Cerebrovascular Event and Stroke Rates in Pediatric Patients with Sickle Cell Disease and Moyamoya Syndrome: a Systematic Review


Authors: Sabrina H. Han, BHS1*, Adam Robert, BS2, Asmaa Hatem, MD2, Gustavo Cortez, MD3, Rodeania Peart, BS1, Ricardo A. Hanel, MD, PhD3, Manisha M. Bansal, MD4, Philipp R. Aldana, MD2

1 University of Florida College of Medicine, Gainesville, Florida USA
2 Division of Pediatric Neurosurgery, University of Florida College of Medicine – Jacksonville and Wolfson Children’s Hospital, Jacksonville, Florida USA
3 Lyerly Neurosurgery, Baptist Neurological Institute, Jacksonville, Florida USA
4 Department of Pediatric Hematology/Oncology, Nemours Children’s Health System and Wolfson Children’s Hospital, Jacksonville, Florida USA

Corresponding author
Philipp R. Aldana, M.D.
Lucy Gooding Pediatric Neurosurgery
836 Prudential Drive, Suite 1205, Jacksonville, FL 32207
Telephone: (904) 633-0793, Facsimile: (904) 633-0781
Email: philipp.aldana@jax.ufl.edu

Acknowledgements: We wish to acknowledge that this work has been supported in part by the Lucy B. Gooding Charitable Foundation Trust and the Baptist Health Foundation of Northeast Florida, both of which are not-for-profit organizations.

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Although children with sickle cell disease (SCD) are at increased risk for cerebrovascular events (CVEs), the added risk due to severe cerebral vasculopathy is understudied. This lack of data regarding the benefits of treating vasculopathy in the context of SCD contributes to uncertainty regarding optimal care of these patients. We sought to review the extent that severe vasculopathy, specifically moyamoya syndrome (MMS), contributes to the occurrence of CVEs in children with SCD.


A systematic review was conducted following PRISMA guidelines. 904 full-text articles were screened; 13 were included.


Of those receiving chronic transfusion therapy, we found that children with SCD and MMS had an elevated CVE occurrence and risk [48.3% (29/60) and 11.15 CVEs/100 patient-years, respectively]; those selected for cerebral revascularization surgery (CRS) had the highest [76.9% (10/13), 29.50 CVEs/100 patient-years]. Following CRS, CVE occurrence and rate decreased to 23.7% (14/59) and 6.37 CVEs/100 patient-years.


Pediatric patients with SCD further complicated with MMS have considerably elevated rates of CVE occurrence and risk. Further studies are needed to help guide physicians treating this complicated patient population.

Key Words: sickle cell disease, moyamoya, transfusion, surgery, vasculopathy, stroke


Sickle cell disease (SCD) is the most common inherited blood disorder and affects up to 100,000 people of African descent in the U.S.1 Stroke is a devastating complication of SCD, with SCD as the most common co-existing risk factor for stroke in African-American children.1 If left untreated, 10% of those with subtype HbSS will suffer ischemic stroke, with an additional 22% experiencing asymptomatic or silent cerebral infarcts before adulthood.2,3

In 1998, the Stroke Prevention Trial in Sickle Cell Anemia (STOP) demonstrated that use of chronic transfusion therapy (CTT) to reduce hemoglobin S content and raise hemoglobin levels could decrease the stroke risk 10-fold in children without previous strokes or cerebrovascular disease and with abnormal transcranial doppler (TCD) velocities, from 10% per year to 1% per year.4 This was further demonstrated by Fullerton et al. with a rate of first stroke as 0.88 per 100 patient-years prior to the STOP trial, which decreased to 0.17 first strokes per 100 patient-years by year 2000.5 In 2014, CTT was also found to reduce the incidence of recurrent silent cerebral infarcts in children with SCD at risk for infarct, from 4.8 to 2.0 cerebrovascular events (CVEs) per 100 patient-years.6 In 2016, the TCD With Transfusions Changing to Hydroxyurea (TWiTCH) trial demonstrated that hydroxyurea was non-inferior to CTT in maintaining TCD velocities and preventing primary stroke for those without severe vasculopathy and after four years of CTT.7

