SECTION EDITOR: IRA SHOULSON, MD

Stroke Prevention and Treatment

in Sickle Cell Disease
Robert J. Adams, MS, MD
W
hile the problemof stroke in the patients with sickle cell disease (SCD) has been
known for more than 75 years, adequate preventive and treatment strategies are
just now being tested. Recent data on prevalence and incidence have been ob-
tained from the Cooperative Study of Sickle Cell Disease of more than 4000 pa-
tients with SCD observed in 23 US clinical centers over a 10-year period.
1
The overall age-specific
incidence of first stroke in SCD (homozygous sickle cell anemia) is low (0.13%) at ages younger
than 24 months, increasing to just over 1% at ages 2 to 5 years, with only a slight decrement to
0.79% at ages 6 to 9 years. The risk of brain infarction declines until a second peak is seen at ages
older than 50 years, when the incidence again increases to nearly 1.3%. Although intracranial hem-
orrhage does occur in young children with SCD, the risk is low compared with older children and
adults. The Cooperative Study of Sickle Cell Disease reported risk factors for infarction to be prior
transient ischemic attack, low steady-state hemoglobin values, and rate and recency of episodes of
acute chest syndrome, as well as elevated systolic blood pressure. Risk factors for intracranial hem-
orrhage included low steady-state hemoglobin values and a high leukocyte count.
1
The burden of
cerebrovascular disease is even higher if subclinical magnetic resonance imaging (MRI) lesions,
presumed to be ischemic, are included. The prevalence of such lesions is more than 22% in pa-
tients with SCD, and most of these patients have not reported symptoms, although specialized neu-
ropsychological testing shows lower scores in children with silent lesions on MRI scans.
2,3
Patients
with a history of clinical stroke typically have infarcts in the cortex and deep white matter, whereas
silent infarcts tend to be more limited to deep white matter. Common infarction patterns are char-
acterized by wedge-shaped lesions of large-vessel territories; border zone infarctions, particularly
of the middle and cerebral artery watershed region; and small punctate lesions of the deep white
matter. Fat embolism to the brain and venous thromboses are encountered rarely.
4
PATHOPHYSIOLOGY OF STROKE
Although vaso-occlusion in the microcir-
culation of other organs is an important
cause of morbidity in SCD, the vascular
disease of the brainis oftenassociated with
a large-vessel vasculopathy primarily lo-
calized to the distal supraclinoid internal
carotid artery and the proximal portions
of the middle and anterior cerebral arter-
ies. Such lesions have been demonstrated
in about 80% of angiograms of patients
with sickle cell anemia and stroke.
5,6
Also
consistent with large-vessel disease as a
prominent cause of stroke in SCD, MRI
and computed tomographic studies of pa-
tients with SCD and stroke have shown
80%to have major distal vessel occlusion
or distal insufficiency patterns. In the later
stages of vasculopathy, there may be a
striking similarity to the angiographic pic-
ture of moyamoya disease, with its abnor-
mal network of subcortical vessels, giv-
ing the puff-of-smoke appearance in as From the Department of Neurology, Medical College of Georgia, Augusta.
NEUROTHERAPEUTICS
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many as 30% of patients with SCD and vasculopathy.
7
Moyamoya disease and SCD show parallels in the risk
of early infarction coupled with a later risk of hemor-
rhage possibly due to rupture of dilated weakened col-
lateral vessels.
8
Pathological examination of diseased vas-
culopathic segments reveals intimal proliferation with
discontinuity of the internal elastic lamina. While endo-
thelial cells may proliferate to resurface denuded areas,
they remain a monolayer, while components of the hy-
perplastic intima include fibroblasts, fibrous tissue, and
scattered smooth muscle cells.
9
Concomitant thrombus
formation in areas of endothelial damage may both per-
petuate the vicious cycle of intimal changes and serve as
the proximate source of artery-to-artery emboli respon-
sible for some distal occlusions.
10
The cause of intimal
hyperplasia, and why it occurs at specific sites in the an-
terior circulation, is not known.
