From www.bloodjournal.org by guest on September 10, 2016. For personal use only.

Review article

Silent cerebral infarcts: a review on a prevalent and progressive cause of

neurologic injury in sickle cell anemia
Michael R. DeBaun,1 F. Daniel Armstrong,2 Robert C. McKinstry,3 Russell E. Ware,4 Elliot Vichinsky,5 and
Fenella J. Kirkham6
1Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, TN; 2Department of Pediatrics, Miller School of Medicine, University of Miami,

and Holtz Children’s Hospital at the University of Miami/Jackson Memorial Medical Center, Miami, FL; 3Departments of Radiology and Pediatrics, Washington
University, St Louis, MO; 4Department of Pediatrics, Baylor College of Medicine, Houston, TX; 5Children’s Hospital & Research Center Oakland, Oakland, CA;
and 6Neurosciences Unit, University College London Institute of Child Health, London, United Kingdom

Silent cerebral infarct (SCI) is the most
common form of neurologic disease in
children with sickle cell anemia (SCA). SCI
is defined as abnormal magnetic reso-
nance imaging (MRI) of the brain in the
setting of a normal neurologic examina-
tion without a history or physical findings
associated with an overt stroke. SCI oc-
curs in 27% of this population before their
sixth, and 37% by their 14th birthdays. In
adults with SCA, the clinical history of
SCI is poorly defined, although recent
evidence suggests that they too may have
ongoing risk of progressive injury. Risk
factors for SCI include male sex, lower
baseline hemoglobin concentration,
higher baseline systolic blood pressure,
and previous seizures. Specific morbidity
associated with SCI includes a decrement
in general intellectual abilities, poor aca-
demic achievement, progression to overt
stroke, and progressive SCI. In addition,
children with previous stroke continue to
have both overt strokes and new SCI
despite receiving regular blood transfu-
sion therapy for secondary stroke preven-
tion. Studies that only include overt stroke
as a measure of CNS injury significantly
underestimate the total cerebral injury
burden in this population. In this review,
we describe the epidemiology, natural
history, morbidity, medical management,
and potential therapeutic options for SCI
in SCA. (Blood. 2012;119(20):4587-4596)

Introduction
One of the most devastating medical complications of sickle cell
anemia (SCA) is cerebral injury, which limits the full potential of
the developing child and adult. The most common neurologic
injury in SCA is silent cerebral infarct (SCI). Although there are
few studies, SCI occurs in approximately one-quarter of children
with SCA before their sixth birthday1 and approximately one-third
before their 14th birthday.2 The first evidence that SCI had clinical
significance was published in a cross-sectional computed tomogra-
phy (CT) scan study of 25 patients. Five had cerebral infarcts but
only 4 had a focal neurologic deficit (overt stroke).3 The investigators
referred to the fifth patient as having a covert stroke,3 a term also used by
others.4 The term SCI or silent stroke has gained widespread use to
describe this condition because the Cooperative Study of Sickle Cell
Disease (CSSCD) used standard clinical magnetic resonance imaging
(MRI) to define the radiologic parameters.5 Subsequently, only a few
studies of SCI have been completed. Until recently, the clinical
importance of identifying SCI did not seem to justify the expense of
MRI requiring sedation or anesthesia in preschool children, particularly
in the absence of an effective intervention. Despite being the most
common type of cerebral injury among children and adults with SCA,
relatively little is known about the cause and optimal therapy of
SCI. We will review the current literature on definition, epidemiol-
ogy, natural history, clinical significance, medical management,
and potential therapeutic options for the treatment of SCI in SCA.
Definition of SCI in children with SCA
The largest longitudinal cohort study to address the prevalence and
incidence of SCI in children with SCA was the CSSCD, an
observational study of children identified as infants and followed
closely over the subsequent decade, which used MRI of the brain to
detect abnormally increased T2-weighted signal intensity on mul-
tiple views (Figures 1 and 2) in children without current focal
neurologic deficits as assessed by a hematologist. Previous neuro-
logic history other than seizures, for example, coma, dizziness,
ataxia, or transient focal weakness, was not explored. Hematolo-
gists may have discounted subtle neurologic findings that may have
classified as abnormal and suggesting a prior overt stroke if
reviewed by neurologists.6 The more precise definition used by
Casella et al7 in The Silent Cerebral Infarct Trial (SIT Trial)7,8
included a MRI lesion measuring at least 3 mm in greatest linear
dimension, visible in at least 2 planes of T2-weighted images (axial
and coronal; Figure 2B-C). The SIT Trial definition excluded prior
seizures and required no current focal neurologic deficit that could
be explained by the anatomic location of the presumed SCI. Thus,
individuals could have a focal neurologic examination, for ex-
ample, compatible with a peripheral neuropathy, but would still
meet the definition of SCI if the location of the infarct would not
account for the neurologic deficit.

Submitted February 28, 2011; accepted January 5, 2012. Prepublished online © 2012 by The American Society of Hematology
as Blood First Edition paper, February 21, 2012; DOI 10.1182/blood-2011-02-
272682.

BLOOD, 17 MAY 2012 䡠 VOLUME 119, NUMBER 20 4587

 From www.bloodjournal.org by guest on September 10, 2016. For personal use only.

4588 DeBAUN et al BLOOD, 17 MAY 2012 䡠 VOLUME 119, NUMBER 20

Figure 1. MRI in sickle cell disease. Coronal T1-weighted MRI (A,E) and axial T2-weighted MRI (B-D,F-H) in patients with homozygous SCA. (A-C) Normal MRI in a
19-year-old man with homozygous SCA. (D) Three years later, there is no change. (E-G) Silent infarction (arrows) in the frontal white matter and basal ganglia in a 15-year-old
girl with cognitive problems affecting school performance but no acute neurologic presentation. (H) Three years later she has further infarcts with evidence of mild generalized
atrophy and had a transient right hemiparesis as well as developing signs of a diplegia.

show corresponding hypointensity on the T1-weighted image

Alternate definition of SCI in adults with SCA
In the first systematic study of SCI in adults with SCA, Vichinsky
et al used a definition of a minimum of 5 mm signal hyperintensity
in the T2-weighted image,9 but to be included, lesions also had to
(Figures 1E, 2A). Normal adults typically accumulate T2 hyperin-
tensities as they age, but children do not. This more restrictive
definition of SCI and the distinction from encephalomalacia and
atrophy (Figures 1H, 2D-H) parallels the descriptions used in
general populations of asymptomatic elderly adults with SCI.10

Figure 2. MRI in sickle cell disease. (A) Coronal T1-weighted MRI, (B) coronal T2-weighted MRI, and (C-H) axial T2-weighted MRI in patients with homozygous SCA.
(A-C) Silent cerebral infarction (white arrows) in the parietal white matter in a 10-year-old girl with headache. (D) Three years later, there is progressive atrophy on MRI in the
context of intermittent ataxia and squint. (E-H) Four cases associated with acute illness. (E) Silent cerebral infarction (black arrows) in the watershed regions between the
anterior, middle, and posterior regions, including the deep white matter, in a patient who had previously had posterior reversible encephalopathy syndrome in the context of
cyclosporine treatment for nephrotic syndrome. (F) Bilateral watershed infarction in a child who had seizures in the context of a facial infection. Motor examination was normal
but his IQ was reduced by 30 points compared with premorbid testing. (G) Encephalomalacia after sagittal sinus thrombosis secondary to pneumococcal meningitis.
(H) Occipital infarction after acute chest crisis. A homonymous visual field defect was detected after the infarct was noted on MRI.
 From www.bloodjournal.org by guest on September 10, 2016. For personal use only.

