Curr Neurol Neurosci Rep (2016) 16:27 DOI 10.1007/s11910-016-0622-0
STROKE (HP ADAMS, SECTION EDITOR)
Sickle Cell Disease and Stroke: Diagnosis and Management Courtney Lawrence 1 & Jennifer Webb 1
# Springer Science+Business Media New York 2016
Abstract Both adult and pediatric patients with sickle cell disease face a higher risk of stroke than the general population. Given the different underlying pathophysiology predisposing these patients to stroke, providers should be aware of differences in guidelines for stroke management. This paper reviews diagnostic considerations and recommendations during the evaluation and acute management of patients with sickle cell disease presenting with stroke, focusing on recent updates in the literature. Given the high recurrence rate of stroke in these patients, secondary prevention and curative measures will also be reviewed. Keywords Sickle cell disease . SCD . Stroke . Cerebrovascular accident . CVA
Introduction Strokes are a significant cause of morbidity and mortality in patients with sickle cell disease (SCD). The Cooperative Study of Sickle Cell Disease (CSSCD) is the largest longitudinal study of patients with SCD, observing a cohort of more This article is part of the Topical Collection on Stroke A special thank you to Dr. John Brust for taking the time to review this article. * Jennifer Webb
[email protected] Courtney Lawrence
[email protected]
1
Children’s National Medical Center, The George Washington School of Medicine and Health Sciences, 111 Michigan Ave. NW, Washington, DC 20010, USA
than 4000 adults and children. The CSSCD found an overall stroke prevalence of 3.75 % [1]. Stroke incidence varies significantly between the different sickle cell genotypes, with the highest frequency in those with the homozygous hemoglobin (Hgb) SS genotype [1, 2]. Stroke incidence further varies by age and type of stroke. The CSSCD study showed the highest incidence of ischemic stroke in Hgb SS patients aged 2 to 9 years, with a second peak after the age of 30 years [1]. In contrast, the incidence of hemorrhagic stroke peaked at ages 20 to 29 years and very rarely occurred in children or adults outside of this age range [1]. While these early studies suggested a predisposition to stroke in early childhood, a retrospective database review of patients with SCD from California showed that the overall highest incidence of ischemic stroke was in middle-aged adults ages 35 to 64 years and elderly adults ages 65 years and older, with stroke risk being threefold higher in middle-aged patients with SCD than in the general African American population [3]. Nevertheless, the burden of stroke in the pediatric sickle cell population has been wellstudied [4–7]. Importantly, the CSSCD study showed an overall 14 % recurrence rate of stroke in Hgb SS patients with a much higher rate in those who had an initial cerebrovascular accident (CVA) at less than 20 years of age [1]. Patients with Hgb SS disease are calculated to have a 24 % chance of stroke by 45 years of age [1]. More common than overt stroke in SCD is a cerebral infarction without focal neurologic deficit by exam or history, also known as silent cerebral infarct (SCI) or silent stroke. SCI occurs in over one quarter of children with homozygous Hgb SS disease by the age of 6 years [8]. SCI is associated with worse neuropsychological functioning and poorer education attainment in patients with SCD [9–11]. SCI is also a risk factor for overt stroke in SCD [12–14], as are history of prior transient ischemic attacks (TIA), low steady-state Hgb, recent acute chest syndrome, elevated systolic blood pressure, and
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abnormally elevated mean cerebral arterial flow velocities on transcranial Doppler (TCD) [1, 15, 16]. Based on evidence from a sibling study, there is also a familial or genetic predisposition to ischemic stroke in SCD [17]. Risk factors for hemorrhagic stroke, in contrast, have little overlap with the risk factors for ischemic stroke in patients with SCD. Risk factors for hemorrhagic stroke include low steady-state Hgb and high leukocyte count [1] as well as association with reported history of hypertension, recent corticosteroid or NSAID use, recent transfusion, and increased hospitalizations for painful vasooclusive crises [18].
