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Prevention of stroke (initial or recurrent) in sickle cell disease

Prevention of stroke (initial or recurrent) in sickle cell disease
Literature review current through: May 2024.
This topic last updated: Jan 20, 2023.

INTRODUCTION — Stroke is a common and potentially devastating manifestation of sickle cell disease (SCD) that can affect children and adults. Stroke prevention requires intensive risk assessment and closely monitored interventions for those with increased risk. For many patients, risk reduction involves indefinite chronic transfusion therapy.

The approach to the prevention of a first or recurrent ischemic stroke (primary and secondary stroke prevention) in individuals with SCD is presented here.

Related aspects of SCD management are discussed in detail separately:

Treatment of acute stroke – (See "Acute stroke (ischemic and hemorrhagic) in children and adults with sickle cell disease".)

Blood transfusion – (See "Red blood cell transfusion in sickle cell disease: Indications and transfusion techniques".)

Hydroxyurea administration – (See "Hydroxyurea use in sickle cell disease".)

Clinical manifestations – (See "Overview of the clinical manifestations of sickle cell disease".)

Management overview – (See "Overview of the management and prognosis of sickle cell disease".)

Mechanisms of vaso-occlusion – (See "Pathophysiology of sickle cell disease".)

DEFINITIONS

Stroke – A stroke is an acute neurologic injury of the brain, retina, or spinal cord that occurs as a result of ischemia or hemorrhage. Stroke is distinct from hypoxic ischemic and traumatic brain or spine injury. Typical stroke symptoms include sudden onset of focal neurologic signs such as paresis, visual loss, speech and language impairment, gait disturbance, and cerebellar ataxia; seizures, headache, and/or change in level of consciousness are not uncommon. In most cases, stroke symptoms and signs last for at least 24 hours and are associated with corresponding neuroimaging findings. Ischemic strokes may sometimes undergo hemorrhagic transformation. The term cerebrovascular accident has fallen out of favor but is still used in some publications.

Silent cerebral infarction – A silent cerebral infarct (SCI), also known as a silent brain infarction or silent stroke, is defined as a lesion visible in at least two planes of T2-weighted magnetic resonance imaging (MRI) images and at least 3 mm in greatest linear dimension, with no associated findings on neurologic exam [1]. SCIs are not truly silent because the presence of these lesions is correlated with neurocognitive and behavioral deficits. Information about SCIs is presented in more detail separately. (See "Clinical diagnosis of stroke subtypes", section on 'Silent brain infarcts'.)

Transient ischemic attack – Transient ischemic attack (TIA) refers to a transient episode of neurologic dysfunction caused by focal brain, spinal cord, or retinal ischemia, without acute infarction. Historically, stroke symptoms or signs that last <24 hours have been defined as a TIA. However, with modern brain imaging, 33 percent of patients with stroke symptoms lasting <24 hours are found to have an infarct when appropriate neuroimaging is completed [2]. This has led to a new, tissue-based definition of TIA, which is a transient episode of neurologic dysfunction caused by focal brain, spinal cord, or retinal ischemia, without acute infarction seen on neuroimaging [3]. (See "Definition, etiology, and clinical manifestations of transient ischemic attack", section on 'Definition of TIA'.)

Primary prevention – Primary prevention refers to interventions to reduce the risk of a first stroke. In SCD, primary prevention is used in those deemed at increased risk of stroke based on transcranial Doppler (TCD) measurements.

Secondary prevention – Secondary prevention refers to interventions to reduce the risk of recurrence in individuals who have already had a first stroke or SCI.

Sickle cell disease – Sickle cell disease (SCD) is an umbrella term that includes all patients who have one copy of the sickle beta globin (βS) allele along with a second altered beta globin allele. The second beta globin allele may also carry the sickle mutation (Hb SS), a beta-thalassemia mutation (resulting in sickle beta-thalassemia), the hemoglobin C mutation (resulting in Hb SC disease), or others.

Transcranial Doppler – TCD is a noninvasive ultrasound-based method of measuring the flow rate of blood in intracranial arteries such as the internal carotid arteries and the arteries of the circle of Willis, including the middle cerebral circulation. TCD readings are not always a marker for intracranial stenosis, but elevated blood flow velocity on TCD is a strong predictor of stroke risk, and they have become standard of care as a screening test for stroke risk in children 2 to 16 years with SCD. (See 'Risk assessment for first stroke' below.)

PATHOPHYSIOLOGY AND RISK FACTORS

Mechanisms — Individuals with SCD are at risk of ischemic and hemorrhagic stroke.

Ischemic stroke is typically due to border zone ischemia secondary to both anemia and cerebral hemodynamic alterations [4-6] or to vascular occlusion caused by intimal proliferation rather than thromboembolic disease [7].

Ischemic stroke is most often associated with occlusion or stenosis of the large intracranial arteries [8-12]. However, some children with strokes will have normal brain magnetic resonance angiography (MRA), particularly those with stroke in the cerebral border zone or watershed area between large artery territories.

Children with strokes who do not have evidence of MRA-defined vasculopathy often have acute clinical events that decrease oxygen delivery to the brain such as acute chest syndrome or parvovirus B19 infection with reticulocytopenia [13].

Regardless of whether an ischemic stroke occurs with evidence of MRA-defined vasculopathy or is temporally associated with an antecedent or concurrent medical event, the initial two years after a stroke is the period with the highest rate of stroke recurrence, even with regular blood transfusion therapy [13].

In SCD, evidence to support altered cerebral hemodynamics as the main cause of overt ischemic and silent cerebral infarcts includes:

The location of the border zone region of the brain [5].

The association of acute ischemic strokes with acute drops in hemoglobin levels, decreases in oxygen saturation, or both [13,14].

Based on the pathophysiology of ischemic stroke in SCD, indefinite regular blood transfusion therapy is the mainstay of treatment for secondary prevention in children and adults with SCD. (See 'Prevention of recurrent ischemic stroke (secondary stroke prophylaxis)' below.)

The mechanisms of vasculopathy in SCD include vaso-occlusion triggered by abnormal interactions between white blood cells (WBC), red blood cells (RBC), platelets, and the vascular endothelium. These abnormal interactions, along with aberrant endothelial regulation by nitric oxide and other signaling molecules, result in abnormal intimal proliferation and progressive stenosis, which in turn produces ischemia in the cerebral microcirculation [11].

There may also be injury to the arterial endothelium and impaired vascular autoregulation, especially in areas of high flow rate [15]. Some individuals may develop a moyamoya syndrome characterized by unilateral or bilateral stenosis or occlusion of the arteries around the circle of Willis (figure 1). (See "Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis".)

Mechanisms underlying hemorrhagic stroke are less well understood; contributing factors may include rupture of weakened primary vessels or fragile collateral vessels [7]. There is also a possible association between SCD and the incidence of intracranial aneurysms.

In a cohort of 709 pediatric and adult SCD patients who had neuroimaging performed, 19 (2.7 percent) had aneurysms. The prevalence of aneurysms was significantly higher among adults (10.8 percent) compared with children (1.2 percent). Ten of the 19 patients had multiple aneurysms, with a mean of 2.3 aneurysms per patient, and the location of aneurysms was often atypical relative to patients without SCD [16].

In another cohort of 251 pediatric patients with SCD, a first intracranial hemorrhage and/or neuroimaging evidence of intracranial aneurysm was present in 7 (2.8 percent), consistent with an estimated risk for a hemorrhagic event of 0.33 per 100 patient-years, which is considerably higher than the estimated risk in the general pediatric population of 0.002 per 100 patient-years [17]. It was hypothesized that common mechanisms of vascular injury may underlie both vessel stenosis and wall weakening.

These studies suggest that aneurysms may contribute to the incidence of hemorrhagic stroke in patients with SCD.

Risk factors: Ischemic stroke — The following characteristics are associated with increased risk of ischemic stroke:

SCD type – SCD type is a major predictor of stroke risk. Types with the greatest disease severity in general (Hb SS or Hb S-beta0-thalassemia) are associated with the greatest stroke risk. In a cohort of 4082 individuals with SCD enrolled in the Cooperative Study of Sickle Cell Disease (CSSCD) from 1978 to 1988, the risk of stroke was highest in those with Hb SS, while individuals with Hb SC disease or Hb S-beta+-thalassemia were at substantially lower risk (figure 2) [18]. In this cohort, patients with Hb S-beta0-thalassemia also appeared to have a very low stroke risk, but this is likely an artifact of the relatively small number of patients of this type in the cohort. There was a dose-response contribution related to the following ischemic stroke risk factors:

Frequent episodes of acute chest syndrome (ACS; relative risk [RR] 2.39 per event per year)

Lower steady state hemoglobin level (RR 1.9 per 1 g/dL decrease)

Higher systolic blood pressure (SBP; RR 1.31 per every 10 mm Hg of SBP).

The major risk factors for hemorrhagic stroke were lower steady state hemoglobin level (RR 1.6 per 1 g/dL decrease) and higher steady state white blood count (WBC; RR 1.9 per 5000/microL increase). Stroke and silent cerebral infarcts (SCI) are reported to be more common in individuals with SCD with a history of seizures, although cause and effect may be difficult to separate [19-21].