TREATMENTS USED FOR STROKE
Transfusion
There have been few studies of stroke in patients with
SCD, and such patients are not often included in clini-
cal trials, such as trials of antiplatelet drugs, that inves-
tigate stroke prevention and treatment. In the 1970s and
1980s, clinical series from several centers indicated that
children with SCD and stroke had a very high early
(3 years) recurrent stroke risk
11
and that if they were
given transfusion therapy this risk was drastically re-
duced.
12,13
In most cases, the transfusion programs were
sufficient to reduce total sickle cell hemoglobin values
to less than 30% of the total hemoglobin values. Al-
though not tested in a clinical trial, long-term transfu-
sion therapy was associated with a reduced recurrence
to as low as 10% and has become routine after stroke in
children.
It has not been established when it is safe to dis-
continue long-term transfusion therapy after stroke. In
practice, many adult hematologists discontinue this
therapy in young adults when they take over their care
owing to the maturation of children with stroke; alter-
natively, some patients tire of the programand fail to con-
tinue with regular transfusions, but the rate of stroke
after discontinuation in these cases has not been system-
atically reported. One group found that discontinuation
of transfusion therapy only 1 to 2 years after stroke led
to recurrence within 1 year in 7 of 10 patients
14
; how-
ever, another group observed no recurrences in 7 chil-
dren who had received transfusions an average of 2 years
before cessation.
15
More recently, Rana et al
16
reported
that 9 patients of various ages who had undergone trans-
fusions for an average of 6 years (minimum, 3 years) had
no strokes over an observation period ranging from 3.0
to 18.5 years. At the time of cessation, 2 patients were
approximately 10 years old, while the remainder were
17 to 25 years old. In opposition to these findings, Wang
et al
17
reportedthat discontinuationof transfusiontherapy
after an average of 9.5 years in 10 patients resulted in 5
recurrent cerebrovascular events in the ensuing 12-
month period. Also, 1 death of unknown cause oc-
curred. The ages of the patients with events at the time
of discontinuationwere 10, 13, 15, 16, and 17 years, while
the ages of the 4 patients without complication were 7,
17, 20, and 21 years. Existing guidelines
18
recommend-
ing that transfusion therapy after infarction continue for
at least 5 years, or until the age of 18 years, are reason-
able in the absence of better data.
The only randomized clinical trial using any therapy
in SCD-related stroke was performed as part of primary
prevention strategy. The Stroke Prevention Trial in Sickle
Cell Anemia
19
tested whether long-term transfusion
therapy can reduce the risk of first stroke by 92%in high-
risk children aged 2 to 16 years selected by screening with
transcranial Doppler ultrasonography (TCD). The chil-
dren randomized in this study, none of whomhad a his-
tory of stroke at entry, were identified by TCD showing
time-averaged mean (as opposed to peak systolic) ve-
locities of 200 cm/s or more in the internal or middle ca-
rotid artery (normal meanSD adult velocities, 6212
cm/s). Children with SCD generally have TCD veloci-
ties in the range of 130 to 140 cm/s, and the 200-cm/s
cutoff is about 2 SDs above normal for children of this
age and degree of anemia. Children in the untreated arm
had a stroke risk of 10% per year, which is about 10 to
20 times the baseline risk in children with SCD in this
age group who are not selected by TCD. Eleven events
occurred in the untreated group compared with only 1
in the group who underwent transfusion therapy
(P.001). These results led to early termination of the
trial and the publication of a clinical alert by the Na-
tional Heart, Lung, and Blood Institute that encouraged
TCDscreening and consideration of transfusion in cases
of high risk based on the results of the Stroke Preven-
tion Trial in Sickle Cell Anemia.
20
Exchange transfusions or simple transfusions are op-
tions; exchange transfusions have the advantage of caus-
ing less ironaccumulationat the price of exposure to more
units of blood and greater expense. In the acute setting,
exchange transfusions avoid the potential adverse effect
of bringing hemoglobin toward a more normal level and
thus raising viscosity. In the long term iron loading is
reduced but exchange transfusion requires more blood
and exposes the patient to more units of blood.
21
Transfusion is also used in the acute setting of stroke
in children immediately after stabilization, but there are
no controlled data on the effect of transfusion on acute
stroke itself. There are also no data supporting its use in
adults, either for prevention or for treatment of stroke.
