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Prepublished online as a Blood First Edition Paper on September 26, 2002; DOI 10.1182/blood-2002-04-1183.
CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
From the Department of Pediatrics, Division of
Pediatric Hematology Oncology, Department of Neurology, Department of
Pediatrics, Mallinkrodt Institute of Radiology, Neuroradiology, and
Department of Psychology, Washington University School of Medicine, St
Louis, MO.
Patients with severe acute chest syndrome (ACS) requiring
endotracheal intubation and erythrocytopheresis are at increased risk
for neurologic morbidity. This study examines patients with sickle cell
disease who developed severe episodes of ACS, leading to endotracheal
intubation, ventilatory support for respiratory failure, and
erythrocytapheresis. Magnetic resonance imaging (MRI) and magnetic
resonance angiography (MRA) studies, a neurologic examination by a
pediatric neurologist, and cognitive testing were done in all patients.
Five consecutive patients, aged 3 to 9 years, were identified with
severe ACS. All patients developed neurologic complications resulting
from ACS episodes, including seizures (n = 2), silent cerebral
infarcts (n = 3), cerebral hemorrhage (n = 2), and reversible
posterior leukoencephalopathy syndrome (n = 3). Children with severe
ACS should have a magnetic resonance image of the brain, neurologic
examination by a neurologist, and cognitive testing to detect the
presence of neurologic morbidity.
(Blood. 2003;101:415-419) Acute chest syndrome (ACS) is one of the leading
causes of hospitalization and mortality in patients with sickle cell
disease.1 Children and adults with ACS are at an increased
risk of respiratory failure requiring intubation and are subsequently
at risk of overt strokes.2 In a large, prospective study
of 538 children and adults, approximately 13% of patients with ACS had
a severe course requiring mechanical ventilation.2 The
rate of overt neurologic complications (seizures, altered mental
status, and strokes) following an episode of ACS was 22% in adults and
8% in children.2 The main limitation of this study is
that important clinical outcomes were not assessed, including silent
cerebral infarcts and cognitive impairment. The identification of
silent cerebral infarcts is particularly important because children
with these lesions have a morbid condition associated with poor
academic performance and low cognitive test scores.3
Further, such children are at risk of subsequent overt strokes and/or
further silent cerebral infarcts.4,5
Given the vulnerability of children with sickle cell disease for
developing cerebral ischemic injury in the context of respiratory failure, coupled with the observation that silent cerebral infarcts are
difficult to detect clinically,6 we elected to perform magnetic resonance imaging (MRI) of brain, obtain a neurologic evaluation by a pediatric neurologist, and obtain cognitive tests after
patients were extubated.
Institutional review board approval was obtained from Washington
University School of Medicine. Consent was not obtained from the
patients or families because all medical information obtained was
identified as part of routine care and was present in their medical
records. Patients' identifications were hidden. This case series
examined all consecutive patients from 1996 to 2001 with hemoglobin SS
diagnosed with ACS requiring endotracheal intubation and mechanical
ventilation at St Louis Children's Hospital (SLCH), a tertiary care
center. A diagnosis of ACS was defined by the radiologic finding of a
new pulmonary radiodensity on chest radiograph in association with
chest pain, fever, tachypnea, wheezing, or cough. Hospital records
regarding the patients' neurologic status were reviewed, and all
patients were examined by a pediatric neurologist (M.N.) following the
ACS episode. MRI and magnetic resonance angiography (MRA) studies were
obtained after stabilization of respiratory status, and all studies
were reviewed by a single neuroradiologist, retrospectively, for the
purpose of this study (R.M.). Silent cerebral infarcts and reversible
posterior leukoencephalopathy syndrome (RPLS) were diagnosed on the
basis of MRI findings and clinical symptoms.7,8 Silent
cerebral infarct was defined in an individual with T2 hyperintensity on
diffusion-weighted images (DWIs) and a decreased diffusion coefficient
in regions of T2 hyperintensity without focal neurologic deficits
lasting more than 24 hours' duration. RPLS was defined in an
individual with an increased diffusion coefficient in areas of T2
hyperintensities on DWI in the context of clinical symptoms or physical
findings associated with RPLS, including headache, seizures, visual
disturbances, and altered level of consciousness.7,8 All
patients underwent cognitive testing following discharge.