Other genetic risk factors – Numerous genetic polymorphisms have been associated with modifications of stroke risk. In one series, concomitant alpha thalassemia was associated with a lower risk of stroke [22]. Genome-wide association studies (GWAS) of 233 patients with SCD also found a protective effect of alpha-thalassemia trait but no association of beta-globin haplotype or the G6PD A- allele with stroke risk [23,24]. Polymorphisms in genes encoding adenylate cyclase 9 (ADCY9), a Golgi apparatus-associated protein (GOLGB1), a transmembrane glycoprotein (ENPP1), the deletion 3.7 allele of the HBA2 locus, annexin A2 (ANXA2), Tek tyrosine kinase (TEK), and the TGF beta receptor 3 (TGFBR3) were identified as modifying stroke risk. The pathophysiologic role and clinical significance of these polymorphisms remain to be determined.

Comorbidities and other clinical factors – Risk factors for ischemic or embolic stroke unrelated to SCD, such as oral contraceptive use, smoking, inherited thrombophilia, or other vasculopathy such as cervical artery dissection, may also play a role in SCD stroke risk [25]. Sleep-disordered breathing and daytime oxygen desaturation (see "Overview of the pulmonary complications of sickle cell disease", section on 'Sleep-disordered breathing') have also been implicated [26,27]. However, these studies have significant limitations and should be interpreted cautiously when applied to clinical management in children with SCD, particularly in children with normal transcranial Doppler (TCD) measurements. Contributions from medical comorbidities appear to persist despite chronic transfusion therapy [13].

Reticulocyte count – A retrospective review of the newborn cohort in the CSSCD study indicated that reticulocytosis, defined as an absolute reticulocyte count (ARC) >194,000/microL before age six months was a good predictor of future ischemic stroke risk [28]. A subsequent prospective study of 121 children with hematologic data available from infancy indicated a significant correlation between rising ARC and dropping hemoglobin concentration and the incidence of abnormal or conditional transcranial Doppler (TCD) velocities, a surrogate of stroke risk. (See 'Risk assessment for first stroke' below.)

Risk factors: Hemorrhagic stroke — Risk factors for hemorrhagic stroke are less well studied. They may include vascular lesions, antiplatelet medications, comorbidities (kidney disease, hypertension), and more severe anemia.

A retrospective review of >3500 participants in the STOP and STOP II trials identified 35 participants with hemorrhagic stroke [29]. Risk factors for hemorrhagic stroke included moyamoya arteriopathy, aneurysms, cavernous malformations, and SCD complications. The risk of hemorrhagic stroke correlated with older age (incidence, 14 per 100,000 person years for age ≤10 years, 103 from age 10 to 20, 139 from 20 to 30 years, and 518 for age >30 years). The use of MRA to screen for vascular abnormalities that could lead to hemorrhagic stroke is discussed below. (See 'MRA screening (noncontrast) in young adulthood' below.)

In a cohort of 255 patients with SCD from the California Patient Discharge Databases, there were significant associations between hemorrhagic stroke and hypertension (odds ratio [OR]: 7.7), kidney disease (OR: 7.2), coagulopathy (OR: 9.9), and atrial fibrillation (OR: 4.3) [30].

Among 15 patients in the CSSCD cohort, risk factors for hemorrhagic stroke included low baseline hemoglobin concentration, elevated steady-state WBC count, previous ischemic stroke, aneurysms, hypertension, recent transfusion, and recent use of glucocorticoids or nonsteroidal antiinflammatory drugs (NSAIDs) [31].

Additional information about screening for hemorrhagic stroke is presented below. (See 'MRA screening (noncontrast) in young adulthood' below.)

Management of hemorrhagic stroke is presented separately. (See "Acute stroke (ischemic and hemorrhagic) in children and adults with sickle cell disease", section on 'Intracranial hemorrhage management' and "Aneurysmal subarachnoid hemorrhage: Treatment and prognosis".)

INCIDENCE — The incidence of a first stroke varies with the type of SCD, patient age, and comorbidities. It has been estimated that without intervention, by age 20 years, 11 percent of patients with SCD will have a clinically apparent stroke, and by age 45 years, one-fourth of patients with SCD will have a stroke [18,32].

The most extensive information on the incidence of stroke and the relative frequency of ischemic versus hemorrhagic stroke comes from the United States Cooperative Study of Sickle Cell Disease (CSSCD), which followed 4082 individuals with all types of SCD for a mean of over five years [18]:

The overall prevalence of stroke at study entry was approximately 4 percent, with prevalence peaking in two cohorts: ages 2 to 5 years and ages 40 to 49 years (approximately 8 percent in both).

The overall incidence of a first stroke was 0.46 per 100 patient-years.

Ischemic stroke was most common in children between the ages of two and nine years, uncommon between the ages of 20 and 29, and showed a second peak in adults over age 29. Hemorrhagic stroke was most frequently seen in individuals between the ages of 20 and 29.

Ischemic stroke accounted for 54 percent of first events, hemorrhagic stroke accounted for 34 percent of first events, and features of both infarction and hemorrhage were seen in 1 percent. Transient ischemic attacks (TIAs) accounted for an additional 8 percent.

Additional information about the incidence of stroke in SCD comes from a cohort of 69,586 children and adults in the California Patient Discharge Databases who were hospitalized for SCD complications from 1998 to 2007 [30]. A total of 255 acute strokes were identified, with the greatest incidence in patients aged 35 years and older (figure 3). Hemorrhagic stroke was less common than ischemic stroke in all age groups but became more common with increasing age.

The incidence of stroke is much lower in SCD types other than Hb SS or Hb S-beta0-thalassemia. (See 'Pathophysiology and risk factors' above.)

The frequency of silent cerebral infarcts (SCI) in SCD increases with age (figure 4). By age 30 years, more than 50 percent have SCI [19,33-41]. Determining the true prevalence of SCI has been challenging, in part because magnetic resonance imaging (MRI) is not typically performed in the absence of neurologic symptoms.

Similar to stroke, SCI is less common in individuals with types of SCD other than Hb SS or Hb S-beta0-thalassemia [38].

Transient, clinically acute silent cerebral ischemic events (ASCIE; acute ischemic lesions on diffusion-weighted MRI sequences without a corresponding neurologic finding) have been observed in asymptomatic children with SCD [42,43]. As an example, one study analyzed data from 652 children who were screened for SCI with MRI; ASCIE were observed on diffusion-weighted MRI scans in 10 children, with an estimated incidence of 47 per 100 patient-years [42]. In two children who had follow-up MRI, SCI in the same location as the previously detected ASCIE was found only in one.

These limited data suggest that children with SCD have relatively frequent acute asymptomatic cerebral ischemic events. Some of these acute lesions may resolve spontaneously, while others persist as SCI. The significance of these findings remains to be established. However, a publication from 2018 showed progressive loss of brain volume on MRI over a three-year period in children with SCD and pre-existing SCI, raising concern that subtle brain injury occurs frequently in individuals with SCD even without the appearance of new SCI [44].

RISK ASSESSMENT FOR FIRST STROKE

Implications of TCD velocity — The primary method of stroke risk assessment in children is transcranial Doppler (TCD) screening, a noninvasive ultrasound-based procedure that can be used to measure the mean blood flow velocity in the large intracranial vessels [45]. TCD velocity can be measured through several bone windows, including transtemporal, suboccipital, and transorbital approaches, and at various depth settings [46].

Children with SCD have TCD velocities that are 40 to 50 percent higher than those in unaffected comparison groups. Blood flow velocity is inversely proportional to arterial diameter, so narrowing of a vessel lumen in the setting of vascular stenosis can be identified by increased flow velocity in the affected segment [46]. A focal increase in velocity usually suggests localized arterial stenosis, whereas a bilateral increase may indicate bilateral arterial disease, or increased blood flow unrelated to intracranial stenosis, perhaps related to cerebral hemodynamic compensation [47-49].

Data are lacking to guide therapy for individuals with abnormally low TCD velocities; it may be prudent to evaluate other stroke risk factors and/or perform a magnetic resonance angiography (MRA) study. (See 'MRA screening (noncontrast) in young adulthood' below.)

Risk factors for abnormal TCD velocity measurements were evaluated in a 2016 prospective study that followed 375 infants with SCD from time of diagnosis [50]. In multivariate analysis, abnormal TCD velocities were correlated with upper or lower airway obstruction (hazard ratios [HR]: 1.47 and 1.76, respectively per year of obstruction), and elevated absolute reticulocyte count (HR: 1.82 per rise of 20,000/microL). Elevated hemoglobin F (Hb F) was protective on multivariate analysis.

Evidence supporting the use of TCD screening — Most strokes occur in children with abnormal TCD velocities. In a series of 190 children with SCD who underwent regular TCD monitoring for an average of 2.5 years, there were seven strokes, six of which occurred in the 23 children with abnormal TCD results [46]. In 209 children in the STOP-1 and STOP-2 trials, there were 20 strokes, and the last TCD examination before the stroke showed abnormal velocities in all cases (table 1) [36,51]. (See 'Evidence for chronic transfusion' below.)