Diagnosis Signs and symptoms of stroke in patients with SCD are similar to signs and symptoms seen in patients without SCD; however, subtle presentations can be missed initially, particularly in the pediatric population where stroke is less frequently encountered. Symptoms may include vision changes, focal neurologic deficits, or language difficulties. Adult patients with SCD have a high prevalence of aneurysms in the posterior circulation [19], so providers should be wary of signs suggestive of stroke in this location, such as dizziness, vertigo, vision changes, and tinnitus. The initial diagnosis may also be delayed by the broad differential of conditions with similar symptomatology that are more frequently seen in patients with SCD. Headaches and migraines are common neurologic complaints of patients with SCD. While studies have failed to demonstrate an association between recurrent headaches and silent cerebral infarcts or overt stroke in pediatric patients with SCD without stroke history [20, 21], one study demonstrated a ten times greater likelihood of acute central nervous system (CNS) events in pediatric patients with SCD presenting for acute hospital care for headache than in their non-sickle cell counterparts [22]. There also appears to be an association between recurrent, severe headache with elevated mean cerebral arterial flow velocities on TCD in adult patients with SCD [23], suggesting vascular reactivity as a potential contributing factor that could portend serious neurologic events. Therefore, urgent imaging is warranted for new onset of severe headache or headache in the presence of accompanying neurologic signs or symptoms. One study noted that the most common CNS event occurring in the context of severe headache in adolescent patients with SCD was cerebral sinus venous thrombosis (CSVT) [22], which may present with headache, emesis, and cranial nerve deficits. SCD has been associated with hypercoagulability with multiple contributing underlying factors, including increased platelet activation and thrombocytosis, procoaguable changes in circulating proteins, endothelial activation, and nitric oxide scavenging from hemolysis [24–26]. The incidence of CSVT is not known but likely underestimated given its
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more subtle early presentation and the need for neuroimaging for diagnosis. Given that untreated CSVT can lead to stroke, diagnosis is important and anticoagulation therapy should be strongly considered. Seizures are also more common in patients with SCD [27, 28]. While a thorough history may help differentiate Todd’s paralysis from stroke, further neuroimaging should be obtained even in this scenario as seizure may be indicative of prior ischemic damage or evolving neurologic injury from underlying vasculopathy. Posterior reversible encephalopathy (PRES) is a rare complication involving reversible white matter edematous changes commonly in the occipital and parietal regions, and has been reported as both a singular and recurrent event in patients with SCD [29–32]. The underlying impaired cerebral autoregulation associated with SCD may predispose patients to PRES, particularly if combined with other risk factors for PRES such as elevated blood pressures, immunosuppressive therapy, and hematopoietic stem cell transplantation [33, 34]. Both hematology and neurology services should be consulted for guidance in the acute management of stroke in patients with SCD. Laboratory assessment should include a complete blood count with reticulocyte count, a type and screen, and a quantitative Hgb S measurement in preparation for potential simple and/or exchange transfusion. A basic metabolic panel with ionized calcium should be sent as electrolyte imbalances can be worsened or precipitated particularly during exchange transfusion. Furthermore, hyponatremia has been associated with poorer outcomes in stroke and may provide prognostic data [35]. Blood glucose levels should be checked initially and with high frequency in early management given the potential relationship of both hypoglycemia and hyperglycemia with worse clinical outcomes [36]. Coagulation studies, including PT, PTT, INR, and fibrinogen, should be sent to assess risk for hemorrhagic complications. For ischemic stroke, a comprehensive hypercoagulability workup to assess for additional thrombosis risk factors should be performed as it may guide therapeutic decision-making. Given an increased risk of encapsulated bacteremia in patients with SCD secondary to impaired splenic function, particularly in those under 5 years of age who have not been fully immunized against Streptococcus pneumoniae [37], lumbar puncture should be considered if patients present with fever along with neurologic signs and symptoms. All patients with SCD with fever or other signs of sepsis should have a blood culture obtained and should be treated empirically with antibiotics during the initial 24–48 h. The American Stroke Association recommends antipyretics for fever control as hyperthermia has been associated with worse outcomes in ischemic and hemorrhagic stroke [38, 39]; however, the clinical benefits of pharmacologic and other cooling maneuvers have not been demonstrated in large patient trials [40]. Magnetic resonance imaging (MRI) with diffusionweighted imaging is the preferred modality for assessment
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of ischemic stroke given its sensitivity to early ischemic changes [41]. CT scan without contrast may be the initial choice to quickly assess for hemorrhage, particularly if MRI must be delayed for a medically unstable patient. A magnetic resonance venogram (MRV) is also initially recommended to assess for CSVT, as anticoagulation may be warranted to prevent progression toward CVA. Magnetic resonance angiography (MRA) to evaluate for underlying stenosis in ischemic stroke or aneurysm in hemorrhagic stroke can be done at this time or soon after the acute period, as this may determine utilization of other therapeutic interventions. If MRA is not available, CT angiography (CTA) of the head and neck can be performed.
