Handbook of Clinical Neurology, Vol. 120 (3rd series)Neurologic Aspects of Systemic Disease Part IIJose 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*

1Pediatric Neurology and Epilepsy Division, Lutheran Medical Center, Brooklyn, NY, USA2South Carolina Stroke Center of Economic Excellence and Medical University of South Carolina Stroke Center,

Charleston, SC, USA

HISTORY

Sickle cell anemia and related hemoglobinopathies aredisorders 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. Thoseafflicted with these hemoglobinopathies commonly suf-fer damage to vital organs, especially to the central ner-vous system, the spleen, the kidney, the lung, and theheart, as a result of microvascular vaso-occlusion bythe sickled erythrocytes.

The genes responsible for the transmission of sicklecell syndromes from one generation to the next were rec-ognized during the 17th century. Herrick (1910) firstrecorded this disease in the medical literature in the USin 1910. The neurologic complications of SCD were firstreported in 1923, when Sydenstricker (Sydenstrickeret al., 1923) detailed the case of a 5-year-old sickle cellpatient with hemiparesis and seizures. Following this,additional case reports of SCD and stroke were soon pub-lished (Arena, 1935). In 1972, Stockman and colleaguespublished the cerebral angiographic results of a seriesof SCD children with neurologic deficits, documentingthe vasculopathy that is seen in the large vessels of the cen-tral 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-thirdof all indigenous inhabitants of Sub-Saharan Africacarry the gene (Platt et al., 1994). The prevalence ofthe disease in the US is approximately 1 in 5000, mostlyaffecting 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 ane-mia. Life expectancy is shortened, with studies reporting

*Correspondence to: Robert J. Adams, M.S., M.D., Professor of N

Avenue - Suite 501 HOT, Charleston, SC 29425, USA. Tel: þ1-843

an average life expectancy of 42 in males and 48 infemales (http://www.nhlbi.nih.gov/health/dci/Diseases/Sca/SCA_Summary.html).

Numerous breakthroughs in the diagnosis and man-agement of central nervous system complications ofSCD have beenmade since. There have been several sem-inal studies and trials establishing guidelines for investi-gation and prevention of the neurologic complications ofSCD. These studies have laid the foundation for theextensive research that is needed for the developmentof optimal prevention and curative treatment of the cere-brovascular complications of SCD.

CLINICAL FINDINGS

The clinical course of patients with SCD is highly vari-able, with much diversity in the expression of the clinicalphenotype.

Central nervous system complications are unfortu-nately common in sickle cell disease. The neurologiccomplications associated with SCD are related to vaso-occlusive phenomena and hemolysis and are manifestas cerebral infarction, transient ischemic attacks, intra-cranial hemorrhage, subsequent cognitive and behav-ioral changes, and seizures. Occasionally aneurysmsand arteriovenous malformations are also seen in thesepatients.

Stroke is clinically characterized by focal symptoms,such as hemiparesis or hemisensory deficits. Symptomsdepend on both the location and size of the lesionsinvolved. The underlying vasculopathy varies from exten-sive, clinically devastating infarcts involving the entire ter-ritory of a large artery to smaller, subtler lacunar infarctsthat may only present with more diffuse symptoms suchas neurocognitive dysfunction. (Pavlakis et al., 1989).

euroscience, Medical University of South Carolina, 19 Hagood

-792-7058, Fax: þ1-843-792-2484, E-mail: adamsrj@musc.edu

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Stroke is one of the major complications of SCD and canaffect �11% of affected individuals by age 20 (Ohene-Frempong et al., 1998).

Intracranial hemorrhage represents a smaller strokephenotype in SCD, often manifesting with dramaticand nonfocal symptoms, including severe headache orcoma. Hemorrhagic stroke is usually caused by hemor-rhagic conversion of a large brain infarction, friablemoyamoya vessels, or ruptured aneurysms (Oyesikuet al., 1991).

One cerebrovascular phenomenon recognized in SCDis the “silent cerebral infarct.” With advanced neuroim-aging techniques and more widespread screening, clini-cally asymptomatic ischemic lesions suggestive of smallvessel occlusion, usually occurring in the arterial borderzones, have been detected in almost 25% of children withSCD (Armstrong et al., 1996). Silent infarct white matterlesions and atrophy are more common in neurologicallyasymptomatic adults compared to community controlswithout SCD (Vichinsky et al., 2010). Children with silentinfarcts identified by MRI may appear asymptomatic,but perform significantly lower on neuropsychologicaltests than their counterparts with a normal MRI(Armstrong et al., 1996). Cognitive deficits are associ-ated with frontal lobe infarction in children with sicklecell disease. Compared with healthy controls, adults withSCD had poorer cognitive performance, which was asso-ciated with anemia and age (Vichinsky et al., 2010). Neu-rocognitive dysfunction has been implicated as animportant 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 significantlymore likely to have a history of seizure.

