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Stroke Prevention and Treatment in Sickle Cell Disease
Robert J. Adams, MS, MD
Arch Neurol. 2001;58:565-568.
INTRODUCTION
While the problem of 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 obtained from the Cooperative Study of Sickle Cell Disease of more
than 4000 patients 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 hemorrhage
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
hemorrhage 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 patients with SCD, and most of these patients have not reported symptoms,
although specialized neuropsychological 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 characterized 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 microcirculation of other organs is an
important cause of morbidity in SCD, the vascular disease of the brain is
often associated with a large-vessel vasculopathy primarily localized to the
distal supraclinoid internal carotid artery and the proximal portions of the
middle and anterior cerebral arteries. 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 patients 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 picture of moyamoya
disease, with its abnormal network of subcortical vessels, giving the puff-of-smoke
appearance in as 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 hemorrhage possibly due to
rupture of dilated weakened collateral vessels.8
Pathological examination of diseased vasculopathic segments reveals intimal
proliferation with discontinuity of the internal elastic lamina. While endothelial
cells may proliferate to resurface denuded areas, they remain a monolayer,
while components of the hyperplastic intima include fibroblasts, fibrous tissue,
and scattered smooth muscle cells.9 Concomitant
thrombus formation in areas of endothelial damage may both perpetuate the
vicious cycle of intimal changes and serve as the proximate source of artery-to-artery
emboli responsible for some distal occlusions.10
The cause of intimal hyperplasia, and why it occurs at specific sites in the
anterior 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 clinical trials, such as trials of antiplatelet
drugs, that investigate 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 risk11
and that if they were given transfusion therapy this risk was drastically
reduced.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. Although not tested
in a clinical trial, long-term transfusion 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 discontinue 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; alternatively, some patients tire of the program
and fail to continue with regular transfusions, but the rate of stroke after
discontinuation in these cases has not been systematically 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 patients14;
however, another group observed no recurrences in 7 children who had received
transfusions an average of 2 years before cessation.15
More recently, Rana et al16 reported that 9
patients of various ages who had undergone transfusions 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 al17 reported that
discontinuation of transfusion therapy 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 occurred. The ages of the patients
with events at the time of discontinuation were 10, 13, 15, 16, and 17 years,
while the ages of the 4 patients without complication were 7, 17, 20, and
21 years. Existing guidelines18 recommending
that transfusion therapy after infarction continue for at least 5 years, or
until the age of 18 years, are reasonable 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 Anemia19 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 children randomized in this study, none
of whom had a history of stroke at entry, were identified by TCD showing time-averaged
mean (as opposed to peak systolic) velocities of 200 cm/s or more in the internal
or middle carotid artery (normal mean ± SD adult velocities, 62 ±
12 cm/s). Children with SCD generally have TCD velocities 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 National Heart,
Lung, and Blood Institute that encouraged TCD screening and consideration
of transfusion in cases of high risk based on the results of the Stroke Prevention
Trial in Sickle Cell Anemia.20
Exchange transfusions or simple transfusions are options; exchange transfusions
have the advantage of causing less iron accumulation at 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 alloimmunization with long-term
transfusion and iron overload, 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 several days a week.18
Long-term compliance with chelation therapy is a problem as there is no oral
chelator.
Hydroxyurea
Hydroxyurea therapy emerged from decades of unsuccessful efforts to
find agents capable of elevating the percentage of fetal hemoglobin, since
observations of populations and a study of natural history have shown that
increased percentages of fetal hemoglobin correlate with reduced disease severity.22 Hydroxyurea is the only chemotherapeutic agent approved
for the treatment of SCD. The double-blind, placebo-controlled study of hydroxyurea
therapy in 299 adults with SCD for the reduction of painful episodes was terminated
early when significant reductions in pain episode frequency, acute chest syndrome,
need for hospitalization, and blood transfusions became evident.23
There were too few strokes 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 prevention in a controlled fashion.
Ware et al24 reported the outcomes of secondary
stroke treatment with hydroxyurea and phlebotomy in 16 young patients in whom
transfusion 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 controls
or and randomization.