Acute Management The primary strategies for treatment of stroke in patients with SCD rely on early recognition, prompt diagnostic imaging, and supportive care. Patients with SCD should have supplemental oxygen supplied to maintain their peripheral capillary oxygen saturation ≥95 % because deoxygenation contributes to increased sickling and hyperviscosity [42]. Intravenous fluids should be provided to achieve a euvolemic state if dehydration is suspected, with caution given to not overhydrate the patient with hypotonic fluids as this may precipitate pulmonary edema and acute chest syndrome [43]. Additional supportive interventions deemed appropriate for patients without SCD are also applicable in the patient population with SCD, including NPO status, blood pressure monitoring with current guidelines suggesting permissive hypertension in the initial period to maintain cerebral perfusion [44], and monitoring of electrolytes to maintain euglycemia and avoid hyponatremia as previously mentioned. Soft recommendations for head-of-bed positioning between 0° and 15° to optimize maintenance of cerebral blood flow in acute ischemic stroke [45] and elevation of the head of the bed to 30° to lower intracranial pressure for patients with intracranial hemorrhage [46] can also be followed, understanding that their effect on clinical outcomes has not been well-demonstrated. Other intensive care measures for acute stroke management may be considered, including neurosurgical consultation for intracranial pressure monitoring, surgical decompression or drain placement, central venous pressure and arterial blood pressure monitoring, or cerebral perfusion monitoring. Continuous EEG is also recommended until recovery of normal mental status to monitor for seizures and allow for prompt pharmacologic intervention. Most stroke patients require initial monitoring in the intensive care unit for frequent neurologic assessments. The use of thrombolytic therapy has not been well-studied in patients with SCD and is isolated to few case reports for acute ischemic stroke and CSVT [47, 48]. There have been
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case reports of pediatric patients without SCD undergoing mechanical and pharmacologic thrombolysis for stroke without significant complications [49]. However, randomized controlled trials evaluating the benefit of use of thrombolytic therapy in pediatric patients are necessary prior to making recommendations for use in this population. Nevertheless, there is no clear evidence against using thrombolysis in adult patients with SCD, and thrombolysis may be considered for adult patients by experienced providers if no other contraindications are present [38]. While the benefit of red blood cell (RBC) transfusion in primary and secondary stroke prevention has been welldemonstrated in large scale randomized clinical trials [16, 50, 51, 52••], the role of transfusions in acute stroke management is less clear. By decreasing Hgb S concentration and maximizing oxygen delivery through non-sickle RBCs, transfusion is thought to decrease vaso-occlusion, thus improving tissue perfusion and decreasing ischemic damage during stroke. A goal post-transfusion hemoglobin of 10 g/dL has been recommended for patients with SCD, above which in vitro studies suggested venous partial pressure of oxygen actually decreases secondary to increased blood viscosity [53, 54]. Likely due to the rigidity of sickle RBCs, Hgb S percentage has also been shown to positively correlate with hyperviscosity independent of the total Hgb [54]. Interestingly, cerebral blood flow also increases with increasing Hgb S percentage when total Hgb is constant [55]. This suggests that a higher Hgb S fraction may lead to vasodilatory hyperemia in patients with SCD who have impaired vasodilatory capacity of their cerebral vasculature [56]. Early rheology studies of Hgb S RBCs in vitro demonstrated increased viscosity even under low shear forces at Hgb S percent greater than 40 % [57]. As a result, transfusion to achieve Hgb S percentage of less than 30 % is recommended in the setting of acute stroke. For most patients with SCD, simple transfusion to the goal hemoglobin does not allow for a large enough packed RBC volume to sufficiently decrease the Hgb S percentage, so exchange transfusion is recommended [58•]. Exchange transfusion may be performed manually or via automated erythrocytapheresis. In a retrospective cohort analysis, exchange transfusion (manually or automated) performed at the time of the first stroke decreased by fivefold the risk of recurrent stroke in pediatric patients with SCD who presented within 24 h of symptom onset [59]. Limited data has shown that automated exchange apheresis more consistently achieves transfusion goals compared to manual exchange; however, adverse events have been comparably low in both groups [60]. Automated exchange does require more hospital resources, such as stable vascular access and availability of the machine and technician; however, longer procedural time and the more direct labor-intensive component of manual exchange are also limiting factors. One study using computerassisted intravital microscopy (CAIM) to analyze