Case 1
Hospital course.
Patient 1, a 6-year-old boy with hemoglobin SS, presented with back
pain, fever, and cough. On hospital day 2, the patient experienced
progressive respiratory distress and ACS requiring erythrocytapheresis
and intubation with aggressive ventilatory support and sedation for 17 days of his 21-day hospitalization. On day 13, the patient became
hypertensive compared with age- and sex-matched children with sickle
cell disease (90th percentile, 108 mm Hg; median, 100 mm
Hg).9 During hospitalization, systolic blood pressures
(SBPs) ranged from 102 to 158 mm Hg, with SBPs greater than 120 mm Hg
from day 11 to day 20. Daily fluid intake averaged 2.35 L/m2 per day with a positive fluid balance of 0.5 L/m2 per day for 4 days prior to the onset of hypertension.
Neurologic examination.
Three days after extubation, on day 20, the patient developed a severe
nonthrobbing headache. No focal neurologic signs or changes in level of
consciousness were identified.
Imaging studies.
One year prior to ACS episode, the patient had a normal MRI
study. MRI on hospital day 20 and 2.5 months following discharge revealed findings consistent with RPLS and silent cerebral
ischemia (Figure 1).
Treatment and follow-up.
For approximately 5 years, the patient has received blood transfusion
therapy with no evidence of subsequent stroke or neurologic morbidity.
Case 2
Hospital course.
Patient 2, a 4.5-year-old boy with hemoglobin SS, was readmitted to the
hospital for abdominal and back pain 2 days following recent discharge.
On hospital day 2, the patient developed respiratory distress, which
progressed to acute respiratory distress syndrome (ARDS) requiring
erythrocytapheresis and intubation with maximum ventilatory support and
heavy sedation for 9 days of his 17-day hospitalization. On day 4, the
patient became hypertensive (SBP, 170 mm Hg) temporally associated with
receiving a blood transfusion and was persistently hypertensive (SBP
range, 140-160 mm Hg) for 4 days when compared with the patient's
baseline (110/70 mm Hg) and age- and sex-matched children with sickle
cell disease (90th percentile, 110 mm Hg; median, 95 mm
Hg).9 The patient was then treated with captopril. Prior
to the onset of hypertension, daily average fluid intake was 2.4 L/m2 per day with a net positive fluid balance of 0.75 L/m2 per day for 5 days.
Neurologic examination.
On day 9, the patient developed generalized and multifocal seizures
with postictal alteration in mental status. Neurologic evaluation
revealed transient, mild right arm weakness and eye deviation to the
left that resolved within 1 hour.
Imaging studies.
One year prior to ACS episode, the patient had normal MRI/MRA and
transcranial Doppler studies. MRI on day 10 and 1 month following
discharge revealed RPLS with superimposed ischemic white matter changes
(Figure 2).
Treatment and follow-up.
The patient is receiving hydroxyurea therapy, antiseizure medication,
and antihypertensive medication. The neurologic examination and MRI of
the brain 8 months later have remained unchanged.
Case 3
Hospital course.
Patient 3, a 3-year-old boy with hemoglobin SS, presented with
abdominal pain and decreased oral intake. Overnight, the patient developed increasing pain and ACS, which progressed further to ARDS and cardiorespiratory arrest. The patient was resuscitated and intubated requiring maximum ventilatory support and neuromuscular blockade for 11 days of his 31-day hospitalization. On hospital day 3, the patient received erythrocytapheresis. The patient was initially
normotensive (SBP, 106 mm Hg) but on day 4 became hypertensive (SBP
range, 120-159 mm Hg) for 8 days when compared with his baseline (106/60 mm Hg) and age- and sex-matched children with sickle cell disease (90th percentile, 104 mm Hg; median, 90 mm Hg).9
Prior to the onset of hypertension, he received an average of 2.4 L/m2 per day of fluid and had an average net positive fluid
balance of 1.1 L/m2 per day for 8 days. The patient was
intermittently treated with furosemide.
Neurologic examination.
