Effect of transfusion therapy on cerebral vasculopathy in children with sickle-cell anemia

This retrospective study assessed the long-term effect of transfusionalexchange therapy on MRA/MRI abnormalities in 24 homozygous sickle-cellanemia (HbSS) children presenting with abnormal brain MRA. Themedian time elapsed from baseline to last available MRA was29 months. Follow-up MRAs showed improvement, stabilizationor worsening of cerebrovascular lesions in 11, 6 and 7 patientsrespectively. Complete normalization of MRA was observed in6 patients within a mean time of 1.4 years, but stenosis recurredat the same location in the 4 patients in whom transfusion therapywas discontinued. Baseline severe stenosis/occlusion of largecerebral arteries and occurrence of moyamoya syndrome were significantlyassociated with an absence of improvement of the cerebral vasculopathy.These data emphasize the heterogeneity of the course of cerebrovasculopathyin SS children receiving chronic transfusion. Further studiesare needed to determine whether different therapeutic approacheshave to be considered according to these different evolutivepatterns in SS children.

Key words: sickle-cell anemia, children, cerebral vasculopathy, stroke.

Introduction

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Introduction

Cerebral vasculopathy is a devastating complication of sicklecell disease.¹ Chronic transfusions are effective in preventingthe short-term recurrence of infarctive stroke² and the occurrenceof a first cerebral infarction in HbSS children who have abnormallyhigh velocities on transcranial Doppler ultrasonography (TCD).³After acute stroke in sickle cell anemia patients, chronic transfusiontherapy has been shown to nearly stop progression of stenosisin most children,^4,5 but progressive large vessel disease hasbeen evidenced in HbSS children presenting with moyamoya syndrome.⁶The purpose of our study was to assess the long-term effectof repeated transfusion on brain magnetic resonance angiography(MRA) in 24 HbSS children presenting with narrowing of largecerebral arteries, regardless of the initial presentation oftheir cerebral vasculopathy.

Design and Methods

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Design and Methods

Patients
One thousand and seventy-five children with sickle cell diseasewere followed in our center between January 2000 and July 2007.HbSS and HbS-β₀ children were screened yearly for cerebralvasculopathy by TCD. Patients with abnormally high velocity(>200 cm/sec) in at least one artery and those with a neurologicalevent were imaged by MRI/MRA. Among them, we retrospectivelyreviewed the records of all patients who i) had cerebral vasculopathyon cerebral MRA; ii) received regular exchange transfusion (ET);iii) who were followed for a minimum of one year after the onsetof transfusion therapy and iv) who had at least two availableMRAs. Patients were assessed for indication for MRA, TCD imaging,brain MRA and MRI and mean hemoglobin S value (Hb S). Oral consentwas obtained from the parents and, when possible, the patients,in keeping with French national recommendations. In accordancewith French regulations, no ethical committee agreement wasneeded for this retrospective study.

Transfusion therapy
Patients who presented with an acute neurological event receivedone exchange transfusion equal to 1/2 of their blood volumewithin 24 hours following stroke. The remaining patients wereput on a monthly transfusion program for three months as soonas abnormal velocities were identified on TCD. Subsequentlyall patients received exchange blood transfusions at 3–5week intervals to maintain hemoglobin levels between 9 and 10g/dL and HbS at less than 30%. Exchange transfusion was definedas either manual exchange transfusion or automated erythrocytopheresis.Reported HbS values where measured prior to each transfusionaltherapy by high performance liquid chromatography.

Transcranial Doppler
Duplex TCD imaging was performed using several ultrasound systems(Hitachi, Toshiba) as previously described.⁷

Brain magnetic resonance angiography and brain magnetic resonance imaging
Brain MRA/MRI was performed within 48 hours following an acutestroke, and within three months following the demonstrationof an abnormal TCD screening. MRI/MRA was repeated every 1–2years in each patient. Patients with moderate vascular diseasehad one more MRI/MRA six months after the first imaging. WhenMRA abnormalities resolved, a second MRA was performed withinsix months to confirm these features. MRI/MRA included brainparenchyma study by axial T1 and FLAIR sequences, coronal T2turbo spin echo, and axial diffusion sequence, and a study ofthe Willis arterial circle by a 3D time-of-flight sequence.