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microvasculature of pediatric patients with SCD in real time pre- and post-exchange transfusion demonstrated improvement of vaso-oclusion with enhancement of capillaries and arterioles that could not be well-visualized pre-transfusion. Somewhat unexpected, however, was the small, nonsignificant decrease in RBC velocity after exchange transfusion rather than the anticipated increase, perhaps secondary to increased blood viscosity post-transfusion [61]. This suggests that transfusion alone likely does not eliminate all factors leading to increased stroke risk. In general, up front exchange transfusion (manual or automated) is recommended in the setting of acute stroke. However, simple transfusion may be undertaken as a temporizing measure for clinically unstable patients, or if significant anemia requires urgent transfusion prior to further invasive procedures. Once patients are stabilized, an electrocardiogram and echocardiogram with bubble study are recommended for patients with SCD and acute ischemic stroke to assess for arrhythmias, cardiac thrombus, and for an atrial-level communication. A prospective cohort study of 29 adults and 26 children with SCD and first-time ischemic stroke showed that underlying cardioembolism and cardiopathies such as patent foramen ovale (PFO), systolic dysfunction, and atrial fibrillation were the likely etiology in 24 % of the adult patients. While cerebral vasculopathy was the attributed cause of ischemic stroke in 92 % of the pediatric patients, it was the attributed cause in only 41 % of the adults, suggesting a wider range of etiologies of ischemic stroke in adult patients [62]. Furthermore, cardioembolism was described as the etiology in four out of nine stroke recurrences in the adults [62]. Pediatric patients with stroke and SCD have also been shown to have an increased incidence of PFO when compared to those without SCD [63]. As suggested in general ischemic stroke guidelines [38], anticoagulation should be considered in patients with a cardioembolic source if intracranial hemorrhage has been excluded and if infarcted territory is small enough to make hemorrhagic transformation a lesser concern. Continuous infusions of heparin are often the preferred choice in the initial 24 to 48 h post-stroke for reversibility in the event of hemorrhagic evolution or imminent surgical intervention. Heparin is of unclear benefit in the acute management of SCD-related stroke if no cardioembolic source is identified.
Chronic Management (Secondary Prevention) Chronic transfusion therapy after initial stroke is the mainstay of secondary stroke prevention [58•]. Early studies indicated a marked reduction in stroke recurrence in pediatric patients with SCD and a history of ischemic stroke after they were placed on chronic partial exchange transfusions [64, 65]. These studies and subsequent trials [16, 50] aimed to maintain a goal Hgb S ≤ 30 % with transfusions at 3–4 week intervals,
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and this remains the general recommendation for the treatment of patients with SCD after an ischemic stroke [58•]. A small cohort study by Cohen et al. [66] suggests that liberalizing the transfusion goal to a maintenance of Hgb S ≤50 % for patients who have had no stroke recurrence after several years on more conservative transfusion therapy may allow for similarly good neurologic outcomes with decreased blood product requirements and decreased rate of iron loading. Chronic transfusion therapy has been demonstrated to be of such significant benefit in the prevention of recurrent strokes that it was studied as a primary prevention strategy. The first Stroke Prevention Study in Sickle Cell Anemia (STOP) trial demonstrated a 92 % risk reduction in initial stroke in pediatric patients with abnormal screening transcranial Doppler ultrasounds (TCD) [16]. Elevated TCD velocities have been shown to be predictive of stroke in patients with SCD as a marker for early stenotic lesions and vasculopathy [67]. The follow-up STOP 2 trial showed that discontinuation of transfusion therapy after a minimum of 30 months of therapy resulted in conversion of normalized time-averaged mean velocity on TCD back to abnormal values along with increased silent and overt strokes [50]. The recently completed Silent Infarct Transfusion (SIT) trial demonstrated that chronic transfusion decreased rates of overt strokes in patients with normal TCDs who had MRI lesions consistent with silent infarct [52••]. However, chronic transfusion therapy