SEARCH

SEARCH BY CITATION

Regular, chronic red cell transfusions (CTX) have been shown to be effective prophylaxis against stroke in sickle cell disease (SCD) in those at risk. Because serial brain imaging is not routinely performed, little is known about the impact of CTX on silent infarcts (SI) and cerebral vascular pathology. Thus, we retrospectively evaluated the magnetic resonance imaging reports of a cohort of SCD patients who were prescribed CTX for either primary or secondary stroke prophylaxis. Seventeen patients with Hb SS were included (mean age 15 years, mean follow-up 4.3 years). Eight patients were on CTX for primary prophylaxis. New SI occurred in 17.6% of patients corresponding to an SI rate of 5.42 per 100 patient-years. Vasculopathy of the cerebral arteries was present in 65% of patients and progressed in 63% of these patients. Those who developed progressive vasculopathy were on CTX for an average of 8 years before lesions progressed. Patients on CTX for secondary prophylaxis had more SIs and evidence of progressive vascular disease than patients on CTX for primary prophylaxis. We conclude that adherence to CTX does not necessarily prevent SI or halt cerebral vasculopathy progression, especially in those with a history of overt stroke.

Cerebrovascular disease is a major complication of sickle cell disease (SCD) and can manifest as an overt stroke, defined as abnormal magnetic resonance imaging (MRI) changes with corresponding clinically apparent neurologic symptoms [1], or a silent infarction (SI), MRI changes occurring without any symptoms. The majority of children with overt strokes have cerebral vasculopathy (injury to intracranial arterial walls) involving the anterior portion of the Circle of Willis [2, 3]. The pathophysiology of vasculopathy in SCD has been attributed to multiple molecular and mechanical mechanisms [4]. Chronic hemolysis in SCD causes decreased nitric oxide availability, which may lead to oxidative damage of vessels. Chronic inflammation in SCD causes increased leukocyte activation, which may also lead to endothelial damage. Finally, damage to arterial walls from high blood flow velocity due to anemia may cause noninflammatory intimal hyperplasia of intracranial arteries, leading to progressive vascular stenosis, establishing a focus for thrombosis, infarction, and overt stroke [5, 6].

The role of cerebral vasculopathy in the development of SI is still unclear. One hypothesis is that stenosis of medium to large cerebral vessels may set up hemodynamic conditions in which perfusion to distal microvascular beds is impaired, leading to neuronal death around affected microvasculature. This theory may be supported by the finding that those with elevated transcranial Doppler ultrasound (TCD) velocities (representing stenosis of medium to large cerebral vessels) and previous SI have a high risk of developing new or progressive SI [1].

Prophylaxis with regular, chronic erythrocyte transfusions (CTX) for cerebral vascular accident (CVA) prevention is currently recommended for children found to have abnormally high mean blood flow velocities in either the proximal middle cerebral artery or distal internal carotid artery as measured by TCD (termed primary CVA prophylaxis) [7] and in patients who have suffered from an overt CVA (termed secondary CVA prophylaxis). Overall, CTX for primary and secondary CVA prophylaxis reduces the relative risk of stroke in both groups by 85% [8].

Few studies have evaluated the longitudinal effects of primary and secondary CVA prophylaxis on SI or vasculopathy in SCD. There is a paucity of data on the effect of CTX on SI incidence, though a multi-center trial is currently being conducted [15]. Older studies have reported inconsistent findings on the effects of CTX on vasculopathy [3, 5, 9–12], while more recent work seems to suggest that CTX does not prevent progressive cerebrovascular disease [13, 14]. Thus, we retrospectively examined the prevalence and incidence of SI and changes in radiological cerebral vasculopathies in a cohort of SCD patients on primary or secondary stroke prophylaxis who had serial surveillance MRI and magnetic resonance angiography (MRA) of the brain.

Patients

Seventeen patients met inclusion criteria, with eight patients on primary stroke prophylaxis and nine patients on secondary stroke prophylaxis. There were nine males and eight females, with a mean patient age of 15 years (range: 6–23 years). The median follow-up for each patient was 1,184 days (3.2 years), with a mean of 1,580 days (4.3 years ± 3.9), and a range of 275 to 5,819 days. A total of 73.83 patient-years were available for analysis, with an average of 2.7 MRI/MRA studies per patient (range 2–6). The average time interval between the first and last MRI/MRA was 4.3 years. Table I outlines the MRI and MRA findings of the 17 patients.

