Handbook of Clinical Neurology, Vol. 120 (3rd series) Neurologic Aspects of Systemic Disease Part II Jose Biller and Jose M. Ferro, Editors © 2014 Elsevier B.V. All rights reserved

Chapter 68

Neurologic complications of sickle cell disease AKILA VENKATARAMAN1 AND ROBERT J. ADAMS2* Pediatric Neurology and Epilepsy Division, Lutheran Medical Center, Brooklyn, NY, USA

1 2

South Carolina Stroke Center of Economic Excellence and Medical University of South Carolina Stroke Center, Charleston, SC, USA

HISTORY Sickle cell anemia and related hemoglobinopathies are disorders of the red cell, in particular the hemoglobin. This group of blood disorders includes sickle cell disease (SCD), sickle C disease, and sickle-b thalassemia. Those afflicted with these hemoglobinopathies commonly suffer damage to vital organs, especially to the central nervous system, the spleen, the kidney, the lung, and the heart, as a result of microvascular vaso-occlusion by the sickled erythrocytes. The genes responsible for the transmission of sickle cell syndromes from one generation to the next were recognized during the 17th century. Herrick (1910) first recorded this disease in the medical literature in the US in 1910. The neurologic complications of SCD were first reported in 1923, when Sydenstricker (Sydenstricker et al., 1923) detailed the case of a 5-year-old sickle cell patient with hemiparesis and seizures. Following this, additional case reports of SCD and stroke were soon published (Arena, 1935). In 1972, Stockman and colleagues published the cerebral angiographic results of a series of SCD children with neurologic deficits, documenting the vasculopathy that is seen in the large vessels of the central nervous system (Stockman et al., 1972). Sickle cell disease, usually presenting in childhood, occurs more commonly in people (or their descendants) from parts of tropical and subtropical regions. One-third of all indigenous inhabitants of Sub-Saharan Africa carry the gene (Platt et al., 1994). The prevalence of the disease in the US is approximately 1 in 5000, mostly affecting Americans of Sub-Saharan African descent, according to the National Institutes of Health (NIH). In the US, about 1 in 500 black births have sickle cell anemia. Life expectancy is shortened, with studies reporting

an average life expectancy of 42 in males and 48 in females (http://www.nhlbi.nih.gov/health/dci/Diseases/ Sca/SCA_Summary.html). Numerous breakthroughs in the diagnosis and management of central nervous system complications of SCD have been made since. There have been several seminal studies and trials establishing guidelines for investigation and prevention of the neurologic complications of SCD. These studies have laid the foundation for the extensive research that is needed for the development of optimal prevention and curative treatment of the cerebrovascular complications of SCD.

CLINICAL FINDINGS The clinical course of patients with SCD is highly variable, with much diversity in the expression of the clinical phenotype. Central nervous system complications are unfortunately common in sickle cell disease. The neurologic complications associated with SCD are related to vasoocclusive phenomena and hemolysis and are manifest as cerebral infarction, transient ischemic attacks, intracranial hemorrhage, subsequent cognitive and behavioral changes, and seizures. Occasionally aneurysms and arteriovenous malformations are also seen in these patients. Stroke is clinically characterized by focal symptoms, such as hemiparesis or hemisensory deficits. Symptoms depend on both the location and size of the lesions involved. The underlying vasculopathy varies from extensive, clinically devastating infarcts involving the entire territory of a large artery to smaller, subtler lacunar infarcts that may only present with more diffuse symptoms such as neurocognitive dysfunction. (Pavlakis et al., 1989).

*Correspondence to: Robert J. Adams, M.S., M.D., Professor of Neuroscience, Medical University of South Carolina, 19 Hagood Avenue - Suite 501 HOT, Charleston, SC 29425, USA. Tel: þ1-843-792-7058, Fax: þ1-843-792-2484, E-mail: [email protected]