How hydroxyurea therapy works in SCD is debatable, but it elevates the
percentage of fetal hemoglobin, improves red blood cell deformability, reduces
the irreversibly sickled cell fraction, and is associated with improvements
in rheology and red blood cell survival.25
Abnormal adhesion of blood cells may also be modified.26
Hydroxyurea therapy has been shown to reduce granulocytes, 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 every
8 to 12 weeks, with monitoring of the levels of platelets, 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 in stroke prevention needs to
be established.
Bone Marrow Transplantion (BMT)
Bone marrow transplantation may be curative in SCD and is potentially
an option for stroke prevention. Data are available on 120 patients that show
that HLA-identical sibling stem cell allografts can successfully replace sickle
cells with normal donor-derived red blood cells and that stable mixed chimerism,
even with a relatively low proportion of donor cells, can ameliorate the symptoms
and complications of SCD, although an effect on stroke specifically is not
clear. Survival has been in the 90% range, and event-free survival about 85%.28 The cumulative incidence of graft rejection or return
of SCD is 11%. Although most patients who have undergone BMT have survived
without developing SCD, approximately 8% have died, and about half of these
deaths occurred in the setting 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 benign complications of the procedure.
The impact of BMT on central nervous system disease in 22 patients with
stable donor engraftment who were followed up for at least 2 years was reported
by Walters et al.28 Ten patients had history
of stroke, 4 had silent infarcts on MRI scans, one had a transient ischemic
attack, and 1 had positive results on TCD screening prior to BMT. Conclusions
based on clinical and MRI follow-up were that no significant central nervous
system events had occurred and that most of the patients had shown "stabilization"
of underlying cerebral vasculopathy. Bernaudin30
reports from France that a history of stroke has become the main indication
for BMT and argues that it should be considered in patients with silent cerebral
infarcts associated with cognitive impairment or TCD evidence of stroke risk.
The paucity of available HLA-identical sibling donors is a major obstacle
to transplantation, and there is no clear consensus on the indications 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 symptom onset and there are no contraindications according to existing
guidelines.31 There is no clear justification
to exclude the adult patient with SCD from thrombolytic therapy. Adequate
hydration, normothermia, and euglycemia 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 transfusion therapy, warfarin therapy is an unproven
alternative and may be reasonable if there is evidence of intracranial 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 SCD
when no other specific stroke prevention strategy 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 vascular disease, surgery is an option. There
have been a few reports of the successful establishment of a collateral supply
using a procedure called encephaloduroarteriosyangiosis, in which a superficial scalp artery with galea is mobilized and passed
through the dura to lie on the arachnoid surface of the brain.33
Modification of other factors unrelated to SCD may contribute to stroke
prevention, and patients with SCD should receive a workup for the cause of
stroke. Although the prevalence of SCD-related vasculopathy is high, other
mechanisms and risk factors for stroke should be considered, especially in
adults with SCD and stroke. Drug abuse, the presence of anticardiolipin antibodies34 and other hypercoagulable states, vasculitides, arterial
dissection, cardioembolic or paradoxical emboli, and elevated homocysteine
levels35 should all be considered. Also, other
modifiable stroke risks, such as smoking, diabetes, hypertension, and obesity,
should be addressed 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 prevention strategies based on transfusion have
recently been established in large multicenter studies, but treatment of acute
stroke and a basic understanding of what causes cerebrovascular disease in
this hemoglobinopathy have progressed very little in recent years. Two newer
treatments for SCD, hydroxyurea therapy and BMT, need to be applied specifically
to stroke prevention in randomized trials. The growing armamentarium for prevention
and treatment of stroke in general (eg, antiplatelet agents, anticoagulation,
thrombolytic approaches, endovascular 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.
AUTHOR INFORMATION
Accepted for publication December 12, 2000.
From the Department of Neurology, Medical College of Georgia, Augusta.