Peripheral nervous system involvement is rare insickle cell disease. Mononeuropathy resulting fromperipheral nerve infarction, as a complication of sicklevaso-occlusive crisis, is uncommon. Reports of patientswith SCD who developed acute mononeuropathy multi-plex in the setting of sickle cell pain crisis suggests amul-tifocal nerve disorder resulting from an ischemic processcaused by a sickle cell vaso-occlusive crisis (Roohi et al.,2001).

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NATURALHISTORY

Much progress has been made during the past severaldecades in understanding the natural history of sicklecell disease and its complications, particularly thoseaffecting the central nervous system.

The Cooperative Study of Sickle Cell Disease(CSSCD), one of the landmark population studies, hasprovided the best evidence for risk factors leading tobrain infarction and hemorrhage.

The overall age-specific incidence of first stroke inSCD is 0.13% at ages younger than 24months, increasingto just over 1% at ages 2–5 years, with only a slight dec-rement to 0.79% at ages 6–9 years. The risk of braininfarction declines until a second peak is seen at agesolder than 50 years, when the incidence again increasesto nearly 1.3% (Ohene-Frempong et al., 1998b). Childrenwith SCD carry a 200-fold increased risk for cerebralinfarction.

The CSSCD observed that the incidence of ischemicstroke was highest in children between 2 and 10 yearsand again in adults older than 30 years, while hemor-rhagic stroke peaks among patients 20–29 years(Powars et al., 2001, 2005). Prior transient ischemicattack, a low steady-state hemoglobin level, hyperten-sion, and a history of acute chest syndromewere the onlyrisk factors found to be significantly associated withbrain infarction (Powars et al., 2001) Risk factors forintracranial hemorrhage included low steady-statehemoglobin values and a high leukocyte count (Ohene-Frempong et al., 1998c). In patients who develop symp-tomatic stroke, the risk of recurrent stroke approaches70% (Powars et al., 2001).

Silent infarct recognized at age 6 years or older isassociated with increased stroke risk (Miller et al.,2001). Lower hemoglobin level, increased leukocytecount, and bS-globin gene haplotype were associatedalso with the presence of silent infarcts (Kinney et al.,1999). Data from the CSSCD revealed a strong associa-tion between silent infarcts and future stroke risk, sug-gesting that these lesions are progressive and may occurwith increased frequency in older patients.

Despite substantial advances in the understanding ofthe pathophysiology and clinical course of sickle cell dis-ease, management of morbidity and mortality remains achallenge for adult patients. However, childhoodmortal-ity has improved considerably as the consequence ofadvances in stroke management (Powars et al., 2005).Recognition of risk factors, prevention of primary andrecurrent strokes, and treatment of neurologic complica-tions with novel therapies all contribute to a shift in thenatural history of sickle cell disease, with better overalloutcomes.

AND R.J. ADAMS

LABORATORY INVESTIGATIONS

The majority of initial laboratory investigations aredirected toward the establishment of the specifichemoglobinopathy.

Diagnostic recommendations set forth by the 1975International Committee for Standardization in Hema-tology expert panel on abnormal HbS and thalassemiasinclude an initial panel of a complete blood count(CBC), electrophoresis at pH 9.2, tests for solubility

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and sickling, and quantification of Hb A2 and Hb F. Fur-ther tests such as electrophoresis at pH 6.0–6.2, globinchain separation, and isoelectric focusing (IEF) wererecommended if an abnormal hemoglobin is identifiedon initial testing (Clarke and Higgins, 2000). Cation-exchange high performance light chromatography(HPLC) (Fisher et al., 1997; Rioux et al., 1997) is now tou-ted as the method of choice for quantification of Hb A2and Hb F and identification of Hb variants (BritishCommittee for Standards in Haematology, 1988;International Committee for Standardization inHaematology, 1988). Diagnosis of sickle cell trait anddisease depends on a typical HPLC and Hb electropho-retic pattern. The %HbS is also an important value toobtain as it guides transfusion protocols to afford pri-mary prevention against strokes.

Further laboratory tests may then be conducted toevaluate the coagulation profile and propensity towardhypercoaguability, to consider differential diagnosesfor the etiology of strokes. These tests include PT,PTT, INR, protein C and S, factor V Leiden mutation,anticardiolipin antibody, antithrombin, and serumhomocysteine, to name a few.