Table I. MRA/MRI Findings of Each Study Subject. All Subjects with Hgb SS Disease
PatientAge (years)/genderTransfusion indicationInitial findingFollow-up findingOverall changesStudy interval (years)
VascularWMDVascularWMD
  1. L, left; R, right; ICA, internal carotid artery; SC-ICA, supraclinoid internal carotid artery; MCA, middle cerebral artery; ACA, anterior cerebral artery; PCA, posterior cerebral artery; O, occlusion; S, stenosis; H, hypoplasia; CO, complete occlusion; N, narrowing; WS, worsened stenosis; NEV, no evidence of vasculopathy; PL, parietal lobe; FL, frontal lobe; TL, temporal lobe; OL, occipital lobe; PVR, periventricular region; CS, centrum semiovale; IC, internal capsule; T, thalamus; P, putamen; CN, caudate nucleus; CCB, corpus callosal body; WSD, watershed distribution; E, encephalomalacia; BL, bilateral; DWMI, deep white matter infarct; WMD, white matter disease; WML, white matter lesions; IWMD, increased white matter disease; CC, cystic change; I, infarct; OI, old infarct; AI, acute infarct; NII, new interval infarct; and NEWMD, no evidence of white matter disease.

120/FIschemic strokeL/ICA/O; R/SC-ICA/S; small caliber L MCA and ACAL/PL/E; BL/CS/DWMIGenerally progressive stenosesStable WMDProgressed vasculopathy; stable WMD11
211/FIschemic strokeL/ACA,MCA/S; R/PCA/SBL/FL/WML; L/PL/DWMI; L/PVR/DWMI w/CCStableStable WMDStable vasculopathy; stable WMD3.4
313/FIschemic strokeL/ACA,MCA, SC-ICA/S; R/MCA/O; R/SC-ICA/S; moyamoyaR/MCA/IL/MCA/OStable WMDProgressed vasculopathy w/moyamoya; stable WMD3.8
421/FIschemic strokeL/SC-ICA/S; L/MCA/S,O; L/ACA/H; R/ACA/S,O; moyamoyaL/MCA/OI; L/PL, TL/E; R/FH/WMLL/MCA/CO; R/ACA/COStable WMDProgressed vasculopathy w/moyamoya; stable WMD5.6
516/MIschemic strokeL/ICA, PCA/N; L/ACA,MCA/O; R/ICA/S; R/MCA/O; R/ACA/N,O; moyamoyaL/MCA/OI,E; R/MCA/OI, EStableStable WMDStable vasculopathy w/moyamoya; stable WMD1.25
623/MIschemic strokeL/ICA/N; L/MCA,ACA/O; R/MCA/N; R/ICA/O; moyamoyaBL/FL/E; BL/PL/WML; BL/FL, CS, IC/WML; R/T/WML; CCB thinningStableStable WMDStable vasculopathy w/moyamoya; stable WMD4.2
78/MIschemic strokeL/SC-ICA,ACA/S; R/SC-ICA, ACA, MCA/SR,WSD/FL/AI; R/PVR/WML; L/FL/WMLL/SC-ICA/O; R/MCA/O; R/ACA,SC-ICA/WSR/FL/IWMDProgressed vasculopathy; Progressed WMD2.9
87/MIschemic strokeL/ACA,MCA/S; R/ACA,SC-ICA/S; moyamoyaL/FL, P, CN/OI; R/PVN/WML; L/PL/AI; R/CS/AIR/ACA/OStable WMDProgressed vasculopathy w/moyamoya; stable WMD1.9
921/FIschemic strokeNEVR/PL/E,WMD; R/FL,CS/WMLL/ACA/S; R/SC-ICA/SR/CS/IWM; R/PL/NIIProgressed vasculopathy; progressed WMD16
1014/FAbnormal TCDsNEVL/FL/WMLNEVStable WMDNEV; Stable WMD1.5
118/MAbnormal TCDsNEVBL/FL/DWMI; R/OL, PL/DWMINEVStable WMDNEV; Stable WMD2.5
1220/FAbnormal TCDsNEVBL/PL/DWMI; L/FL/DWMINEVStable WMDNEV; Stable WMD1.7
1321/MAbnormal TCDsNEVNEWMDNEVNEWMDNEV; NEWMD7.25
146/MAbnormal TCDsNEVNEWMDNEVNEWMDNEV; NEWMD0.75
1516/FAbnormal TCDsNEVNEWMDR/ICA/SL/FL, PVR/WMLNew vasculopathy; new WMD1.6
1617/MAbnormal TCDsL/SC-ICA, MCA, ACA/S; R/SC-ICA/SBL/CS/WMLStableStable WMDStable vasculopathy; stable WMD3.25
1716/MAbnormal TCDsNEVNEWMDNEVNEWMDNEV; NEWMD5.25