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Stroke is one of the major complications of SCD and can affect 11% of affected individuals by age 20 (OheneFrempong et al., 1998). Intracranial hemorrhage represents a smaller stroke phenotype in SCD, often manifesting with dramatic and nonfocal symptoms, including severe headache or coma. Hemorrhagic stroke is usually caused by hemorrhagic conversion of a large brain infarction, friable moyamoya vessels, or ruptured aneurysms (Oyesiku et al., 1991). One cerebrovascular phenomenon recognized in SCD is the “silent cerebral infarct.” With advanced neuroimaging techniques and more widespread screening, clinically asymptomatic ischemic lesions suggestive of small vessel occlusion, usually occurring in the arterial border zones, have been detected in almost 25% of children with SCD (Armstrong et al., 1996). Silent infarct white matter lesions and atrophy are more common in neurologically asymptomatic adults compared to community controls without SCD (Vichinsky et al., 2010). Children with silent infarcts identified by MRI may appear asymptomatic, but perform significantly lower on neuropsychological tests than their counterparts with a normal MRI (Armstrong et al., 1996). Cognitive deficits are associated with frontal lobe infarction in children with sickle cell disease. Compared with healthy controls, adults with SCD had poorer cognitive performance, which was associated with anemia and age (Vichinsky et al., 2010). Neurocognitive dysfunction has been implicated as an important contributor to the poor social, economic, and quality-of-life factors reported in adult SCD (Watkins et al., 1998; Noll et al., 2001; Powars et al., 2001). Patients who had silent infarcts were significantly more likely to have a history of seizure. Peripheral nervous system involvement is rare in sickle cell disease. Mononeuropathy resulting from peripheral nerve infarction, as a complication of sickle vaso-occlusive crisis, is uncommon. Reports of patients with SCD who developed acute mononeuropathy multiplex in the setting of sickle cell pain crisis suggests a multifocal nerve disorder resulting from an ischemic process caused by a sickle cell vaso-occlusive crisis (Roohi et al., 2001).

The overall age-specific incidence of first stroke in SCD is 0.13% at ages younger than 24 months, increasing to just over 1% at ages 2–5 years, with only a slight decrement to 0.79% at ages 6–9 years. The risk of brain infarction declines until a second peak is seen at ages older than 50 years, when the incidence again increases to nearly 1.3% (Ohene-Frempong et al., 1998b). Children with SCD carry a 200-fold increased risk for cerebral infarction. The CSSCD observed that the incidence of ischemic stroke was highest in children between 2 and 10 years and again in adults older than 30 years, while hemorrhagic stroke peaks among patients 20–29 years (Powars et al., 2001, 2005). Prior transient ischemic attack, a low steady-state hemoglobin level, hypertension, and a history of acute chest syndrome were the only risk factors found to be significantly associated with brain infarction (Powars et al., 2001) Risk factors for intracranial hemorrhage included low steady-state hemoglobin values and a high leukocyte count (OheneFrempong et al., 1998c). In patients who develop symptomatic stroke, the risk of recurrent stroke approaches 70% (Powars et al., 2001). Silent infarct recognized at age 6 years or older is associated with increased stroke risk (Miller et al., 2001). Lower hemoglobin level, increased leukocyte count, and bS-globin gene haplotype were associated also with the presence of silent infarcts (Kinney et al., 1999). Data from the CSSCD revealed a strong association between silent infarcts and future stroke risk, suggesting that these lesions are progressive and may occur with increased frequency in older patients. Despite substantial advances in the understanding of the pathophysiology and clinical course of sickle cell disease, management of morbidity and mortality remains a challenge for adult patients. However, childhood mortality has improved considerably as the consequence of advances in stroke management (Powars et al., 2005). Recognition of risk factors, prevention of primary and recurrent strokes, and treatment of neurologic complications with novel therapies all contribute to a shift in the natural history of sickle cell disease, with better overall outcomes.

NATURAL HISTORY

LABORATORY INVESTIGATIONS

Much progress has been made during the past several decades in understanding the natural history of sickle cell disease and its complications, particularly those affecting the central nervous system. The Cooperative Study of Sickle Cell Disease (CSSCD), one of the landmark population studies, has provided the best evidence for risk factors leading to brain infarction and hemorrhage.

The majority of initial laboratory investigations are directed toward the establishment of the specific hemoglobinopathy. Diagnostic recommendations set forth by the 1975 International Committee for Standardization in Hematology expert panel on abnormal HbS and thalassemias include an initial panel of a complete blood count (CBC), electrophoresis at pH 9.2, tests for solubility