Despite best medical management, some children with SCD are still at significant stroke risk, especially those with cerebral vasculopathy. Moyamoya syndrome (MMS) is a severe form of cerebral steno-occlusive vasculopathy with varied manifestations that is characterized by progressive narrowing of intracranial arteries followed by collateral vessel formation.8 Forty-one percent of those with SCD and MMS suffered additional strokes or transient ischemic attacks (TIAs) while on CTT.9 Progressive cerebral vasculopathy has also been associated with new cerebral infarctions.8,10 Indeed, many have perceived the presence of severe cerebral vasculopathy to predict a worse course of ischemic disease in SCD patients, yet the treatment options for stroke prevention are limited as the trials evaluating the efficacy of CTT and hydroxyurea excluded those with severe vasculopathy.4,6,7 This treatment gap has stimulated research in additional treatments to decrease stroke risk, including cerebral revascularization surgery (CRS) or hematopoietic stem cell transplant (HSCT). Few studies have focused on determining the rates of these strokes and TIAs in children with SCD and MMS (a severe form of vasculopathy), and less have examined the effects of additional surgical treatments.

Through a systematic review, we examined the burden of cerebral ischemic disease in children with MMS in SCD who are receiving established forms of stroke-reducing therapy – CTT and hydroxyurea as well as newer forms of therapy – cerebral revascularization surgery and HSCT.


Literature Search and Screening

A systematic review of studies reporting stroke rates in pediatric patients with SCD and MMS was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.11 The search was designed for maximal inclusion of articles dealing with cerebral vasculopathy and not only moyamoya. The databases used were PubMed, Embase, Web of Science, and Cochrane Central Register of Controlled Trials (CENTRAL) and the following terms were employed in the search: pediatric, sickle cell disease, cerebral vasculopathy, moyamoya, medical treatment, transfusion, hydroxyurea, surgical treatment, bone marrow transplant, aspirin, stroke, and transient ischemic attack (TIA). Search strategy is described in Supplementary Table 1.

Selection Criteria

Articles were imported into EndNote (Clarivate 2013), duplicates were removed, and remaining articles were uploaded onto Rayyan, a Cochrane-recommended Web application, to ensure blinded screening.12 Titles and abstracts were independently screened by four reviewers (S.H.H., R.P., A.H., A.R.) using predefined inclusion and exclusion criteria. Disagreement was resolved through inter-reviewer discussion and consultation with a fifth reviewer (P.R.A.).

Inclusion criteria for eligible studies were: 1) pediatric patients with SCD (HbSS subtype) and MMS; 2) reported intervention of CTT, hydroxyurea, HSCT, or cerebral revascularization surgery; 3) reported CVEs (consisting of strokes, or TIAs, or silent infarcts); and 4) a minimum of 12 months of follow up. Conference abstracts and presentations, editorials, commentaries, reviews, and non-English studies were excluded.

Manuscripts were reviewed for clinical and radiographic findings pertinent to stroke. Each study reviewed utilized its own definitions for these findings which may have varied between studies. The following are general definitions for the pertinent clinical and radiographic findings that were tracked in this review. Cerebral vasculopathy was defined as imaging evidence of cerebral arterial anatomic pathology as detected by computed tomography angiography (CTA), magnetic resonance angiography (MRA), or digital subtraction catheter angiogram, as indicated in the study reviewed. Studies that defined cerebral vasculopathy solely by elevated transcranial doppler (TCD) velocities (> 200 cm/s) were excluded. While TCD has been validated and demonstrated to identify SCD patients at high risk for stroke with high sensitivity and is largely inferred as “vasculopathy” in a patient, its specificity and positive predictive value are low for cerebral arterial anatomic pathology when compared to CTA, MRA, digital subtraction catheter angiogram.13 MMS is defined as a chronic occlusive arterial cerebrovascular disorder characterized by progressive stenosis of the bilateral supraclinoid internal carotid arteries followed by formation of tortuous arterial collaterals at the base of the brain due to an associated underlying disease, such as SCD.14 CVE is defined as any stroke, silent infarct, or TIA. Stroke is defined as persistent neurologic abnormalities or transient symptoms accompanied by a new cerebral lesion consistent with the patient’s clinical presentation. Silent infarct is defined as a magnetic resonance imaging (MRI) signal abnormality, at least 3 mm, with either a normal neurologic examination or an abnormality on examination that could not be explained by the location of the brain lesion(s).6 TIA is defined as a motor or sensory deficit lasting less than 24 hours without a corresponding acute cerebral infarct on MRI.