In addition, it is unclear whether transfusion is helpful
in preventing recurrent intracranial brain hemorrhage,
although it is frequently administered in this setting in
preparation for cerebral angiography. It may be able to
reduce hemodynamic stress on a continuing basis, which
may lower the risk of aneurysm rupture, but studies are
needed to test the impact of transfusion on hemorrhage.
Transfusion has many drawbacks, including allo-
immunization with long-termtransfusion and iron over-
load, which becomes a problem after only a few years of
therapy and has to be treated with chelation. Chelation
therapy with the only available agent, desferoxamine, is
usually recommended when serum ferritin levels reach
5618 pmol/L. The initial dose is 50 mg/kg administered
by subcutaneous infusion over an 8-hour period daily for
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several days a week.
18
Long-term compliance with che-
lation therapy is a problem as there is no oral chelator.
Hydroxyurea
Hydroxyurea therapy emerged from decades of unsuc-
cessful efforts to find agents capable of elevating the per-
centage of fetal hemoglobin, since observations of popu-
lations and a study of natural history have shown that
increased percentages of fetal hemoglobin correlate with
reduced disease severity.
22
Hydroxyurea is the only che-
motherapeutic agent approved for the treatment of SCD.
The double-blind, placebo-controlled study of hydroxy-
urea therapy in 299 adults with SCD for the reduction
of painful episodes was terminated early when signifi-
cant reductions in pain episode frequency, acute chest
syndrome, need for hospitalization, and blood transfu-
sions became evident.
23
There were too fewstrokes in this
study, however, to determine any effect of the drug on
the risk of stroke. No study has addressed the issue of
whether hydroxyurea therapy has efficacy in stroke pre-
vention in a controlled fashion. Ware et al
24
reported the
outcomes of secondary stroke treatment with hydroxy-
urea and phlebotomy in16 young patients inwhomtrans-
fusion was no longer an option. Their results of a 19%
recurrent event incidence are encouraging but need to
be compared with an appropriate control. In this single
report, the sample size was small and there were no con-
trols or and randomization.
How hydroxyurea therapy works in SCD is debat-
able, but it elevates the percentage of fetal hemoglobin,
improves red blood cell deformability, reduces the irre-
versibly sickled cell fraction, and is associated with im-
provements in rheology and red blood cell survival.
25
Ab-
normal adhesion of blood cells may also be modified.
26
Hydroxyurea therapy has been shown to reduce granu-
locytes, reticulocytes, and platelets, but it is not clear if
it has a beneficial effect on pain crises.
27
Hydroxyurea
therapy is initiated at a dosage of 15 mg/kg per day, and
the dosage is typically escalated by 5 mg/kg per day ev-
ery 8 to 12 weeks, with monitoring of the levels of plate-
lets, reticulocytes, and neutrophils and interruption of
treatment temporarily or permanently if toxic effects are
evident. Few patients can tolerate a dosage higher than
30 mg/kg. It is not clear how important it is to increase
the dosage to the maximal tolerated dose as opposed to
lower doses for the control of pain crises. In any case,
the role of hydroxyurea therapy instroke preventionneeds
to be established.
Bone Marrow Transplantion (BMT)
Bone marrowtransplantation may be curative in SCDand
is potentially an option for stroke prevention. Data are
available on 120 patients that show that HLA-identical
sibling stemcell allografts can successfully replace sickle
cells with normal donor-derived red blood cells and that
stable mixed chimerism, even with a relatively low pro-
portion of donor cells, can ameliorate the symptoms and
complications of SCD, although an effect on stroke spe-
cifically is not clear. Survival has been in the 90%range,
and event-free survival about 85%.
28
The cumulative in-
cidence of graft rejection or return of SCD is 11%. Al-
thoughmost patients who have undergone BMThave sur-
vived without developing SCD, approximately 8% have
died, and about half of these deaths occurred in the set-
ting of graft-vs-host disease.
29
In addition to acute and
chronic graft-vs-host disease, seizures and intracerebral
hemorrhage have been reported in patients with stroke
who undergo BMT, and there are other transient but be-
nign complications of the procedure.