Additional evidence for a correlation between higher arterial flow velocity values on TCD and increasing stroke risk in SCD derives from a study of 190 children and adolescents with SCD (age 3 to 18 years) who underwent prospective TCD screening with nonimaging TCD [46]. Time-averaged mean of the maximum velocities (TAMMV) in the internal carotid artery (ICA) and middle cerebral artery (MCA) correlated strongly with stroke risk and with narrowing on cerebral angiography. There was no absolute threshold above which stroke became more likely, but in an extension study, the incidence of stroke in those with TAMMV <170 cm/sec was 2 percent, that in patients with velocities between 170 and 200 cm/sec was 7 percent, and that in patients with velocities >200 cm/sec was 40 percent (figure 5) [52].

The utility of TCD screening in patients over the age of 16 years has not been established in controlled trials. In one study, the mean TCD velocity of adults with SCD was significantly higher than that seen in healthy controls (110.9 ± 25.7 cm/sec versus 71.1 ± 12.0 cm/sec) but lower than that reported in children with SCD, indicating that the TAMMV thresholds established for stroke risk classification in children would not apply to adults [53]. In a subsequent report, 50 patients with SCD who were >16 years old were evaluated by both magnetic resonance imaging (MRI)/MRA and TCD to determine the association between abnormal findings on these imaging studies and TCD velocities [54]. Among these patients, 36 (72 percent) had stenosis or tortuosity of the ICA or MCA on MRA, and these patients had significantly higher TCD velocities than those with normal MRA results. These results suggest that TCD screening of adults with SCD could be useful in adults, but they do not establish its utility in predicting the onset of cerebral vasculopathy or in preventing stroke.

Abnormally low TCD velocities in any major vessel may also be an indication of significant cerebral vasculopathy.

In a series of five children with SCD, a variety of neurologic abnormalities were preceded by abnormally low flow velocities in the internal carotid arteries (ICA), middle cerebral artery (MCA), or anterior cerebral artery (ACA) in the range of 40 to 78 cm/sec. Subsequent MRI and MRA studies in these patients identified significant vascular and parenchymal abnormalities [55].

These findings were corroborated in the SWiTCH trial of secondary stroke prevention, which found that patients with low TCD velocities (50 to 70 cm/sec) or unevaluable studies had significantly higher rates of stenosis in the MCA region than those with normal velocities [56].

These results suggest that children with repeated low flow velocities or unevaluable studies of the ICA, MCA, or ACA should be assessed closely for other risk factors for stroke, such as low hemoglobin levels. Additionally, children who have repeated unevaluable TCD studies may benefit from a screening MRA study. There are, however, no evidence-based guidelines to be followed in this situation.

TCD screening protocol — Children with Hb SS or Hb S-beta0-thalassemia should be screened with TCD studies of the internal carotid artery and large arteries of the circle of Willis (eg, ICA and MCA stem) beginning at age 2 years and continuing through age 16 years. Screening is repeated at an interval based on the highest flow velocity in any artery:

Flow velocity <170 cm/sec: normal; repeat annually.

Flow velocity between 170 cm/sec and 185 cm/sec: low conditional; repeat in three to six months.

Flow velocity between 185 cm/sec and 200 cm/sec: high conditional [51,52]; repeat in one to three months.

Flow velocity ≥200 cm/sec: abnormal, stroke risk 10.7 events per 100 person-years [51,52]; repeat within one to two weeks.

These TCD risk stratification parameters were established with the nonimaging modality of TCD ultrasonography; parameters with the imaging TCD modality (TCDi), used at many medical centers, are typically 15 cm/sec lower (ie, normal velocities are less than 155 cm/sec, conditional velocities between 155 and 180 cm/sec, and abnormal velocities above 180 to 185 cm/sec) [57].

If two studies within a one- to two-week period demonstrate persistently abnormal flow velocity (≥200 cm/sec for TCD ultrasonography or >180 to 185 cm/sec for TCDi) in the ICA or proximal MCA, we initiate primary prophylaxis with a chronic transfusion protocol. Guidelines do not recommend transfusion of patients for elevated ACA velocities. (See 'Prevention of a first ischemic stroke (primary stroke prophylaxis)' below.)

Abnormally low TCD velocities (eg, <50 to 70 cm/sec) do not necessarily trigger initiation of transfusion therapy, but do necessitate further evaluation for cerebral vasculopathy.

TCD screening is not required for individuals with other SCD types (eg, Hb SC disease, Hb S-beta+-thalassemia), although it may be appropriate in those with hemolysis similar in magnitude to Hb SS [58]. If performed, it should be noted that the TAMMV risk stratification parameters established for patients with Hb SS may not apply to those with other SCD types. In an observational study, TCD velocities were lower in patients with Hb SC disease than those with Hb SS or Hb S-beta0-thalassemiaand; the relationship between TCD values and stroke risk was not assessed [59].

For adolescents over 16 years of age and adults, no significant evidence has emerged that primary stroke prevention strategies improve outcomes. As a result, TCD screening is not recommended beyond 16 years of age given the absence of data supporting the utility of TCD screening above age 16 years and the changing patterns of cerebral blood flow velocities above this age [60-62].

Limitations of TCD screening — Despite the evidence supporting a correlation between TCD velocities and stroke risk, abnormal TCD velocities are only a surrogate measure for vasculopathy and stroke risk. A small proportion of patients with normal and conditional TCD velocities do experience ischemic strokes [52].

TCD velocities may also vary over time for the same individual, as was demonstrated both in the STOP cohort and in a longitudinal study [63,64]. On the first TCD measurement, the majority of children in the longitudinal cohort (84 percent) had a normal TCD result. Among this group, 25 of 153 (16 percent) converted to a conditional result. An additional four patients (3 percent) converted directly from a normal to an abnormal result. These data illustrate the importance of continued monitoring of patients regardless of prior TCD results.

Additional caveats with TCD screening include the dependence of quality and reliability on operator training and experience, the transient elevation of TCD velocities during intercurrent illness, and the transient lowering of TCD velocities by recent transfusion. Routine TCD screening should be performed by experienced operators and should be deferred if the patient is experiencing any illness or received a transfusion in the preceding two weeks.

Many children with SCD are not screened with TCD, despite the established value of TCD-based interventions to reduce stroke risk. Impediments include lack of access to centers where TCD is performed, lack of access to chronic transfusion therapy should screening identify an abnormal TCD velocity, and the costs and burdens of regular screening and interventions, which may be substantial [65,66]. One approach to improving access to TCD screening is to make it routinely available on the same day as a regular clinic visit. In a study from a tertiary center that instituted this approach, 99 percent of patients at risk for stroke were able to be screened [67].

TCD screening is ineffective in identifying increased risk for silent cerebral infarction (SCI). In a cohort study of participants in the Cooperative Study of Sickle Cell Disease (CSSCD) and STOP studies, there was a discordance rate of 29 percent between TCD and MRI results, with only 5 out of 17 patients with abnormal MRI findings also having abnormal TCD results [68]. TCD also appears to be ineffective in identifying children at risk of intracerebral hemorrhage (ICH), identifying only one of nine patients (11 percent) in the STOP cohort who developed ICH [64].

MRI screening for silent infarcts — SCI are an independent risk factor for both overt strokes and additional SCI. Further, children with SCI are at risk for cognitive impairment, further neurologic injury, and grade failure at school. In untreated children with SCI and normal or conditional TCD measurement, the incidence rate of infarct recurrence was 4.8 events per 100 person years. Even with regular blood transfusion therapy, the infarct recurrence rate was 2 events per 100 person years in the Silent Cerebral Infarct Trial (SIT) [69]. The number needed to treat with regular blood transfusion therapy to reduce the incidence of SCI is 13, a value that some parents, caregivers, and clinicians may consider too high to initiate regular blood transfusion therapy. Regardless of whether transfusion therapy is chosen or not, detection of SCIs can facilitate other interventions to improve cognitive outcomes.

The 2020 American Society of Hematology (ASH) guidelines for management of cerebrovascular disease in SCD recommend that school-aged children and young adults with Hb SS or Hb S-beta0-thalassemia be screened at least once for silent cerebral infarcts with an MRI of the brain without sedation [58].

In addition to SCI screening, MRI should also be considered for those with any other neurologic abnormality (seizures, TIAs, syncopal episodes), and for those with significant neurocognitive deficits.

MRA screening (noncontrast) in young adulthood — MRA studies of the cerebral vasculature may be useful to assess for the development of significant vasculopathy, moyamoya arteriopathy, or cerebral aneurysm, but there are no clear criteria for identifying patients who should undergo such screening. Based on the age-associated increase in hemorrhagic stroke, we often obtain a noncontrast MRA in young adulthood at the same time as MRI screening. (See 'Risk factors: Hemorrhagic stroke' above.)

