Blood, 1 April 2001, Vol. 97, No. 7, pp. 2165-2167
BRIEF REPORT
Stroke in hemoglobin (SD) sickle cell disease with
moyamoya: successful hydroxyurea treatment after cerebrovascular
bypass surgery
Markus Schmugge,
Hannes Frischknecht,
Yasuhiro Yonekawa,
Ralf W. Baumgartner,
Eugen Boltshauser, and
James Humbert
From the Departments of Hematology and Neurology,
University Children's Hospital, Zürich; and the Departments of
Neurosurgery, Neurology, and Pediatrics/Hematology-Oncology Unit,
University Hospital, Geneva, Switzerland.
 |
Abstract |
An 11-year-old boy with hemoglobin sickle disease
(HbSD), bilateral stenosis of the intracranial carotid arteries, and
moyamoya syndrome had recurrent ischemic strokes with aphasia and right hemiparesis. His parents (Jehovah's Witnesses) refused blood
transfusions. After bilateral extracranial-intracranial (EC-IC) bypass
surgery, hydroxyurea treatment increased hemoglobin F (HbF) levels to
more than 30%. During a follow-up of 28 months, flow velocities in the
basal cerebral arteries remained stable, neurologic sequelae regressed,
and ischemic events did not recur. This is the first report of
successful hydroxyurea treatment after bypass surgery for intracranial
cerebral artery obstruction with moyamoya syndrome in sickle cell
disease. The patient's religious background contributed to an
ethically challenging therapeutic task.
(Blood. 2001;97:2165-2167)
© 2001 by The American Society of Hematology.
| |
Introduction |
Vascular occlusions are the typical complication of
homozygous sickle cell disease (SCD). Patients who are double
heterozygotes for HbSD (
2
6Val 121 Gln) occasionally
have severe occlusive cerebrovascular disease and stroke.1
Moyamoya syndrome, characterized by the angiographic findings of
bilateral occlusive lesions at the terminal portion of the internal
carotid artery and an abnormal vascular network at the cerebral
base,2 has been reported in patients with SCD who have had
strokes.3-9 Reports about cerebral artery bypass surgery
for moyamoya syndrome in SCD5,8 are rare, and no data
exist about recurrence rate with or without chronic transfusion after
bypass surgery.
We report on the 28-month follow-up of a patient with HbSD and moyamoya
syndrome who was treated successfully with bilateral EC-IC bypass
surgery and who received only hydroxyurea (HU) as supportive treatment.
| |
Study design |
HbSD Los Angeles-Punjab was diagnosed in the patient at the age
of 18 months (initial Hb chromatography: HbA2, 2.5%; HbF, 32%; HbS,
29%; HbD, 37%). Double heterozygote HbS (6Glu-Val) and D
(121Glu-Gln) Los Angeles-Punjab was identified by isoelectric focusing, ion exchange high-pressure liquid chromatography, and DNA
analysis. At follow-up visits, when the patient was between the ages of
5 to 10 years, HbF ranged from 4% to 9%. When he was 8 years old, a
decrease in school performance was observed, and he had episodes of
somnolence and ataxia. A viral infection was followed by a transient
right hemiparesis. Clinical examination revealed murmurs over both
carotid bifurcations. Transcranial color duplex (TCD) sonography and
magnetic resonance angiography (MRA) showed high-grade stenosis of the
terminal left internal carotid artery, with cross-flow through the
anterior and posterior communicating arteries. Magnetic resonance
imaging (MRI) revealed ischemic infarctions of the left caudate nucleus
and frontal periventricular white matter. The hemiparesis regressed
spontaneously. When he was 91/2 and 10 years of age, 2 episodes
of transient right hemiparesis occurred. MRI showed additional
left-sided infarctions in the callosal body, frontal white matter, and
corona radiata. The parents refused blood transfusions for religious
reasons. When he was 10 years of age, the patient had an ischemic
stroke with aphasia and right hemiplegia a few days after HU treatment
was initiated. MRI revealed infarctions of the left frontal
supraorbital region and the central gyrus. TCD, MRA, and angiography
showed subtotal stenosis of the internal carotid arteries, collateral
flow through the posterior communicating arteries and the
leptomeningeal collaterals, and abnormal vascular network (moyamoya) at
the cerebral base. Judicial permission was obtained for an emergency
exchange transfusion against parental will, and, 16 hours after the
stroke, the patient received a half blood volume exchange transfusion,
which reduced HbSD to 30%.
Subsequently, he underwent EC-IC bypass surgery on the left side
(anastomosis of the superficial temporal artery to the middle and the
anterior cerebral arteries) and, 1 month later, on the right side. HU
treatment was increased to 30 mg/kg per day, and HbF rose to 30% to
36% in 3 months (Figure 1). In addition,
acetylsalicylic acid was started (2 mg/kg by mouth every second day).
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| Figure 1.
Cerebral artery flow velocities measured by transcranial color
duplex sonography.