White matter disease/SI

No patient in this study was found to have had an overt stroke during the observation period. Four of eight (50%) patients on primary CVA prophylaxis had evidence of focal deep white matter lesions on initial imaging, with only one of these patients (patient 15) developing new white matter disease. The rest of the patients on primary prophylaxis did not progress. All nine patients prescribed secondary prophylaxis had white matter disease (WMD) on their initial imaging, with two patients (patients 7 and 9) developing new and/or progressive WMD over the course of approximately 3 and 4 years, respectively. Overall, we found three progressive and one new white matter lesions in three patients, all of which were asymptomatic based on clinical reports. Thus, in this cohort, we observed a rate of 5.42 silent infarcts per 100 patient-years while on CTX, and a prevalence of 17.6%.

Vasculopathy

Overall, 11 of 17 (65%) patients had evidence of cerebral macrovascular pathology, either at initial or subsequent imaging. Of these patients, 63% (7 of 11) had progressive vasculopathy while on CTX. Patients who developed progressive vascular disease were receiving transfusions for an average of 8 years (median = 9.1 years) before their imaging studies revealed progressive vasculopathy. The median time interval between studies for those patients with evidence of progressive vasculopathy and those without evidence of progression was 3.8 years (mean: 6 years) and 3.1 years (mean: 3 years), respectively. Progressive lesions were primarily characterized by increased degree of stenosis of vessels initially affected, rather than involvement of previously unaffected vessels.

Primary prophylaxis

Eight subjects were on primary stroke prophylaxis with two (25%) patients having abnormal macrovascular pathology. One (patient 15) had normal initial imaging, but developed de novo 50% stenosis of the right internal carotid artery (RICA) after a total of 10 years, while the other (patient 16) had vasculopathy on baseline imaging which remained stable over 4 years of observation. The other remaining six (75%) patients had no evidence of vasculopathy (Table II).

Table II. Comparison of Patients on Primary Stroke Prophylaxis and Secondary Stroke Prophylaxis
 Number of subjectsProgressive vasculopathyNew silent infarcts
  1. Patients on secondary stroke prophylaxis are at higher risk for development of progressive vasculopathy, and possibly silent infarct.

Total1773
Primary prophylaxis811
Secondary prophylaxis962

Secondary prophylaxis

A total of nine patients were on secondary stroke prophylaxis and eight (89%) had evidence of initial vasculopathy. Six of the nine (67%) patients had evidence of progressive vasculopathy, with the remaining three patients (33%) exhibiting stable vasculopathy. Five patients had evidence of moyamoya and based on clinical reports, the moyamoya had developed in these patients while receiving CTX (Table II).

Our results suggest that CTX does not necessarily halt the progression of vasculopathy in children with SCD on secondary stroke prophylaxis. These observations are consistent with those of Brousse et al. who used a standardized scoring system to grade vascular lesions [13]. Their results demonstrated that in a group of 18 patients on primary and secondary CVA prophylaxis, vasculopathy progressed in patients on secondary prophylaxis, but did not progress in patients receiving primary CVA prophylaxis. A post-hoc analysis of data from the Stroke Prevention Trial in Sickle Cell Anemia (STOP) also found that vasculopathy is not likely to progress in those without a history of overt stroke [16].