BLOOD, 17 MAY 2012 䡠 VOLUME 119, NUMBER 20 REVIEW OF SILENT INFARCTS IN SCA 4589

Figure 3. A 10-year-old boy with sickle cell disease and history of acute chest syndrome now presents with pain crisis. MRI of the brain was requested for episodic
slurred speech. Axial FLAIR MR image (left) and DWI (middle) illustrate many of the manifestations of SCD in the brain. The arrowheads on the FLAIR image point out areas of
old (silent) infarctions in the white matter of the centrum semiovale on the right and at the posterior aspect of the left superior frontal gyrus. The DWI shows an additional area of
signal abnormality in the anterior aspect of the right superior frontal gyrus, representing a recent infarction. In addition, there is atrophy of the left cerebral hemisphere, which is
seen in the setting of sickle cell–associated vasculopathy manifest by nonvisualization of the left middle cerebral artery by MRA (arrows on the right image). The MRA also
shows subtle collaterals (moyamoya vessels) in the lenticulostriate distribution on the left (arrowhead).

cohort, the prevalence of SCI at baseline was 21.2%.15 SCIs

Challenges with the definition of SCI
In addition to the varying definitions of SCI, lesion detection is
dependent on the magnetic resonance (MR) technique (fluid
attenuation inversion recovery [FLAIR] or diffusion-weighted
imaging [DWI], see Figure 3, vs traditional T2-weighted images),
the slice thickness,11 and the magnetic field strength. As further
advances in imaging are made and medical centers transition from
1.5 Tesla to 3.0 Tesla magnets, more individuals with SCA will be
detected with SCI, and quantitative techniques are likely to detect
subtle abnormality in those without SCI on T2-weighted MRI.12,13
Use of the greater magnet strength will most likely have an impact
on measures of incidence and prevalence of SCI, especially in
longitudinal studies and CNS-related clinical trials. Thus, investiga-
tors must consider the anticipated change in the magnetic strength
of the scanner over time when conducting a longitudinal study.
Strict guidelines for radiographic assessment of SCI require the
ability to distinguish SCI from acute and chronic mimics of SCI
(Figure 4). Because of the possibility of misclassification of a
diagnosis of SCI when a new lesion is suspected, a dialogue
between the neuroradiologist, neurologist, and hematologist should
occur so both the clinical history and differential diagnoses can be
carefully considered.
As is required by this definition, children with SCI do not have
any obvious evidence of symptoms, other than perhaps academic or
behavioral difficulties. Quite often, the presence of SCI is detected
when the child presents with subtle neurologic findings prompting
a brain MRI. The neuroradiologist may identify additional previous
infarcts and distinguish an acute cerebral infarct from a previously
unknown SCI (Figure 3A). A focal DWI hyperintensity indicates an
ischemic injury within the last 8 to 10 days14 (Figure 3B), while the
presence of brain atrophy suggests a chronic process.
Clinical significance of SCIs
As part of the protocol for the observational CSSCD cohort, the
leadership group added serial surveillance MRI scans of the brain
of children beginning at 6 years of age. A total of 266 children with
SCA hemoglobin SS (HbSS) completed both a MRI of the brain
and a battery of age-appropriate tests of cognitive function. The
average age at initial scan was 8.3 years with each child having at
least 1 follow-up scan at a mean of 12.1 years of age. The mean
interval between first and follow-up studies was ⬃ 2 years. In this
commonly differ in size and location compared with overt strokes.
Whereas overt strokes are typically located in both cortex and deep
white matter,16 SCI in the CSSCD typically occurred in the deep
white matter of the frontal (81%; Figure 1E-F) or parietal (45%)
lobes (Figure 2A-D), followed in frequency by the basal ganglia
(Figure 1G-H) or thalamus (16%) and the temporal lobes (9%).15
Similar observations were reported for an unselected cohort of
132 children with SCA in Créteil, France undergoing brain MRI as
part of routine medical care2 and in other studies.4,5,17,18 SCI in SCA
are typically smaller in size compared with overt strokes. In the
CSSCD participants, 83% of the children with overt strokes, but
only 16% of those with SCI, had lesions that were at least 1.5 cm.15
The CSSCD results supported early observations that the
presence of SCI is a risk factor for additional neurologic injury,19
with a higher risk of both clinical stroke (14-fold), and progressive
silent infarction. Approximately 25% of the children with SCI, but
only 2.5% of the children without SCI, had new and/or enlarging
lesions on follow-up MRI scan. The incidence rates of new or more
extensive SCI were 1.0 and 7.0 events per 100 patient-years,
respectively, for children with or without preexisting SCI.15 SCI is
most common in patients with hemoglobin SS but may also be
identified in individuals with heterozygous genotypes includ-
ing sickle ␤-thalassemia and hemoglobin SC (HbSC) disease.
Approximately 3% to 38% of patients with sickle
␤-thalassemia,17,18,20,21 and 5% to 31% of those with HbSC
disease,15,22 will have SCI. However, limited sample size allows no
significant inferences about the rate of progression or potential
benefit of therapy.
One of the greatest limitations in defining the epidemiology of
SCI is the lack of longitudinal studies looking at incidence rate in
different age groups. Existing studies do not fully address when
SCI first occur in young children or whether the incidence of SCI
falls in adolescents. Both the CSSCD and the French cohorts
included children who were older than 6 years of age; thus, the
youngest age at which SCI occurred in these 2 studies could not be
determined. Three small studies have provided some estimates as
to when SCI may start to occur. In a single-center study, 39 children
with SCA with no history of a stroke underwent MRI between
7 and 48 months of age23; 4, including all 3 with a history of
seizures, had SCI. In the second study, a multicenter phase 3 study
(BABY HUG), MRI scans were performed in 23 infants with SCA
at an average age of 13.7 months; 3 (13%) had SCI.24 In the third
study, as part of routine medical care in children before their sixth
birthday, 27.7% (18 of 65) of the asymptomatic children with SCA
 From www.bloodjournal.org by guest on September 10, 2016. For personal use only.

