Role of Revascularization Surgery to treat Moyamoya Syndrome in Sickle Cell Disease: Updates from the Stroke in Sickle Cell Revascularization Surgery (SiSCRS) Study Group

Salvador F. Gutierrez-Aguirre, MD^1,2; Edward R. Smith, MD, MBA^3,4; Lauren A Beslow, MD⁵; Nomazulu Dlamini, MBBS, MSc, PhD^6,7; Melissa G. Chung, MD^8,9; Lisa R. Sun, MD¹⁰; Sudhakar Vadivelu, DO^11,12; Kristin P. Guilliams, MD, MSCI¹³; Adikarige Haritha Dulanka Silva, MPhil, MD, FRCS^14,15; Aleksandra Mineyko, MD^16,17; Lori C Jordan, MD¹⁸; Otavio F de Toledo, MD^1,2; Ricardo A. Hanel, MD¹, PhD; Philipp R. Aldana, MD¹⁹.

¹Lyerly Neurosurgery, Baptist Neurological Institute, Jacksonville, FL, USA.
²Research Department, Jacksonville University, Jacksonville, FL, USA.
³Department of Neurosurgery, Children’s Hospital Boston, Boston, MA, USA.
⁴Harvard Medical School, Boston, MA, USA.
⁵Division of Neurology, Departments of Neurology and Pediatrics, Children’s Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.
⁶Neurosciences and Mental Health Program, Stroke Imaging Laboratory for Children, The Hospital for Sick Children, Toronto, ON, Canada.
⁷Stroke Program, Division of Neurology, Department of Paediatrics, The Hospital for Sick Children, Toronto, ON, Canada.
⁸Divisions of Critical Care Medicine and Pediatric Neurology, Nationwide Children’s Hospital, Columbus, OH, USA.
⁹Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH, USA.
¹⁰Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹¹Department of Neurosurgery and Radiology, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
¹²Division of Pediatric Neurosurgery, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA.
¹³Departments of Neurology, Pediatrics, and Radiology, Washington University School of Medicine, St. Louis, MO, USA.
¹⁴Great Ormond Street Hospital for Sick Children, London, England.
¹⁵Department of Paediatric Neurosurgery, Great Ormond Street Hospital for Children, London, England.
¹⁶Department of Pediatrics, University of Calgary, Calgary, Canada.
¹⁷Section of Neurology, Department of Pediatrics, Alberta Children’s Hospital, Calgary, Canada.
¹⁸Department of Pediatrics, Division of Pediatric Neurology, Vanderbilt University Medical Center, Nashville, TN, USA; Department of Neurology, Vanderbilt University Medical Center, Nashville, TN, USA; Department of Radiology and Radiological Sciences, Vanderbilt University Medical Center, Nashville, TN, USA.
¹⁹Division of Pediatric Neurosurgery, University of Florida Health Jacksonville and Wolfson Children’s Hospital Jacksonville, Florida, USA.

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Corresponding Author:
Philipp R Aldana, MD,
Director, Division of Pediatric Neurosurgery
University of Florida, Department of Neurosurgery
Jacksonville, FL
Phone: (904) 633-0992
Email: Philipp.Aldana@jax.ufl.edu.

Abstract

Sickle Cell Disease (SCD) is an inherited disorder resulting from a mutation in the HBB gene, leading to conditions like sickle cell anemia (SCA), HbSC, and HbSβ-thalassemia, with a high prevalence in Sub-Saharan, Indian, and Middle Eastern populations. SCD causes multisystemic complications due to the pathological polymerization of hemoglobin S (HbS), forming sickle-shaped red blood cells that can lead to ischemia and vasculopathy, characterized by stenosis and occlusion. SCD is a major risk factor for stroke in children, particularly African Americans, with Transcranial Doppler (TCD) used for risk stratification, though it does not fully rule out abnormalities. Moyamoya syndrome (MMS), a severe form of vasculopathy, significantly increases the risk of cerebrovascular events (CVEs) despite treatments like chronic blood transfusions or hydroxyurea. This literature review examines the role of revascularization techniques in treating pediatric SCD-MMS patients. Growing evidence suggests that revascularization surgery, particularly indirect techniques, significantly lowers the likelihood of CVEs over long-term follow-up, even in patients with worse preoperative conditions. Postsurgical outcomes indicate a markedly lower likelihood of CVEs, with minimal and manageable complications. Indications for revascularization surgery, though not well-defined, typically include neurovascular symptoms and significant arterial stenosis. Further prospective studies are necessary to determine the efficacy and safety of combining surgical revascularization with chronic blood transfusions for secondary stroke prevention. Additionally, aspirin might reduce ischemic stroke risk, particularly in non-surgical patients. However, significant gaps remain in understanding cerebral vasculopathy and its impact on childhood brain development. Future research should identify risk factors, evaluate treatment impacts, and address access disparities, especially in low-resource settings. Emerging evidence supports cerebral revascularization surgery as a potential stroke prevention strategy in children with SCD and MMS, necessitating further rigorous studies globally.