When study data allowed CVE rate calculations, the following formula was used: CVE rate = (total # of CVEs in the study) ÷ (total # of follow up years) x 100 patient-years.

​​Statistical Analysis

A meta-analysis was not performed. The differences across the studies, including poor reporting quality, protocol diversity, lack of control group, and inconsistent outcome reporting precluded statistical synthesis of the included studies other than basic descriptive statistics.


Search Strategy

904 references were identified. After exclusion of non-English, duplicate, and non-relevant references, 72 potentially relevant articles were assessed by full-text evaluation. A final 13 studies met inclusion criteria with 10 reporting individual patient data for further data extraction (Figure 1). The remaining 3 reported grouped summary data that could not be consolidated but were included. All 13 studies included subjects with MMS.

Cerebrovascular Events on Medical Therapy

Three studies reported summary data on groups of patients with SCD and MMS who were treated with CTT and later went on to receive cerebral revascularization surgery and/or HSCT. 54.1% (20/37) of patients experienced a CVE while on CTT preoperatively (Table 1).15-17 Four studies (Table 2A) reported on detailed outcomes of 40 patients on CTT as the sole treatment for stroke prevention (without cerebral revascularization surgery).8,18-20 40.4% (19/47) of patients had a CVE while on treatment with a rate of 8.60 CVEs/100 patient-years. 19.1% (9/47) had a stroke and 27.7% (13/47) had a TIA, with rates of 3.23 strokes/100 patient-years and 4.73 TIAs/100 patient-years.

In two surgical studies (Table 2B), 76.9% (10/13) of patients had a CVE while on CTT, prior to cerebral revascularization surgery.18,20 30.8% (4/13) had a stroke and 46.2% (6/13) had a TIA. These patients had the highest observed rates with 29.50 CVEs/100 patient-years, 7.76 strokes/100 patient-years, and 15.53 TIAs/100 patient-years.

These two subsets of patients with MMS treated with CTT had a collective 60 patients (Table 2A+B).8,18-20 48.3% (29/60) had a CVE, 21.7% (13/60) had a stroke, and 31.7% (19/60) had a TIA. Event rates calculated to 11.15 CVEs/100 patient-years, 3.78 strokes/100 patient-years, and 6.05 TIAs/100 patient-years.

Cerebrovascular Events in Patients Undergoing Cerebral Revascularization Surgery

All patients treated with cerebral revascularization surgery were treated with CTT initially. There were three studies with group level data, all had small sample sizes (12 or less) (Table 3).15-17 Two studies reported 50.0% (12/24) of patients had CVEs prior to surgery.16,17 After surgery, three studies showed an aggregate decrease in CVE occurrence to 15.2% (5/33).15-17

Eight studies provided detailed individual patient data on 59 patients following cerebral revascularization surgery.19-26 All patients had MMS and were managed with CTT prior to surgery (Table 4). 23.7% (14/59) of patients had a CVE after the procedure, with a rate of 6.37 CVEs/100 patient-years (Table 4). 10.2% (6/59) had a stroke and 13.6% (8/59) had a TIA, with rates of 2.39 strokes/100 patient-years and 3.98 TIAs/100 patient-years.

Two of these studies allowed comparison of the same patient group on CTT before and after cerebral revascularization surgery.19,21 CVE occurrence decreased 2-fold [from 76.9% (10/13) to 38.5% (5/13)], stroke occurrence decreased 4-fold [30.8% (4/13) to 7.7% (1/13)], and TIA occurrence decreased from 46.2% (6/13) to 30.8% (4/13). The overall CVE rate decreased from 29.50 CVEs/100 patient-years while on CTT to 11.90 CVEs/100 patient-years after surgery. The stroke and TIA rates/100 patient-years also decreased from 7.76 and 15.53 to 1.70 and 10.20, respectively. The Alamri et al. study did not note CTT utilization but did allow for a comparison of pre- and post-surgical CVE rates. Pre-surgically, the CVE rate was 10.75 CVEs/100 patient-years (7.53 strokes/100 patient-years and 2.15 TIAs/100 patient-years). The post-surgical CVE rate dropped to 3.75 CVEs/100 patient-years (3.75 strokes/100 patient-years and 0.0 TIAs/100 patient-years).22