4590 DeBAUN et al BLOOD, 17 MAY 2012 䡠 VOLUME 119, NUMBER 20

Figure 4. Differential diagnosis of silent infarction (images from patients without SCA). (A) Mimics of SCI: periventricular leukomalacia (PVL). A 20-month-old boy with
cerebral palsy characterized by spastic diplegia. Axial FLAIR MR images illustrate classic findings of PVL. The image on the left is at the level of the centrum semiovale and
demonstrates bilateral hyperintensities in the parietal lobe white matter. This appearance of the white matter overlaps with the presentation of SCI. The image on the right at the
level of the basal ganglia illustrates dysmorphic lateral ventricles, thinning of the periventricular white matter and periventricular signal hyperintensity in a predominantly
posterior distribution. Taken together, the images are consistent with the diagnosis of PVL in the setting of prematurity and cerebral palsy rather than SCI. (B) Terminal zones of
myelination. A 2-year-old boy with a normal MRI of the brain. The Axial FLAIR MR image (left) shows ill-defined hyperintensity bilaterally in the deep white matter adjacent to the
atria of the lateral ventricles (arrows). The T2-weighted image on the right illustrates that there are well-defined linear perivascular spaces (arrowheads) traversing the area of
vague hyperintensity. This combination of findings is classic for the terminal zones of myelination, the last areas of the deep white matter to myelinate and displace free water.
The terminal zones of myelination remain prominent through the second year of life and become progressively less conspicuous over time. They may be visible into the middle
of the first decade of life. (C) Virchow-Robin spaces. A 12-year-old boy withT2-weighted (left) and Axial FLAIR (right) MR images with a normal MRI. The T2-weighted images
reveal multiple punctuate white matter hyperintensities that suppresses on FLAIR indicating that the hyperintensities are indistinguishable from cerebrospinal fluid. The fluid
attenuation feature of the FLAIR image helps to differentiate perivascular (Virchow-Robin) spaces from SCI. The arrows illustrate another feature of perivascular spaces which
is that they appear linear when running within the slice. (D) Posterior reversible encephalopathy syndrome (PRES). A 14-year-old girl with altered mental status and seizures.
Axial FLAIR MR images demonstrate hyperintensities bilaterally in the subcortical white matter and overlying cortex with predominant subcortical involvement. The distribution
of the signal abnormalities is predominantly posterior and peripheral, a typical distribution for PRES. In contradistinction, SCIs favor the deep white matter of the frontal lobes.
Nevertheless, clinical context is the key to differentiating PRES from SCIs. This is especially challenging in patients with SCD because they are prone to development of PRES
and SCI. (E) Acute disseminated encephalomyelitis (ADEM). A 5-year-old boy with fever and headache. Axial FLAIR MR images demonstrate patchy, bilateral hyperintensities
in the white matter of the centrum semiovale and corona radiata (arrows). Although the image on the left could be confused for SCI in the frontal border zone distribution, the
middle and right image show subcortical and patchy hyperintensities that would be atypical in location, size, and lesion definition for SCI. The clinical information is the key to
distinguishing lesions of ADEM from SCI.