Introduction

Sickle Cell Disease (SCD) is an inherited disorder resulting from a missense mutation in the HBB gene encoding the β-globin hemoglobin subunit.¹ This disease encompasses various inherited conditions such as sickle cell anemia (SCA), HbSC, and HbSβ-thalassemia.² An estimated 300,000 infants worldwide are born annually with this medical condition, with a high prevalence among the Sub-Saharan, Indian, and Middle Eastern populations. However, due to the diaspora of these communities, SCD has spread globally.³ Due to its prevalence, SCD is a growing global health concern. Studies have revealed that the SCD burden is distributed unequally among the population. Diverse factors, such as income and healthcare access, can significantly impact patient outcomes, resulting in a higher mortality burden for pediatric patients in Africa.^4,5

The main mechanism for the multisystemic presentation of SCD is the pathological polymerization of hemoglobin S (HbS), which forms sickle-shaped red blood cells that can cause ischemia and infarction. SCD can also lead to vasculopathy; despite no standardized definition of vasculopathy, it is typically characterized by stenosis and occlusion.⁶ Vasculopathy mechanisms include but are not limited to endothelial dysfunction, abnormal blood viscosity, hemolysis, decreased nitric oxide, and inflammatory response. These changes can cause progressive damage to the arteries and microcirculation, leading to complications such as priapism, leg ulceration, pulmonary hypertension, and stroke.^7-9

SCD is the most common risk factor for stroke in children, and the peak incidence of stroke ranges between 2 to 9 years old.¹⁰ Post-stroke patients may have permanent neurologic deficits causing socioeconomic burdens, particularly if the onset is in childhood.^11,12 The incidence of cerebral vasculopathy in the population of children with SCD has not been well studied.

Transcranial Doppler (TCD) has been used to guide stroke prevention by stratifying the risk of stroke, with elevated velocities interpreted as a sign of a compensatory increase in cerebral blood flow velocity due to vasculopathy, thereby increasing the risk for stroke. Primary stroke prevention consists of chronic transfusion therapy (CBT) or hydroxyurea guided by elevated TCD velocities.¹³

Patients with normal TCD velocities (<170 cm/s) are considered to be at low risk for stroke and are typically not recommended to undergo primary stroke prevention therapy. However, even with normal TCD velocities, underlying abnormalities such as stenosis or occlusion cannot be completely ruled out. Magnetic resonance imaging (MRI) has shown that among the population with low-risk TCD velocities, 10.5% have intracranial arterial stenosis, and 37.7% have silent infarcts.¹⁴ A recent article by O’Brien et al.¹⁵ also reported that 1% of individuals developed new neurologic symptoms despite normal TCD. As a result, some guidelines recommend annual TCD scanning and an additional MRA/MRI in patients with clinical signs or symptoms suggestive of ischemia.^16-18

In the TWITCH study, 21.7% of children with SCD and abnormal TCD velocities (>200 cm/s) had cerebral vasculopathy. Of these, 9.8% had mild to moderate, and 11.9% had severe (moderate stenosis in >2 arterial segments or severe stenosis or occlusion in ≤2 segments).¹⁹ For the patients with conditional TCD velocities (>170-200 cm/s), cerebral vasculopathy may also be present; however, studies examining this have not been done. Potentially, more than 30% of children with SCD could have cerebral vasculopathy of varying degrees.²⁰ It appears that patients with moyamoya syndrome (MMS), a severe form of cerebral vasculopathy, are at the highest risk for cerebrovascular events (CVE- stroke or TIA). Notably, recurrent CVE is twice as high in those with MMS compared to those without MMS (58% vs 28%) despite treatment with chronic blood transfusions.^21,22