Cerebrovascular Events Following Bone Marrow Transplantation/Hematopoietic Stem Cell Transplant

Two studies reported on CVE occurrence after HSCT.15,19 Four out of 8 (50%) patients had CVEs after HSCT. There were no studies with sufficiently detailed data to extract individual patient data.


In our systematic review, we found that children with SCD and MMS receiving CTT for history of CVEs had significant CVE occurrence and rates [40.4% (19/47) and 8.60 CVEs/100 patient-years, respectively], and even worse disease courses in those who later underwent surgery [76.9% (10/13) and 29.50 CVEs/100 patient-years, respectively]. Following cerebral revascularization surgery, CVEs decreased to 23.7% (14/59) and 6.37 CVEs/100 patient-years, respectively.

Pathophysiology of cerebral vasculopathy in SCD and significance of MMS

Stroke in children with SCD can occur due to progressive stenosis of blood vessels, leading to reduction in cerebral blood flow and infarction. Pathologic examination reveals endothelial damage to mid- to large-sized arteries of the brain. Damage is mediated by multiple mechanisms including red blood cell adhesion and viscosity, intravascular hemolysis, arterial wall dissection, endothelial activation, inflammatory responses, and procoagulant factors.27-29 The degree of arterial stenosis and its vascular distribution impacts the extent and severity of the stroke.29 Distal arteries can be affected resulting in subcortical, clinically silent infarcts.30-32

In moyamoya disease, the most common site of stenosis is the terminal bifurcation of the internal carotid artery and the proximal middle cerebral artery and anterior cerebral artery. With decreased intracranial perfusion, compensatory mechanisms stimulate the formation of collateral arteries. Arterioles from the circle of Willis can present with a characteristic angiographic appearance resembling a “puff of smoke”, or “moyamoya”, the term given by the Japanese investigators that first described it.33-36

The progression of cerebral arterial pathology in moyamoya disease has been described in detail.37 Initially there is progressive arterial stenosis of the large intracranial arteries which can cause ischemic strokes. This is followed by collateral vessel formation (including the moyamoya collaterals found at the base of the brain) with eventual occlusion of the large intracranial arteries and collateral vessels taking over major cerebral blood supply. If the progressive cerebral arterial pathology is secondary to a disease (e.g., sickle cell disease) or agent (e.g., ionizing radiation) resulting in the changes described, the term moyamoya syndrome is used. If there is no known etiology to the vascular pathology, then it is called moyamoya disease. Recently, a gene mutation in RNF213 has been linked to some forms of primary moyamoya disease.38,39

Patients with primary moyamoya disease are known to have high rates of stroke.40,41 To decrease the risk of stroke, cerebral revascularization surgery has been an established treatment – first reported for moyamoya disease in 1967 and for moyamoya syndrome with sickle cell disease in 1996.21,42 The surgery involves increasing cerebral blood flow by implanting arteries from the extracranial circulation to the intracranial compartment.43-45 In both children and adults, the procedure has been shown to reduce stroke risk.46-52 The results of these studies led pediatric hematology centers to utilize cerebral revascularization surgery to reduce stroke risk in MMS due to SCD when able.