undergoing MRI had an SCI.1 In the French study, the incidence of
SCI was 28.2% by age 8 years of age and 37.4% by age 14 years of
age,2 suggesting absence of an incidence plateau (Figure 5),
providing one of the reasons for current and future secondary and
primary SCI prevention trials.
SCIs in adults with SCA
Solid estimates of the prevalence of SCI in adults with SCA are
limited by both the number of studies and study participants within
and across studies. In the first longitudinal study published among
patients with SCI, Kugler et al enrolled 16 individuals with SCA,
but no history of stroke or transient neurologic events and normal
neurologic examination, to undergo MRI of the brain at a mean age
of 20 years.19 The primary aim of this study was to determine the
predictive value of SCI as a risk factor for clinically apparent
strokes. Patients were followed for a mean of 3.7 years. Eight
(50%) had SCI, of whom 4 (25% of the total) had progressive
abnormalities on MRI, with 3 developing focal neurologic deficits.
In the 8 patients with normal brain MRI, there was no evidence of
progression on MRI or clinically. Although not a focus, this study
also found that the majority of the patients had significant deficits
on cognitive testing regardless of the presence of SCI.19
In another study of 50 adults, including 4 with overt stroke,
Silva et al found that leukoencephalopathy was the most common
abnormality (48%),25 followed by atrophy (28%; Figures 1H, 2D),
 From www.bloodjournal.org by guest on September 10, 2016. For personal use only.
BLOOD, 17 MAY 2012 䡠 VOLUME 119, NUMBER 20
Figure 5. Prevalence of SCI with 95% CIs plotted against age from
4 studies.1,2,23,24
encephalomalacia (6%; Figure 2F-H), and lacunes (Figure 1E-H;
4%). Vichinsky et al completed brain MRI in adults with SCA as an
initial component of a randomized trial.9 Entry into the study
required that the participants had a baseline hemoglobin concentra-
tion below 10 g/dL without any history of stroke or focal neuro-
logic deficits, known brain imaging abnormalities, serious cogni-
tive impairment, or evidence of depression. Nevertheless, in this
group of highly selected adults with SCA, SCI, referred to as
lacunar infarction, was present in 13% of the surveillance MRIs
compared with 2% of the ethnic and age-matched controls without
SCA. In contrast, white matter lesions occurred in 15% of
individuals with SCA and 7% of controls, atrophy was seen in 23%
of patients and 16% of controls, and a cortical infarct was detected
in one individual with SCA and one control. The difference in SCI
prevalence compared with the published pediatric cohorts may be
related to either (1) the highly selected group of well-functioning
adults with SCA or (2) a subtle, but important, variation in the
definition of SCI, related either to the difference in minimum size
(5 mm vs 3 mm) or to the requirement for T1 hypointensity, as well
as T2 hyperintensity in the adult study. A longitudinal study that
includes children, adolescents and adults with SCA is required to
determine the true natural history and sequelae of SCI. Based on
the high prevalence of SCI in adults with SCA, screening MRI of
the brain may be considered standard care, despite the lack of
evidence-based therapy, because detection of SCI may help facili-
tate employment or vocational options along with realistic expecta-
tions for the management of a complex chronic illness. Ultimately,
better data are required to understand the clinical course and
relevance of SCI in adults with SCA.
Neurocognitive outcomes associated with
SCIs
Children with SCI have lower cognitive test scores compared with
children with a normal MRI of the brain. Poorer global intellectual
function17,22,26-28 has been reported in several studies, with function
below the average range for the general population, but better than
that of children with overt strokes. In a summary of global
intelligence quotient in children with SCA and controls, Hogan
et al graphically displayed data from multiple studies that included
the Full Scale IQ (FSIQ) in controls without SCA, children with
SCA with or without SCI, and children with SCA and overt
stroke.29 The gradient in FSIQ demonstrated the following consis-
tent pattern: ethnically matched control children without SCA had a
mean FSIQ greater than children with SCA and without SCI, who
REVIEW OF SILENT INFARCTS IN SCA 4591
in turn had a FSIQ greater than those with SCI and covert and overt
strokes (Figure 6).29 The severity of the chronic anemia,9,17 and
other factors such as the home environment, are additional factors
to consider when assessing the impact of SCI on cognition in SCI
cognitive outcome.
Specific areas of deficit have been associated with SCI,
including executive functions like selective attention, card sorting,
working memory, and processing speed,4,30-32 visual motor speed
and coordination,4,22 vocabulary,17,22,28,33 visual memory,34 and
abstract reasoning and verbal comprehension.17,35 As a conse-
quence of these specific deficits, academic achievement in math
and reading are also affected, with one study reporting that the 35%
of children with SCA and SCI had twice the chance of academic
difficulties as those without SCI.26
Using the definition from the CSSCD, along with a negative
neurologic examination by a pediatric neurologist, the group at
Washington University demonstrated that lesion location correlated
with deficits attributable to the corresponding cognitive domain,36
that the volume of the SCI was associated with the magnitude of
cognitive deficit,37,38 and that the presence of SCI was associated
with poor academic attainment compared with controls.27 Together
these data clearly demonstrate that SCI are associated with a
specific cognitive profile correlating with their distribution in the
frontal lobe, and are associated with cognitive deficits and aca-
demic difficulties compared with children with SCA but normal
MRI as well as unaffected siblings (Figures 6 and 7).
Pathology
Large infarcts in an arterial territory, or in the border zones between
anterior and middle cerebral arteries, have been described in
patients dying after a documented overt stroke,39,40 in association
with endothelial hyperplasia, fibroblastic reaction, hyalinization
Figure 6. Mean Wechsler FSIQ scores obtained from children with SCD and
sibling controls as reported in 8 studies. The horizontal black line represents the
mean value for each category of children. FSIQ scores have a mean of 100 (SD 15).
Scores above 80 are within the average range according to Wechsler classification.27
(A) Armstrong et al22 (Normal MRI, n ⫽ 105; Silent Infarct, n ⫽ 21; Clinical History of
Stroke, n ⫽ 9; age range, 6-12 years). (B) Steen et al33 (Historical Control Data,
n ⫽ 30; Normal cMRI, n ⫽ 12; Abnormal cMRI, n ⫽ 10; mean age, 10 years;
SD, 3 years). (C) Watkins et al4 (Control, n ⫽ 15; SCD/nm, n ⫽ 15; Asymptomatic,
n ⫽ 4; Symptomatic, n ⫽ 5; age range, 5-16 years). (D) Bernaudin et al17 (Siblings,
n ⫽ 76; Normal MRI, n ⫽ 104; Silent Stroke, n ⫽ 17; With (Overt) Stroke,
n ⫽ 11; age range, 5-15 years). (E) Brown et al31 (no cerebrovascular accident [CVA],
n ⫽ 30; Silent, n ⫽ 11; CVA, n ⫽ 22; age range, 6-17 years). (F) Wang et al28 (Normal
MRI, n ⫽ 122; Silent Infarct, n ⫽ 43; Stroke, n ⫽ 20; age range, 6-18 years).
(G) Thompson et al64 (First Visit: Normal, n ⫽ 93; Silent Infarct, n ⫽ 29; Stroke,
n ⫽ 6; age range, 5-15 years). (H) Steen et al65 (African-American Controls, n ⫽ 30;
Patients, n ⫽ 30; mean age, 10 years; SD, 2.9 years).
 From www.bloodjournal.org by guest on September 10, 2016. For personal use only.
4592 DeBAUN et al
Figure 7. The proportion of students with SCA with and without SCIs and
sibling controls that have either failed a grade or received special services.26
and fragmentation of the internal elastic lamina, and thrombi in
large and small vessels.39 There are no autopsy studies from the
neuroimaging era that have focused specifically on the pathology
of subclinical brain damage, such as SCI, in SCA. Pathologies
inferred to account for the typical small necrotic lesions in the
border between the cortex and the subcortical white matter include
acute demyelination41 and venous sinus thrombosis,39 as well as
disease of the small arteries and arterioles.
Risk factors for SCIs
Only a few studies have specifically evaluated risk factors for
SCI in SCA. The CSSCD compared 42 children with SCA and
SCI with 188 children with SCA but without SCI. In a
multivariable logistic regression, clinical risk factors associated
with SCI included a history of seizures, low pain event rate,
elevated white blood cell count, and the SEN ␤S globin gene
haplotype.6 Two significant limitations should be considered,
however, when interpreting these results. First, the CSSCD
research team later updated their results from this same cohort
and acknowledged that their adjudication process for SCI
improved.15 Second, the sample size of children with SCI was
relatively small, limiting the ability to detect small differences
and resulting in odds ratios (ORs) with large confidence
intervals (CIs). In a single-center study of the risk factors for
SCI in a longitudinal prospective cohort,2 the only independent
risk factor for SCI was baseline low hemoglobin level.
In the SIT Trial cross-sectional study, in which participants with
epilepsy, as well as those with abnormal transcranial Doppler
(TCD), were excluded, 814 children with SCI-like lesions were
examined by a pediatric neurologist to confirm that the cerebral
lesions were not associated with any focal neurologic deficit, a
critical feature of SCI. Neuroradiology and neurology committees
adjudicated the presence of SCI, which was diagnosed in 30.8% of
participants. In a multivariable logistic regression analysis, the
following were statistically significantly associated with an in-