Hb and HbF concentrations before and after cerebral artery surgery and
during HU treatment. Peak mean flow velocities in the left (A) and
right (B) anterior (ACA), middle (MCA), and posterior (PCA) cerebral
arteries. Total Hb and HbF levels before and during HU treatment (C).
|
|
Peak mean blood flow velocities of the anterior, middle, and posterior
cerebral arteries were measured monthly (and later bimonthly).
During the follow-up, basal cerebral artery flow velocities remained
stable (Figure 1). Flow velocities were decreased in both middle
cerebral arteries because of the presence of bilateral downstream
carotid stenoses and was high in anterior and right posterior cerebral
arteries supplying leptomeningeal collaterals. Eighteen months after
the last stroke, neither MRI nor MRA showed any new ischemic lesions.
Neuropsychological evaluation 10 months after the stroke indicated the
patient had a global IQ in the low-normal range and mildly reduced
visual-motor integration. His mental processing was slow, and his
school performance was impaired. By 28 months after the last stroke,
all neuromotor abnormalities had disappeared, except for inconstant
right Babinski sign, mild weakness in the right arm, and asymmetric
tendon reflexes.
| |
Results and discussion |
The patient reported here is unusual for several reasons. First,
the association of SCD and moyamoya disease is rare and, to our
knowledge, has never been reported in HbSD. Second, successful HU
treatment after neurovascular bypass surgery has never been reported in
SCD with moyamoya syndrome. Third, his religious background created an
ethically challenging therapeutic task.
Acute cerebral infarction occurs in approximately 7% to 10% of
children with SCD, with a peak incidence between 5 and 10 years of age.
The initial mortality rate is high (20%), and the recurrence rate is
nearly 70% in nontransfused patients.9-11 In HbSD, the incidence of stroke is uncertain. Risk factors include prior transient ischemic attack, abnormal TCD, low steady state Hb level, and high
leukocyte count; all were present in our patient.11-13
The standard approach in a patient with SCD who has central nervous
system (CNS) abnormalities with or without vasculopathy is to initiate
a chronic transfusion program and to monitor cerebral blood flow
velocity with TCD.11,12,14 Surgical intervention is now an
accepted therapy for children with moyamoya disease who have CNS
infarction,2,9 but only 2 descriptions have been reported
in the literature of bypass surgery for moyamoya syndrome in SCD
patients. One patient underwent encephaloduroarteriosynangiosis (EDAS) that had to be repeated after 18 months; occipital arteries were
used the second time.5 In the other report, a bilateral EC-IC bypass procedure was successful; neurologic symptoms improved, but follow-up time was not reported.8 Experience from
patients with moyamoya disease shows that direct vascularization with
multiple EC-IC bypass, though technically more difficult than EDAS, is more effective at achieving additional perfusion to the affected CNS
regions. In a smaller study, this procedure also showed a lower
incidence of stroke recurrence.15,16
This patient's parents refused blood transfusions because of their
religious beliefs. In view of the vital risk posed by the child's last
stroke episode, we obtained a single judicial permission for an
emergency exchange transfusion. After EC-IC bypass surgery and in the
absence of clear vital emergency, our ethics committee recommended that
we follow the will of the parents, and we started HU therapy. This
decision took into account the possible negative impact of enforced
chronic transfusion treatment on the child's psychosocial development.
Recent therapeutic approaches to SCD have focused on the use of HU to
stimulate HbF production. It reduces the frequency of pain crisis,
chest crisis, and hospital admission for pain crisis in children with
SCD.17-19 No consistent hematopoietic or developmental abnormalities have been observed in a 3-year follow-up of treated children.18 In addition, in children aged 1 to 5 years, a
2- to 3-year follow-up study reported a favorable response and an absence of toxicity, but 2 children had strokes after 1 to 2 years of
treatment.20,21 In another study, recurrence occurred in 20% of children who received HU instead of chronic
transfusions.22 Therefore, the efficacy of HU in
preventing ischemic strokes is still open to question. In comparison
with data shown previously,18,20,21 an unusually high
increase in HbF to 36% during HU treatment was seen in our patient. In
agreement with recent data on chest syndrome in SCD,23
high (greater than 30%) HbF levels may be sufficient in specific
situations to prevent the progression of CNS vasculopathy. In addition,
EC-IC bypass surgery is a valuable therapy in severe CNS vasculopathy.
Longer follow-up times and comparative studies are needed for an
examination of the efficacy of HU to prevent the progression of CNS
disease in SCD.
| |
Acknowledgments |
We thank Marlies Schmid and Chantale Marguet for their help in data
analysis and in preparation of the manuscript.
| |
Footnotes |
Submitted July 17, 2000; accepted November 2, 2000.
The publication costs of this
article were defrayed in part by
page charge payment. Therefore,
and solely to indicate this fact,
this article is hereby marked
"advertisement"
in accordance with 18 U.S.C.
section 1734.
Reprints: James Humbert, Department of
Pediatrics/Hematology-Oncology Unit, Geneva Children's Hospital,
Geneva; Switzerland; e-mail: james.humbert{at}hcuge.ch.
| |
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Abstract
Introduction