The utility of noncontrast MRA to assess for cerebral vasculopathy depends on the type of SCD, age of the patient, and clinical situation.

Low utility – Situations where there is negligible probability of finding an MRA abnormality that will change the clinical care of the child include:

Hb SC disease and no neurological history

Hb SS with a normal TCD measurement.

Note that only 2 in 110 children in the SIT trial with normal TCD velocities had an abnormal MRA [69]. MRA is unlikely to be useful in low-risk patient groups.

High utility – In children, with Hb SS and overt strokes, MRA assessment has significant clinical utility. Progressive MRA vasculopathy is an important predictor of new cerebral infarcts or overt strokes in children with prior stroke who are receiving regular blood transfusion therapy.

In a prospective single arm study of blood transfusion therapy in 40 children with Hb SS who had a history of strokes, recurrent cerebral infarcts occurred while receiving chronic transfusions in 18 of 40 (45 percent); seven had a second overt stroke, and 11 had a new silent cerebral infarct (SCI) [70]. Worsening cerebral vasculopathy was associated with new overt or silent cerebral infarction (relative risk [RR] 12.7, 95% CI 2.7-60.5).

Thus, children and presumably adults with overt strokes may benefit from surveillance MRA with MRI to determine if there is an increased risk for (or presence of) infarct recurrence. In either case, the patient, family or caregivers, and clinician may elect for additional therapy to attenuate the risk of cerebral infarct recurrence such as hematopoietic stem cell transplant.

In children with Hb SS and abnormal TCD velocities placed on regular blood transfusions as standard care, the presence of MRA-defined vasculopathy will determine eligibility to transition to hydroxyurea after at least one year of regular transfusions.

Other predictors of stroke — Other techniques for assessing the risk of stroke in children with SCD have been proposed including the use of more readily available laboratory testing to stratify for the need for TCD measurements, measurement of flow velocities using a submandibular TCD approach, and measuring flow velocity in vessels of the eye [71-73]. None of these methods have been validated prospectively. Given the association between anemia and reticulocytosis in early infancy and future risk for stroke and abnormal TCD results described above, however, it is worth considering the early initiation of hydroxyurea therapy and TCD screening in infants with these findings. (See "Hydroxyurea use in sickle cell disease".)

PREVENTION OF A FIRST ISCHEMIC STROKE (PRIMARY STROKE PROPHYLAXIS)

Overview of primary prevention — For children at increased risk of stroke based on two transcranial Doppler (TCD) velocity measurements ≥200 cm/sec within a one- to two-week period, we recommend chronic red blood cell (RBC) transfusion therapy for primary stroke prevention. This is considered the standard approach and is consistent with recommendations from the National Heart, Lung, and Blood Institute 2014 guidelines, the American Society of Hematology (ASH) 2020 guidelines for management of cerebrovascular disease, and practices in other countries [58,62,74].

Chronic transfusion therapy may also be appropriate for children with abnormally low flow velocities (<50 to 70 cm/sec), especially if magnetic resonance imaging (MRI) shows silent infarctions and/or if magnetic resonance angiography (MRA) demonstrates large artery stenosis.

The goals of chronic transfusion therapy are to lower and maintain the hemoglobin S level at 30 percent or less of total hemoglobin and to maintain a pretransfusion hemoglobin concentration of approximately 9 g/dL. Of note, patients should not be transfused to a post-transfusion hemoglobin concentration >12.5 g/dL due to the risk of hyperviscosity and decreased tissue oxygen delivery with increasing hematocrit [75]. These issues and additional information regarding transfusions are presented in detail separately. (See "Red blood cell transfusion in sickle cell disease: Indications and transfusion techniques".)

Once a patient has initiated a prophylactic transfusion program, it usually should be continued indefinitely. Two notable exceptions include the following:

Patients with a good response to chronic transfusion can be evaluated for transition to hydroxyurea after a period of one or more years of transfusion.  

The transition to hydroxyurea approach applies only to carefully screened patients, is carried out gradually with a period of overlapping transfusions and hydroxyurea therapy, and should be performed in a closely monitored setting. Qualifying patient characteristics and details of transition are discussed below. (See 'Chronic transfusion followed by transition to hydroxyurea' below.)

Not all patients with SCD at risk for stroke will have access to, or will be able to tolerate, indefinite chronic transfusion. For such patients, hydroxyurea therapy is a viable approach, ideally preceded by transfusion therapy for the longest possible interval and with transfusion continued during escalation to the maximum tolerated dose of hydroxyurea. The 2022 Stroke Prevention Trial in Nigeria (SPRING) demonstrated that when blood transfusions are not available or are unacceptable, hydroxyurea at a dose of 10 or 20 mg/kg daily is effective for primary stroke prevention [76]. (See 'Alternatives for primary prophylaxis in special populations' below and "Sickle cell disease in sub-Saharan Africa", section on 'Primary and secondary prevention (stroke)'.)

We also perform MRI of the brain and MRA of the cerebral vasculature within a few months of initiating chronic transfusion therapy to assess for silent cerebral infarcts (SCI) and to quantify any vasculopathy.

Most clinicians do not continue TCD screening for primary stroke prevention after a patient has been placed on chronic transfusion therapy; this is because regular blood transfusion therapy dramatically decreases the incidence rate of strokes to less than 1 per 100 person years. In the STOP trial, among 88 children with serial TCD data after starting regular blood transfusion therapy, TCD measurements remained abnormal in 21.6 percent of the children, with none of the children developing a stroke. Thus, in children with an abnormal TCD measurement who are started on blood transfusion therapy, the presence of persistently abnormal TCD measurements does not appear to predict future strokes.

There are no clear evidence-based guidelines for the management of children with normal or conditional TCD velocities who have other findings of concern such as neurocognitive deficits or seizures. At a minimum, all such patients should undergo MRI and MRA imaging of the brain to screen for parenchymal or vascular abnormalities and should be considered for chronic transfusion therapy if significant abnormalities, such as SCI or severe vasculopathy, are identified.

Evidence for chronic transfusion — We recommend chronic transfusion therapy for primary stroke prevention in children with persistent TCD velocity ≥200 cm/sec. Chronic transfusion may also be appropriate for children with SCI and significant cerebrovascular stenosis. (See 'Overview of primary prevention' above.)

Benefits of chronic transfusion – Evidence for the superiority of regular transfusion relative to observation comes from the following randomized trials (table 1):

The Stroke Prevention Trial in Sickle Cell Anemia (STOP) trial, later renamed STOP-1, demonstrated the superiority of chronic transfusion over observation in preventing a first stroke in children with a TCD velocity >200 cm/sec on two repeated studies [36]. The STOP-1 trial randomly assigned 130 children with SCD (mean age eight years) to a prophylactic chronic transfusion program with a goal Hb S of <30 percent of total hemoglobin or to observation and standard care. The trial was terminated prematurely at a mean follow-up of 20 months due to a marked reduction in strokes in the prophylactic transfusion group (figure 6); there was one stroke on the transfusion arm (2 percent) versus 10 strokes and one cerebral hemorrhage on the observation arm (16 percent).

The Silent cerebral Infarct Transfusion (SIT) trial demonstrated the superiority of chronic transfusion over observation in preventing a first stroke or new SCI in children with SCI on brain MRI regardless of TCD findings [69]. The SIT trial randomly assigned 196 children with SCI to a prophylactic chronic transfusion program or observation for a median of three years. There were significantly fewer events in the transfusion group (one stroke and five new or enlarged SCIs [6 percent]) compared with the observation group (seven strokes and seven new or enlarged SCIs [14 percent]). This translated to an incidence of new brain lesions of 2.0 versus 4.8 per 100 years at risk (incidence ratio 0.41, 95% CI 0.12-0.99). There were an additional three TIAs, all in the observation group. There were no significant changes in cognitive function.

The following observations also support the greater efficacy of chronic transfusion compared with observation alone in primary stroke prevention (table 1):

Higher rate of strokes when transfusions are discontinued:

-A continuation study following the completion of the STOP-1 trial allowed 127 patients who were enrolled in STOP-1 to continue, resume, or initiate chronic transfusions [77]. Over a period of approximately 2.5 years, there was one additional stroke (1.3 percent) among the 79 patients in the transfusion group and five strokes (10.4 percent) among the 48 patients not receiving transfusions. The one patient in the transfusion group who experienced a stroke was no longer receiving transfusions at the time the stroke occurred.

-The STOP-2 trial randomly assigned 79 children with initial abnormal TCD results who had received chronic transfusions for 30 or more months with normalization of TCD measurements to discontinue or continue transfusions [51]. The trial was terminated early due to a high risk of stroke and/or elevated TCD measurements in those who discontinued transfusions. Among 41 patients in the discontinuation group, there were two strokes (5 percent) and 14 cases of increased TCD measurements indicative of reversion to high stroke risk (34 percent), versus no strokes or elevated TCD measurements in the group that continued transfusions.