Corresponding author and reprints: Robert J. Adams, MS, MD, Department
of Neurology, Medical College of Georgia, 1467 Harper St, HB-2060, Augusta,
GA 30912.
REFERENCES
| |
1. Ohene-Frempong K, Weiner SJ, Sleeper LA, et al. Cerebrovascular accidents: rates and risk factors. Blood. 1998;91:288-294.
FREE FULL TEXT
2. 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;17:965-972.
ABSTRACT
3. Armstrong FD, Thompson RJ Jr, Wang W, et al. Cognitive functioning and brain magnetic resonance imaging in children
with sickle cell disease. Pediatrics. 1996;97:864-870.
FREE FULL TEXT
4. Adams RJ, Nichols FT, McKie V, McKie K, Milner P, Gammal TE. Cerebral infarction in sickle cell anemia: mechanism based on CT and
MRI. Neurology. 1988;38:1012-1017.
FREE FULL TEXT
5. Jeffries BF, Lipper MH, Kishore PRF. Major intracerebral involvement in sickle cell disease. Surg Neurol. 1980;14:291-295.
ISI
| PUBMED
6. Gerald B, Sebes JI, Langston JW. Cerebral infarction secondary to sickle cell disease: arteriographic
findings. AJR Am J Roentgenol. 1980;134:1209-1212
ABSTRACT
7. Seeler RA, Royal JE, Powe L, Goldberg HR. Moyamoya in children with sickle cell anemia and cerebrovascular occlusion. J Pediatr. 1978;93:808-810.
ISI
| PUBMED
8. Suzuki J, Takaku A. Cerebrovascular moyamoya disease: disease showing abnormal net-like
vessels in the base of the brain. Arch Neurol. 1969;20:288-299.
ISI
| PUBMED
9. Rothman SM, Fulling KH, Nelson JS. Sickle cell anemia and central nervous system infarction: a neuropathological
study. Ann Neurol. 1986;20:684-690.
FULL TEXT
|
ISI
| PUBMED
10. Merkel KHH, Ginsberg PL, Parker JC, Post MJD. Cerebrovascular disease in sickle cell anemia: a clinical pathological
and radiological correlation. Stroke. 1978;9:45-52.
FREE FULL TEXT
11. Powers D, Wilson B, Imbus C, et al. The natural history of stroke in sickle cell disease. Am J Med. 1978;65:461-471.
FULL TEXT
|
ISI
| PUBMED
12. 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;63:162-169.
FREE FULL TEXT
13. Pegelow CH, Adams RJ, McKie V, et al. Risk of recurrent stroke in patients with sickle cell disease treated
with erythrocyte transfusions. J Pediatr. 1995;126:896-899.
FULL TEXT
|
ISI
| PUBMED
14. Wilimas J, Goff JR, Anderson HR, Langston JW, Thompson E. Efficacy of transfusion for one to two years in patients with sickle
cell disease and cerebrovascular accidents. J Pediatr. 1980;96:205-208.
FULL TEXT
|
ISI
| PUBMED
15. Moohr JW, Wilson H, Pang E. Strokes and their management in sickle cell disease. In: Fried W, ed. Comparative Clinical Aspects of
Sickle Cell Disease. Amsterdam, the Netherlands: Elsevier Science Publishers;
1982:101-111.
16. Rana S, Houston PE, Surana N, Shalaby-Rana EI, Castro OL. Discontinuation of long-term transfusion therapy in patients with sickle
cell disease and stroke. J Pediatr. 1997;131:757-760.
FULL TEXT
|
ISI
| PUBMED
17. Wang WC, Kovnar EH, Tonkin IL, et al. High risk of recurrent stroke after discontinuation of five to twelve
years of transfusion therapy in patients with sickle cell disease. J Pediatr. 1991;118:377-382.
FULL TEXT
|
ISI
| PUBMED
18. Charache S, Lubin B, Reid CD. Management and Therapy of Sickle Cell Disease. Washington, DC: Public Health Service, US Dept of Health and Human
Services; 1992:22. NIH publication 92-2117.