NEUROLOGIC COMPLICATIONS OF SICKLE CELL DISEASE 1017 and sickling, and quantification of Hb A2 and Hb F. Furimaging (DWI) detects brain ischemia within an hour ther tests such as electrophoresis at pH 6.0–6.2, globin after stroke onset and is able to distinguish ischemic chain separation, and isoelectric focusing (IEF) were stroke from other conditions. recommended if an abnormal hemoglobin is identified MRI is also useful in detecting silent cerebral infarcts. on initial testing (Clarke and Higgins, 2000). CationSilent cerebral infarcts are diagnosed on the basis of an exchange high performance light chromatography abnormal MRI of the brain and a normal neurologic (HPLC) (Fisher et al., 1997; Rioux et al., 1997) is now touexamination. Some studies using brain MR imaging have ted as the method of choice for quantification of Hb A2 showed infarction/ischemia in the absence of a recognized and Hb F and identification of Hb variants (British cerebrovascular accident in 13% of patients (Moser et al., Committee for Standards in Haematology, 1988; 1996). It is twice as common as clinical infarction and may International Committee for Standardization in occur in up to 22% of children with sickle cell disease by 12 Haematology, 1988). Diagnosis of sickle cell trait and years of age (Moritania et al., 2004). A silent cerebral disease depends on a typical HPLC and Hb electrophoinfarct has been defined as an area of abnormally retic pattern. The %HbS is also an important value to increased signal intensity on the intermediate and obtain as it guides transfusion protocols to afford priT2-weighted pulse sequences of MRI. The area of abnormary prevention against strokes. mal signal must have an appearance consistent with Further laboratory tests may then be conducted to infarction and include a focal 3 mm or larger area of evaluate the coagulation profile and propensity toward abnormally increased signal intensity on the T2-weighted hypercoaguability, to consider differential diagnoses image in more than one view (Armstrong et al., 1996). for the etiology of strokes. These tests include PT, Another common finding on MRI in patients with PTT, INR, protein C and S, factor V Leiden mutation, sickle cell disease is cerebral atrophy. This is a nonspecianticardiolipin antibody, antithrombin, and serum fic finding that serves as a marker for disease severity in homocysteine, to name a few. the brain. Liver biopsy is considered the most accurate and senBased on MR studies, cortical infarction is often seen sitive method to assess the iron burden after long-term to be unilateral and in the frontoparietal location, and transfusion therapy in patients with SCD. However, this related to large vessel disease. White matter infarction is an invasive technique and hepatic iron measurements is often bilateral and in the frontoparietal location and from a liver biopsy specimen may be confounded by this appears to be related to small vessel vasculopathy hepatic fibrosis and uneven tissue distribution of iron (Moritania et al., 2004). (Bonkovsky et al., 1990). The neurologic complications of sickle cell disease The most promising newer methods to noninvasively occur mainly as a result of the vasculopathy of the cenmeasure iron are based on measurement of hepatic magtral nervous system (Stockman et al., 1972). It is therenetic susceptibility, either using superconducting quanfore most logical to investigate the disease process tum interference device susceptometry (SQUID) or with neuroimaging that is primarily based on evaluating magnetic resonance susceptometry (MRS) (Brittenham the vasculature of the nervous system. Magnetic resoand Badman, 2003; Fischer et al., 2003; Carneiro et al., nance angiography (MRA) provides critical information 2005). At present, biomagnetic susceptometry is possion the status of the cerebral vasculature, and has bly the most reliable noninvasive method for measurereplaced intra-arterial catheter angiography as an accument of tissue iron stores (Fischer et al., 1999). Special rate and noninvasive technique to detect cerebral artery imaging software with MRI has now become available lesions (Kandeel et al., 1996). Moyamoya, a description for reliable noninvasive liver iron results (St Pierre that comes from the Japanese for “puff of smoke” et al., 2005). because of the angiographic appearance of secondary extensive collateral formation, is a secondary complication of the cerebral vasculopathy of SCD. It is seen in NEUROIMAGING 35% of sickle cell disease patients at conventional angiAlmost all modalities of neuroimaging are useful in ography. In comparison, moyamoya vessels were seen in sickle cell disease, considering the extent of cerebrovas20% at MRI/MRA (Moritania et al., 2004). cular disease that is seen in this condition. Brain imaging abnormalities were reported in up to Cranial computed tomography (CT) is typically the 44% of children with sickle cell disease. The frequency initial study performed in situations where clinically a of brain imaging abnormalities detected by MRI/MRA stroke, hemorrhagic or infarct, is suspected. However, in adults with sickle cell disease was higher than that CT has limitations in detecting very early brain ischemia. described for children (Silva et al., 2009). Conventional MRI is much more sensitive and speThe prevention of stroke in children with SCD has cific for parenchymal lesions. Diffusion-weighted been markedly advanced by the introduction and testing