Lower rate of strokes in a general SCD population after STOP-1 results became available in 1998:

A retrospective study in the state of California demonstrated that the number of hospital admissions for a first stroke in children with SCD declined as transfusion became incorporated in routine management [78]. Rates were as follows:

-1991 to 1998 – 0.88 events per 100 person-years

-1999 – 0.50 events per 100 person-years

-2000 – 0.17 events per 100 person-years

Reduction in SCI with chronic transfusion:

In addition to reducing the risk of stroke, several trials have shown a benefit of transfusion in reducing the risk of SCI, including STOP-1, STOP-2, SIT, and TWiTCH. As an example, of 58 children in STOP-2 who had a normal baseline MRI, there were no new SCI in those randomly assigned to continue transfusions, versus six SCIs in 30 patients (20 percent) assigned to discontinue transfusions [79]. SCIs in turn are thought to be associated with an increased risk of future stroke as well as with neuropsychological impairment [1]. (See 'MRI screening for silent infarcts' above.)

Risks and burdens of chronic transfusion – Despite the benefits noted above, chronic transfusion therapy poses certain risks, including alloimmunization, transfusion reactions, and iron overload, as well as a significant investment of time and resources. In practice, few patients are able to continue chronic prophylactic transfusions into adulthood because of the development of alloantibodies, iron overload, and other costs and burdens of this approach. These risks and burdens, and strategies to reduce their frequency and severity, are presented separately. (See "Red blood cell transfusion in sickle cell disease: Indications and transfusion techniques".)

Hydroxyurea in primary stroke prevention — Hydroxyurea is commonly used to prevent vaso-occlusive complications of SCD and has been shown to be effective in many settings such as acute painful episodes and acute chest syndrome. Additional advantages of hydroxyurea compared with transfusions include a lower risk of adverse events for most patients, greater ease of administration, and lower cost (see "Hydroxyurea use in sickle cell disease"). For several reasons, however, hydroxyurea is not the optimal first-line therapy for primary stroke prophylaxis:

The efficacy of hydroxyurea as up-front primary prevention (omitting a preceding period of transfusion therapy) in comparison with chronic transfusion has not been tested in randomized trials.

Typically, at least six months of therapy are required to reach the maximum tolerated dose and maximal clinical response to hydroxyurea, during which time the patient may not have adequate protection from progressive vasculopathy and stroke risk.

Response to hydroxyurea therapy is highly variable among patients, and there is no means of predicting whether an individual patient will have a good response. There is also no established level of response that can be used confidently to define adequate protection from the risk of stroke.

Response to hydroxyurea therapy is also highly dependent on individual adherence to therapy, which is difficult to document and maintain.

Selected children may be treated with hydroxyurea, either because they may be able to transition to hydroxyurea following a period of chronic transfusion or because regular transfusion is not feasible. However, the clinician must clearly explain the potentially suboptimal outcomes of this therapy to the patient, family, and caregivers, especially in higher-risk patients. (See 'Chronic transfusion followed by transition to hydroxyurea' below and 'Alternatives for primary prophylaxis in special populations' below and "Sickle cell disease in sub-Saharan Africa", section on 'Primary and secondary prevention (stroke)'.)

Additional details regarding administration of hydroxyurea are presented separately. (See "Hydroxyurea use in sickle cell disease", section on 'Initial dosing'.)

Chronic transfusion followed by transition to hydroxyurea — The TWiTCH (TCD With Transfusions Changing to Hydroxyurea) trial demonstrated that for a subset of patients with SCD on chronic transfusion for primary stroke prophylaxis, hydroxyurea is a viable alternative to indefinite transfusions [37].

The TWiTCH trial randomly assigned 121 children with SCD on chronic transfusion therapy for a minimum of one year to transition from transfusions to hydroxyurea or to continue transfusions [37]. The primary outcome was noninferiority for TCD velocity at 24 months. Patients on the hydroxyurea arm were gradually transitioned from chronic transfusions to hydroxyurea over a period of several months (table 2). The TWiTCH trial was terminated early after 37 percent of patients had exited the study because the first interim analysis revealed noninferiority for the primary endpoint of TCD velocity (figure 7). No strokes or SCI were reported. There were three TIAs in each group (5 percent for each). One child on the transfusion arm had progressive vasculopathy on MRA.

The conclusion drawn from the study was that hydroxyurea can be considered as a substitute therapy for the maintenance of TCD velocities (and by extension, the minimization of stroke risk) in selected children after a period of transfusion therapy. The study also demonstrated that phlebotomy could be a viable alternative to pharmacologic chelation to address transfusional iron overload in patients with a good response to hydroxyurea therapy.

There are some caveats to be considered in applying the results of the TWiTCH trial to the wider population of SCD patients on chronic transfusion for primary stroke prophylaxis:

Although persistence of abnormal TCD velocities was not an exclusion criterion, the vast majority of patients on both arms of the TWiTCH trial had a significant reduction of TCD velocities on chronic transfusion [37]. Additionally, patients with grade 4 or greater vasculopathy on MRA, defined as moderate (50 to 74 percent) stenosis in more than two arterial segments, or severe stenosis (75 to 99 percent) or occlusion in one or two arterial segments [56], were excluded from the study [37].

Virtually all patients in TWiTCH had a remarkably strong response to hydroxyurea, with a mean hemoglobin concentration maintained at 9.1 ± 1.1 g/dL and a mean Hb F of 24.4 ± 7.9 percent of total hemoglobin. In contrast, adherence to hydroxyurea therapy varies widely in the larger population of SCD patients, and a small proportion have limited response despite escalation to maximum tolerated dose.

The published duration of follow-up in the TWiTCH trial was relatively short (24 months). Therefore, it is not possible to exclude the possibility of longer-term progression of SCD vasculopathy and increased stroke risk in patients on hydroxyurea, as was seen in the French cohort described below.

In a French cohort of 92 patients with abnormal TCD velocities who were treated with a period of transfusion therapy, 76 (83.5 percent) had normalization of TCD velocities after a mean duration of transfusion of 1.4 ± 1.3 years [80]. Forty-five patients were transitioned to hydroxyurea therapy (mean duration of preceding transfusion, 2.7 ± 1.7 years; mean age, 6.4 ± 1.9 years), with a period of overlap between transfusion and hydroxyurea during escalation to maximum tolerated dose. Of these 45 patients, 13 (29 percent) had reversion to abnormal TCD velocities within 1.1 ± 1.1 years of transitioning to hydroxyurea (range, 0.2 to 3.9 years). Patients who had reversion to abnormal TCDs were once again placed on chronic transfusion therapy, and none were reported to have worsened clinical status. Multivariate regression analysis of potential risk factors for TCD reversion identified a baseline absolute reticulocyte count (ARC) >400,000/microL before the age of three years, higher white blood count (WBC) on hydroxyurea, and lower maximum tolerated dose of hydroxyurea as independent risk factors for reversion.

Based on these studies, we consider patients on chronic transfusion to be eligible for transition to hydroxyurea if they meet the following criteria:

Completion of one to two years of chronic transfusions with consistently good control of Hb S levels during this interval.

Normalization or improvement of TCD velocities on transfusions

No evidence of severe (grade 4 or higher) vasculopathy on MRA, as defined above [56].

Ability to adhere to a hydroxyurea treatment protocol.

Demonstration of a robust response to hydroxyurea, as measured by suppression of the absolute neutrophil count, a rise in the hemoglobin concentration, and/or a significant rise in fetal hemoglobin (Hb F) level.

Our rationale for limiting this approach to patients who meet these criteria balances the costs, burdens, and challenges of continuing chronic transfusions indefinitely against the devastating effects of stroke.

For patients who do not resemble the TWiTCH population, the risk of a first stroke may increase if they are switched from transfusions to hydroxyurea therapy, and it would be advisable to continue chronic transfusions for primary stroke prophylaxis. (See 'Overview of primary prevention' above.)

A detailed protocol for the transition from chronic transfusion therapy to hydroxyurea based on the approach followed in the TWiTCH trial is provided in the table (table 2). Details on maintenance therapy with hydroxyurea are presented separately. (See "Hydroxyurea use in sickle cell disease", section on 'Administration and dosing'.)

Alternatives for primary prophylaxis in special populations — Chronic prophylactic transfusions may not be an option in some settings due to lack of resources, complications of past transfusions, or refusal by the patient/family/caregivers.

Hydroxyurea – For patients at increased risk of a first stroke who do not have access to prophylactic transfusions, hydroxyurea therapy may be superior to observation alone.

Several studies suggest that effective hydroxyurea therapy alone may reduce the risk of a first stroke:

In the 2011 BABY HUG trial, which evaluated outcomes in asymptomatic very young children (ages 9 to 18 months at entry) randomly assigned to receive hydroxyurea or observation, those on the hydroxyurea arm did not have as prominent an age-related increase in TCD velocities, suggesting some protection of cerebral vasculature [81]. (See "Hydroxyurea use in sickle cell disease", section on 'Indications and evidence for efficacy'.)

