimulus was quantified by sampling the end-tidal partial pressures of each exhaled breath. In addition, T1 weighted structural imaging was performed to identify grey and white matter regions for analysis. The TFA method generated maps representing both the relative magnitude change of the BOLD signal in response to the stimulus (Gain), as well as the BOLD signal speed of response (Phase) for each subject. These were compared to CVR maps calculated from conventional analysis. The effect of applying TFA on data from SCD patients versus controls was also examined., Results: The Gain measures derived from TFA were significantly higher than CVR values based on conventional analysis in both SCD patients and healthy controls, but the difference was greater in the SCD data. Moreover, while these differences were uniform across the grey and white matter regions of controls, they were greater in white matter than grey matter in the SCD group. Phase was also shown to be significantly correlated with the amount that TFA increases CVR estimates in both the grey and white matter., Conclusions: We demonstrated that conventional CVR analysis underestimates vessel reactivity and this effect is more prominent in patients with SCD. By using TFA, the resulting Gain and Phase measures more accurately characterize the BOLD response as it accounts for the temporal dynamics responsible for the CVR underestimation. We suggest that the additional information offered through TFA can provide insight into the mechanisms underlying CVR compromise in cerebrovascular diseases.

Cerebrovascular accidents were until recently responsible for much mortality and morbidity in children with sickle cell disease; the likelihood of a child with HbSS having a stroke was 11% before age 20 years, with a peak incidence of ischemic stroke between 2 and 5 years of age, and of hemorrhagic strokes between 20 and 29 years of age. Vessels occlusion is likely initiated by intimal proliferation and amplified by inflammation, excessive adhesion of cells to activated endothelium, hypercoagulable state, and vascular tone dysregulation. Silent infarcts may occur and are associated with decreased cognitive functions. Transcranial Doppler ultrasonography (TCD) was more recently demonstrated able to achieve early detection of the children at high risk for clinical strokes. A randomized study demonstrated that a first stroke may be prevented by monthly transfusion in children with abnormal TCD, leading to a recommendation for annual TCD screening of children aged between 2 and 16 years and monthly transfusion for those with abnormal results. In children who have had a first stroke, the risk of recurrence is more than 50% and is greatly reduced by chronic transfusion, although not completely abolished. Hematopoietic stem cell transplant is indicated in children with cerebral vasculopathy who have an HLA-identical sibling., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Increased blood flow velocity (BFV) in basal cerebral arteries measured by transcranial color-coded sonography (TCCS) is a stroke risk factor in sickle cell disease (SCD). Raised BFV may be caused by vessel narrowing or by hyperperfusion. In 44 SCD patients and 14 controls, intracranial arterial BFVs and global cerebral blood flow (CBF) were analyzed by TCCS and extracranial duplex ultrasound, respectively. Magnetic resonance imaging and magnetic resonance angiography were performed in all patients with pathologic intracranial BFV rise. Intracranial BFVs and CBF in SCD were significantly higher than in controls. CBF in SCD correlated with BFV in all intracranial arteries and correlated inversely with age and hemoglobin values. Magnetic resonance angiography failed to demonstrate any stenosis in our SCD patients, thus raised intracranial BFVs must be interpreted as an anemia-dependent cerebral hyperperfusion. These findings suggest that the pathomechanism of stenosis-derived arterio-arterial embolism might be less relevant in SCD-related ischemic stroke, and other factors like small vessel disease or sickle cell-induced microvascular blood clotting have to be considered., (Copyright © 2012 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.)

Transcranial Doppler US, a non-invasive tool for evaluating the cerebral arteries, has evolved significantly during the last two decades. This review describes the practical procedure, and summarises and illustrates its established and "work-in-progress" indications in children. Indications for a transcranial Doppler US examination include, but are not limited to: (1) evaluation of cerebral blood flow velocities in the circle of Willis in patients with sickle cell anaemia to guide transfusion therapy; (2) diagnosis and follow-up of vasculopathy, such as moyamoya disease; (3) diagnosis and monitoring of acute cerebrovascular disorders in intensive care patients, in particular following traumatic brain injury, and during cardiovascular surgery; and (4) confirmation of a clinical diagnosis of brain death by documentation of cerebral circulatory arrest.