creased risk of a SCI: (1) hemoglobin in the lowest quartile,
⬍ 7.6 g/dL, compared with the highest quartile, ⱖ 8.6 g/dL (OR
2.12, 95% CI 1.45-3.10, P ⬍ .001); (2) systolic blood pressure
(SBP) in the highest quartile, ⬎ 113 mmHg, compared with the
lowest quartile, ⬍ 104 mmHg (OR 1.73, 95% CI 1.18-2.54,
P ⫽ .013); and (3) male sex compared with the reference popula-
tion female sex (OR 1.42, 95% CI 1.04-1.93, P ⫽ .026).8
BLOOD, 17 MAY 2012 䡠 VOLUME 119, NUMBER 20
SCIs and cerebrovascular disease
(TCD and MRA)
No established relationship exists between SCI and abnormal TCD
measurements or magnetic resonance angiography (MRA) imag-
ing. In the STOP (Stroke Prevention Trial in SCA) Trial, the
prevalence of SCI at randomization to regular blood transfusion or
standard treatment in those with abnormal TCD was 47 (37%) of
127 patients with SCD and abnormal TCD.42 This is similar to a
recent report from France in a single-center population not selected
for TCD abnormality.2 In a retrospective study of 78 children with
SCA from 5 centers participating in both the CSSCD and the STOP
Trial, including 17 children with SCI, Wang et al found no
significant statistical relationship between the presence of SCI and
abnormal TCD measurements.43 The majority of children with SCI
in the context of SCD do not have evidence of cerebral vasculopa-
thy as assessed by MRA of the circle of Willis.44 However, a larger,
more systematic, analysis is needed to formally address the
relationship between TCD measurements, SCI, and MRA
abnormalities.
Pathophysiology
SCI is believed to be a small vessel disease, although direct
evidence supporting this postulate is lacking. In fact, in 9 adults
without SCA, but with carotid occlusion, small lesions were
identified in the deep white matter, similar in character to SCI and
likely to be related to poor cerebrovascular hemodynamic re-
serve.45 In SCD, focal perfusion abnormalities are common46 and
are often, but not always, related to infarction (overt and silent) and
cerebrovascular disease. One MR perfusion study included
48 patients, 8 and 14 with overt stroke and SCI, respectively, and
25 with perfusion abnormality. Only 4 patients with small SCI had
no detectable perfusion abnormality.46 Studies exploring other
reasons for reduced perfusion, including imaging of the heart and
neck vessels, are required to exclude cardiac, carotid, or vertebro-
basilar occlusive disease as possible mechanisms.47 The predilec-
tion for SCI to occur in the border zone areas of the brain suggests
that hemodynamic factors could play a role in the pathogenesis.
Regardless of the etiology, chronic anemia is associated with
SCI and lower global IQ.17,48,49 Anemia results in hyperemia,
hypervolemia, and cerebral vasculature vasodilatation50 to main-
tain constant cerebral metabolic rate for oxygen. The intrinsic
compensatory mechanisms to maintain constant global cerebral
blood flow (CBF) are already close to the maximum levels, so any
decrease in CBF for physiologic reasons, for example, increased
carbon dioxide tension,50,51 compromised cardiac function,52 or
increased metabolic demand of the brain tissue, which carries a risk
of imbalance between demand and supply of oxygen to the brain.
As would be anticipated, children with SCA and acute illness that
results in either a decrease in oxygen delivery, such as acute chest
syndrome, or an increase in metabolic demands of the brain, such
as seizure or fever, would be expected to be at risk for SCI.
Dowling et al demonstrated that children with SCA and normal
MRA of the brain had evidence of SCI temporally associated with
clinical events that included, but were not limited to, acute drops in
their hemoglobin secondary to infection, decrease in oxygen
delivery secondary to acute chest syndrome, or increase in the
metabolic demands of the brain from fever.53 Thus, this small but
important case series, along with the recent data demonstrating that
 From www.bloodjournal.org by guest on September 10, 2016. For personal use only.
BLOOD, 17 MAY 2012 䡠 VOLUME 119, NUMBER 20
Figure 8. Potentially synergistic factors leading to SCI in SCA. Modified from
DeBaun et al54 with permission. Equation 1: The CMRO2 is the cerebral metabolic
rate for oxygen. The brain relies on a constant delivery of oxygen to maintain CMRO2.
If the delivery is inadequate, permanent tissue injury can occur, depending on the
depth and duration of the ischemia. The equation above relates cerebral blood flow
(CBF; the bulk delivery of blood to the brain), oxygen extraction fraction (OEF; the
fraction of available oxygen blood that leaves the blood by passive diffusion as it
passes through the circulation), and the arterial oxygen content (CaO2). Equation
2: CaO2, in turn, is a product of the hemoglobin content of blood and the arterial
oxygen saturation. Reduced hemoglobin (Hgb; or oxygen carrying capacity of the
existing Hgb) or hypoxia may reduce the arterial oxygen content. One can see the
potentially synergystic effects of these relationships in reducing the oxygen delivery
to the brain below critical thresholds. CaO2 can fall because of anemia and hypoxia
and CBF can fall because of the large artery vasculopathy. Patients with preexisting
arteriopathy may be more likely to suffer an ischemic stroke than other patients with
the same degree of anemia or hypoxia.
baseline low hemoglobin is a risk factor for SCI,2,8 provide proof of
principle that an alteration in either the delivery of oxygen (based
on a low hemoglobin) or increase in cerebral metabolic demand
(Figure 8), may provide sufficient cause for unsuspected SCI that
will only be detected with a low threshold to perform brain MRI.54
SCI may result from additional causes beyond hemodynamic
insufficiency. Some SCI may result from thromboemboli, for
example, related to patent foramen ovale53 or intrapulmonary
shunts, although the prevalence of SCI-associated patent foramen
ovale is probably similar to that in the general pediatric popula-
tion.53 The role of other mechanisms, such as posterior reversible
encephalopathy syndrome,55 venous sinus thrombosis,56 and demy-
elination,57 in the development of SCI has not been extensively
explored.
Clinical management of SCIs
Given the observation that SCI are associated with current morbid-
ity, including poor educational attainment26 and future cerebral
infarcts,15 evidence-based medical interventions are needed. How-
ever, currently no established therapy is available for primary or
secondary prevention of SCI.
Children with SCA with both SCI and abnormal TCD are at
higher risk of developing an overt stroke42 than those with only an
abnormal TCD measurement. In the STOP Trial, comparing
participants in the observation arm with both SCI and abnormal
REVIEW OF SILENT INFARCTS IN SCA 4593
TCD measurements versus those with only an abnormal TCD
measurement, the rate of a stroke was significantly greater: 52%
(15 of 29) compared with 21% (9 of 42; P ⫽ .008). These results
suggest that the presence of SCI in the setting of an abnormal TCD
measurement is associated with increased risk of stroke. In the
same study, the investigators demonstrated that blood transfusion
therapy attenuated the rate of strokes in the group with both SCI
and elevated TCD measurements compared with only elevated
TCD measurement, 0% (0 of 18) and 5% (2 of 38) respectively.
Twelve patients developed new or enlarged SCI after 36 months of
follow-up, only 1 of whom was randomized to transfusion. These
results provided preliminary evidence that regular blood transfu-
sion therapy may be effective in preventing neurologic injury and
served as strong preliminary data for the SIT Trial.7 In a follow-up
study, the results were similar. At the end of STOP2, when children
with elevated TCD measurements were randomized to continue or
to stop transfusion, 8% of participants who continued transfusion
developed new brain MRI lesions compared with 28% who
stopped. The total number of lesions decreased from 25 to 24 in the
continued-transfusion group while increasing from 27 to 45 in
those who stopped.58 Taken together, data from both STOP and
STOP2 indicated that children with SCA and both SCI and elevated
TCD measurements are at extremely high risk to have progressive
SCI. However, we do not know whether children with SCA, SCI,
and elevated TCD measurements below the transfusion threshold
are at increased risk of SCI and if so, whether the magnitude of the
risk outweighs the burden and benefit of regular blood transfusion
therapy.
Based on the high prevalence of SCI, the presence of cognitive
and educational morbidity, coupled with the progressive nature of
SCI, King et al performed a single-arm feasibility study demonstrat-
ing that parents were willing to accept blood transfusion therapy as
an intervention.59 These results also provided preliminary evidence
for the short-term efficacy of blood transfusion therapy to prevent
progression of neurologic injury in patients with SCI. Subse-
quently, the SIT Trial (NCT00072761) was funded.7 The primary
hypothesis of the SIT Trial is that children randomly allocated to
blood transfusion will have an 86% relative risk reduction of an
overt stroke or progressive SCI compared with children randomly
allocated to observation.7 A total of 1211 children with SCA
between the ages of 5 and 15 years were screened for SCI, of whom
196 were randomly allocated to either arm. The study is fully
enrolled; although, a 3-year follow-up is required, thus results from
this trial are not expected until after June 2013.
No other systematic strategy for the treatment of SCI has been
established. Hydroxyurea and HSCT are potential options for
primary and secondary prevention of SCI. There are preliminary
data for both therapies in single-arm studies, suggesting efficacy as
a secondary preventive strategy for SCI. Two groups have docu-
mented that no new SCI have occurred after successfully engrafted