The 2022 SPRING trial was a double-blind, parallel-group, randomized, controlled, phase 3 trial conducted in Nigeria of 220 children aged 5 to 12 years with Hb SS and abnormal TCD velocities of ≥200 cm/sec [76]. Participants were randomly allocated to receive hydroxyurea at a low dose (10 mg/kg daily) or moderate-dose (20 mg/kg daily) and followed for a median of two to four years. In the low-dose group, 3 of 109 participants had strokes (incidence rate, 1.19 per 100 person-years); in the moderate-dose group, 5 of 111 had strokes (incidence rate of 1.92 per 100 person-years); this difference was not statistically significant. These incidence rates are superior to that seen in the observation arm of the STOP study (9.77 per 100 patient-years) but are inferior to that in the transfusion arm in STOP (0.91 per 100 patient-years).

In the SCATE study, hydroxyurea relative to observation alone appeared to be effective in preventing progression from conditional to abnormal TCD velocities and in decreasing abnormal velocities [82].

In a Belgian cohort of 34 children with abnormal TCD results started on hydroxyurea therapy rather than chronic transfusion, only one developed any overt neurologic abnormalities over 96 patient-years of therapy, although the closeness of follow-up evaluations was limited [83].

In an observational study in Nigeria, 396 children with SCD (Hb SS) were screened with TCD, and 68 individuals with elevated TCD velocities of ≥170 cm/sec and regular clinic attendance received hydroxyurea therapy with dose escalation to 25 to 35mg/kg per day [84]. Two children had overt strokes at 38 and 42 months after starting hydroxyurea. Hydroxyurea therapy was associated with a statistically significant decline in TCD velocities from abnormal or high conditional values to low conditional values.

These studies indicate that hydroxyurea therapy is superior to observation for primary stroke prevention but that it has not been shown to be comparable to or better than chronic transfusion therapy or transfusion followed by transition to hydroxyurea. This approach of starting primary prevention using hydroxyurea should therefore not be considered unless transfusion therapy is not feasible.

Hematopoietic stem cell transplantation – Hematopoietic stem cell transplantation (HSCT) is also a potential strategy for primary stroke prophylaxis in high-risk patients for whom a suitable donor is available. Given concerns about transplant-related morbidity and mortality, consideration of HSCT should be individualized in SCD. (See "Curative therapies in sickle cell disease including hematopoietic stem cell transplantation and gene therapy".)

In a study in which 67 children with elevated TCD velocities were treated with HSCT or standard care (chronic transfusions with the option to switch to hydroxyurea after the first year), follow-up at three years showed no strokes or deaths in either group and no differences in cognitive performance [85]. HSCT was associated with fewer silent cerebral infarcts (0 with HSCT versus 3 with standard care) and a greater reduction in TCD velocities.

Newer therapeutic agents There are no studies to support the safety and efficacy of voxelotor, L-glutamine, or crizanlizumab for primary stroke prophylaxis in SCD. These agents are not used for this purpose.

PREVENTION OF RECURRENT ISCHEMIC STROKE (SECONDARY STROKE PROPHYLAXIS)

Overview of secondary stroke prophylaxis — The risk of recurrent stroke is high in SCD, especially in children and adolescents. For those not receiving secondary prophylaxis, recurrence in up to two-thirds of patients has been reported [8,86-89]. Recurrence is often seen within two years of the initial event, and the risk is particularly high in patients under age 20 years.

Chronic transfusion therapy is the treatment of choice for secondary ischemic stroke prophylaxis. Hematopoietic stem cell transplantation (HSCT) is also highly effective but is limited in availability. There is limited evidence for the effectiveness of hydroxyurea therapy in this patient population. (See 'Chronic transfusions for secondary prophylaxis' below.)

As for any individual who has had a stroke, it is also important to address any other comorbidities or risk factors that may have contributed to stroke risk, such as hypertension, smoking, and hypercoagulable states such as inherited thrombophilia or antiphospholipid antibody syndrome. (See "Antihypertensive therapy for secondary stroke prevention" and "Overview of secondary prevention of ischemic stroke" and "Overview of secondary prevention for specific causes of ischemic stroke and transient ischemic attack" and "Long-term antithrombotic therapy for the secondary prevention of ischemic stroke" and "Ischemic stroke in children: Management and prognosis".)

Chronic transfusions for secondary prophylaxis — Chronic transfusion therapy is superior to observation alone for secondary ischemic stroke prevention. Chronic transfusion is also superior to hydroxyurea for secondary prevention based on available evidence (table 1):

Transfusions versus observation – Observational studies have demonstrated a reduced risk of recurrent stroke in children treated with regular transfusions compared with observation. As an example, in a retrospective cohort of 137 children treated with chronic transfusions over a 10-year period, 31 (22 percent) had a second stroke, for a rate of 2.2 per 100 patient-years [13]. By comparison, the prevalence of recurrent stroke without transfusion has been estimated at 47 percent to over 90 percent [90]. A number of additional smaller series have also demonstrated a reduced risk of recurrent stroke with regular transfusions compared with observation, with typical reductions in recurrent stroke rate from approximately two-thirds of patients to below 10 percent [87,88,90-93].

Whether chronic transfusion therapy can be stopped after a longer period of transfusions in a patient with a prior stroke remains unclear. Evidence from the primary prevention setting (see 'Evidence for chronic transfusion' above) and from small series of patients who have discontinued transfusions for secondary prevention suggests that this practice may be associated with an increased risk of stroke, even after several years of stable transfusion therapy [91,94]. In one report of 10 patients who received transfusion therapy for a mean of 9.5 years after an initial stroke, five had a recurrent ischemic event within one year after the cessation of therapy [94].

The Stroke With Transfusions Changing to Hydroxyurea (SWiTCH) trial evaluated whether hydroxyurea could be substituted for chronic transfusions after a period of chronic transfusion therapy as a means of reducing excess iron stores without increasing the risk of recurrent stroke [95]. In the SWiTCH trial, 133 children and adolescents with SCD who had a history of stroke and had received at least 18 months of transfusion therapy were randomly assigned to transition to a maximum tolerated dose (MTD) of hydroxyurea with phlebotomy or to continue transfusions with iron chelation. The primary endpoint was a composite of noninferiority for stroke prevention and superiority for reduction of liver iron content. The trial was terminated early at the first scheduled interim analysis for futility for the composite endpoint, which required superiority of phlebotomy over iron chelation for reducing excess iron stores. The incidence of stroke on the hydroxyurea plus phlebotomy arm was higher (7 of 67 patients; 10.4 percent) than in the transfusion plus chelation arm (1 of 66 patients; 1.5 percent). The results of this trial indicate that transition to hydroxyurea therapy is inferior to continued chronic transfusion for secondary stroke prevention.

Transfusions after TIA – The role of transfusion therapy as a prophylactic measure for patients with SCD following a transient ischemic attack (TIA) has not been studied in a systematic fashion. Despite the lack of such studies, guidelines published by the American Heart Association and the American Stroke Association recommend chronic transfusion therapy for such patients [96]. The 2014 National Heart, Lung, and Blood Institute Guidelines do not recommend prophylactic transfusions following TIA [62]. The 2020 American Society of Hematology (ASH) central nervous system disease guidelines recommend chronic transfusions for secondary prevention after TIA but do not specify the duration of therapy [58]. A reasonable approach in a patient with no recurrence of TIAs on chronic transfusion and no evidence of significant cerebral vasculopathy or silent infarcts on magnetic resonance imaging (MRI)/magnetic resonance angiography (MRA) studies would be to consider a gradual transition to hydroxyurea therapy after 6 to 12 months of chronic transfusion therapy.

Transfusions are titrated to achieve and maintain a pretransfusion hemoglobin S (Hb S) level of ≤30 percent. In the setting of an acute ischemic stroke, it is critical to rapidly lower the hemoglobin S level below this threshold by emergent automated exchange transfusion, as discussed in detail separately. (See "Acute stroke (ischemic and hemorrhagic) in children and adults with sickle cell disease".)

Subsequently, transfusions can be performed every three to six weeks to maintain the pretransfusion Hb S level at ≤30 percent, the pretransfusion total hemoglobin concentration at approximately 9 g/dL, and the post-transfusion hemoglobin concentration no higher than 12.5 g/dL. These thresholds are based on the values used in some of the landmark studies and trials in this area. (See 'Evidence for chronic transfusion' above.)

Efforts have also been made to reduce the frequency and volume of chronic transfusions (eg, by raising the target for percent Hb S). However, the clinical utility of increasing the target Hb S percentage is not well defined and is counter to the evidence that lower Hb S levels have a larger effect on lowering transcranial Doppler (TCD) velocities than raising the hemoglobin level [97].

Additional information regarding administration of transfusions in individuals with SCD are presented in detail separately. (See "Red blood cell transfusion in sickle cell disease: Indications and transfusion techniques", section on 'Transfusion techniques'.)