After extubation, the patient was slow to recover to his baseline level
of alertness. Strength was reduced symmetrically to 2+/5. The patient
was nonresponsive to visual confrontation and had difficulty focusing
and following commands. By discharge, the patient was alert, active,
and mobile; strength and speech were normal.
Imaging studies.
The initial clinical reading of the MRI, 1 day following endotracheal
extubation, was bilateral ischemic infarcts and biparietal hemorrhages.
The subsequent research reading of the initial MRI and follow-up MRI at
1 month and 15 months following discharge revealed findings consistent
with RPLS complicated by hemorrhage; there was no evidence of
infarction (Figure 3).
Treatment and follow-up.
The patient received blood transfusion therapy for 2 years, based on
the clinical reading of cerebral infarction and severe ACS without any
evidence of progressive neurologic disease on the basis of annual MRI
examinations. The parents were given the option to continue blood
transfusion therapy or to receive hydroxyurea therapy, and they chose
the latter.
Case 4
Hospital course.
Patient 4, a 3.5-year-old girl with hemoglobin SS, presented with fever
and abdominal pain. On hospital day 2, the patient developed ACS and
ARDS requiring erythrocytapheresis, and the patient was intubated for
58 days of her 176-day hospitalization because of chronic respiratory
failure. On day 59, the patient had a tracheostomy for prolonged
ventilatory support. SBP ranged from 112 to 130 mm Hg for 16 days
following erythrocytapheresis, and on day 18 the patient became
markedly hypertensive (SBP range, 130-178 mm Hg) compared with baseline
(118/80 mm Hg) and age- and sex-matched children (median, 90 mm Hg;
90th percentile, 100 mm Hg) for approximately 25 days. The patient was
treated with nifedipine, captopril, and furosemide during periods of
hypertension. During the 5 days prior to the onset of hypertension, the
patient received an average of 1.6 L/m2 per day with a net
positive fluid imbalance of approximately 0.5 L/m2 per day.
Following tracheostomy, the patient was normotensive.
Neurologic examination.
On initial neurologic examination, tone proximally was reduced but
increased at the ankles. She had markedly reduced endurance because of
deconditioning and required intensive physical, occupational, and
speech therapy. At discharge, on day 176, the neurologic examination was normal except for minimal delays in age-appropriate
developmental skills.
Imaging studies.
MRI was recommended during hospitalization and declined by the family
at that time. Four months following discharge, MRI revealed laminar
cortical necrosis associated with incomplete infarction. MRA revealed
an early moyamoya pattern.
Treatment and follow-up.
The patient has been receiving blood transfusion therapy for 4 months
with no evidence of subsequent overt stroke. She continues to require
ventilatory support at night and intermittently during the day.
Case 5
Hospital course.
Patient 5, a 9-year-old boy with hemoglobin SS, presented to the
emergency department with abdominal pain. The next day, the patient
experienced progressive pain in conjunction with worsening respiratory
function. On day 3, because of ACS and ARDS, the patient received
erythrocytapheresis and was intubated for 10 days of a 19-day
hospitalization with maximal ventilatory support and heavy sedation.
The patient received an average of 1.5 L/m2 per day and had
a net fluid balance throughout his intensive care unit course. His
blood pressure remained normal throughout hospitalization.
Neurologic examination.
On hospital day 15, the patient developed complex partial
seizures with secondary generalization. Neurologic examination after the seizure episode revealed increased tone, reflexes, and clonus on
the left side lasting more than 24 hours.
Imaging studies.
The initial clinical reading of the MRI, on hospital day 16, revealed a
cerebral infarct in the frontoparietal area. Subsequent MRI reading for
research purposes showed a subarachnoid hemorrhage without signs of
infarction. MRA showed multifocal areas of narrowing of several vessels.
Treatment and follow-up.
Blood transfusion therapy was recommended, but the family declined. The
patient has not had any signs of neurologic morbidity in the 3 years
since his ACS episode.