HSCT57,60 although one HSCT study documented that new SCI
may occur in the immediate posttransplantation period.61 No
clinical trial has been undertaken to determine the relative benefits
and burden of HSCT as secondary prevention of SCI.
Recently, in a prospective multicenter, single-arm study,
Hulbert et al demonstrated that children with overt strokes receiv-
ing blood transfusion therapy may still develop new SCI.62 Forty
children with overt strokes were followed for ⬃ 5 years with
surveillance MRI and MRA performed every 1-2 years. The mean
pretransfusion hemoglobin S concentration was ⬍ 30% throughout
the treatment period. Approximately two-thirds of the patients had
MRA evidence of cerebral vasculopathy at baseline. Despite the
 From www.bloodjournal.org by guest on September 10, 2016. For personal use only.
4594 DeBAUN et al
Table 1. Clinical characteristics of overt strokes and silent cerebral infarcts in sickle cell anemia
Overt strokes
Frequency prior to 6th birthday 2%-5%
Mean global IQ 71
Primary prevention Transcranial Doppler followed by blood transfusion therapy
Secondary prevention Blood transfusion therapy HLA-matched sibling transplant
revascularization for moyamoya
rigorous transfusion regimen, 18% (7 of 40) and 28% (11 of 40) had
new overt or SCI, respectively. These data strongly challenge the
paradigm that blood transfusion therapy is an optimal therapy for
secondary prevention of stroke or SCIs when there is preexisting
vasculopathy. Furthermore, for children with overt strokes who are
receiving blood transfusion therapy, surveillance MRI of the brain
every 1-2 years should be done to assess whether there is progres-
sive neurologic disease because as many as 25% of this population
may develop new SCI,62 and alternative therapies, for example,
revascularization for moyamoya, might be considered.
Screening for SCIs
Despite the lack of evidence for an established medical treatment
for SCI, there is sufficient support that identifying SCI is of clinical
benefit to the child with SCA. Screening for SCI is currently
performed in selected hematology centers where multidisciplinary
teams are evaluating cognitive services and medical interventions,
for example, hydroxyurea or HSCT for children with SCA and
infarcts of the brain.1,2,63 Based on the high prevalence of SCI, at
least 27% before 6 years of age, coupled with the well-established
cognitive deficits, performing screening MRI examination in
students at least once is a reasonable strategy. Early diagnosis of a
SCI in a child with cognitive or behavioral problems may enable
teachers to alter strategies and may secure additional education
resources to help the student gain the skills necessary for successful
academic attainment. Services include, but may not be limited to,
occupational therapy, parent counseling, physical therapy, social
work services, speech/language pathology, assistive technology,
recreation, and counseling services. In the United States, special
services are provided in a least restrictive educational setting and
are designed specific to the needs of the students through Individual
Education Programs (IEPs). Eligibility for special education ser-
vices is identified by the school through a full evaluation of the
child in all areas of suspected disability. If the student is found
eligible for services, the school is required to convene the IEP team
annually and develop an appropriate plan for the child. The
presence of SCI in children with SCA, coupled with significant
deficits on cognitive test scores, greatly increases the likelihood of
obtaining an IEP in the United States or a statement of educational
needs in Europe. Similar strategies, namely assessment of re-
sources for adults with SCI, have not been studied.
Summary
Among children with SCA, SCI are prevalent and associated with
significant cognitive and academic morbidity. SCI is a distinct
BLOOD, 17 MAY 2012 䡠 VOLUME 119, NUMBER 20
Silent cerebral infarcts
27%
83
None established; ongoing limited institution studies of
hydroxyurea and HLA-matched sibling transplantation
None established; await the results of the Silent
Cerebral Infarct Transfusion Trial
clinical entity compared with overt stroke (see Table 1). The natural
history and risk factors for SCI are incompletely understood. SCIs
occur in infants as young as 1 year of age and continue throughout
childhood with the highest incidence rate in children ⬍ 6 years of
age. The frequency and natural history of new SCI occurring
among adults is not well defined. Among individuals with preexist-
ing SCI, there is a significant risk for new SCI or overt strokes
compared with individuals without SCI. The only method available
to reliably identify SCI is brain MRI. Children with SCD who
perform poorly in the classroom or have an acute decline in
academic performance should be considered for evaluation for SCI
using MRI, a neurologic examination, and cognitive testing. Adults
with SCA have at least a one-third chance of having a SCI. Given
the high neurologic disease burden, screening and detection of SCI
has become standard care where supportive services are readily
available. For children with SCA and SCI, an ongoing multicenter
international trial will determine whether blood transfusion therapy
is an efficacious treatment in preventing further neurologic injury
compared with observation.7 Until the results of this trial are
known, the use of transfusions should not be considered a standard
of care and only considered on a case-by-case basis. Likewise,
there is no high-level evidence to support the use of hydroxyurea or
HSCT for SCI. Future work should focus on the risk factors and
potential primary prevention of SCI, particularly in the highest risk
group, young children between infancy and 6 years of age.
Acknowledgments
The authors thank Diana Truran-Sacrey, MD, for initial comments
before preparing the manuscript; Mark Roedigher for preparing
Figure 5; and Cindy Terrill for manuscript preparation.
This work was supported by funding from the National Institute
of Neurological Disorders and Stroke (U01 NS042804; M.R.D.);
Burroughs Wellcome Translational Research Award no. 1006671
(M.R.D.); Action Medical Research (F.J.K.); and The Wellcome
Trust (0353521/A/92&94/Z and 056325/Z/98; F.J.K.).
Authorship
Contribution: M.R.D., F.D.A., R.C.M., R.E.W., E.V., and F.J.K.
analyzed the data and wrote the manuscript.
Conflict-of-interest disclosure: The authors declare no compet-
ing financial interests.
Correspondence: Michael R. DeBaun, Department of Pediat-
rics, Vanderbilt University School of Medicine, Nashville, TN
37232; e-mail: m.debaun@vanderbilt.edu.
 From www.bloodjournal.org by guest on September 10, 2016. For personal use only.
BLOOD, 17 MAY 2012 䡠 VOLUME 119, NUMBER 20
References
1. Kwiatkowski JL, Zimmerman RA, Pollock AN,
et al. Silent infarcts in young children with sickle
cell disease. Br J Haematol. 2009;146(3):300-
305.
2. Bernaudin F, Verlhac S, Arnaud C, et al. Impact of
early transcranial Doppler screening and inten-
sive therapy on cerebral vasculopathy outcome in
a newborn sickle cell anemia cohort. Blood. 2011;
117(4):1130-1140, quiz 1436.
3. Hindmarsh PC, Brozovic M, Brook CG, Davies SC.
Incidence of overt and covert neurological dam-
age in children with sickle cell disease. Postgrad
Med J. 1987;63(743):751-753.
4. Watkins KE, Hewes SKM, Connelly A, et al. Cog-
nitive deficits associated with frontal-lobe infarc-
tion in children with sickle cell disease. Dev Med
Child Neurol. 1998;40(8):536-543.
5. Moser FG, Miller ST, Bello JA, et al. The spec-
trum of brain MR abnormalities in sickle-cell dis-
ease: a report from the Cooperative Study of
Sickle Cell Disease. Am J Neuroradiol. 1996;
17(5):965-972.
6. Kinney TR, Helms RW, O’Branski EE, et al.
Safety of hydroxyurea in children with sickle cell
anemia: results of the HUG-KIDS study, a phase
I/II trial. Pediatric Hydroxyurea Group. Blood.
1999;94(5):1550-1554.
7. Casella JF, King AA, Barton B, et al. Design of the
silent cerebral infarct transfusion (SIT) trial. Pedi-
atr Hematol Oncol. 2010;27(2):69-89.
8. DeBaun MR, Sarnaik SA, Rodeghier MJ, et al.
Associated risk factors for silent cerebral infarcts
in sickle cell anemia: low baseline hemoglobin,
gender and relative high systolic blood pressure
[published online ahead of print November 17,
2011]. Blood. doi:10.1182/blood-2011-05-349621.
9. Vichinsky EP, Neumayr LD, Gold JI, et al. Neuro-
psychological dysfunction and neuroimaging ab-
normalities in neurologically intact adults with
sickle cell anemia. JAMA. 2010;303(18):1823-
1831.
10. Zhu YC, Dufouil C, Tzourio C, Chabriat H. Silent
brain infarcts: a review of MRI diagnostic criteria.
Stroke. 2011;42(4):1140-1145.
11. Steen RG, Emudianughe T, Hankins GM, et al.
Brain imaging findings in pediatric patients with
sickle cell disease. Radiology. 2003;228(1):216-
225.
12. Baldeweg T, Hogan AM, Saunders DE, et al. De-
tecting white matter injury in sickle cell disease
using voxel-based morphometry. Ann Neurol.
2006;59(4):662-672.
13. Chen R, Pawlak MA, Flynn TB, Krejza J,
Herskovits EH, Melhem ER. Brain morphometry
and intelligence quotient measurements in chil-
dren with sickle cell disease. J Dev Behav Pedi-
atr. 2009;30(6):509-517.
14. Provenzale JM, Sorensen AG. Diffusion-weighted
MR imaging in acute stroke: theoretic consider-
ations and clinical applications. AJR Am J Roent-
genol. 1999;173(6):1459-1467.
15. Pegelow CH, Macklin EA, Moser FG, et al. Longi-
tudinal changes in brain magnetic resonance im-
aging findings in children with sickle cell disease.
Blood. 2002;99(8):3014-3018.
16. Moser FG, Miller ST, Bello JA, et al. The spec-
trum of brain MR abnormalities in sickle-cell dis-
ease: a report from the Cooperative Study of
Sickle Cell Disease. AJNR Am J Neuroradiol.
1996;17(5):965-972.
17. Bernaudin F, Verlhac S, Freard F, et al. Multi-