Liver biopsy is considered the most accurate and sen-sitive method to assess the iron burden after long-termtransfusion therapy in patients with SCD. However, thisis an invasive technique and hepatic iron measurementsfrom a liver biopsy specimen may be confounded byhepatic fibrosis and uneven tissue distribution of iron(Bonkovsky et al., 1990).

The most promising newer methods to noninvasivelymeasure iron are based onmeasurement of hepatic mag-netic susceptibility, either using superconducting quan-tum interference device susceptometry (SQUID) ormagnetic resonance susceptometry (MRS) (Brittenhamand Badman, 2003; Fischer et al., 2003; Carneiro et al.,2005). At present, biomagnetic susceptometry is possi-bly the most reliable noninvasive method for measure-ment of tissue iron stores (Fischer et al., 1999). Specialimaging software with MRI has now become availablefor reliable noninvasive liver iron results (St Pierreet al., 2005).

NEUROLOGIC COMPLICATIO

NEUROIMAGING

Almost all modalities of neuroimaging are useful insickle cell disease, considering the extent of cerebrovas-cular disease that is seen in this condition.

Cranial computed tomography (CT) is typically theinitial study performed in situations where clinically astroke, hemorrhagic or infarct, is suspected. However,CT has limitations in detecting very early brain ischemia.

Conventional MRI is much more sensitive and spe-cific for parenchymal lesions. Diffusion-weighted

imaging (DWI) detects brain ischemia within an hourafter stroke onset and is able to distinguish ischemicstroke from other conditions.

MRI is also useful in detecting silent cerebral infarcts.Silent cerebral infarcts are diagnosed on the basis of anabnormal MRI of the brain and a normal neurologicexamination. Some studies using brain MR imaging haveshowed infarction/ischemia in the absence of a recognizedcerebrovascular accident in 13% of patients (Moser et al.,1996). It is twice as common as clinical infarction andmayoccur in up to 22%of childrenwith sickle cell disease by 12years of age (Moritania et al., 2004). A silent cerebralinfarct has been defined as an area of abnormallyincreased signal intensity on the intermediate andT2-weighted pulse sequences of MRI. The area of abnor-mal signal must have an appearance consistent withinfarction and include a focal 3 mm or larger area ofabnormally increased signal intensity on the T2-weightedimage in more than one view (Armstrong et al., 1996).

Another common finding on MRI in patients withsickle cell disease is cerebral atrophy. This is a nonspeci-fic finding that serves as a marker for disease severity inthe brain.

Based onMR studies, cortical infarction is often seento be unilateral and in the frontoparietal location, andrelated to large vessel disease. White matter infarctionis often bilateral and in the frontoparietal location andthis appears to be related to small vessel vasculopathy(Moritania et al., 2004).

The neurologic complications of sickle cell diseaseoccur mainly as a result of the vasculopathy of the cen-tral nervous system (Stockman et al., 1972). It is there-fore most logical to investigate the disease processwith neuroimaging that is primarily based on evaluatingthe vasculature of the nervous system. Magnetic reso-nance angiography (MRA) provides critical informationon the status of the cerebral vasculature, and hasreplaced intra-arterial catheter angiography as an accu-rate and noninvasive technique to detect cerebral arterylesions (Kandeel et al., 1996). Moyamoya, a descriptionthat comes from the Japanese for “puff of smoke”because of the angiographic appearance of secondaryextensive collateral formation, is a secondary complica-tion of the cerebral vasculopathy of SCD. It is seen in35% of sickle cell disease patients at conventional angi-ography. In comparison, moyamoya vessels were seen in20% at MRI/MRA (Moritania et al., 2004).

Brain imaging abnormalities were reported in up to44% of children with sickle cell disease. The frequencyof brain imaging abnormalities detected by MRI/MRAin adults with sickle cell disease was higher than thatdescribed for children (Silva et al., 2009).

The prevention of stroke in children with SCD hasbeen markedly advanced by the introduction and testing

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of transcranial Doppler (TCD) as a noninvasive diagnos-tic test indicating high risk of first stroke. TCD usespulsed Doppler to measure the velocity and pulsatilityof blood flow within the major intracranial arteries ofthe circle of Willis. In children with sickle cell disease,there is involvement of the distal intracranial internalcarotid artery (ICA) and the proximal portions of themiddle (MCA) and anterior (ACA) cerebral arteries(Jeffries et al., 1980). The risk of stroke increasesdramatically as TCD flow velocity increases in thesebasal arteries, first probably on the basis of increasedflow velocity generally, and due to stenosis in the laterstages. The risk of stroke rises about 30% for each10cm/second increase above the median velocity forchildren with SCD (Adams et al., 2004). A large singlecenter prospective study demonstrated the likelihoodof stroke in children with sickle cell anemia was pre-dicted by TCD in the absence of regular transfusion(Adams et al., 1992, 1997).