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of transcranial Doppler (TCD) as a noninvasive diagnostic test indicating high risk of first stroke. TCD uses pulsed Doppler to measure the velocity and pulsatility of blood flow within the major intracranial arteries of the circle of Willis. In children with sickle cell disease, there is involvement of the distal intracranial internal carotid artery (ICA) and the proximal portions of the middle (MCA) and anterior (ACA) cerebral arteries (Jeffries et al., 1980). The risk of stroke increases dramatically as TCD flow velocity increases in these basal arteries, first probably on the basis of increased flow velocity generally, and due to stenosis in the later stages. The risk of stroke rises about 30% for each 10 cm/second increase above the median velocity for children with SCD (Adams et al., 2004). A large single center prospective study demonstrated the likelihood of stroke in children with sickle cell anemia was predicted by TCD in the absence of regular transfusion (Adams et al., 1992, 1997). Using TCD, a multicenter randomized controlled trial, the Stroke Prevention Trial in Sickle Cell Anemia (STOP trial) confirmed that TCD, using a cutoff of 200 cm/second velocity or higher, was associated with a 10% risk of stroke in the untreated group for the 2 years that the trial was allowed to continue. In those children who were randomized to regular transfusions (every 4 weeks or so), however, the stroke risk was less than 1% (p < 0.001). The STOP study confirmed both the remarkable predictive power of TCD (10–20 times the background risk of stroke for unselected children with SCD) and the striking reduction of stroke with regular transfusions (Adams et al., 1998). The STOP study led to a clinical alert, issued by the National Heart, Lung, and Blood Institute (NLBHI), recommending TCD screening of children with sickle cell disease between the ages of 2 and 16 years as effective for assessing stroke risk. TCD screening, followed by regular transfusion in cases with high risk TCD, has now become the standard of care for children with SCD and is recommended by the NHLBI (http://www.nhlbi.nih.gov/health/dci/Diseases/Sca/SCA_Treatments.html) and the American Stroke Association (Goldstein et al., 2011). Transcranial Doppler velocities in adult patients with intracranial stenoses have been shown to be lower than those described for the pediatric population with sickle cell disease and it is not clear how predictive TCD is for adults with SCD and stroke risk (Valadi et al., 2006; Silva et al., 2009). Sibling studies have been conducted with TCD to investigate the possibility of a familial predisposition to elevated cerebral blood flow velocity. The presence of a sibling with a positive TCD result was significantly associated with an elevated cerebral blood flow

velocity in other siblings with SCD, consistent with a familial predisposition to cerebral vasculopathy in SCD (Kwiatkowski et al., 2003). Other tests indicate abnormalities in glucose metabolism and microvascular blood flow, particularly in the frontal lobes, demonstrated in SCD patients using positron emission tomography (PET). The addition of PET to MRI identifies a greater proportion of children with sickle cell disease with neuroimaging abnormalities, particularly in those who had no history of overt neurologic events (Rodgers et al., 1988; Powars et al., 1999; Reed et al., 1999). Perfusion magnetic resonance (dynamic susceptibility contrast MRI) and blood oxygen level-dependent (BOLD) MRI are additional imaging modalities to assess cerebral blood flow and perfusion. Perfusion abnormalities are associated with neurologic symptoms in patients with SCD, whether or not MRI, MRA, and TCD are abnormal (Kirkham et al., 2001a). Voxel-based morphometry analysis of MRI images is a sensitive method to detect widespread white matter injury in SCD patients in border zones between arterial territories even in the absence of evidence of infarction (Baldeweg et al., 2006).

GENETICS Sickle cell disease (SCD) and b-thalassemia, caused by lesions that affect the b-globin gene, form the most common human genetic disorders worldwide. The autosomal recessive genetic mutation producing sickle hemoglobin is a single nucleotide substitution (GTG for GAG) at codon 6 of the b-globin gene on chromosome 11 that results in the substitution of valine for glutamic acid in the b-globin peptide. In an environment of hypoxia, this causes HbS to polymerize and form stiff bundles that distort the red cell, which in turn are less compliant through the microcirculation and result in vascular occlusion and the eventual chronic end organ damage. These RBCs are also prematurely removed from the circulation, resulting in a chronic hemolytic anemia. Sickle cell disease is phenotypically complex, with different clinical courses ranging from early childhood mortality to a virtually unrecognized condition. Considering the well characterized molecular details of HbS polymerization, the explanation for the broad phenotypic heterogeneity in patients with identical genetic mutations is still under investigation. If the primary mutation is the same, variations in disease severity generally are due to genetic modifiers. In most genetic diseases involving b-globin, the most clear-cut influence on phenotype results from elevated fetal hemoglobin levels (Rund and Fucharoen, 2008). Other factors include b-globin cluster haplotypes, a-globin gene