The impact of BMT on central nervous system dis-
ease in 22 patients with stable donor engraftment who
were followed up for at least 2 years was reported by Wal-
ters et al.
28
Ten patients had history of stroke, 4 had si-
lent infarcts on MRI scans, one had a transient ischemic
attack, and 1 had positive results on TCDscreening prior
to BMT. Conclusions based on clinical and MRI fol-
low-up were that no significant central nervous system
events had occurred and that most of the patients had
shown stabilization of underlying cerebral vasculopa-
thy. Bernaudin
30
reports from France that a history of
stroke has become the main indication for BMT and ar-
gues that it should be considered in patients with silent
cerebral infarcts associated with cognitive impairment or
TCDevidence of stroke risk. The paucity of available HLA-
identical sibling donors is a major obstacle to transplan-
tation, and there is no clear consensus on the indica-
tions for its use in SCD, but it remains an option for some
patients, especially for those who are at highest risk of
significant adverse events, including stroke.
Other Treatments
Intravenous tissue plasminogen activator therapy should
be considered in adults with acute ischemic stroke, if the
therapy can be delivered within 3 hours of symptomon-
set and there are no contraindications according to ex-
isting guidelines.
31
There is no clear justification to ex-
clude the adult patient with SCD from thrombolytic
therapy. Adequate hydration, normothermia, and eugly-
cemia should be maintained, and hypotension should be
avoided in the setting of acute stroke.
In terms of stroke prevention, in adults with stroke,
or in children who cannot undergo long-term transfu-
sion therapy, warfarin therapy is an unproven alterna-
tive and may be reasonable if there is evidence of intra-
cranial arterial stenosis. There is no systematic experience
with either anticoagulation or antiplatelet agents in this
setting, but given the support for use of these agents in
adults generally, it is reasonable to use them in adults
with SCDwhen no other specific stroke prevention strat-
egy is available on the basis of existing guidelines for their
use.
32
In cases of treatment failure and recurrent strokes
despite medical therapy, and in the setting of severe vas-
cular disease, surgery is an option. There have been a few
reports of the successful establishment of a collateral sup-
ply using a procedure called encephaloduroarteriosyan-
giosis, in which a superficial scalp artery with galea is mo-
bilizedandpassedthroughthe dura tolie onthe arachnoid
surface of the brain.
33
Modification of other factors unrelated to SCDmay
contribute to stroke prevention, and patients with SCD
should receive a workup for the cause of stroke. Al-
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though the prevalence of SCD-related vasculopathy is
high, other mechanisms and risk factors for stroke should
be considered, especially in adults with SCDand stroke.
Drug abuse, the presence of anticardiolipin antibodies
34
and other hypercoagulable states, vasculitides, arterial
dissection, cardioembolic or paradoxical emboli, and
elevated homocysteine levels
35
should all be consid-
ered. Also, other modifiable stroke risks, such as smok-
ing, diabetes, hypertension, and obesity, should be ad-
dressed in cases of SCD.
CURRENT STATE OF KNOWLEDGE
Stroke remains one of the important complications of SCD
and is especially critical in the care of children with this
disorder. The epidemiology of stroke and primary and
secondary preventionstrategies based ontransfusionhave
recently been established in large multicenter studies, but
treatment of acute stroke and a basic understanding of
what causes cerebrovascular disease in this hemoglobi-
nopathy have progressed very little in recent years. Two
newer treatments for SCD, hydroxyurea therapy andBMT,
need to be applied specifically to stroke prevention in ran-
domized trials. The growing armamentariumfor preven-
tion and treatment of stroke in general (eg, antiplatelet
agents, anticoagulation, thrombolytic approaches, en-
dovascular treatment, and neuroprotection) need to be
considered, and the most promising of these should be
applied in well-designed studies to add to the available
choices for clinicians and patients seeking to protect the
brain of the patient with SCD.
Accepted for publication December 12, 2000.
Corresponding author and reprints: Robert J. Adams,
MS, MD, Department of Neurology, Medical College of Geor-
gia, 1467 Harper St, HB-2060, Augusta, GA 30912.
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