This retrospective study assessed the long-term effect of transfusional exchange therapy on MRA/MRI abnormalities in 24 homozygous sickle-cell anemia (HbSS) children presenting with abnormal brain MRA. The median time elapsed from baseline to last available MRA was 29 months. Follow-up MRAs showed improvement, stabilization or worsening of cerebrovascular lesions in 11, 6 and 7 patients respectively. Complete normalization of MRA was observed in 6 patients within a mean time of 1.4 years, but stenosis recurred at the same location in the 4 patients in whom transfusion therapy was discontinued. Baseline severe stenosis/occlusion of large cerebral arteries and occurrence of moyamoya syndrome were significantly associated with an absence of improvement of the cerebral vasculopathy. These data emphasize the heterogeneity of the course of cerebrovasculopathy in SS children receiving chronic transfusion. Further studies are needed to determine whether different therapeutic approaches have to be considered according to these different evolutive patterns in SS children.

Background: Environmental factors interfere on sickle cell anaemia (SCA). Transcanial Doppler (TCD) is important to evaluate cerebrovascular disease., Objective: To evaluate brain haemodynamic profile of children with SCA in Sergipe., Methods: Cross sectional study (group1: SCA patients aged 3-18; group2: age and sex matched healthy individuals). Baseline brain flow was evaluated., Results: Group1=34 patients; group 2=81 controls. SCA patients had mean velocity (MV)=125.69 cm/s+/-23.40; pulsatility index (PI)=0.66+/-0.10; middle cerebral artery ratio (MCAr)=14.53+/-15.23; right anterior cerebral artery/right middle cerebral artery=0.77+/-0.20; left anterior cerebral artery/left middle cerebral artery=0.78+/-0.20. Controls had MV=79.44+/-15.54; PI=0.82+/-0.11; MCAr=13.19+/-13.77; right anterior cerebral artery/right middle cerebral artery=0.80+/-0.16; left anterior cerebral artery/left middle cerebral artery=0.84+/-0.18. MV and PI differences were statistically significant between groups. MV was related to age but not to gender., Conclusion: MV evaluation using TCD was similar to international standards and possible to be used in our setting.

Objective: Neurological complications have been reported in patients with sickle-cell disease (SCD) using positron emission tomography (PET), magnetic resonance imaging (MRI), and computed tomography (CT), but not with single photon emission computed tomography (SPECT). The objective of this study was to investigate brain perfusion in the patients with SCD using SPECT after technetium-99m hexamethylpropylene amine oxime (99mTc-HMPAO), was administered and compare the findings with those of demography, physical examination, MRI and hematological profile., Methods: The study involved 21 patients (12 males, 9 females, age at study 8-45 years) who were known to be having SCD for a duration of at least 5 years. The patients were not in acute crisis and had normal neurological assessments with no known history of stroke or transient ischemic episode or previous abnormal CT or MRI brain scan, and were right-handed. The brain SPECT was performed after intravenous injection of 740 MBq (20 mCi) 99mTc-HMPAO in adults or an appropriate dose in pediatric patients. The scans were visually interpreted by two nuclear medicine physicians and a decision was reached by consensus. An MRI done 3 months later was interpreted by a radiologist. The demographic data and hematological profile were obtained from the medical records of the patients., Results: Of the 21 patients, 7 (age 11-22 years) had brain perfusion deficit mostly in the frontal lobe either alone or in combination with temporal and/or parietal lobe. The MRI was abnormal in 2 patients. The brain perfusion deficit was not associated with the demographic data of the patients or hematological profiles., Conclusions: The findings show that SPECT was useful in detecting brain perfusion deficit in SCD patients, and such an early detection may be clinically useful in the subsequent follow-up of such patients, since it is known that cerebral perfusion deficit can lead to silent infarct and/or overt stroke, and affect cognitive skills.