center prospective study of children with sickle
cell disease: radiographic and psychometric cor-
relation. J Child Neurol. 2000;15(5):333-343.
18. Zafeiriou DI, Prengler M, Gombakis N, et al. Cen-
tral nervous system abnormalities in asymptom-
atic young patients with Sbeta-thalassemia. Ann
Neurol. 2004;55(6):835-839.
19. Kugler S, Anderson B, Cross D, et al. Abnormal
cranial magnetic resonance imaging scans in
sickle-cell disease. Neurological correlates and
clinical implications. Arch Neurol. 1993;50(6):
629-635.
20. Manfre L, Giarratano E, Maggio A, Banco A,
Vaccaro G, Lagalla R. MR imaging of the brain:
findings in asymptomatic patients with thalasse-
mia intermedia and sickle cell-thalassemia dis-
ease. AJR Am J Roentgenol. 1999;173(6):1477-
1480.
21. Marouf R, Gupta R, Haider MZ, Adekile AD. Silent
brain infarcts in adult Kuwaiti sickle cell disease
patients. Am J Hematol. 2003;73(4):240-243.
22. Armstrong FD, Thompson RJ Jr, Wang W, et al.
Cognitive functioning and brain magnetic reso-
nance imaging in children with sickle cell disease.
Neuropsychology Committee of the Cooperative
Study of Sickle Cell Disease. Pediatrics. 1996;
97(6 Pt 1):864-870.
23. Wang WC, Langston JW, Steen RG, et al. Abnor-
malities of the central nervous system in very
young children with sickle cell anemia. J Pediatr.
1998;132(6):994-998.
24. Wang WC, Pavlakis SG, Helton KJ, et al. MRI
abnormalities of the brain in one-year-old children
with sickle cell anemia. Pediatr Blood Cancer.
2008;51(5):643-646.
25. Silva GS, Vicari P, Figueiredo MS, Carrete H Jr,
Idagawa MH, Massaro AR. Brain magnetic reso-
nance imaging abnormalities in adult patients
with sickle cell disease: correlation with transcra-
nial Doppler findings. Stroke. 2009;40(7):2408-
2412.
26. Schatz J, Brown RT, Pascual JM, Hsu L,
DeBaun MR. Poor school and cognitive function-
ing with silent cerebral infarcts and sickle cell dis-
ease. Neurology. 2001;56(8):1109-1111.
27. Schatz J, White DA, Moinuddin A, Armstrong M,
DeBaun MR. Lesion burden and cognitive mor-
bidity in children with sickle cell disease. J Child
Neurol. 2002;17(12):891-895.
28. Wang W, Enos L, Gallagher D, et al. Neuropsy-
chologic performance in school-aged children
with sickle cell disease: a report from the Cooper-
ative Study of Sickle Cell Disease. J Pediatr.
2001;139(3):391-397.
29. Hogan AM, Kirkham FJ, Prengler M, et al. An ex-
ploratory study of physiological correlates of neu-
rodevelopmental delay in infants with sickle cell
anaemia. Br J Haematol. 2006;132(1):99-107.
30. DeBaun MR, Schatz J, Siegel MJ, et al. Cognitive
screening examinations for silent cerebral infarcts
in sickle cell disease. Neurology. 1998;50(6):
1678-1682.
31. Brown RT, Davis PC, Lambert R, Hsu L, Hopkins K,
Eckman J. Neurocognitive functioning and mag-
netic resonance imaging in children with sickle
cell disease. J Pediatr Psychol. 2000;25(7):503-
513.
32. Hogan AM, Pit-ten Cate IM, Vargha-Khadem F,
Prengler M, Kirkham FJ. Physiological correlates
of intellectual function in children with sickle cell
disease: hypoxaemia, hyperaemia and brain in-
farction. Dev Sci. 2006;9(4):379-387.
33. Steen RG, Reddick WE, Mulhern RK, et al. Quan-
titative MRI of the brain in children with sickle cell
disease reveals abnormalities unseen by conven-
tional MRI. J Magn Reson Imaging. 1998;8(3):
535-543.
34. White DA, Moinuddin A, McKinstry RC, Noetzel M,
Armstrong M, DeBaun M. Cognitive screening for
silent cerebral infarction in children with sickle cell
disease. J Pediatr Hematol Oncol. 2006;28(3):
166-169.
35. Steen RG, Miles MA, Helton KJ, et al. Cognitive
impairment in children with hemoglobin SS sickle
cell disease: relationship to MR imaging findings
REVIEW OF SILENT INFARCTS IN SCA 4595
and hematocrit. AJNR Am J Neuroradiol. 2003;
24(3):382-389.
36. White DA, Salorio CF, Schatz J, DeBaun M. Pre-
liminary study of working memory in children with
stroke related to sickle cell disease. J Clin Exp
Neuropsychol. 2000;22(2):257-264.
37. Schatz J, Craft S, Koby M, et al. Neuropsycho-
logic deficits in children with sickle cell disease
and cerebral infarction: The role of lesion site and
volume. J Child Neuropsychol. 1999;5(2):92-103.
38. Schatz J, Buzan R. Decreased corpus callosum
size in sickle cell disease: relationship with cere-
bral infarcts and cognitive functioning. J Int Neu-
ropsychol Soc. 2006;12(1):24-33.
39. Rothman SM, Fulling KH. Sickle cell anemia and
central nervous system infarction: a neuropatho-
logical study. Ann Neurol. 1986;20:684-690.
40. Koshy M, Thomas C, Goodwin J. Vascular le-
sions in the central nervous system in sickle cell
disease (neuropathology). J Assoc Acad Minor
Phys. 1990;1(3):71-78.
41. Kimmelsteil P. Vascular occlusion and ischemic
infarction in sickle cell disease. Am J Med Sci.
1948;216(1):11-19.
42. Pegelow CH, Wang W, Granger S, et al. Silent
infarcts in children with sickle cell anemia and
abnormal cerebral artery velocity. Arch Neurol.
2001;58(12):2017-2021.
43. Wang WC, Gallagher DM, Pegelow CH, et al.
Multicenter comparison of magnetic resonance
imaging and transcranial Doppler ultrasonogra-
phy in the evaluation of the central nervous sys-
tem in children with sickle cell disease. J Pediatr
Hematol Oncol. 2000;22(4):335-339.
44. Thangarajh M, Fuchs D, Ponision R, et al. Mag-
netic resonance angiography-defined intracranial
vasculopathy is associated with silent cerebral
infarcts in children with sickle cell anemia. 61st
Annual American Academy of Neurology, Seattle,
WA. April 25-May 2, 2009.
45. Waterston JA, Brown MM, Butler P, Swash M.
Small deep cerebral infarcts associated with oc-
clusive internal carotid artery disease: a hemody-
namic phenomenon? Arch Neurol. 1990;47(9):
953-957.
46. Kirkham FJ, Calamante F, Bynevelt M, et al. Per-
fusion magnetic resonance abnormalities in pa-
tients with sickle cell disease. Ann Neurol. 2001;
49(4):477-485.
47. Telfer PT, Evanson J, Butler P, et al. Cervical ca-
rotid artery disease in sickle cell disease: clinical
and radiological features. Blood. 2011;118(23):
6192-6199.
48. Zafeiriou DI, Prengler M, Pavlakis S, Kirkham FJ.
Congenital and acquired anaemias. In: Ganesan
V, Kirkham F, eds. Stroke and Cerebrovascular
Disease in Childhood–International Review of
Child Neurology. London, United Kingdom: Mac
Keith Press; 2011.
49. Kobayashi S, Ikeda T, Moriya H, Ohtake T,
Kumagai H. Asymptomatic cerebral lacunae in
patients with chronic kidney disease. Am J Kid-
ney Dis. 2004;44(1):35-41.
50. Prohovnik I, Hurlet-Jensen A, Adams R, De Vivo D,
Pavlakis SG. Hemodynamic etiology of elevated
flow velocity and stroke in sickle-cell disease.
J Cereb Blood Flow Metab. 2009;29(4):803-810.
51. Kedar A, Drane WE, Shaeffer D, Nicole M,
Adams C. Measurement of cerebrovascular flow
reserve in pediatric patients with sickle cell dis-
ease. Pediatr Blood Cancer. 2006;46(2):234-238.
52. Johnson MC, Kirkham FJ, Redline S, et al. Left
ventricular hypertrophy and diastolic dysfunction
in children with sickle cell disease are related to
asleep and waking oxygen desaturation. Blood.
2010;116(1):16-21.
53. Dowling MM, Quinn CT, Rogers ZR, Buchanan GR.
Acute silent cerebral infarction in children with
 From www.bloodjournal.org by guest on September 10, 2016. For personal use only.
4596 DeBAUN et al
sickle cell anemia. Pediatr Blood Cancer. 2010;
54(3):461-464.
54. DeBaun MR, Derdeyn CP, McKinstry RC III. Etiol-
ogy of strokes in children with sickle cell anemia.
Ment Retard Dev Disabil Res Rev. 2006;12(3):
192-199.
55. Henderson JN, Noetzel MJ, McKinstry RC,
White DA, Armstrong M, DeBaun MR. Reversible
posterior leukoencephalopathy syndrome and
silent cerebral infarcts are associated with severe
acute chest syndrome in children with sickle cell
disease. Blood. 2003;101(2):415-419.
56. Sebire G, Tabarki B, Saunders DE, et al. Cerebral
venous sinus thrombosis in children: risk factors,
presentation, diagnosis and outcome. Brain.
2005;128(Pt 3):477-489.
57. Walters MC, Hardy K, Edwards S, et al. Pulmo-
nary, gonadal, and central nervous system status
after bone marrow transplantation for sickle cell
BLOOD, 17 MAY 2012 䡠 VOLUME 119, NUMBER 20
disease. Biol Blood Marrow Transplant. 2010;
16(2):263-272.
58. Abboud MR, Yim E, Musallam KM, Adams RJ.
Discontinuing prophylactic transfusions increases
the risk of silent brain infarction in children with
sickle cell disease: data from STOP II. Blood.
2011;118(4):894-898.
59. King AA, White DA, McKinstry RC, Noetzel M,
Debaun MR. A pilot randomized education reha-
bilitation trial is feasible in sickle cell and strokes.
Neurology. 2007;68(23):2008-2011.
60. Bernaudin F, Socie G, Kuentz M, et al. Long-term
results of related myeloablative stem-cell trans-
plantation to cure sickle cell disease. Blood.
2007;110(7):2749-2756.
61. Woodard P, Helton KJ, Khan RB, et al. Brain pa-
renchymal damage after haematopoietic stem
cell transplantation for severe sickle cell disease.
Br J Haematol. 2005;129(4):550-552.
62. Hulbert ML, McKinstry RC, Lacey JL, et al. Silent
cerebral infarcts occur despite regular blood
transfusion therapy after first stroke in children
with sickle cell disease. Blood. 2011;117(3):772-
779.
63. King A, Herron S, McKinstry R, et al. A multidisci-
plinary health care team’s efforts to improve edu-
cational attainment in children with sickle-cell
anemia and cerebral infarcts. J Sch Health. 2006;
76(1):33-37.
64. Thompson RJ Jr, Link CL, Pegelow CH, Moser F,
Wang WC. A prospective study of the relationship
over time of behavior problems, intellectual func-
tioning, and family functioning in children with
sickle cell disease: a report from the Cooperative
Study of Sickle Cell Disease. J Pediatr Psychol.
2003;28(1):59-65.
65. Steen RG, Fineberg-Buchner C, Hankins G,
Weiss L, Prifitera A, Mulhern RK. Cognitive defi-
cits in children with sickle cell disease. J Child
Neurol. 2005;20(2):102-107.
 From www.bloodjournal.org by guest on September 10, 2016. For personal use only.