Five patients were admitted to the hospital for pain and developed
ACS within 3 days of admission. Chest radiographs in all patients
revealed progression to extensive multilobar involvement. All patients
presented with oxygen saturation levels less than 92% on room air with
a mean decrease from baseline of 9.4%. They subsequently required
intubation, aggressive ventilatory support, and heavy sedation, and
they experienced a prolonged hospitalization. All patients had
hemoglobin levels less than 70 g/L (7.0 g/dL), with a mean
decrease of 22.2 g/L (2.22 g/dL) from baseline and received multiple
transfusions, including erythrocytapheresis to decrease hemoglobin S to
less than 30%. The clinical features associated with the ACS episode
are summarized in Table 1.
Prior to the ACS episode, none of the patients were diagnosed with
hypertension or prior neurologic morbidity. Two children had normal MRI
studies within 1 year of their severe ACS episode. One of 2 children
also had a normal transcranial Doppler velocity measurement within a
year of the episode. All 3 patients diagnosed with RPLS exhibited
characteristic MRI changes, positive fluid balance, and hypertension
immediately prior to focal neurologic findings and clinical features
associated with RPLS (Table 2).
This case series demonstrates that children with sickle cell disease and severe ACS requiring intubation and erythrocytapheresis are at high risk of neurologic morbidity, including silent cerebral infarcts, RPLS, and cerebral hemorrhage. Despite the high prevalence of silent cerebral infarcts (approximately 20%) in children with sickle cell anemia and the association with poor cognition and poor academic performance, no risk factor has been identified for silent cerebral infarcts.3,10 Conducting imaging studies to identify silent cerebral infarcts is important because children with prior silent cerebral infarcts are at an increased risk of subsequent overt stroke (8.1%) and silent cerebral infarcts (24.5%).5,11 The pathogenesis of RPLS in children with sickle cell disease, ACS, and respiratory failure is unclear. On the basis of the presentation of the patients in our case series, we postulate that children with sickle cell disease and hypoxemia, positive fluid balance resulting in hypertension, and poor cerebrovascular autoregulation12 are vulnerable to RPLS. Typically, RPLS is characterized by hypertension, headache, altered mental status, seizures, and/or visual changes associated with radiologic abnormalities, often reversible, in the white matter and occasionally gray matter.7,8,13 This syndrome has not previously been reported in children with sickle cell disease. RPLS is difficult to distinguish from acute cerebral infarcts
clinically and radiographically. The distinction is important because
cerebral infarction implies irreversible damage and warrants blood
transfusion therapy for an indefinite period. Conversely, RPLS is
potentially reversible but may require judicious hypertensive management. In this case series, 2 patients were originally diagnosed as having cerebral infarcts according to the clinical reading of
the MRI, one of whom was subsequently determined to have RPLS and the
other with cerebral hemorrhage. Appropriate MRI techniques and
interpretation play a key role in differentiating RPLS from cerebral
infarct (Figure 4). Both RPLS and
cerebral infarct present with T2-weighted hyperintensities.
DWIs typically show hyperintense signal in cerebral infarcts,
whereas DWIs in RPLS are ambiguous because of T2 shine-through
effects.8,14 Producing images of the diffusion coefficient
eliminates this ambiguity.
As with any case series, this study has limitations. We could not determine the time of a neurologic injury in children who were intubated and sedated. Thus, overt neurologic events may have been masked. Despite this limitation, all evidence would support that the neurologic events in the children occurred after endotracheal intubation and were temporally associated with their acute illness. We could not exclude the possibility that erythrocytapheresis increased the risk of silent cerebral infarcts in children who are acutely ill. At least one previous study (n = 6) has identified exchange transfusion, for the treatment of priapism, as a possible risk factor for overt strokes (3 of 6).15 Regardless of whether severe ACS or erythrocytapheresis is the primary risk factor for cerebral infarcts, when both events occur together, a MRI of the brain is warranted to guide patient management. In summary, children with severe ACS requiring endotracheal intubation and erythrocytapheresis are at increased risk of significant neurologic morbidity and should undergo MRIs of the brain, neurologic evaluations by a neurologist, and cognitive assessments after their acute episode.
We thank Bradley Schlagger, MD, PhD, Jean Holowach Thurston, MD, and Rebecca Ichord, MD, for their valuable input.
Submitted April 24, 2002; accepted July 24, 2002.