Children and adolescents enrolled in a chronic transfusion program for stroke should continue to have surveillance MRI with MRA because progressive vasculopathy, recurrent strokes, and silent cerebral infarcts (SCI) may occur despite regular transfusion therapy. This need for continued surveillance was demonstrated in two observational studies:

In a multicenter observational study of children on regular blood transfusions for secondary stroke prevention after first overt stroke, when followed over five years, 45 percent of children (18 of 40) had a new infarct recurrence (overt or SCI) and of these the majority, 14 of 18 (78 percent), had significant cerebral vasculopathy [70].

In a retrospective review of 44 patients with SCD who had a stroke and received chronic transfusions for secondary stroke prevention, 18 (41 percent) had a recurrent stroke over six and a half years of observation [98]. The rate of recurrent stroke was higher in those with moyamoya-like collateral vessels than in those who lacked these findings (11 of 19 [58 percent] versus 7 of 25 [28 percent]; hazard ratio [HR] 2.40, 95% CI 0.85-6.75).

Patients who develop neurologic symptoms suggestive of stroke or SCI while receiving chronic transfusions should be evaluated and treated for the possibility of a new stroke. (See "Acute stroke (ischemic and hemorrhagic) in children and adults with sickle cell disease".)

Patients receiving chronic transfusion require attention to excess iron stores, which can become a severe problem. As an example, the median hepatic iron levels in the SWiTCH trial were 13 mg/gram dry weight and the median serum ferritin level was 3164 ng/mL [99]. Our approach to monitoring and treating excess iron stores with chelation therapy as well as discussions of other potential complications of chronic transfusion such as alloimmunization and transfusion reactions are presented separately. (See "Transfusion in sickle cell disease: Management of complications including iron overload".)

The ASH 2020 guidelines on transfusion therapy in SCD recommend exchange transfusion (apheresis) for all patients on chronic transfusion therapy. Exchange transfusion offers several advantages over simple transfusion, including better control of anemia and hemoglobin S fraction and less iron loading, but is more resource-intensive [100]. (See "Red blood cell transfusion in sickle cell disease: Indications and transfusion techniques", section on 'Simple versus exchange transfusion'.)

Alternatives for secondary prophylaxis in special populations — Although regular transfusions are the preferred therapy for secondary stroke prevention in most patients with SCD, some individuals will not be able to tolerate this approach, and some may not have access to regular transfusions due to complications (eg, alloimmunization) or lack of resources. Others may have recurrent stroke despite chronic transfusions. Alternative therapies for such patients include hydroxyurea alone or HSCT.

Hydroxyurea alone – In the SPRINT trial conducted in Nigeria, children with acute stroke who were randomly assigned to hydroxyurea 10 versus 20 mg/kg/day; both doses were similarly effective at reducing recurrent stroke risk [101].

HSCT – HSCT may be a good option for secondary stroke prevention for individuals with a matched related donor [102].

A 2014 review of published experience identified 81 patients with SCD who had neurologic abnormalities and underwent HSCT [103]. Of 45 who had follow-up cerebral imaging, abnormalities were stable in 32 (71 percent), improved in six (13 percent), and worsened in seven (16 percent). The risk of stroke or transient ischemic attack after successful engraftment was estimated at 1.2 percent, compared with 22 percent in patients on chronic transfusion for secondary prophylaxis.

A 2022 review of patients with SCD who underwent HSCT revealed that of 159 patients who had brain imaging after transplantation, 3.8 percent had a progressive SCI and 4.4 percent had a new overt cerebral infarct [104].

In a 2019 trial of 67 children with abnormal TCD velocities who were assigned to chronic transfusion therapy or HSCT based on availability of a matched sibling donor, HSCT was associated with lower TCD velocities than chronic transfusion therapy (129.4 cm/s vs. 169.3 cm/s) as well as with lower incidence of SCIs at one year of follow-up [85]. In an extension study of this cohort, HSCT in stroke-free children with abnormal TCDs and vascular stenosis was also associated with greater improvement in stenosis scores relative to chronic transfusion therapy [105].

Importantly, though, none of these studies directly compared the safety and efficacy of HSCT to chronic transfusion therapy for patients with prior stroke, making a direct comparison between the two treatment modalities impossible.

The applicability of HSCT is limited by the availability of matched related donors, the ability of the recipient to tolerate the preparative regimen for transplantation, and the small but real possibility of transplant-related morbidity and mortality. The determination of HSCT eligibility, donor selection, and risk-benefit analysis in SCD are discussed in detail separately. (See "Curative therapies in sickle cell disease including hematopoietic stem cell transplantation and gene therapy".)

Hydroxyurea is inferior to chronic transfusion therapy in secondary stroke prophylaxis. It may, however, offer some protection in patients who are unable to continue chronic transfusions and do not have access to HSCT. (See 'Hydroxyurea in primary stroke prevention' above.)

Antiplatelet therapy — There is no evidence to support any form of antiplatelet therapy as monotherapy or in combination with regular blood transfusion, hydroxyurea, or both in SCD. Antiplatelet therapy such as aspirin is a mainstay of secondary ischemic stroke prevention in children and adults without SCD, and may be included as a component of secondary prevention in patients with SCD who have had a prior ischemic stroke [106]. (See "Long-term antithrombotic therapy for the secondary prevention of ischemic stroke" and "Ischemic stroke in children: Management and prognosis".)

Individuals with silent cerebral infarctions — SCI are infarctions identified only by neuroimaging with no accompanying clinical history of stroke or TIA. They are not truly silent because they are likely to contribute to neuropsychologic deficits in individuals with SCD. (See 'Definitions' above and 'Management of cognitive and behavioral dysfunction' below.)

In 2020, ASH recommended screening for SCI in children and adults with SCD who have Hb SS or Hb S-beta0-thalassemia [58]. Specifically, the ASH guideline panel suggests at least a one-time MRI screening without sedation to detect SCI in early school-aged children and again in young adults [58]. This recommendation was based on the high prevalence of SCI (figure 4) and the high incidence of infarct recurrence (overt stroke or SCI) in children and adults [107].

Results from the SIT trial, as discussed above, suggest that a chronic transfusion program in patients found to have SCIs can reduce the risk of stroke, the progression of SCIs, and the development of new SCI lesions. (See 'Evidence for chronic transfusion' above.)

Studies in adults are not available to guide SCI management. Until further data are forthcoming, treatment should be individualized to the patient's circumstances and risk factors. (See 'Evidence for chronic transfusion' above.)

It is reasonable to perform cognitive testing in patients with SCI to evaluate the clinical impact of the lesions and the need for other educational or rehabilitative interventions. (See "Developmental-behavioral surveillance and screening in primary care".)

Revascularization procedures for moyamoya syndrome — Some individuals with SCD develop moyamoya syndrome, characterized by unilateral or bilateral stenosis or occlusion of the arteries around the circle of Willis, with prominent arterial collateral circulation. The clinical manifestations of moyamoya include transient ischemic attack, ischemic infarction, and rarely, intracerebral hemorrhage. (See "Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis".)

Small observational studies suggest that revascularization surgery can be beneficial in reducing the risk of subsequent stroke [108-116]. Some examples are:

In a retrospective study of 14 pediatric patients with SCD and moyamoya syndrome on chronic transfusion therapy, the rate of stroke prior to revascularization procedures was 1 per 7.8 patient-years compared with 1 per 39.3 patient-years after revascularization [115].

In a retrospective cohort study of 29 patients with SCD and moyamoya syndrome, the calculated stroke rates were 1 per 5.37 patient years in those who received chronic transfusion therapy alone, compared with 1 per 23.14 patient-years in those who underwent revascularization procedures [116].

The 2020 ASH guidelines for cerebrovascular complications of SCD reviewed all of the available literature concerning revascularization procedures and SCD [58]. The panel was unable to pool published studies due to the heterogeneity of the five different neurosurgery procedures (pial synangiosis, encephalo-duro-arterio-myo-synangiosis, encephalo-duro-arterio-synangiosis, encephalo-myo-arterio-synangiosis, multiple burr holes), and the absence of rigorous postoperative assessment with prospective evaluation of neurologic outcomes, including assessment of the brain for new cerebral lesions or neurologic assessment (surveillance of MRI of the brain and neurology assessment for infarct recurrence). Additionally, a review of the one-month postoperative period revealed a high rate of events associated with ischemic injury of the brain.

Ultimately, the ASH committee recommended that patients with moyamoya disease and a history of stroke or TIA be evaluated by a multidisciplinary team for revascularization surgery in addition to regular blood transfusions, albeit as a conditional recommendation with low certainty in evidence about effect [58]. Ideally, individuals who are treated surgically should do so as part of a regional or national protocol that allows for systemic collection of data and ongoing assessment of the risks and benefits.

Additional details of the evaluation and management of moyamoya syndrome are presented separately. (See "Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis" and "Moyamoya disease and moyamoya syndrome: Treatment and prognosis".)

PREVENTION OF HEMORRHAGIC STROKES — There is very little evidence for effective primary or secondary prophylaxis of hemorrhagic strokes in patients with SCD, other than those established for the general population. The potential benefits of chronic transfusion or hydroxyurea therapy have not been established, but either would be a reasonable option, especially if there is evidence of significant cerebral vasculopathy. (See 'Prevention of recurrent ischemic stroke (secondary stroke prophylaxis)' above.)