Revascularization Surgery Outcomes

Growing evidence supports the safety and efficacy of cerebral revascularization surgery as a treatment to prevent secondary stroke in children with SCD and MMS.^23-30 The Stroke in Sickle Cell Revascularization Surgery Retrospective Study (SiSCRS) study, a recent multicenter retrospective study,³⁰ compared the risk of stroke and transient ischemic attacks (TIAs) in pediatric patients with SCD-MMD who underwent either medical therapy alone (regular blood transfusions or hydroxyurea) or medical therapy plus surgical treatment. The study included 141 patients, 63 receiving medical therapy alone and 78 receiving medical therapy combined with revascularization surgery (95% were indirect anastomoses). The study reported that, preoperatively, the surgery group had a younger age at moyamoya diagnosis, worse disability scores according to the Modified Rankin Scale (mRS), and an increased prevalence of CVE. However, despite these findings, the group that received revascularization surgery in addition to medical treatment exhibited a 3.7 times lower likelihood (odds ratio = 0.27, 95% confidence interval [CI] = 0.08-0.94, p = 0.040) of developing CVE over a mean of 8.7 years of follow-up compared to the group that received medical treatment alone. Furthermore, when comparing patients in the surgery group during the presurgical versus postsurgical periods, the postsurgical group was 4.5 times less likely to experience a CVE (odds ratio = 0.22, 95% CI = 0.08-0.58, p = 0.002). There were no mortalities associated with surgery, and 5% had major adverse events – two patients required surgery for wound infection and subdural hematoma; two developed ischemic strokes with full recovery of their deficits.

Indications for Surgery

The indications for performing revascularization surgery to decrease stroke risk in patients with SCD-MMS have not been well defined. Previously described indications include the presence of neurovascular symptoms with evidence of progressive vascular disease and ischemic changes as revealed by MRI/MRA and MMS. Other groups have recommended surgery in patients with evidence of stenotic anterior cerebral artery (ACA) and reduced blood flow in the ACA territory evidenced by ACA territory infarction or ivy sign.^28,31

A recent Delphi survey that examined indications for revascularization by neurosurgeons contributing to the SiSCRS retrospective study found consensus to offer surgery for patients with all ischemic conditions (stroke, TIA), with 50% or more significant arterial stenosis matching the ischemic distribution in the presence of moyamoya collaterals. Consensus was also reached to offer surgery for conditions with greater than 70% arterial stenosis matching the ischemic distribution, even without moyamoya collaterals.³²

Surgical Techniques

Various revascularization techniques are available for treating MMS: direct, indirect, and combined anastomosis. While comparative studies on SCD-MMS are limited, current evidence suggests both techniques are effective.^33,34 Indirect revascularization is the most commonly used technique in pediatric patients, particularly because of its technical simplicity compared to direct anastomosis. Indirect revascularization reduces the risk of stroke through progressive neovascularization over time, while direct revascularization provides immediate high-flow augmentation.³⁵ A meta-analysis has indicated that direct revascularization is associated with superior long-term angiographic outcomes; however, this has not consistently led to lower rates of stroke or mortality.³⁶ The choice of surgical technique should be individualized based on patient-specific factors such as age, comorbidities, vessel size, severity of vasculopathy, and institutional or surgeon expertise.³⁵ Younger children with small-caliber vessels, or those with comorbidities and stable symptoms, may benefit more from indirect approaches, allowing time for neovascularization to develop. Conversely, older patients or those with advanced vasculopathy and hemodynamic compromise may gain more from direct or combined bypass procedures.

Revascularization procedures can be performed unilaterally or bilaterally, and both approaches have demonstrated effectiveness. Current guidelines do not express a preference for one over the other.¹³ Both strategies have been associated with reduced stroke rates compared to medical management alone, with no significant difference in functional outcomes.³⁷ A recent retrospective study in patients with MMD also found no difference in postoperative functional outcomes or complication rates between unilateral and bilateral procedures.³⁸ However, there was a higher, though not statistically significant, trend toward perioperative stroke in the bilateral group.

Building on the results of the SiSCRS retrospective study, a prospective study will be needed to provide high-quality evidence to determine the efficacy and safety of surgical revascularization in addition to CBT over CBT alone to prevent secondary stroke. Prior to implementation, additional studies will be needed to determine clinical equipoise and the potential for patient participation. International patient participation may leverage the recruitment of a sample size that is sufficiently large to demonstrate efficacy. Outcomes evaluated must include those relevant to clinicians, patients, and their families.

Aspirin for Stroke Prevention

While acetylsalicylic acid (ASA) intake to prevent stroke is well established in adults, similar evidence to support its use in children is lacking, particularly in the presence of sickle cell disease and arteriopathy.²⁰ The effect of ASA intake on the risk of ischemic stroke in children with SCD and moyamoya syndrome was examined in a subset of patients from the SiSCRS study. Preliminary analysis from this retrospective observational cohort suggests that ASA use was associated with a reduction of nearly half in the rates of ischemic stroke during periods when patients were on ASA compared to periods without ASA intake. No increase in hemorrhagic stroke was observed with aspirin use. Notably, the reduction in stroke incidence was even more pronounced among children with less severe clinical presentations (non surgical group), where ASA use was associated with an approximately fourfold decrease in stroke occurrence.³⁹ However, larger prospective and randomized studies are needed to confirm these findings.