Other studies have attempted to assess cerebral vascular changes in those with SCD on CTX for CVA prophylaxis. Two small studies reported progression of vasculopathy in 35–47% of patients [12, 17]; however these findings are confounded by nonadherence with CTX in 33–50% of those observed to have progressive vasculopathy. Though these rates of vasculopathy progression are similar to our finding of progression in 41% (7 of 17) of patients, our patients are known to be adherent to CTX as documented in their medical records. The significance of progressive vasculopathy, however, remains unclear. No patients in our cohort had an overt stroke during the period in which they were observed. It has been suggested that even if vasculopathy persists, smoothing of vascular luminal surfaces due to CTX may prevent recurrent stroke in affected patients [9]. In our analysis, vasculopathy may progress even after a decade of CTX therapy. Further long-term follow up is needed to better determine the impact of CTX on SCD vasculopathy.

The Cooperative Study of Sickle Cell Disease (CSSCD) sampled an unselected group of 266 children with HbSS and found a SI prevalence of 21.8% and an incidence rate of 7.06 per 100 patient-years [11]. In our cohort, we found a 17.6% SI prevalence and an incidence rate of 5.42 per 100 patient-years. Due to our small sample size, we were unable to calculate whether this is a statistically meaningful difference. Thus, the role of CTX in SI prophylaxis remains unclear. However, King et al. have recently reported that CTX is a feasible treatment option for prophylaxis of progression of SI and are conducting a large multicenter study (the Silent Cerebral Infarct Transfusion trial, or SIT trial) to assess the efficacy of CTX in preventing progression of SI in patients with SI at baseline [18].

Technological advances in imaging techniques over the period of observation in our study may represent another study limitation. Our initial imaging techniques may not have picked up true WMD due to low resolution, leading to the conclusion of development of new WMD once higher resolution MRI scanners were employed over a long observation period. In one published study, a higher SI prevalence in SCD patients was found when compared with historical controls using a higher Tesla MRI scanner [19]. Other limitations of our study include its retrospective design and the subjective nature of radiologic reading.

In conclusion, in SCD patients receiving stroke prophyaxis, new vasculopathy may develop and progress despite CTX. Patients on primary prophylaxis had less progression than those on secondary prophylaxis, consistent with other published reports. This supports the clinical observation that early detection and intervention are key components to maintaining normal or stable cerebral vasculature in the setting of SCD. In addition, SIs can occur in high risk SCD patients despite CTX, although our study could not determine any effects of CTX on SI development due to small sample size. The SIT trial will be better able to clarify the efficacy of this intervention. Our study highlights MRI/MRA as an important, noninvasive tool in monitoring cerebral pathology in patients with SCD and stroke risk. Further longitudinal studies are needed to understand the significance of progressive vasculopathy in SCD.

Methods

An IRB-approved retrospective chart review was performed on patients at Lucile Packard Children's Hospital and Children's Hospital Oakland with the diagnosis of hemoglobin SS who were receiving either primary or secondary stroke prevention as per the National Institute of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI) guidelines. Inclusion criteria included adherence with transfusion therapy as documented by the medical records and hemoglobin S levels, and undergoing at least two MRI and MRA images taken while receiving CTX. Age at study entry, age at CTX initiation, duration of CTX, history of stroke and neurologic studies, and signs and symptoms suggestive of stroke were recorded. MRI and MRA images and reports were centrally reviewed by a board-certified neuroradiologist at Lucile Packard Children's Hospital blinded to all clinical data.

Acknowledgements

We would like to thank the staff of the Sickle Cell Program at Children's Hospital and Research Center at Oakland for all of their help on this project. We would also like to acknowledge the Stanford University Medical Scholars program, which provided funding for this study.