CVEs in the absence of MMS while on conservative treatment

The STOP trial in 1998 studied the effects of transfusion therapy for the prevention of primary CVEs in those of the pediatric SCD population with abnormal TCD velocities.4 In this trial, 11 children (16.4%) in the standard care group (without blood transfusions) had a stroke, while one child (1.6%) in the transfusion group had a stroke. The impact of this treatment later demonstrated a decline in admission rates for stroke in pediatric SCD patients with an observed first stroke rate of 0.17 strokes/100 patient-years.5 The SIT study in 2014 investigated the effect of CTT in preventing recurrent silent infarcts in those with at least one infarct detected on MRI in those with normal TCD velocities.6 In this study, 16 children (16.5%) in the observation group had a CVE while only 6 children (6.1%) in the transfusion group had a CVE. CVE rates in the observation and transfusion groups were 5.6 and 2.0 CVEs/100 patient-years, respectively. Majumdar et al. reported an even lower recurrent stroke rate of 0.66 strokes/100 patient-years amongst 27 patients receiving CTT.53 In the TWiTCH trial in 2016 (comparing non-inferiority of hydroxyurea to CTT), the majority of patients did not have vasculopathy findings (10 of the 110 had mild-moderate vasculopathy, none with MMS).7 In this study, 6 patients (5.4%) had TIAs, equally distributed between treatment groups, demonstrating non-inferiority of hydroxyurea (after one year of CTT) to CTT. Ware et al. additionally reported a rate of 3.6 strokes/100 patient-years for patients treated with hydroxyurea.54

It is important to recognize that the STOP, SIT, and TWiTCH trials4,6,7 are not ideal comparators to the smaller, less standardized studies reported in our results, as each focused on a different patient sub-population in those with SCD, as well as different endpoints. The studies included in this review were all retrospective and did not distinguish between primary or secondary stroke prevention. The STOP trial investigated patients treated for primary stroke prevention with abnormal TCDs and did not screen for arterial stenosis with angiograms. The TWiTCH trial investigated the non-inferiority of hydroxyurea in similar patients who had been on CTT without evidence of vasculopathy, while the SIT study investigated those treated for secondary silent infarct prevention with normal TCDs and no vasculopathy.4,6,7 This lack of data from comparable studies highlights the need to conduct prospective studies that focus on the effect of severe cerebral vasculopathy, such as MMS, on stroke in SCD.

CVEs in the presence of MMS while on conservative treatment

Compared to studies that did not include patients with MMS, the proportion of patients who had a CVE on CTT is markedly higher in studies of patients exhibiting MMS.4 The group level data of patients with MMS managed on CTT showed that 54.1% (20/37) had a CVE while on treatment (Table 1). The studies with MMS patients on CTT (Table 2A+B) had 30x greater stroke occurrence compared to the STOP trial [48.3% (29/60) versus 1.6%, respectively].4 The CVE rate of the MMS population was over 5x greater than those in the SIT study (11.15 CVEs/100 patients-years and 2.0 CVEs/100 patient-years, respectively).6 Likewise, the stroke rate was also 5x greater at 3.78 strokes/100 patient-years, compared to 0.77 strokes/100 patient-years in the Fullerton study.5

Our findings are consistent with others that showed the presence of MMS, has been associated with a worse course of CVEs when compared to patients without any form of vasculopathy.8,10,30,55 While the results demonstrated that CTT can reduce the proportion and rate of CVE occurrence in the presence of MMS, these patients still experience a markedly elevated CVE incidence compared to those without MMS despite continued treatment. It is speculated that the vascular changes found in MMS signify a late stage in the progression of vascular stenosis where the structural vessel wall changes are irreversible and result in a permanent increase in the risk of stroke. Future studies can characterize the progression of and development of MMS in SCD and measure the efficacy of CTT in halting or reversing the development of this type of vasculopathy. If the point at which this vasculopathy becomes irreversible is known, it may help guide the treatment of these patients and shift them to alternative therapies earlier in addition to CTT to decrease their stroke risk.

CVEs following Cerebral Revascularization Surgery and HSCT 

In our review, we found that patients who were treated with either cerebral revascularization surgery or HSCT in addition to CTT had worse CVE history than those that were not. The series available for review were all limited by their small sample size and retrospective nature.