Children with sickle cell anemia (SS) have an increased risk for cerebral vasculopathy with stroke (CVA) and cognitive impairment. The present study examines the extent to which adding positron emission tomography (PET) to magnetic resonance imaging (MRI) can improve the detection of cerebral vasculopathy. Whereas MRI has been the prime modality for showing anatomical lesions, PET excels at assessing the functional metabolic state through glucose utilization 2-deoxy-2 [18F] fluoro-D-glucose (FDG) and microvascular blood flow ([15O]H2O). Forty-nine SS children were studied. Among them, 19 had clinically overt CVA, 20 had life-threatening hypoxic episodes or soft neurologic signs, and 10 were normal based on neurological history and examination. For the entire sample of 49 subjects, 30 (61%) had abnormal MRI findings, 36 (73%) had abnormal PET findings, and 44 (90%) showed abnormalities on either the MRI or the PET or both. Of the 19 subjects with overt CVA, 17 had abnormal MRI (89%), 17 had abnormal PET (89%), and 19 (100%) had either abnormal MRI or PET or both. Among the 20 subjects with soft neurologic signs, 10 (50%) had abnormal MRI, 13 (65%) had abnormal PET, and 17 (85%) had abnormal MRI and/or PET. Six (60%) of the 10 neurologically normal subjects had abnormal PET. Among the 30 subjects with no overt CVA, 25 (83%) demonstrated imaging abnormalities based on either MRI or PET or both, thus, silent ischemia. Lower than average full-scale intelligence quotient (FSIQ) was associated with either overt CVA or silent ischemic lesions. Four subjects who received chronic red blood cell transfusion showed improved metabolic and perfusion status on repeat PET scans. In conclusion, (1) the addition of PET to MRI identified a much greater proportion of SS children with neuroimaging abnormalities, particularly in those who had no history of overt neurologic events. (2) PET lesions are more extensive, often bihemispheric, as compared with MRI abnormalities. (3) PET may be useful in management as a tool to evaluate metabolic improvement after therapeutic interventions, and (4) the correlation of PET abnormalities to subsequent stroke or progressive neurologic dysfunction requires further study.

Background: Blood transfusions prevent recurrent stroke in children with sickle cell anemia, but the value of transfusions in preventing a first stroke is unknown. We used transcranial Doppler ultrasonography to identify children with sickle cell anemia who were at high risk for stroke and then randomly assigned them to receive standard care or transfusions to prevent a first stroke., Methods: To enter the study, children with sickle cell anemia and no history of stroke had to have undergone two transcranial Doppler studies that showed that the time-averaged mean blood-flow velocity in the internal carotid or middle cerebral artery was 200 cm per second or higher. The patients were randomly assigned to receive standard care or transfusions to reduce the hemoglobin S concentration to less than 30 percent of the total hemoglobin concentration. The incidence of stroke (cerebral infarction or intracranial hemorrhage) was compared between the two groups., Results: A total of 130 children (mean [+/-SD] age, 8.3+/-3.3 years) were enrolled; 63 were randomly assigned to receive transfusions and 67 to receive standard care. At base line, the transfusion group had a slightly lower mean hemoglobin concentration (7.2 vs. 7.6 g per deciliter, P=0.001) and hematocrit (20.4 vs. 21.7 percent, P=0.002). Ten patients dropped out of the transfusion group, and two patients crossed over from the standard-care group to the transfusion group. There were 10 cerebral infarctions and 1 intracerebral hematoma in the standard-care group, as compared with 1 infarction in the transfusion group -- a 92 percent difference in the risk of stroke (P<0.001). This result led to the early termination of the trial., Conclusions: Transfusion greatly reduces the risk of a first stroke in children with sickle cell anemia who have abnormal results on transcranial Doppler ultrasonography.

Stroke is an important complication of sickle cell disease. Stroke prediction is clinically important because it offers the possibility of primary prevention. In 1992, transcranial Doppler (TCD) evidence of elevated intracranial internal carotid or middle cerebral artery velocity was demonstrated to be associated strongly with an increased risk of ischemic stroke. This study extends the original study and includes 125 more children, longer follow-up, and intracranial hemorrhage in the stroke-risk model. Elevated time averaged mean maximum blood flow velocity, especially when velocity is 200 cm/sec or greater by TCD, was associated strongly with stroke risk. The cases not predicted by TCD point to the need for more information on the optimal timing of TCD surveillance for stroke risk.

Background and Purpose: Cerebral infarction in sickle cell disease is associated with arterial narrowing or occlusions of intracranial arteries. Primary stroke prevention would be feasible if a noninvasive screening test could be developed to detect intracranial disease in patients before symptoms develop., Methods: To determine the sensitivity and specificity of transcranial Doppler in detecting significant (greater than or equal to 50% lumen diameter reduction) intracranial arterial lesions, we compared transcranial Doppler and cerebral angiography in a primarily young, symptomatic group of 33 patients (18 males and 15 females) with sickle cell disease., Results: From a total of 34 examinations, transcranial Doppler detected significant abnormalities in 26 of 29 (sensitivity 90%, specificity 100%). Five were normal by both techniques. The transorbital examination detected abnormalities in two patients whose studies were otherwise unremarkable., Conclusions: Transcranial Doppler is sensitive and specific for the detection of arterial vasculopathy of sickle cell disease. Screening should include a transorbital examination of the distal internal carotid artery as well as examination using the transtemporal approach.