as both a primary and secondary stroke prevention strategy is not without risks, including alloimmunization, transfusion transmitted infection, and iron overload. Iron overload can be mitigated by chelation therapy or by utilizing manual or automated exchange transfusion instead of simple transfusions [68–70]. Alloimmunization risks can be decreased by matching RBCs for the common immunogenic antigens (C, E, and K) which are generally recommended for the SCD population or through donor limitation strategies [71]. Given the risks and challenges of chronic transfusion therapy, particularly in resource-poor nations, patients and providers have looked toward alternatives for primary and secondary stroke prevention in patients with SCD. The drug hydroxyurea (HU) appears to yield its benefit through multiple mechanisms, most notably through inducing the preferential expression of fetal Hgb over Hgb S and increasing the production of RBCs less prone to sickling and hemolysis. HU has been shown to decrease other SCD-related complications in adult and pediatric patients, including acute chest syndrome and recurrent vaso-oclusive pain events [72, 73, 74••]. Results from the Pediatric Hydroxyurea Phase 3 Clinical Trial (BABY HUG), a randomized controlled clinical trial of HU initiation in 9 to 18-month-old patients with SCD, demonstrated that young patients treated with HU had a decreased rate of rise in their TCD velocities while on therapy [75]. Other smaller studies of older pediatric patients with SCD have similarly
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shown decrease in TCD velocity in those on HU therapy [76–78], including a recent randomized phase III trial which was terminated early due to slow accrual of patients [79]. Despite promising data demonstrating the effect of HU in decreasing TCD velocity and other complications of SCD, there remains limited data in examining the role of HU as a sole therapy for primary or secondary stroke prevention. The Stroke With Transfusions Changing to Hydroxyurea (SWiTCH) trial, designed to demonstrate non-inferiority of HU with phlebotomy compared to chronic transfusion, ended early due to failure to achieve the primary combined outcome allowing for increased stroke events with improved iron overload. There were 7 overt strokes (6 ischemic, 1 fatal hemorrhagic) in the 67 patients switched to the HU and phlebotomy arm and 0 overt strokes in the 66 patients continued on chronic transfusion. Of note, when transient ischemic attacks (TIA) were included as neurologic events, there was no significant difference between the two arms [51]. The recently published TCD with Transfusions Changing to Hydroxyurea (TWiTCH) study demonstrated the non-inferiority of HU as a primary stroke prevention strategy in those patients with abnormal TCDs who had received several years of transfusion therapy as demonstrated by equivalent TCD velocities between both the HU and the transfusion arms of the study [80]. The most recent expert panel guidelines for patients with SCD published in JAMA in 2014 recommends the initiation of HU as adjunctive therapy to chronic transfusion therapy or for patients who are unable to be started on transfusion therapy [58•]; however, with the recently published TWiTCH study, these recommendations will likely be updated. Anticoagulation therapy has been debated as a potential strategy in further stroke prevention in patients with SCD. In the general adult population, aspirin therapy has been proven effective in the prevention of secondary ischemic stroke [81] and has not been shown to increase the risk of hemorrhagic stroke [81, 82]. Furthermore, studies have recently suggested that aspirin therapy may be protective against intracranial hemorrhage in adult patients with known cerebral aneurysms, possibly due to the inhibition of inflammatory mediators thought to contribute to aneurysmal growth and rupture [83, 84]. This suggests relative safety and likely efficacy in the patient with SCD without current or previous hemorrhagic stroke, though studies are lacking in this population. Aspirin use in stroke prevention for pediatric patients is less well-studied, although non-randomized studies suggest no complications and a potential trend for fewer recurrent events when compared to no therapy [85, 86]. A recent review article by Charnesky and Congdon reviewed the limited studies analyzing the use of antiplatelet and anticoagulant medication in SCD [87]. The highlighted studies involving aspirin