19. Adams RJ, Mckie VC, Hsu L, et al. Prevention of first stroke by transfusions in children with sickle
sell anemia and abnormal results on transcranial ultrasonography. N Engl J Med. 1998;339:5-11.
FREE FULL TEXT
20. National Heart, Lung, and Blood Institute Clinical Alert. Washington, DC: US Dept of Health and Human Services; September 18,
1997.
21. Wayne AS, Kevy SV, Nathan DG. Transfusion management of sickle cell disease. Blood. 1993;81:1109-1123.
FREE FULL TEXT
22. Platt OS, Thorington BD, Brambilla DJ, et al. Pain in sickle cell disease: rates and risk factors. N Engl J Med. 1991;325:11-16.
ABSTRACT
23. Charache S, Terrin ML, Moore RD, et al. Effect of hydroxyurea on the frequency of painful crisis in sickle
cell anemia. N Engl J Med. 1995;332:1317-1322.
FREE FULL TEXT
24. Ware WE, Zimmerman SA, Schultz WH. Hydroxyurea as an alternative to blood transfusions for the prevention
of recurrent stroke in children with sickle cell disease. Blood. 1999;94:3022-3026.
FREE FULL TEXT
25. Ballas SK, Marcolina MJ, Dover GJ, Barton FB. Erythropoietic activity in patients with sickle cell anaemia before
and after treatment with hydroxyurea. Br J Haematol. 1999;105:491-496.
FULL TEXT
|
ISI
| PUBMED
26. Styles LA, Lubin B, Vichinsky E, et al. Decrease of very late activation of antigen-4 and CD-36 on reticulocytes
in sickle cell patients treated with hydroxyurea. Blood. 1997;89:2554-2559.
FREE FULL TEXT
27. Kinney TR, Helms RW, O'Branski EE, et al. Safety of hydroxyurea in children with sickle cell disease: results
of the HUG-KIDS Study, a phase I/II trial: Pediatric Hydroxyurea Group. Blood. 1999;94:1550-1554.
FREE FULL TEXT
28. Walters MC, Storb R, Patience M, et al. Impact of bone marrow transplantation for symptomatic sickle cell disease:
an interim report. Blood. 2000;95:1918-1924.
FREE FULL TEXT
29. Walters MC. Bone marrow transplantation for sickle cell disease: where do we go
from here? J Pediatr Hematol Oncol. 1999;21:467-474.
FULL TEXT
|
ISI
| PUBMED
30. Bernaudin F. Results and current indications of bone marrow allograft in sickle
cell disease. Pathol Biol (Paris). 1999;47:59-64.
PUBMED
31. Adams HP, Brott TG, Furlan AJ, et al. Guidelines for thrombolytic therapy for acute stroke: a supplement
to the guidelines for the management of patients with acute ischemic stroke:
a statement for healthcare professionals from a special writing group of the
Stroke Council, American Heart Association. Stroke. 1996;27:1711-1718.
32. Wolf PA, Clagett GP, Easton JD, et al. Preventing ischemic stroke in patients with prior stroke and transient
ischemic attack: a statement for healthcare professionals from the Stroke
Council of the American Heart Association. Stroke. 1999;30:1991-1994.
FREE FULL TEXT
33. Vernet O, Montes JL, O'Gorman AM, Baruchel S, Farmer JP. Encephaloduroarteriosynangiosis in a child with sickle cell disease
and moyamoya disease. Pediatr Neurol. 1996;14:226-230.
FULL TEXT
|
ISI
| PUBMED
34. Westerman MP, Green D, Gilman-Sacks A, et al. Antiphospholipid antibodies, proteins C and S and coagulation changes
in sickle cell disease. J Lab Clin Med. 1999;134:352-362.
FULL TEXT
|
ISI
| PUBMED
35. Houston PE, Rana S, Sekhsaria S, Perlin E, Kim KS, Castro OL. Homocysteine in sickle cell disease: relationship to stroke. Am J Med. 1997;103:192-196.
FULL TEXT
|
ISI
| PUBMED
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