NEUROLOGIC COMPLICATIONS OF SICKLE CELL DISEASE number, and fetal hemoglobin expression. The b-globin haplotypes are associated with different severities in sickle cell disease probably due to the variation in fetal hemoglobin concentration, which is protective against the stroke risk. The a-globin gene also influences the risk and protection against different complications of sickle cell anemia (Ashley-Koch et al., 2000). Studies of sickle cell disease have drawn attention to the importance of modifier genes and of gene–gene interactions in determining stroke risk (Dichgans, 2007). Modifier genes might interact to determine the susceptibility to stroke. To find additional genetic modulators of disease, genotype-phenotype association studies, where single nucleotide polymorphisms (SNPs) in candidate genes are linked with a particular phenotype, have been informative (Steinberg, 2009). A candidate gene study involving the analysis of 28 genetic polymorphisms in 20 candidate genes, including mutations in coagulation factor genes (factor V, prothrombin, fibrinogen, factor VII, factor XIII, PAI-1), platelet activation/function (GpIIb/IIIa, GpIb IX-V, GpIa/IIa), vascular reactivity (ACE), endothelial cell function (MTHFR, thrombomodulin, VCAM-1, E-selectin, L-selectin, P-selectin, ICAM-1), inflammation (TNF-a), lipid metabolism (Apo A1, Apo E), and cell adhesion (VCAM-1, E-selectin, L-selectin, P-selectin, ICAM-1) has been proposed. A genome-wide screen of validated single nucleotide polymorphisms (SNPs) to study the possible association of additional polymorphisms with the high-risk phenotype has also been designed (Adams et al., 2003). Studies of genetic risk factors for stroke in SCD (in addition to the sickle mutation) have included association studies of predisposition genes for thrombosis and human leukocyte antigen (HLA) loci. Both class I HLA-B and class II HLA-DRBI (DR3) and DQBI (DQ2) alleles were associated with stroke risk in patients with clinical stroke and silent infarction on MRI (Zimmerman and Ware, 1998; Driscoll and Prauner, 1999; Styles et al., 2000; Hoppe et al., 2004). VCAM-1 is a cell adhesion molecule postulated to play a critical role in the pathogenesis of SS disease. In a study of single nucleotide polymorphisms (SNPs) within the VCAM1 gene locus, Taylor identified a variant that appears to be protective (Taylor et al., 2002). There is also a familial predisposition to stroke noted in sickle cell disease (Driscoll et al., 2003). This should prompt studies to identify genetic modifiers with family-based studies.

PATHOLOGY The events clinically recognized as sickle cell disease are set off by a cascade of pathophysiological processes triggered by red cell injury secondary to the sickled

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hemoglobin polymer. These include general cellular and tissue damage caused by hypoxia, oxidant damage, and inflammation and reduced nitric oxide bioavailability (Steinberg, 2008). Recurrent inflammation and vasculopathy occur in sickle cell disease, during crises, and in steady state. During the inflammatory process, leukocytes and vascular endothelial cells are activated and increase their expression of adhesion molecules. Adhesion of leukocytes to other blood cells and endothelium contributes to vasoocclusion in sickle cell disease. High-level expression of adhesion molecules by leukocytes is associated with clinically severe disease (Anyaegbu et al., 1998; Awogu, 2000). Pancellular membrane lipid abnormalities, including reduced proportions of v-3 fatty acids, also occur in sickle cell disease. These lipid abnormalities are more severe in patients with disease complications and in those with a greater degree of anemia (Okpala, 2006). Other markers of inflammation seen in sickle cell disease include platelets (Okpala, 2002), C-reactive protein, a2-macroglobulin, transferrin (Hedo et al., 1993), interleukin (IL)-2, IL-4, IL-6, IL-8, fibrinogen, and activated circulating vascular endothelial cells (Hebbel et al., 2004). On a cellular membrane level in the erythrocyte, after recurrent episodes of sickling, membrane damage occurs and the cells are no longer capable of resuming the biconcave shape upon reoxygenation. Thus, they become irreversibly sickled. When erythrocytes sickle, they gain Naþ and lose Kþ. Membrane permeability to Caþþ increases, possibly due, in part, to impairment in the Caþþ pump that is dependent on adenosine triphosphatase (ATPase). The membrane becomes more rigid, possibly due to changes in cytoskeletal protein interactions. The pathophysiology of cerebrovascular disease in sickle cell anemia may involve stenosis of large arteries of the circle of Willis, intracranial hemorrhage, and/or microvascular disease (Stockman et al., 1972; Moser et al.,1996) Cerebral infarction, a common complication of sickle cell disease, usually occurs in the distribution of the large vessels comprising the anterior circle of Willis, most often as a result of stenosis or occlusion in the area of the bifurcation of the carotid artery (Pavlakis et al., 1989). Vascular neuroimaging of patients with sickle cell anemia often demonstrates progressive narrowing of the large vessels with collateral vessel development in a pattern very similar to moyamoya disease (Dobson et al., 2002). Patients with this moyamoya-like vasculature are at a higher risk for strokes. Histology of these narrowed vessels is suggestive of intimal hyperplasia and proliferation of the internal elastic lamina, consistent with endothelial damage (Rothman et al., 1986). Presumably, stroke is caused by perfusion failure in areas of stenosis or to arterial embolization. Factors that