Imaging data were reviewed by two pediatric radiologists (MEB,SV) and included the presence or absence of vascular lesions,their locations and severity, the presence or absence of moyamoyasyndrome, and the presence or absence of parenchymal lesions;a score was assigned to each lesion. Degree of vessel stenosis(stenosis score) was assessed by the reviewers for each arteryby a code number: 4-occluded vessel, 3-severely stenosed (75%),2-moderately stenosed (50%), 1-mildly stenosed (25%), 0-normalvessel; moyamoya syndrome was defined as absent, moderate orsevere (codes of 0, 1, 2 respectively). MRA score was obtainedby summarizing the codes of each lesion, and ranged from 0 to35. Brain lesions were classified as absent, white matter lesions,jonctional infarct, territory infarct (codes of 0, 1, 2, 3 respectively);cerebral atrophy was classified as absent, mild, moderate orsevere (codes of 0, 1, 2, 3 respectively). MRI score was obtainedby summarizing the codes of each lesion, and ranged from 0 to21. Mild and moderate stenoses were grouped under the term "moderateabnormality".

Statistical analysis
Discrete data were reported as frequencies. Non-normally distributeddata are reported as median (first, third quartile). Discretedata were compared by the Fischer test. Continuous variableswere compared by the Wilcoxon-Mann Whitney test. Monthly HbS values were entered as time-dependent covariate in a Cox model.All tests were bilateral and alpha level of 5% was consideredas statistically significant. Statistical analysis was performedusing the SAS 9.1 (SAS Inc, Cary, NC, USA) software package.

Results and Discussion

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Results and Discussion

Twenty-four HbSS patients (14 males, 10 females) were included.Indication for MRA/MRI was abnormally high velocities on TCDscreening in 17 patients or occurrence of an acute neurologicalevent in 7 patients. Acute stroke occurred at a median age of2.1 years (range, 1–6.6), and abnormally high velocitieson TCD screening was detected at a median age of 8.5 years (range,2.1–13.7) in the 17 remaining patients. The main baselineclinical and radiological characteristics of the patients arelisted in Table 1. Baseline MRI was normal in 6 patients, andrevealed territory infarct, jonctional infarct and white matterlesions in 12, 4 and 4 patients respectively.

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Table 1. Baseline clinical and radiological characteristics of the 24 SS children under regular transfusion regimen for cerebral vasculopathy.

The median time elapsed from baseline to last available MRAwas 29 months. Three evolutive patterns were observed. Cerebralvasculopathy improved in 11 patients with a decrease of medianMRA score from 3 (range, 1–9) to 0 (range, 0–6).It remained stable in 6 patients (median MRA 5, range, 2–13).It worsened in 7 patients with an increase of median MRA scorefrom 10 (range, 2–16) to 14 (range, 4–20), includingthe single patient who experienced a recurrent stroke. Thesethree patterns were observed in the patients who presented withstroke at baseline (2/7, 2/7 and 3/7 patients respectively),as well as in the remaining patients who underwent a systematicscreening (9/17, 4/17 and 4/17 patients respectively). The newstenoses involved mostly anterior cerebral arteries (5 stenoses)and less frequently internal carotid arteries (2 stenoses).Complete normalization of MRA was observed in 6 patients withina mean time of 1.4 years (range, 1–1.8 years); TCD wasinformative in 3 of these patients in whom normal cerebral velocitieswere evidenced. Transfusion therapy was stopped in 4/6 patients,but mild or moderate stenosis recurred at the same location,10–16 months after the last exchange transfusion; cerebralvelocities returned to conditional (2 patients) or abnormalvalues (2 patient). Baseline median MRI score was 2 (range,0–8). None of the patients developed new or more extensivebrain lesions, except for cerebral atrophy in 5 patients. Baselinesevere stenosis/occlusion of large cerebral arteries and occurrenceof moyamoya syndrome were significantly associated with an absenceof improvement of the cerebral vasculopathy (Table 2). Conversely,MRI score, number of cerebral stenosis, median time elapsedfrom baseline to last available MRA and HbS value did not differsignificantly between the patients who experienced an improvementin cerebral vasculopathy and those who did not (Table 2). Patientswho presented with stroke where less likely to show an improvementin their cerebral vasculopathy than those who were diagnosedthrough systematic TCD screening, but the number of patientswas low, and the difference did not reach significance.