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administration in pediatric and young adult patients with SCD only evaluated pain crises as the clinical measure of vaso-oclusion and did not show benefit over placebo; furthermore, adverse events were not addressed. However, one recent retrospective study showed no significant difference in overall and event-free survival curves for 31 pediatric patients with SCD followed after initial stroke on adjunctive aspirin therapy versus those on standard therapies [88], suggesting overall safety of aspirin therapy in this population. Given the potential association of aspirin use in febrile illness with Reye Syndrome [89], the risk-to-benefit ratio must be considered, and pediatric patients on aspirin therapy should receive all immunizations including the annual influenza vaccine [90]. Of note, recommendations by the American Heart Association Stroke Council have indicated that aspirin is a reasonable therapy for patients with risk of cardioembolism, patients with moyamoya syndrome or disease, and even those without known increased risk for recurrent embolism; however, they did not extend this recommendation to include patients with SCD [90]. There have been no large trials looking at the use of anticoagulants for secondary prevention of strokes in patients with SCD. Though other vaso-occlusive complications of SCD may be improved with low-molecular-weight heparin [91] via the inhibitory effect of heparin on erythrocyte adhesion to P-selectin [92], the role of low-molecular-weight heparin in secondary stroke prevention remains unclear. Trials of the use of vitamin K antagonists in the population with SCD are too limited to draw meaningful conclusions in regards to their safety and efficacy for the prevention or treatment of stroke or other vaso-occlusive complications. Despite optimal transfusion, over 20 % of patients with SCD and a history of stroke will have a recurrent stroke while on chronic transfusion therapy [93]. Thirty to forty-three percent of patients with SCD and a history of stroke have been found to have moyamoya syndrome (MMS) on MRA or standard cerebral angiography [94, 95•]. MMS refers to stenosis of larger intracranial arteries that lead to the development of capillary collaterals that yield a characteristic Bpuff of smoke^ appearance on angiographic imaging, and it can be either a primary idiopathic condition (referred to as moyamoya disease or MMD) or secondary to other etiologies such as SCD. Patients with both SCD and MMS appear to be at higher risk for recurrent stroke while on chronic transfusion therapy than those without MMS [96], further supporting the recommendation to obtain MRA imaging in patients with SCD and a history of stroke. Surgical strategies for revascularization should be considered for patients with SCD and a history of stroke who are found to have MMS. Direct bypass techniques where the superficial temporal artery (or, less commonly, the occipital or middle meningeal artery) is anastomosed to the middle cerebral artery allow for immediate reperfusion of the brain, but
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these techniques are more invasive and complicated in younger children with smaller arteries. Indirect revascularization techniques that primarily aim at stimulating angiogenesis in under-perfused areas have increasingly gained popularity and can involve one or a combination of several techniques. Encephaloduroarteriosynangiosis (EDAS) is the most commonly utilized indirect technique. EDAS involves transpositioning the superficial temporal artery directly onto the cortical surface, suturing the vessel to the opened dura mater or pia (called pial synangiosis) and ultimately promoting transdural spontaneous anastomoses between cortical and scalp vasculature. Other techniques such as encephalomyosynangiosis (EM), omental transposition, and encephalogaleo(periosteal)synangiosis (EGS or EGPS), similarly involve the application of vascular tissue onto the cortex, allowing for neovascular collateralization [97, 98]. A recent study followed a cohort of 14 pediatric patients with SCD on chronic transfusion therapy for previous stroke or elevated TCD velocities who underwent indirect revascularization for MMS and were continued on chronic transfusion therapy. The study showed a fivefold reduction rate of both first-time and recurrent strokes in the 34 month follow-up period of these patients post-procedure when compared to the prior rate while on chronic transfusion therapy alone [95•]. Another review of indirect revascularization performed in a combined cohort of 30 pediatric patients with SCD demonstrated similar efficacy [98]. The role of revascularization surgery has not been wellstudied in adults with SCD and MMS and may be of less benefit given diminished angiogenic capability with age [97]. However, further studies are needed. The only curative treatment for SCD is an allogeneic hematopoietic stem cell transplant (HSCT). The first HSCT in a patient with SCD was performed in 1984 with a HLAmatched sibling donor (MSD) [99]. Currently, overall survival ranges from 91 to 100 % with event-free survival ranging from 73 to 100 % for patients with SCD undergoing MSD HSCT with myeloablative conditioning (MAC) [100•]. After noting increased neurologic complications for patients with SCD in the peri-transplant period [101], most commonly seizures and intracranial hemorrhage, preventative strategies have been incorporated into most supportive care protocols for SCD HSCTs. These measures include exchange transfusion to achieve Hgb S ≤ 30 % prior to transplant, anticonvulsant prophylaxis while on immunomodulating therapy, frequent correction of magnesium deficiency, maintenance of strict blood pressure parameters, and transfusion parameters of a goal Hgb of 9– 11 g/dL and platelet count ≥ 50,000/mcL [102]. Neurologic outcomes for pediatric patients with SCD who underwent MSD HSCT are promising [103]. One study demonstrated that in 81 of 196 patients who had evidence of CVA on neuroimaging prior to transplant, transplant-related neurologic events were limited to one patient who had a TIA in the peri-transplant period and one who had a TIA more than
50 days post-transplant. Of the 45 patients who had subsequent neuroimaging during the mean follow-up period of 36 to 72 months, 71 % had no new or progressive lesions, 13 % showed improvement of lesions, and 16 % showed progression of previous lesions [103]. In the Dallas et al. cohort of 22 patients with SCD who underwent MSD or haploidentical HSCT, none of the patients with successful engraftment had progression of neurovascular abnormalities on neuroimaging at the 5-year follow-up, and all had normal TCDs [104]. Given the risk of transplant-associated mortality from severe immunosuppression and chemotherapy-associated organ toxicity with standard myeloablative conditioning [104], reduced-intensity conditioning (RIC) is being explored for patients with SCD and a history of stroke. These regimens utilize decreased doses of cytotoxic drugs, sometimes in combination with total body irradiation to increase immunosuppressive effect, along with a T cell-depleting agent to help prevent graft failure. While graft failure precipitated by incomplete recipient myeloablation was an initial concern, studies using RIC with MSD HSCT for pediatric and adult patients with SCD have shown 85 to 100 % long-term engraftment, most with stable mixed myeloid lineage chimerism that results in primarily donor erythropoiesis with similarly good neurologic outcomes [105–107]. Unfortunately, less than 20 % of patients with SCD are estimated to have an HLA-identical sibling [108], driving the need for investigation of alternative donor sources. The Bone Marrow Transplantation in Young Adults With Severe Sickle Cell Disease (STRIDE) protocol through the National Heart, Lung, and Blood Institute (NHLBI) is currently investigating the use of RIC for adult patients with SCD for both MSD and matched unrelated donors (MUD) [109]. Only 19 % of African American HSCT candidates will have an ideal eight of eight HLA-matched unrelated donor on the National Marrow Donor Program registry [110]. Limited studies of high-risk patients with SCD who underwent umbilical cord blood transplant (UCBT) after RIC show high rates of graft failure [111, 112] and recommendations to use higher nucleated cell dose per recipient weight of UCB to minimize graft failure place further limitations on available donor supply [112]. HSCT with familial haploidentical donor with T cell depletion is another option that is currently at the beginning stages of investigation [100•]. Promotion of donor recruitment, particularly among minorities, and cord blood banking, are critical to making HSCT an option for many patients with SCD.
Conclusion While patients with SCD have similar clinical presentations of stroke as patients without SCD, the unique underlying pathophysiology behind cerebrovascular events has profound implications for the acute and chronic management of these
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patients. It is crucial that neurologists, neurosurgeons, interventional radiologists, critical care physicians, and hematologists work collaboratively to optimize the outcomes of these patients. Pediatric care providers should be particularly alert to the possibility of stroke in any child with SCD. Rapid neuroimaging is critical to confirm the diagnosis. Laboratory workup and intensive care intervention should be expanded from standard stroke protocols to include the preparation for exchange transfusion. In addition to chronic transfusion and hydroxyurea therapy, revascularization techniques and hematopoietic stem cell transplantation should be investigated as potential therapeutic options for SCD patients who have had a stroke.
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12. Compliance with Ethical Standards Conflict of Interest Courtney Lawrence and Jennifer Webb declare that they have no conflict of interest. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.
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