1020 A. VENKATARAMAN AND R.J. ADAMS have been implicated in the development of the vascular antiplatelet agents or anticoagulants in stroke in children lesions in the brain include the above mentioned inflamwith SCD either acutely or long term. Antiplatelet agents matory processes such as leukocyte-mediated injury to (e.g., aspirin) and heparins (e.g., low molecular weight the endothelium, damage caused directly by the sickled heparin) have been used on an individual patient basis red cells, inflammation mediated by cytokines, and in children with arterial ischemic strokes (Nowak-Gottl quantitative and qualitative platelet abnormalities et al., 2003; Soman et al., 2006). There have been no ran(Francis, 1991; Hebbel and Vercellotti, 1997). The disease domized controlled clinical trials with thrombolytics in also involves enhanced angiogenic propensity, activation the treatment of acute ischemic stroke in children and of coagulation, disordered vasoregulation, and a compoalthough the risk of hemorrhage may be higher, SCD nent of chronic vasculopathy (Hebbel et al., 2004b). does not represent a known contraindication to tPA In conjunction with diminished NO bioavailability, use in adults. these processes likely underlie the chronic vasculopathy Physical, occupational, and speech therapy are imporcomponent of sickle disease. Endothelium-derived nitric tant and should be initiated early in the children who have oxide (NO) plays a major role in the regulation of vasosuffered a stroke. Early rehabilitation has a more favormotor tone. These results suggest that endothelial dysable prognosis for recovery of function. function may prevent vasoregulation, which may also One of the essential interventions in the management contribute to the pathophysiology of vaso-occlusive of acute ischemic stroke in children with SCD is emercrisis in patients with sickle cell disease (Belhassen gent blood transfusion to reduce the HbS level below et al., 2001). Reduced activity of naturally occurring anti30%. The multicenter STOP trial demonstrated that coagulants protein C and protein S may contribute to transfusion to maintain HbS < 30% decreased the incivaso-occlusion in sickle cell disease (Schnog et al., 2004). dence of first stroke in high-risk pediatric patients, idenA growing body of evidence supports the existence of tified by transcranial Doppler (TCD). This is the only a novel mechanism of human disease, namely, proven paradigm with class I evidence for primary hemolysis-associated smooth muscle dystonia, stroke prevention in SCD (Adams et al., 1998b). Transfuvasculopathy, and endothelial dysfunction (Rother sion should be continued at least until age 18; HbS may be et al., 2005). Given the pathophysiological processes allowed to rise to approximately 50% in older adolesmentioned above, it is a possibility that this mechanism cents and young adults by reducing either the intensity of disease is essentially the hallmark of the pathology of or frequency of transfusions. The STOP II study showed sickle cell disease. that discontinuing chronic transfusions after 30 months, even though the TCD values had dropped from above 200 to < 170 cm/second (considered low risk or normal MANAGEMENT at that point), nonetheless resulted in a high rate of reverWhen contemplating management of the neurologic sion to abnormal TCD values and stroke (class I) (Adams complications of SCD, one must take into account treatand Brambilla, 2005). ment of acute cerebrovascular accidents and its The role of chronic transfusion for the prevention of sequelae, while also considering prophylactic methods recurrent events has not been defined for patients with for long-term better outcomes. their initial stroke as an adult. In the acute setting, stroke, particularly hemorrhagic, It has also been shown that the incidence of silent may initially require intensive monitoring of intracranial infarcts (radiologically detected) were decreased in pressures, treatment of vasospasm with volume expanpatients receiving chronic transfusion as compared to sion and/or nimodipine, and aggressive treatment of seistandard care showing that chronic transfusion therapy zures if any. Craniotomy may be necessary to prevent may also prevent silent infarcts in children with SCD herniation or for clipping or wrapping of the cerebral (Pegelow et al., 2001). However, chronic transfusion aneurysm. Other strategies such as adequate hydration, therapy is associated with complications such as iron normothermia, and euglycemia should be maintained overload, alloimmunization, and infections. Erythrocyand hypotension should be avoided in the setting of acute tapheresis, an automated method of red blood cell stroke. exchange, is a safe method of controlling HbS levels Antiplatelet therapy is generally recommended in and limiting or preventing iron load in chronically transadults after ischemic stroke, and there are no apparent fused SCD patients (Kim et al., 1994; Marques Junior reasons why this should not be advocated in adults with et al., 1995; Adams et al., 1996). ischemic stroke who have SCD. Other options are disHemosiderosis is well known consequence of intencussed in the American Stroke Association Guidelines sive and long-term transfusion therapy. Although both on Secondary Stroke Prevention (Furie et al., 2011). There SCD and thalassemia patients suffer from iron-induced are no specific recommendations regarding the use of organ injury, the onset of clinical manifestations due to