2012 119: 4587-4596

doi:10.1182/blood-2011-02-272682 originally published
online February 21, 2012

Silent cerebral infarcts: a review on a prevalent and progressive cause

of neurologic injury in sickle cell anemia
Michael R. DeBaun, F. Daniel Armstrong, Robert C. McKinstry, Russell E. Ware, Elliot Vichinsky and
Fenella J. Kirkham

Updated information and services can be found at:

http://www.bloodjournal.org/content/119/20/4587.full.html
Articles on similar topics can be found in the following Blood collections
<a href="/content/by/section/Editorials">Editorials</a> (149 articles)
Clinical Trials and Observations (4389 articles)
Free Research Articles (4037 articles)
Pediatric Hematology (478 articles)
Red Cells, Iron, and Erythropoiesis (728 articles)
Review Articles (650 articles)
Sickle Cell Disease (123 articles)

Information about reproducing this article in parts or in its entirety may be found online at:
http://www.bloodjournal.org/site/misc/rights.xhtml#repub_requests

Information about ordering reprints may be found online at:

http://www.bloodjournal.org/site/misc/rights.xhtml#reprints

Information about subscriptions and ASH membership may be found online at:
http://www.bloodjournal.org/site/subscriptions/index.xhtml

Blood (print ISSN 0006-4971, online ISSN 1528-0020), is published weekly by the American Society
of Hematology, 2021 L St, NW, Suite 900, Washington DC 20036.
Copyright 2011 by The American Society of Hematology; all rights reserved.