Prepublished online as Blood First Edition Paper, September 26, 2002; DOI 10.1182/blood-2002-04-1183.
Supported by the Doris Duke Clinical Scholars Foundation.
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: Michael R. DeBaun, St Louis Children's Hospital, Campus Box 8116, One Children's Pl, St Louis, MO 63110; e-mail: debaun_m{at}kids.wustl.edu.
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Platt OS, Brambilla DJ, Rosse WF, et al.
Mortality in sickle cell disease. Life expectancy and risk factors for early death.
N Engl J Med.
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Vichinsky EP, Neumayr LD, Earles AN, et al.
Causes and outcomes of the acute chest syndrome in sickle cell disease.
N Engl J Med.
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Schatz J, Brown RT, Pascual JM, Hsu L, DeBaun MR.
Poor school performance and cognitive deficits in children with silent cerebral infarcts and sickle cell disease.
Neurology.
2001;56:1109-1111 4. Miller S, Macklin E, Pegelow C, et al. Silent infarction as a risk factor for overt stroke in children with sickle cell anemia: a report from the Cooperative Study of Sickle Cell Disease. J Pediatr. 2001;139:385-390[CrossRef][Medline] [Order article via Infotrieve].
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Pegelow CH, Wang W, Granger S, et al.
and STOP Trial. Silent infarcts in children with sickle cell anemia and abnormal cerebral artery velocity.
Arch Neurol.
2001;58:2017-2021 6. Glauser T, Lee B, Siegel M, DeBaun M. Accuracy of neurologic examination and history in detecting evidence of MRI-diagnosed cerebral infarctions in children with sickle cell hemoglobinopathy. J Child Neurol. 1995;10:88-92[Medline] [Order article via Infotrieve].
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Hinchey J, Chaves C, Appignani B, et al.
A reversible posterior leukoencephalopathy syndrome.
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Mukherjee P, McKinstry RC.
Reversible posterior leukoencephalopathy syndrome: evaluation with diffusion-tensor MR imaging.
Radiology.
2001;219:756-765 9. Pegelow CH, Colangelo L, Steinberg M, et al. Natural history of blood pressure in sickle cell disease: risks for stroke and death associated with relative hypertension in sickle cell anemia. Am J Med. 1997;102:171-177[CrossRef][Medline] [Order article via Infotrieve].
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Pegelow CH, Macklin EA, Moser FG, et al.
Longitudinal changes in brain magnetic resonance imaging findings in children with sickle cell disease.
Blood.
2002;99:3014-3018 11. Miller S, Macklin E, Sleeper L, et al. Risk factors for stroke in children with sickle cell disease: a report from the cooperative study (CSSCD). J Pediatr. 2001;139:385-390[CrossRef][Medline] [Order article via Infotrieve].
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Prohovnik I, Pavlakis SG, Piomelli S, et al.
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Pavlakis SG, Frank Y, Chusid R.
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1999;14:277-281
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Provenzale JM, Engelter ST, Petrella JR, Smith JS, MacFall JR.
Use of MR exponential diffusion-weighted images to eradicate T2 "shine-through" effect.
Am J Roentgenol.
1999;172:537-539 15. Rackoff W, Ohene-Frempong K, Month S, Scott J, Neahring B, Cohen A. Neurologic events after partial exchange transfusion for priapism in sickle cell disease. J Pediatr. 1992;120:882-885[CrossRef][Medline] [Order article via Infotrieve].
© 2003 by The American Society of Hematology.
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  J. J. Strouse, M. L. Hulbert, M. R. DeBaun, L. C. Jordan, and J. F. Casella Primary Hemorrhagic Stroke in Children With Sickle Cell Disease Is Associated With Recent Transfusion and Use of Corticosteroids Pediatrics, November 1, 2006; 118(5): 1916 - 1924. [Abstract] [Full Text] [PDF]
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 S. T. Miller, S. P. Rao, J. H. Boyd, and M. R. DeBaun Acute chest syndrome, transfusion, and neurologic events in children with sickle cell disease Blood, August 15, 2003; 102(4): 1556 - 1557. [Full Text] [PDF]
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Abstract
Introduction