NEUROLOGIC COMPLICATIONS OF SICKLE CELL DISEASE 1021 iron overload appears to be more gradual in SCD monitoring of the platelets, reticulocytes, and neutropatients, suggesting a relative protection from ironphils. Hydroxyurea was tested for secondary stroke prerelated organ injury (Finch, 1982). Exchange transfuvention in children with SCD based on a single center sions and chelation therapy are two methods to manage study by Ware et al. (2004). They discontinued chronic transfusion-related iron overload. Iron chelation therapy transfusion (after more than 2 years of treatment) in is done with deferoxamine at a dose of 25 mg/kg/day as a 35 children and put them on hydroxyurea. These patients subcutaneous or intravenous infusion. Complications of also received phlebotomies for iron overload. Although this chelation method include ototoxicity, rash, and these phase II results showed a promising trend, the rangrowth retardation in young children. The US Food domized controlled trial called SWiTCH was terminated and Drug Administration (FDA) recently approved early due to futility. deferasirox for treatment of chronic iron overload due The results are not yet published but the following to blood transfusions in patients aged 2 years and older. information was available from the sponsor’s website The drug is taken orally once daily which may improve on NHLBI (http://www.nih.gov/news/health/jun2010/ compliance over deferoxamine. Chelation therapy with nhlbi-03.htm): more than one agent offers the possibility of more effecThe 26-site trial, Stroke With Transfusions tive removal of iron without compromising safety or Changing to Hydroxyurea, or SWiTCH, studied compliance. 133 participants between the ages of 5 and 18 Recent studies have documented alloimmunization who had already experienced a stroke. All had rates as high as 47% in adult and 27% in pediatric transbeen receiving the standard treatment of blood fused SCD patients, respectively (Rosse et al., 1990; transfusions for at least 18 months and high levels Vichinsky et al., 1990; Tahhan et al., 1994; Aygun of iron before entering the study. Without further et al., 2002). One method to decrease the rates of alloimpreventive measures, these children were at high munization and hemolytic transfusion reactions is using risk of another stroke as well as life-threatening leuko-depleted red cells matched for E, C, and Kell anticonditions due to iron overload. gens. Other strategies to minimize alloimmunization The study tested whether the drug hydroxyinclude PEG-coating of red cells to mask red cell antiurea, known to prevent complications of sickle gens from antibodies (Fisher, 2000), as well as artificial cell disease in adults, was as effective as transfublood substitutes, such as perfluorocarbon emulsions sions, the standard therapy, in reducing the risk of and hemoglobin-based substitutes (Lowe, 2003; Habler recurrent strokes. Hydroxyurea is the only FDAet al., 2005; Maevsky et al., 2005). approved drug for treating sickle cell anemia. The use of leukocyte-depleted red cell transfusions The study also compared two approaches to has had a significant effect on reducing the transmission remove excess iron, a consequence of regular of intracellular viruses such as cytomegalovirus (CMV), blood transfusions. Participants who continued human lymphotrophic virus, Epstein–Barr virus (EBV), to receive transfusion therapy were given the stanand human herpes virus 6, 7, 8 infectious complications dard oral iron-removal drug deferasirox, and par(Fergusson et al., 2003). Transmission of HIV, hepatitis ticipants who were switched to hydroxyurea B and C, and human T cell leukemia/lymphoma virus-1 underwent regular phlebotomy (blood removal) has dramatically decreased with improved donor selecto eliminate excess iron that had accumulated tion criteria and screening of banked units (AuBuchon from their earlier transfusions. et al., 1997). Phlebotomy did not reduce liver iron better For adult patients who decide to discontinue transfuthan deferasirox therapy. Analysis of the available sions, or those with problematic alloimmunization, iron data indicated that continuing the trial was overload, or other impediments to chronic red blood cell unlikely to show that phlebotomy would provide administration, hydroxyurea (HU) therapy should be a greater benefit than deferasirox to control iron considered to prevent recurrent events. Based on results accumulation. Without the ability to provide benfrom the double blind, placebo-controlled Multicenter efits for the management of liver iron, the potenStudy of Hydroxyurea (MSH), HU was approved in tial risks of continuing study treatments were no adults with SCD to decrease the frequency of vasolonger warranted. occlusive episodes and blood transfusion requirements . . . The DSMB noted that no strokes occurred (Charache et al., 1995). Follow-up data from the MSH in the 66 participants who received the standard have confirmed a reduced mortality after 9 years of therapy of blood transfusions and deferasirox. In HU therapy (Steinberg et al., 2003). Hydroxyurea thercontrast, seven strokes occurred in the group of apy is started at a dose of 15 mg/kg/day and increased 67 participants who received hydroxyurea with by 5 mg/kg/day every 8–12 weeks with monthly