Using TCD, a multicenter randomized controlledtrial, the Stroke Prevention Trial in Sickle Cell Anemia(STOP trial) confirmed that TCD, using a cutoff of200 cm/second velocity or higher, was associated witha 10% risk of stroke in the untreated group for the 2 yearsthat the trial was allowed to continue. In those childrenwho were randomized to regular transfusions (every 4weeks or so), however, the stroke risk was less than1% (p<0.001). The STOP study confirmed both theremarkable predictive power of TCD (10–20 times thebackground risk of stroke for unselected children withSCD) and the striking reduction of stroke with regulartransfusions (Adams et al., 1998). The STOP study ledto a clinical alert, issued by the National Heart, Lung,and Blood Institute (NLBHI), recommending TCDscreening of children with sickle cell disease betweenthe ages of 2 and 16 years as effective for assessingstroke risk.

TCD screening, followed by regular transfusion incases with high risk TCD, has now become the standardof care for children with SCD and is recommended bythe NHLBI (http://www.nhlbi.nih.gov/health/dci/Dis-eases/Sca/SCA_Treatments.html) and the AmericanStroke Association (Goldstein et al., 2011).

Transcranial Doppler velocities in adult patients withintracranial stenoses have been shown to be lower thanthose described for the pediatric population withsickle cell disease and it is not clear how predictiveTCD is for adults with SCD and stroke risk (Valadiet al., 2006; Silva et al., 2009).

Sibling studies have been conducted with TCD toinvestigate the possibility of a familial predispositionto elevated cerebral blood flow velocity. The presenceof a sibling with a positive TCD result was significantlyassociated with an elevated cerebral blood flow

1018 A. VENKATARAM

velocity in other siblings with SCD, consistent with afamilial predisposition to cerebral vasculopathy inSCD (Kwiatkowski et al., 2003).

Other tests indicate abnormalities in glucose metabo-lism and microvascular blood flow, particularly in thefrontal lobes, demonstrated in SCD patients using posi-tron emission tomography (PET). The addition of PET toMRI identifies a greater proportion of children withsickle cell disease with neuroimaging abnormalities, par-ticularly in those who had no history of overt neurologicevents (Rodgers et al., 1988; Powars et al., 1999; Reedet al., 1999).

Perfusion magnetic resonance (dynamic susceptibil-ity contrast MRI) and blood oxygen level-dependent(BOLD)MRI are additional imagingmodalities to assesscerebral blood flow and perfusion. Perfusion abnormal-ities are associated with neurologic symptoms in patientswith SCD, whether or not MRI, MRA, and TCD areabnormal (Kirkham et al., 2001a). Voxel-based mor-phometry analysis of MRI images is a sensitive methodto detect widespread white matter injury in SCD patientsin border zones between arterial territories even in theabsence of evidence of infarction (Baldeweg et al.,2006).

AND R.J. ADAMS

GENETICS

Sickle cell disease (SCD) and b-thalassemia, caused bylesions that affect the b-globin gene, form themost com-mon human genetic disorders worldwide. The autosomalrecessive genetic mutation producing sickle hemoglobinis a single nucleotide substitution (GTG for GAG) atcodon 6 of the b-globin gene on chromosome 11 thatresults in the substitution of valine for glutamic acidin the b-globin peptide. In an environment of hypoxia,this causes HbS to polymerize and form stiff bundlesthat distort the red cell, which in turn are less compliantthrough the microcirculation and result in vascularocclusion and the eventual chronic end organ damage.These RBCs are also prematurely removed from the cir-culation, resulting in a chronic hemolytic anemia.

Sickle cell disease is phenotypically complex, withdifferent clinical courses ranging from early childhoodmortality to a virtually unrecognized condition. Consid-ering the well characterized molecular details of HbSpolymerization, the explanation for the broad pheno-typic heterogeneity in patients with identical geneticmutations is still under investigation. If the primarymutation is the same, variations in disease severity gen-erally are due to genetic modifiers. In most genetic dis-eases involving b-globin, the most clear-cut influence onphenotype results from elevated fetal hemoglobinlevels (Rund and Fucharoen, 2008). Other factorsinclude b-globin cluster haplotypes, a-globin gene

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number, and fetal hemoglobin expression. The b-globinhaplotypes are associated with different severities insickle cell disease probably due to the variation in fetalhemoglobin concentration, which is protective againstthe stroke risk. The a-globin gene also influences the riskand protection against different complications of sicklecell anemia (Ashley-Koch et al., 2000).