Management of unruptured brain aneurysms in individuals with SCD, including criteria for intervention, should generally follow the approaches in individuals without SCD, which is presented separately. (See "Unruptured intracranial aneurysms".)

There is a high rate of cerebral aneurysms in adults with SCA (approximately 9 to 10 percent) compared with the general population (approximately 3 percent), and the incidence of hemorrhagic stroke in SCD increases with age [16,33,117-120]. This suggests that obtaining a single noncontrast magnetic resonance angiography (MRA) of the head in young adulthood to screen for aneurysms is reasonable [120]. However, the clinical history of aneurysm in adults with SCD is poorly defined. Thus, even when aneurysms are identified, consultation with a neurosurgeon is encouraged to determine individualized management. The time interval for any follow-up screening is unknown and should be individualized.

MANAGEMENT OF COGNITIVE AND BEHAVIORAL DYSFUNCTION — Although numerous studies have been performed, drawing conclusions from cognitive and behavioral evaluations of children with SCD has been difficult. Limitations include challenges related to controlling for socioeconomic and other variables and limitations of available testing for subtle deficits in intelligence, attention, and other behavioral complications of stroke and silent cerebral infarct (SCI) [121-126].

The impact of stroke and SCI on intelligence quotient (IQ) in children with SCD was addressed in a 2016 meta-analysis [127]. This found that children with a prior stroke had a mean IQ score 10 points lower than those with SCIs, while children with SCIs had a mean IQ score 6 points lower than those with no detectable abnormalities on magnetic resonance imaging (MRI). Importantly, children with SCD and normal MRIs also had IQ scores significantly lower than healthy controls, indicating that other biological and environmental factors contribute to neuropsychological impairment in SCD.

Prior to this, the impact of stroke on cognitive and behavioral function was illustrated in the Cooperative Study of Sickle Cell Disease (CSSCD), which evaluated 135 children with SCD using MRI and neuropsychologic testing [40]. On most measures of neuropsychologic evaluation, children with a history of stroke had significantly worse performance compared with children with normal MRIs or SCI alone (without overt stroke). In turn, children with SCI alone had worse performance on tests of mathematics, vocabulary, and visual-motor speed and coordination than children with no MRI abnormalities. Other studies have reported similar findings [128]. The location of the infarct is the primary determinant of neuropsychologic impairment [128-131].

Additional data on SCI were reported in the SIT trial, which randomly assigned children with SCI to transfusions or observation. Testing of full-scale IQ in 150 children in the trial showed that SCI was associated with a 5.2 point decrease in IQ, a reduction similar to that seen with absence of college education for the head of household in the same population [132].

The 2020 American Society of Hematology (ASH) guidelines for cerebrovascular complications of SCD recommend screening by a pediatrician with validated tool or referral for formal screening by a psychologist if there are concerns about developmental delays in preschool-age children or concerns about neurodevelopmental disorders in school-age children with SCD, including academic or behavioral problems, or symptoms of inattention, hyperactivity, or impulsivity [58]. For adults with SCD, the ASH guideline panel recommended surveillance for cognitive impairment and formal referral to a psychologist for a more in-depth cognitive evaluation if concerns are identified.

Regardless of whether there is a history of stroke or SCI, all individuals with neurocognitive and/or behavioral dysfunction should receive a cognitive and medical evaluation to diagnose any related disorders and to identify modifiable risk factors for cognitive impairments [58]. Those with impaired cognition should be offered age-appropriate educational resources, and the cognitive domain-specific evidence-based guidelines for these conditions should be followed to provide appropriate interventions such as cognitive rehabilitation. (See "Specific learning disorders in children: Educational management".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Sickle cell disease and thalassemias" and "Society guideline links: Stroke in children".)

PATIENT PERSPECTIVE TOPIC — Patient perspectives are provided for selected disorders to help clinicians better understand the patient experience and patient concerns. These narratives may offer insights into patient values and preferences not included in other UpToDate topics. (See "Patient perspective: Sickle cell disease".)

SUMMARY AND RECOMMENDATIONS

Scope – Individuals with sickle cell disease (SCD), especially those with Hb SS or Hb S-beta0-thalassemia, are at risk of ischemic and hemorrhagic stroke and silent cerebral infarct (SCI). Up to one-fourth of individuals may have a stroke by adulthood, and SCI may affect a greater proportion at an earlier age (figure 4). Patients who have experienced a first stroke or who have significant cerebral vasculopathy (grade ≥4) are at high risk of recurrent stroke or progressive vasculopathy. (See 'Definitions' above and 'Pathophysiology and risk factors' above and 'Incidence' above.)

Screening

Ischemic stroke risk – Children with Hb SS or Hb S-beta0-thalassemia should be screened from ages 2 to 16 using transcranial Doppler (TCD), with the frequency of screening determined by TCD velocities. Children with abnormal TCD results and those with neurocognitive or other neurologic deficits should be evaluated by magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA). Formal evidence to support screening in other types of SCD is lacking. (See 'Risk assessment for first stroke' above.)

SCI and vasculopathy – Early school-age children should have at least one screening brain MRI to assess for SCI, when MRI can be completed without sedation. Screening should be repeated in young adulthood. MRA (noncontrast) during young adulthood at the time of MRI may be used to screen for vasculopathy such as moyamoya arteriopathy or aneurysms. (See 'MRI screening for silent infarcts' above and 'MRA screening (noncontrast) in young adulthood' above.)

Neurocognitive deficits – All patients being treated for primary or secondary stroke prophylaxis, transient ischemic attack (TIA), and SCI should be screened for neurocognitive deficits and behavioral dysfunction. Those with concerns for such problems should undergo formal neuropsychological testing to diagnose any related disorders and to identify modifiable cognitive impairments.

Hemorrhagic stroke risk – Hemorrhagic stroke increases in frequency with age and has a high degree of associated morbidity and mortality. Few proven screening and preventive measures exist. MRA screening for aneurysms can be done in early adulthood, with neurosurgical consultation if aneurysms are found.

Primary stroke prophylaxis – TCD velocity ≥200 cm/sec is associated with ischemic stroke in up to 40 percent of children. Chronic transfusion can lower risk substantially (to as low as 2 percent per 20-month period). For children at increased risk of a first ischemic stroke based on two TCD velocity measurements ≥200 cm/sec within a one- to two-week period, we recommend chronic transfusion therapy rather than no treatment (Grade 1A). (See 'Prevention of a first ischemic stroke (primary stroke prophylaxis)' above.)

Limited data suggest that hydroxyurea therapy without prior chronic transfusion can be effective for primary stroke prophylaxis. However, given the limitations of hydroxyurea therapy, the likely superiority of chronic transfusion therapy for prophylaxis, and the devastating effects of stroke, up-front hydroxyurea for stroke prevention should be limited to situations in which chronic transfusion therapy is not feasible. Hydroxyurea has many other indications in SCD, as discussed separately. (See "Hydroxyurea use in sickle cell disease", section on 'Indications and evidence for efficacy'.)

Technical aspects of a regular transfusion program are discussed in detail separately. (See "Red blood cell transfusion in sickle cell disease: Indications and transfusion techniques".)

No supporting data exist for voxelotor, crizanlizumab, or L-glutamine in primary or secondary stroke prophylaxis.

Transition to hydroxyurea for primary stroke prophylaxis – Some patients at increased risk for a first ischemic stroke may safely transition to hydroxyurea after a period of chronic transfusion. For children who meet criteria as detailed above, we suggest transition to hydroxyurea after one or more years of chronic transfusion (Grade 2C). Close monitoring of TCD velocities, MRA, and assessment of hematologic response to hydroxyurea are required (table 2). (See 'Chronic transfusion followed by transition to hydroxyurea' above.)

Secondary stroke prophylaxis – For children who have had an ischemic stroke or severe (grade ≥4) cerebral vasculopathy, we recommend indefinite chronic transfusions (Grade 1B). Children with matched related donors who have had an ischemic stroke should also be evaluated for hematopoietic stem cell transplantation (HSCT). Transition to hydroxyurea was demonstrated to be inferior to continued chronic transfusions for secondary stroke prophylaxis and should not be undertaken unless absolutely necessary. Surgical revascularization procedures have not been rigorously tested. (See 'Prevention of recurrent ischemic stroke (secondary stroke prophylaxis)' above.)

Individuals who cannot receive transfusions – Some children who qualify for chronic transfusion for primary or secondary stroke prophylaxis may not have access to, or may not be able to tolerate, this therapy. For these children, we suggest hydroxyurea rather than no treatment (Grade 2B). (See 'Alternatives for primary prophylaxis in special populations' above and 'Alternatives for secondary prophylaxis in special populations' above.)

Acute stroke management – (See "Acute stroke (ischemic and hemorrhagic) in children and adults with sickle cell disease".)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges extensive contributions of Donald H Mahoney, Jr, MD to earlier versions of this topic review.

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Topic 106228 Version 27.0

References

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