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 greater than or equal to 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 less than 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.

Although long-term transfusion therapy is at least 90% effective in preventing recurrent strokes after an initial cerebrovascular accident in patients with sickle cell disease, it is unknown how long transfusion therapy should be continued. To address this question, we prospectively discontinued transfusions in 10 patients with sickle cell disease whose median duration of transfusion therapy after an initial stroke was 9 1/2 years (range 5 to 12 years). Before the transfusions were discontinued, patients were examined by cerebral angiography, magnetic resonance imaging of the head, neuropsychologic testing, electroencephalography, and a complete neurologic examination. Within 12 months after transfusion therapy was stopped, 5 of 10 patients had had an ischemic event. Three events caused relatively mild deficits in the same areas as those originally affected. Two were associated with massive intracranial hemorrhage, including one on the contralateral side of original involvement. An additional patient died suddenly of unknown causes. Of the four remaining patients, three declined to resume transfusion and are relatively well at greater than or equal to 18 months after therapy was stopped. The studies performed before transfusions were stopped were not predictive of recurrent stroke. The risk of recurrent cerebrovascular accident in this group was significantly greater than the estimated risk of 10% in patients who are receiving long-term transfusion therapy (p = 0.002). This adverse outcome suggests that patients with sickle cell disease who have had a stroke must receive long-term transfusion indefinitely or a suitable therapeutic alternative must be devised.

Cerebral blood flow (CBF) has been studied by the xenon-133 (133Xe) inhalation method in 16 children with suspected sickle cell cerebrovascular disease. Abnormalities consisting of decreases in total, hemispheral, or regional CBF were found in 17 of 26 studies. Eleven studies performed immediately after stroke, transient ischemic attack, or depression of state of alertness showed abnormalities. In addition to confirming regional cerebrovascular insufficiency in children with stroke due to major cerebral artery occlusion, the method detected diffuse decrease in CBF in children with stupor, coma, and seizures who had normal angiographic findings. In contrast, six of seven studies obtained after exchange transfusion or during maintenance on hypertransfusion therapy showed normal findings. The difference between results in patients with acute neurologic disturbances and those receiving transfusion therapy was statistically significant (P less than .005). The data indicate that the 133Xe method reliably demonstrates cerebrovascular impairment in sickle cell disease. They also suggest that CBF changes in patients with sickle cell disease can be reversed by exchange transfusion and by hypertransfusion therapy. The 133Xe CBF method may be useful for following up children with sickle cell disease who are at high risk for recurrent stroke.

Computed tomography (CT) findings in the intracranial complications of leukemia, hemophilia, and sickle cell anemia were reviewed in 19 children with these hematologic disorders. CT demonstrated intracranial hemorrhage, infarction, intracerebral mass, and post-therapeutic atrophy and leukoencephalopathy in leukemic children. Intracerebral, subarachnoid, subdural, and epidural hemorrhage was documented in patients with hemophilia. Bland and hemorrhagic infarctions were identified in children with sickle cell anemia. CT proved valuable in documenting the presence and extent of these abnormalities, titrating factor replacement in hemophiliac patients, and monitoring therapeutic toxicity in leukemic patients.

An opportunity to study cerebrovascular changes in sickle cell anemia (SCA) presented itself when a black child with this disorder died of bihemispheric strokes. Angiography demonstrated severe occlusive vascular disease involving primarily the circle of Willis and major bifurcations of both internal carotid arteries. Collateral circulation to the distal branches of the internal carotid arteries occurred through transdural anastomoses from the external carotid system and via the leptomeningeal route. Perfusion of the basal ganglia was accomplished by vessels arising from the proximal internal carotid arteries. These changes resembled those of Moyamoya disease. Autopsy showed old and recent cerebral infarcts. Two vascular processes were responsible for the arterial occlusions: (1) exuberant intimal hyperplasia, and (2) old and recent thrombi with partial recanalization. The former has been described only once before in SCA. Small vessels in the basal ganglia were exceptionally numerous and dilated. We conclude that intimal hyperplasia within large cerebral arteries may be responsible for infarction and small vessel prliferation in basal ganglia in patients with SCA.