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phlebotomy. Study participants and their families have been contacted, and they will discuss future care options with their health care providers. (http://www.nih.gov/news/health/jun2010/ nhlbi-03.htm, 2010) A study of similar design called TWiTCH, comparing hydroxyurea to regular blood transfusion for primary stroke prevention (based on the STOP protocol), will begin enrolling patients in 2011 (http://ccct.sph.uth.tmc. edu/twitch/, 2009). Allogeneic bone marrow transplantation (BMT) from HLA-identical siblings is an accepted treatment for both thalassemia and sickle cell disease. Related cord blood transplantation for hemoglobinopathies is reported to offer a good probability of success (Locatelli et al., 2003). Bone marrow transplantation (BMT) is potentially curative alternative for secondary stroke prevention (Walters et al., 2004). Lack of an eligible HLA-compatible sibling donor and potential transplant-related complications remain substantial barriers to BMT in SCD. Novel conditioning regimens that minimize transplant-associated toxicity and alternative stem cell sources show promise for the wider application of BMT in SCD. Moyamoya patients with ischemic symptoms and poor perfusion on a cerebral blood flow study are good candidates for direct or indirect bypass procedures. Encephaloduroarteriosynangiosis (EDAS) permits neovascularization to develop over a larger area of the brain than observed with direct anastomosis and has been revealed to cause cessation of symptomatic attacks much sooner than the natural course of the disease. The EDAS procedure is a safe and effective treatment option in patients with sickle cell anemia who develop moyamoya disease (Fryer et al., 2003). Operative treatment of moyamoya syndrome using pial synangiosis appears to be safe and confers long-lasting protection against further stroke in this population, and provides an alternative for failure of optimal medical therapy in patients (Smith et al., 2009). Emerging novel primary prophylaxis regimens being tested include citrulline and arginine, aspirin, short-chain fatty acids, lovastatin, decitibine, and overnight oxygen supplementation. Screening for, and appropriate management of, nocturnal hypoxemia might be a safe and effective alternative to prophylactic blood transfusion for primary prevention of central nervous events in sickle cell disease (Kirkham et al., 2001b). Antioxidant therapy using a stable and long-acting molecule such as an intravascular superoxide dismutase mimetic polynitroxyl albumin may have a potential in ameliorating SS red cell adhesion and related vaso-occlusion (Kaul et al., 2006).

There are several studies underway to investigate the promise of some of the above-mentioned therapies in primary prevention and prevention of recurrent strokes in patients with SCD, and possibly even curative in this condition.

CONCLUSIONS Sickle cell disease and related hemoglobinopathies are complex conditions, with patients exhibiting a vast variety of neurologic complications. The health burden for children with SCD and their families is profound and may be exacerbated by barriers to accessing comprehensive medical care (Boulet et al., 2010). SCD patients are reported to experience health-related quality of life worse than the general population. Greater public awareness of the neurocognitive effects of SCD and their impact on child outcomes is a critical step toward improved treatment, adaptation to illness, and quality of life (Schatz and McClellan, 2006). In spite of all the progress in the understanding of the complicated nature of neurologic sequelae of SCD, there remains much work to be done in this field to aid in the prevention and cure of this disease. For now, prevention of first stroke is one important step that can be taken to lower the stroke burden in SCD.

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