Studies of sickle cell disease have drawn attention tothe importance of modifier genes and of gene–geneinteractions in determining stroke risk (Dichgans,2007). Modifier genes might interact to determine thesusceptibility to stroke. To find additional genetic mod-ulators of disease, genotype-phenotype association stud-ies, where single nucleotide polymorphisms (SNPs) incandidate genes are linked with a particular phenotype,have been informative (Steinberg, 2009).

A candidate gene study involving the analysis of 28genetic polymorphisms in 20 candidate genes, includingmutations in coagulation factor genes (factor V, pro-thrombin, fibrinogen, factor VII, factor XIII, PAI-1),platelet activation/function (GpIIb/IIIa, GpIb IX-V,GpIa/IIa), vascular reactivity (ACE), endothelial cellfunction (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) hasbeen proposed. A genome-wide screen of validated singlenucleotide polymorphisms (SNPs) to study the possibleassociation of additional polymorphisms with the high-riskphenotype has also been designed (Adams et al., 2003).

Studies of genetic risk factors for stroke in SCD (inaddition to the sickle mutation) have included associa-tion studies of predisposition genes for thrombosisand human leukocyte antigen (HLA) loci. Both class IHLA-B and class II HLA-DRBI (DR3) and DQBI(DQ2) alleles were associated with stroke risk in patientswith clinical stroke and silent infarction on MRI(Zimmerman and Ware, 1998; Driscoll and Prauner,1999; Styles et al., 2000; Hoppe et al., 2004). VCAM-1is a cell adhesion molecule postulated to play a criticalrole in the pathogenesis of SS disease. In a study of sin-gle nucleotide polymorphisms (SNPs) within the VCAM1gene locus, Taylor identified a variant that appears to beprotective (Taylor et al., 2002).

There is also a familial predisposition to stroke notedin sickle cell disease (Driscoll et al., 2003). This shouldprompt studies to identify genetic modifiers withfamily-based studies.

NEUROLOGIC COMPLICATIO

PATHOLOGY

The events clinically recognized as sickle cell disease areset off by a cascade of pathophysiological processestriggered by red cell injury secondary to the sickled

hemoglobin polymer. These include general cellularand tissue damage caused by hypoxia, oxidant damage,and inflammation and reduced nitric oxide bioavailabil-ity (Steinberg, 2008).

Recurrent inflammation and vasculopathy occur insickle cell disease, during crises, and in steady state. Dur-ing the inflammatory process, leukocytes and vascularendothelial cells are activated and increase their expres-sion of adhesion molecules. Adhesion of leukocytes toother blood cells and endothelium contributes to vaso-occlusion in sickle cell disease. High-level expression ofadhesion molecules by leukocytes is associated with clin-ically severe disease (Anyaegbu et al., 1998; Awogu,2000). Pancellular membrane lipid abnormalities, includ-ing reduced proportions of v-3 fatty acids, also occur insickle cell disease. These lipid abnormalities are moresevere in patients with disease complications and in thosewith a greater degree of anemia (Okpala, 2006). Othermarkers of inflammation seen in sickle cell diseaseinclude platelets (Okpala, 2002), C-reactive protein,a2-macroglobulin, transferrin (Hedo et al., 1993), interleu-kin (IL)-2, IL-4, IL-6, IL-8, fibrinogen, and activated cir-culating vascular endothelial cells (Hebbel et al., 2004).

On a cellular membrane level in the erythrocyte, afterrecurrent episodes of sickling, membrane damageoccurs and the cells are no longer capable of resumingthe biconcave shape upon reoxygenation. Thus, theybecome irreversibly sickled. When erythrocytes sickle,they gain Naþ and lose Kþ. Membrane permeabilityto Caþþ increases, possibly due, in part, to impairmentin the Caþþ pump that is dependent on adenosinetriphosphatase (ATPase). The membrane becomes morerigid, possibly due to changes in cytoskeletal proteininteractions.

The pathophysiology of cerebrovascular disease insickle cell anemia may involve stenosis of large arteriesof the circle of Willis, intracranial hemorrhage, and/ormicrovascular disease (Stockman et al., 1972; Moseret al.,1996) Cerebral infarction, a common complicationof sickle cell disease, usually occurs in the distribution ofthe large vessels comprising the anterior circle of Willis,most often as a result of stenosis or occlusion in the areaof the bifurcation of the carotid artery (Pavlakis et al.,1989). Vascular neuroimaging of patients with sickle cellanemia often demonstrates progressive narrowing of thelarge vessels with collateral vessel development in a pat-tern very similar to moyamoya disease (Dobson et al.,2002). Patients with this moyamoya-like vasculatureare at a higher risk for strokes. Histology of these nar-rowed vessels is suggestive of intimal hyperplasia andproliferation of the internal elastic lamina, consistentwith endothelial damage (Rothman et al., 1986).