References

  1. Top of page
  • 1
    Wong WY,Powars DR. Overt and incomplete (silent) cerebral infarction in sickle cell anemia: Diagnosis and management. Hematol Oncol Clin North Am 2005; 19: 839855, vi.
  • 2
    Debaun MR,Derdeyn CP,McKinstry RCIII. Etiology of strokes in children with sickle cell anemia. Ment Retard Dev Disabil Res Rev 2006; 12: 192199.
  • 3
    Goldberg HI,Zimmerman RA. Central nervous system. Semin Roentgenol 1987; 22: 205212.
  • 4
    Kato GJ,Hebbel RP,Steinberg MH,Gladwin MT. Vasculopathy in sickle cell disease: Biology, pathophysiology, genetics, translational medicine, and new research directions. Am J Hematol 2009; 84: 618625.
  • 5
    Gerald B,Sebes JI,Langston JW. Cerebral infarction secondary to sickle cell disease: Arteriographic findings. AJR Am J Roentgenol 1980; 134: 12091212.
  • 6
    Morris CR. Mechanisms of vasculopathy in sickle cell disease and thalassemia. Hematol Am Soc Hematol Educ Prog 2008: 177185.
  • 7
    Adams RJ,McKie VC,Hsu L, et al. Prevention of a first stroke by transfusions in children with sickle cell anemia and abnormal results on transcranial Doppler ultrasonography. N Engl J Med 1998; 339: 511.
  • 8
    Buchanan GR,DeBaun MR,Quinn CT,Steinberg MH. Sickle cell disease. Hematol Am Soc Hematol Educ Program 2004: 3547.
  • 9
    Russell MO,Goldberg HI,Hodson A, et al. Effect of transfusion therapy on arteriographic abnormalities and on recurrence of stroke in sickle cell disease. Blood 1984; 63: 162169.
  • 10
    Moser FG,Miller ST,Bello JA, et al. The spectrum of brain MR abnormalities in sickle-cell disease: A report from the cooperative study of sickle cell disease. AJNR Am J Neuroradiol 1996; 17: 965972.
  • 11
    Pegelow CH,Macklin EA,Moser FG, et al. Longitudinal changes in brain magnetic resonance imaging findings in children with sickle cell disease. Blood 2002; 99: 30143018.
  • 12
    Moritani T,Numaguchi Y,Lemer NB, et al. Sickle cell cerebrovascular disease: Usual and unusual findings on MR imaging and MR angiography. Clin Imaging 2004; 28: 173186.
  • 13
    Brousse V,Hertz-Pannier L,Consigny Y, et al. Does regular blood transfusion prevent progression of cerebrovascular lesions in children with sickle cell disease? Ann Hematol 2009; 88: 785788.
  • 14
    Mirre E,Brousse V,Berteloot L, et al. Feasibility and efficacy of chronic transfusion for stroke prevention in children with sickle cell disease. Eur J Haematol 2010; 84: 259265.
  • 15
    Casella JF,King AA,Barton B, et al. Design of the silent cerebral infarct transfusion (SIT) trial. Pediatr Hematol Oncol 2010; 27: 6989.
  • 16
    Abboud MR,Cure J,Granger S, et al. Magnetic resonance angiography in children with sickle cell disease and abnormal transcranial Doppler ultrasonography findings enrolled in the STOP study. Blood 2004; 103: 28222826.
  • 17
    Minniti CP,Gidvani VK,Bulas D, et al. Transcranial Doppler changes in children with sickle cell disease on transfusion therapy. J Pediatr Hematol Oncol 2004; 26: 626630.
  • 18
    King AA,Noetzel M,White DA, et al. Blood transfusion therapy is feasible in a clinical trial setting in children with sickle cell disease and silent cerebral infarcts. Pediatr Blood Cancer 2008; 50: 599602.
  • 19
    Steen RG,Emudianughe T,Hankins GM, et al. Brain imaging findings in pediatric patients with sickle cell disease. Radiology 2003; 228: 216225.

Elsie Gyang*, Kristen Yeom†, Carolyn Hoppe‡, Sonia Partap§, Michael Jeng*, * Department of Pediatrics, Stanford University School of Medicine, Palo Alto, California, † Department of Radiology, Stanford University School of Medicine, Palo Alto, California, ‡ Department of Pediatric Hematology/Oncology, Children's Hospital and Research Center Oakland, Oakland, California, § Department of Neurology, Stanford University School of Medicine, Palo Alto, California.