Imaging Considerations

Imaging modalities play a critical role in evaluating or revascularization, as well as in assessing its effectiveness and prognosis by measuring cerebral hemodynamics and cerebrovascular reserve. Digital Subtraction Angiography (DSA) remains the benchmark for assessing vascular anatomy and collateral formation. Additionally, MR perfusion techniques can evaluate cerebral blood flow and identify perfusion deficits. When combined with acetazolamide-challenged arterial spin labeling (ASL), MR perfusion can also assess cerebrovascular reactivity by evaluating autoregulatory vasodilation, serving as a prognostic indicator and aiding in determining the effectiveness of revascularization procedures.^40,41 Other modalities, including CT perfusion (CTP) and CT angiography (CTA), may be useful alternatives when ASL or DSA are unavailable, particularly in low-resource settings.^17,42

Gaps in Knowledge and Future Directions

We recognize multiple gaps in knowledge related to cerebral vasculopathy, MMS, and cerebral ischemia in SCD. Gaps related to the pathobiology of the disease include the natural history of cerebral steno-occlusive vasculopathy and cerebral ischemia in this population and the effects of stroke prevention treatments on vasculopathy and ischemia. It is also crucial to identify risk factors that predispose SCD patients to the development of vasculopathy and stroke in order to influence treatment decisions and prevent vasculopathy. Genetic, biological, clinical, and social risk factors must be carefully evaluated for this objective. Access to care is critical, as large-volume centers with experience treating these complex arteriopathies can provide better outcomes with lower costs, underscoring the impact of socioeconomic factors in this population.^43,44 Moreover, it is important to evaluate the effects of cerebral vasculopathy and stroke on childhood brain development both radiographically and clinically to assess the functional impact.

Finally, research on stroke prevention strategies needs to include children with SCD who are at the highest risk for ischemic complications, including those who live in developing countries. Cost remains a major barrier to accessing all the treatment modalities. While hydroxyurea therapy has been shown to be effective and feasible in low-resource settings like Nigeria and Tanzania,^45-48 other medical therapies for stroke prevention, such as chronic blood transfusions or hematopoietic stem cell transplantation, are not available in these settings. Surgical revascularization may be more available in these settings to prevent stroke in those with severe vasculopathy. Improvements in care for these children are unlikely to happen without prioritization and a major commitment of healthcare resources globally.

Conclusion

There is emerging evidence to support cerebral revascularization surgery as a treatment option to prevent stroke in Moyamoya syndrome due to SCD in children. Further rigorous study will be needed to determine its role in preventing stroke in SCD in both high and low-resource settings globally. These future studies should also build on existing knowledge and address disparities in access and outcomes through well-designed, adequately funded to minimize bias and improve equity in care.⁴⁹ This article is a narrative review based on selected peer-reviewed literature and expert opinion. As such, it may not capture all available data, and much of the current evidence is limited by retrospective design and single-center experiences.

Table 1. Updates from the Stroke in Sickle Cell Revascularization Surgery (SiSCRS) Study Group

Indications for Cerebral Revascularization for Moyamoya Syndrome in Pediatric Sickle Cell Disease Determined by Delphi Methodology32	All ischemic conditions (stroke, TIA), with 50% or more significant arterial stenosis matching the ischemic distribution in the presence of moyamoya collaterals. For ischemic conditions with greater than 70% arterial stenosis matching the ischemic distribution, even without moyamoya collaterals. Perfusion imaging plays a key role in borderline cases, helping to guide decisions when stenosis severity, collateral presence, or ischemia distribution are inconclusive.
Outcomes of The Stroke in Sickle Cell Revascularization Surgery Retrospective Study (SiSCRS) study30	A total of 141 patients with SCD and MMS were included; 78 underwent cerebral revascularization surgery plus medical management, and 63 received medical therapy alone. Surgery group had a 3.7-fold lower odds of developing a CVE over a mean of 8.7 years. Within the surgical group, post-surgery period showed a 4.5-fold lower risk of CVE compared to the pre-surgical period. No surgery-related mortalities; 5% experienced major adverse events.
Preliminary Results on Acetylsalicylic Acid: Subgroup Analysis of the Stroke in Sickle Cell Revascularization Surgery (SiSCRS) Study39	ASA use was associated with a reduction of nearly 50% in ischemic stroke rates during periods of intake. No increase in hemorrhagic stroke was observed. The effect appeared more pronounced in less severe cases, with stroke incidence reduced by almost fourfold.

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