Presumably, stroke is caused by perfusion failure inareas of stenosis or to arterial embolization. Factors that

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have been implicated in the development of the vascularlesions in the brain include the above mentioned inflam-matory processes such as leukocyte-mediated injury tothe endothelium, damage caused directly by the sickledred cells, inflammation mediated by cytokines, andquantitative and qualitative platelet abnormalities(Francis, 1991; Hebbel and Vercellotti, 1997). The diseasealso involves enhanced angiogenic propensity, activationof coagulation, disordered vasoregulation, and a compo-nent of chronic vasculopathy (Hebbel et al., 2004b).

In conjunction with diminished NO bioavailability,these processes likely underlie the chronic vasculopathycomponent of sickle disease. Endothelium-derived nitricoxide (NO) plays a major role in the regulation of vaso-motor tone. These results suggest that endothelial dys-function may prevent vasoregulation, which may alsocontribute to the pathophysiology of vaso-occlusivecrisis in patients with sickle cell disease (Belhassenet al., 2001). Reduced activity of naturally occurring anti-coagulants protein C and protein S may contribute tovaso-occlusion in sickle cell disease (Schnog et al., 2004).

A growing body of evidence supports the existence ofa novel mechanism of human disease, namely,hemolysis-associated smooth muscle dystonia,vasculopathy, and endothelial dysfunction (Rotheret al., 2005). Given the pathophysiological processesmentioned above, it is a possibility that this mechanismof disease is essentially the hallmark of the pathology ofsickle cell disease.

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MANAGEMENT

When contemplating management of the neurologiccomplications of SCD, one must take into account treat-ment of acute cerebrovascular accidents and itssequelae, while also considering prophylactic methodsfor long-term better outcomes.

In the acute setting, stroke, particularly hemorrhagic,may initially require intensive monitoring of intracranialpressures, treatment of vasospasm with volume expan-sion and/or nimodipine, and aggressive treatment of sei-zures if any. Craniotomy may be necessary to preventherniation or for clipping or wrapping of the cerebralaneurysm. Other strategies such as adequate hydration,normothermia, and euglycemia should be maintainedand hypotension should be avoided in the setting of acutestroke.

Antiplatelet therapy is generally recommended inadults after ischemic stroke, and there are no apparentreasons why this should not be advocated in adults withischemic stroke who have SCD. Other options are dis-cussed in the American Stroke Association Guidelineson Secondary Stroke Prevention (Furie et al., 2011). Thereare no specific recommendations regarding the use of

antiplatelet agents or anticoagulants in stroke in childrenwith SCD either acutely or long term. Antiplatelet agents(e.g., aspirin) and heparins (e.g., low molecular weightheparin) have been used on an individual patient basisin children with arterial ischemic strokes (Nowak-Gottlet al., 2003; Soman et al., 2006). There have been no ran-domized controlled clinical trials with thrombolytics inthe treatment of acute ischemic stroke in children andalthough the risk of hemorrhage may be higher, SCDdoes not represent a known contraindication to tPAuse in adults.

Physical, occupational, and speech therapy are impor-tant and should be initiated early in the childrenwho havesuffered a stroke. Early rehabilitation has a more favor-able prognosis for recovery of function.

One of the essential interventions in the managementof acute ischemic stroke in children with SCD is emer-gent blood transfusion to reduce the HbS level below30%. The multicenter STOP trial demonstrated thattransfusion to maintain HbS<30% decreased the inci-dence of first stroke in high-risk pediatric patients, iden-tified by transcranial Doppler (TCD). This is the onlyproven paradigm with class I evidence for primarystroke prevention in SCD (Adams et al., 1998b). Transfu-sion should be continued at least until age 18; HbSmay beallowed to rise to approximately 50% in older adoles-cents and young adults by reducing either the intensityor frequency of transfusions. The STOP II study showedthat discontinuing chronic transfusions after 30 months,even though the TCD values had dropped from above200 to< 170 cm/second (considered low risk or normalat that point), nonetheless resulted in a high rate of rever-sion to abnormal TCD values and stroke (class I) (Adamsand Brambilla, 2005).