Of the surgical series, up to 76.9% (10/13) of these patients had CVEs prior to surgery, higher than the non-surgical series of MMS patients [40.4% (19/47)] and again, much higher than even the highest of the non-vasculopathy studies (6.1%).6 Following surgery, 23.7% (14/59) had a CVE, less than half of the preoperative proportion (Table 4). There is a relative lack of thorough investigation, as only two studies of the surgical series directly reported on CVE rates before and after cerebral revascularization surgery; however, when pooled, they showed a considerable 2.5x decrease in the post-surgical CVE rate (29.50 CVEs to 11.90 CVEs/100 patient-years), and an even greater 4.5x decrease in stroke rate (7.76 strokes to 1.70 strokes/100 patient-years).19,21 Although there are substantial decreases in CVE proportion and rate following cerebral revascularization surgery in patients with MMS, these are still significantly higher than the CVE rates seen in patients without vasculopathy. The pooled post-operative CVE rate of 6.37 CVEs/100 patient-years (Table 4) and the stroke rate of 2.39 strokes/100 patient-years both remain 3x higher than that reported in the SIT trial6 and the Fullerton study.5

The reduction in CVEs following surgery needs further study to determine the magnitude of the effect of surgery versus the natural history of the disease (where there is an observed decrease in ischemic stroke risk over time). Rigorous prospective studies are needed to evaluate the efficacy and risk of cerebral revascularization surgery in order to determine its role in stroke prevention in children with SCD. In the absence of such studies and other effective treatments, careful consideration of surgical intervention by an experienced team of hematologists and neurosurgeons can be made in the setting of MMS in SCD in for secondary stroke prevention, as recommended in recent guidelines on the management of stroke in sickle cell disease.56

Even fewer studies have explored the effects of HSCT on CVE rates in those without vasculopathy. As found in our review, 4 out of 8 patients with MMS had a CVE after HSCT (Table 5). Since this review’s database retrieval, a new retrospective study has been published on post-HSCT CVE rates in a cohort of 44 children, of which 52% had vasculopathy. It found that in the post-HSCT cohort overall, the rate of subsequent stroke was 1.6 events/100 patient-years and the rate of SCIs was 2.2 events/100 patient-years. In those with history of symptomatic infarcts, the rate decreased from 13.7 CVEs/100 patient-years to 4.4 CVEs/100 patient-years, nearly 3x the rate of the cohort overall.57 Furthermore, of patients who presented with a pre-treatment symptomatic infarct, only those with moderate/severe vasculopathy experienced a CVE after HSCT. In addition, those with mild-moderate arterial stenosis did not progress; however, those with severe vasculopathy did not improve, adding evidence that these vessel wall changes may be irreversible. Several prospective studies are underway on HSCT in patients with severe SCD and this will hopefully shed light on its effect on stroke risk reduction.58-61


The limitations are due largely to the heterogeneous nature of our source material. Our review included studies which focused primarily on hematological or neurosurgical objectives, making it difficult to standardize them for comparison. The comparator non-vasculopathy study results were large prospective trials, while the results pulled in our review are from small single-center studies without standardization. The varied detail of reporting of outcomes was one of the largest hurdles in comparing outcomes between studies. Additionally, the included studies were conducted throughout a wide period in which there were several advancements in sickle cell disease care and treatment (i.e., STOP trial, TWiTCH trial, etc.), yielding outcome differences that may modulate the interpretation. Further, many did not report on CVEs other than strokes, potentially lowering CVE rates. Another limitation stems from the natural history of stroke and its effects on the resulting data of patients who progress to receive cerebral revascularization surgery or HSCT. As such, there may also be a bias of surgery candidate selection, which could not be ascertained. The risk of ischemic stroke decreases as the patients age, and patients undergoing these more invasive treatments could have an inherent decrease in risk. Studies that consider additional adjustments for time after stroke in this patient population are lacking.


Children with SCD and MMS experience a much higher CVE occurrence and rate compared to those without vasculopathy, despite treatment for stroke prevention. We found that these patients have a CVE rate up to 11.15 CVEs/100 patient years and a stroke rate up to 3.78 strokes/100 patient-years, both 5x greater, compared to patients without vasculopathy. Additional treatment with cerebral revascularization surgery or HSCT in those with MMS decreases CVE rates and occurrences; however, these outcomes remain elevated compared to those without vasculopathy. More research needs to be conducted on alternative treatments to decrease stroke risk in patients with SCD and MMS.

Conflict of Interest Statement
The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.


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CVE Rates in Pediatric SCD and Moyamoya

Pediatr Stroke. 2024;8: 33-85


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