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Table 2. Baseline clinical and radiological characteristics and HbS values of the 24 SS children under regular transfusion regimen for cerebral vasculopathy according to their pattern of the course of cerebrovasculopathy.

The present study emphasizes the wide heterogeneity of the courseof cerebral vasculopathy in HbSS children on regular transfusionprotocol. Vessel abnormalities have been reversed in one quarterof the patients, while MRA evidenced progressive large vesseldisease in one other quarter. The pathophysiology of SCD cerebrovasculopathyremains poorly understood, and might be determined by a geneticfactor, such as VCAM polymorphisms, which alters stroke risk.⁸Different therapeutic approaches might be considered accordingto these different patterns of evolution. Hydroxyurea (HU) hasbeen proposed as an alternative to transfusion therapy in childrenwith cerebrovascular disease.⁹ Multiple properties may explainthe beneficial effects of HU: decrease in expression of redcell and endothelial-cell adhesion molecules, decrease in neutrophiland reticulocyte counts, inhibition of erythrocyte sicklingby increasing fetal hemoglobin and decrease in the plasma-freehemoglobin by giving nitric-oxyde.¹⁰ HU decreased elevated TCDvelocities,^11,12 or allowed transfusion to be stopped in somepatients who had normalized high velocities upon transfusiontherapy.⁷ However, in all these studies, a subset of patientsdid not respond to HU, presenting with a higher rate of strokerecurrence than expected with transfusion therapy,^11,12 or redevelopinghigh velocities when off transfusion.⁷ Multicenter trials areneeded to identify a selected SS children population who mightbe switched from transfusion regimen to HU therapy. In our series,recurrence of arterial stenosis at the same location was observedin 4 children after discontinuation of transfusion therapy,as previously reported in 2 children.⁴ These features suggestthe persistence of endothelial dysfunction as the result ofintimal hypertrophy, as evidenced in Kawasaki disease afterregression of coronary aneurysms.¹³ Thus, treatment must notbe disrupted even after disappearance of cerebral stenosis onMRA imaging. The respective indications for regular transfusionregimen and HU therapy in these patients remain to be determined.Conversely, progressive large vessel changes were observed inone quarter of patients and was associated with high baselinestenosis and moyamoya scores, reflecting a severe endothelialinvolvement. Moyamoya syndrome had been previously shown tobe associated with progressive vessel narrowing in childrenwho received transfusion therapy.⁶ Risk of recurrence of strokeis decreased from 25.6/100 patient-years in non-transfused childrento 4.2/100 patient-years in children receiving chronic transfusion,²but not completely suppressed, as evidenced in our series. Thus,new therapeutic approaches are needed in the subset of patientspresenting with progressive cerebral vascular disease leadingto recurrent strokes despite transfusion therapy.

Finally, our data emphasize the heterogeneity of the courseof cerebrovasculopathy in SS children receiving chronic transfusion.Further studies are needed to determine if different therapeuticapproaches have to be considered according to these differentpatterns of evolution.

Acknowledgments

we thank Mrs Priscilla Armoogum for her help with statisticalanalysis.

Footnotes

Authorship and Disclosures

BB-M, SV, ME-B, GI, FS, SF, FM, RD, AB, MB have participatedin the conception of the study, in the analysis of the dataand in writing the manuscript. CA, IZ have participated in theanalysis and statistical interpretation of data.

The authors reported no potential conficts of interest.

Received for publication July 4, 2008. Revision received September 8, 2008. Accepted for publication September 15, 2008.

References

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