The role of chronic transfusion for the prevention ofrecurrent events has not been defined for patients withtheir initial stroke as an adult.

It has also been shown that the incidence of silentinfarcts (radiologically detected) were decreased inpatients receiving chronic transfusion as compared tostandard care showing that chronic transfusion therapymay also prevent silent infarcts in children with SCD(Pegelow et al., 2001). However, chronic transfusiontherapy is associated with complications such as ironoverload, alloimmunization, and infections. Erythrocy-tapheresis, an automated method of red blood cellexchange, is a safe method of controlling HbS levelsand limiting or preventing iron load in chronically trans-fused SCD patients (Kim et al., 1994; Marques Junioret al., 1995; Adams et al., 1996).

Hemosiderosis is well known consequence of inten-sive and long-term transfusion therapy. Although bothSCD and thalassemia patients suffer from iron-inducedorgan injury, the onset of clinical manifestations due to

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iron overload appears to be more gradual in SCDpatients, suggesting a relative protection from iron-related organ injury (Finch, 1982). Exchange transfu-sions and chelation therapy are two methods to managetransfusion-related iron overload. Iron chelation therapyis donewith deferoxamine at a dose of 25 mg/kg/day as asubcutaneous or intravenous infusion. Complications ofthis chelation method include ototoxicity, rash, andgrowth retardation in young children. The US Foodand Drug Administration (FDA) recently approveddeferasirox for treatment of chronic iron overload dueto blood transfusions in patients aged 2 years and older.The drug is taken orally once daily which may improvecompliance over deferoxamine. Chelation therapy withmore than one agent offers the possibility ofmore effec-tive removal of iron without compromising safety orcompliance.

Recent studies have documented alloimmunizationrates as high as 47% in adult and 27% in pediatric trans-fused SCD patients, respectively (Rosse et al., 1990;Vichinsky et al., 1990; Tahhan et al., 1994; Aygunet al., 2002). One method to decrease the rates of alloim-munization and hemolytic transfusion reactions is usingleuko-depleted red cells matched for E, C, and Kell anti-gens. Other strategies to minimize alloimmunizationinclude PEG-coating of red cells to mask red cell anti-gens from antibodies (Fisher, 2000), as well as artificialblood substitutes, such as perfluorocarbon emulsionsand hemoglobin-based substitutes (Lowe, 2003; Hableret al., 2005; Maevsky et al., 2005).

The use of leukocyte-depleted red cell transfusionshas had a significant effect on reducing the transmissionof intracellular viruses such as cytomegalovirus (CMV),human lymphotrophic virus, Epstein–Barr virus (EBV),and human herpes virus 6, 7, 8 infectious complications(Fergusson et al., 2003). Transmission of HIV, hepatitisB and C, and human T cell leukemia/lymphoma virus-1has dramatically decreased with improved donor selec-tion criteria and screening of banked units (AuBuchonet al., 1997).

For adult patients who decide to discontinue transfu-sions, or those with problematic alloimmunization, ironoverload, or other impediments to chronic red blood celladministration, hydroxyurea (HU) therapy should beconsidered to prevent recurrent events. Based on resultsfrom the double blind, placebo-controlled MulticenterStudy of Hydroxyurea (MSH), HU was approved inadults with SCD to decrease the frequency of vaso-occlusive episodes and blood transfusion requirements(Charache et al., 1995). Follow-up data from the MSHhave confirmed a reduced mortality after 9 years ofHU therapy (Steinberg et al., 2003). Hydroxyurea ther-apy is started at a dose of 15 mg/kg/day and increasedby 5 mg/kg/day every 8–12 weeks with monthly

NEUROLOGIC COMPLICATIO

monitoring of the platelets, reticulocytes, and neutro-phils. Hydroxyurea was tested for secondary stroke pre-vention in children with SCD based on a single centerstudy by Ware et al. (2004). They discontinued chronictransfusion (after more than 2 years of treatment) in35 children and put them on hydroxyurea. These patientsalso received phlebotomies for iron overload. Althoughthese phase II results showed a promising trend, the ran-domized controlled trial called SWiTCH was terminatedearly due to futility.

The results are not yet published but the followinginformation was available from the sponsor’s websiteon NHLBI (http://www.nih.gov/news/health/jun2010/nhlbi-03.htm):

The 26-site trial, Stroke With Transfusions

Changing to Hydroxyurea, or SWiTCH, studied

133 participants between the ages of 5 and 18

who had already experienced a stroke. All had

been receiving the standard treatment of blood

transfusions for at least 18 months and high levels

of iron before entering the study. Without further

preventive measures, these children were at high

risk of another stroke as well as life-threatening

conditions due to iron overload.

The study tested whether the drug hydroxy-

urea, known to prevent complications of sickle

cell disease in adults, was as effective as transfu-

sions, the standard therapy, in reducing the risk of

recurrent strokes. Hydroxyurea is the only FDA-

approved drug for treating sickle cell anemia.

The study also compared two approaches to

remove excess iron, a consequence of regular

blood transfusions. Participants who continued

to receive transfusion therapy were given the stan-

dard oral iron-removal drug deferasirox, and par-

ticipants who were switched to hydroxyurea

underwent regular phlebotomy (blood removal)

to eliminate excess iron that had accumulated

from their earlier transfusions.

Phlebotomy did not reduce liver iron better

than deferasirox therapy. Analysis of the available

data indicated that continuing the trial was

unlikely to show that phlebotomy would provide

a greater benefit than deferasirox to control iron

accumulation. Without the ability to provide ben-

efits for the management of liver iron, the poten-

tial risks of continuing study treatments were no

longer warranted.

. . . The DSMB noted that no strokes occurred

in the 66 participants who received the standard

therapy of blood transfusions and deferasirox. In

contrast, seven strokes occurred in the group of

67 participants who received hydroxyurea with

S OF SICKLE CELL DISEASE 1021

AN

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, comparinghydroxyurea to regular blood transfusion for primarystroke prevention (based on the STOP protocol), willbegin enrolling patients in 2011 (http://ccct.sph.uth.tmc.edu/twitch/, 2009).

Allogeneic bonemarrow transplantation (BMT) fromHLA-identical siblings is an accepted treatment for boththalassemia and sickle cell disease. Related cord bloodtransplantation for hemoglobinopathies is reported tooffer a good probability of success (Locatelli et al.,2003). Bone marrow transplantation (BMT) ispotentially curative alternative for secondary strokeprevention (Walters et al., 2004). Lack of an eligibleHLA-compatible sibling donor and potentialtransplant-related complications remain substantial bar-riers to BMT in SCD. Novel conditioning regimens thatminimize transplant-associated toxicity and alternativestem cell sources show promise for the wider applicationof BMT in SCD.

Moyamoya patients with ischemic symptoms andpoor perfusion on a cerebral blood flow study are goodcandidates for direct or indirect bypass procedures.Encephaloduroarteriosynangiosis (EDAS) permits neo-vascularization to develop over a larger area of the brainthan observed with direct anastomosis and has beenrevealed to cause cessation of symptomatic attacksmuch sooner than the natural course of the disease.The EDAS procedure is a safe and effective treatmentoption in patients with sickle cell anemia who developmoyamoya disease (Fryer et al., 2003). Operative treat-ment of moyamoya syndrome using pial synangiosisappears to be safe and confers long-lasting protectionagainst further stroke in this population, and providesan alternative for failure of optimal medical therapyin patients (Smith et al., 2009).

Emerging novel primary prophylaxis regimens beingtested include citrulline and arginine, aspirin, short-chainfatty acids, lovastatin, decitibine, and overnightoxygen supplementation. Screening for, and appropriatemanagement of, nocturnal hypoxemia might be a safeand effective alternative to prophylactic blood transfu-sion for primary prevention of central nervous eventsin sickle cell disease (Kirkham et al., 2001b). Antioxidanttherapy using a stable and long-acting molecule such asan intravascular superoxide dismutase mimetic polyni-troxyl albumin may have a potential in amelioratingSS red cell adhesion and related vaso-occlusion(Kaul et al., 2006).

1022 A. VENKATARAM

There are several studies underway to investigate thepromise of some of the above-mentioned therapies inprimary prevention and prevention of recurrent strokesin patients with SCD, and possibly even curative in thiscondition.

AND R.J. ADAMS

CONCLUSIONS

Sickle cell disease and related hemoglobinopathies arecomplex conditions, with patients exhibiting a vast vari-ety of neurologic complications. The health burden forchildren with SCD and their families is profound andmay be exacerbated by barriers to accessing comprehen-sive medical care (Boulet et al., 2010). SCD patients arereported to experience health-related quality of lifeworse than the general population. Greater public aware-ness of the neurocognitive effects of SCD and theirimpact on child outcomes is a critical step towardimproved treatment, adaptation to illness, and qualityof life (Schatz and McClellan, 2006).

In spite of all the progress in the understanding of thecomplicated nature of neurologic sequelae of SCD, thereremains much work to be done in this field to aid in theprevention and cure of this disease. For now, preventionof first stroke is one important step that can be taken tolower the stroke burden in SCD.

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