PEDIATRICS Vol. 118 No. 5 November 2006, pp. 1916-1924 (doi:10.1542/peds.2006-1241)
ARTICLE |
Primary Hemorrhagic Stroke in Children With Sickle Cell Disease Is Associated With Recent Transfusion and Use of Corticosteroids
a Division of Pediatric Hematology, Department of Pediatrics
d Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland
b Division of Pediatric Hematology/Oncology
c Department of Pediatrics, Washington University School of Medicine, St Louis, Missouri
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONREFERENCES |
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OBJECTIVES. Primary hemorrhagic stroke is an uncommon complication of sickle cell disease, with reported mortality rates of 24% to 65%. Most reported cases are in adults; little is known about its occurrence in children. Proposed risk factors include previous ischemic stroke, aneurysms, low steady-state hemoglobin, high steady-state leukocyte count, acute chest syndrome, and hypertransfusion. We performed a retrospective case-control study to evaluate risk and prognostic factors for primary hemorrhagic stroke among children with sickle cell disease.
PATIENTS AND METHODS. Case subjects (sickle cell disease and primary hemorrhagic stroke) and control subjects (sickle cell disease and ischemic stroke) were identified at 2 children’s hospitals from January 1979 to December 2004 by reviewing divisional records and the discharge databases.
RESULTS. We identified 15 case subjects (mean age: 10.4 ± 1.3 years) and 29 control subjects (mean age: 5.2 ± 0.4 years). An increased risk of hemorrhagic stroke was associated with a history of hypertension and recent (in the last 14 days) transfusion, treatment with corticosteroids, and possibly nonsteroidal antiinflammatory drugs. Average blood pressures at well visits (adjusted for age and gender) were similar between the 2 groups, suggesting that hypertension was intermittent
CONCLUSIONS. In this group of children with sickle cell disease, hemorrhagic stroke was associated with a history of hypertension or antecedent events including transfusion or treatment with corticosteroids. Improved understanding of risk and prognostic factors, especially those that are modifiable, may help prevent this devastating complication in children with sickle cell disease.
Key Words: sickle cell disease • cerebral hemorrhage • transfusions • stroke • case-control study
Abbreviations: SCD—sickle cell disease • HbSS—sickle cell anemia • ACS—acute chest syndrome • TIA—transient ischemic attack • OR—odds ratio • CI—confidence interval • NSAID—nonsteroidal antiinflammatory drug
Primary hemorrhagic stroke is one of the most devastating neurologic complications of sickle cell disease (SCD). The definition of hemorrhagic stroke is quite broad and includes intraparenchymal, subarachnoid, and intraventricular hemorrhage and is responsible for almost all of the mortality from stroke in SCD.1 The incidence of hemorrhagic stroke is greatly increased in patients with sickle cell anemia (HbSS) compared with the general population and disproportionately affects children and young adults.2 In the Cooperative Study of Sickle Cell Disease, the incidence increased with age from 0.17 per 100 patient-years for children <10 years old to a peak of 0.44 per 100 patient-years for patients 20 to 29 years old. Hemorrhage accounted for more than one quarter of the strokes in patients <20 years of age.1 Approximately 3% of children with HbSS will have a hemorrhagic stroke by 20 years of age, and 25% to 50% of these patients will die within 2 weeks of the hemorrhagic event.1,2 This is nearly a 250-fold increase in the risk of hemorrhagic stroke compared with all children.3
The natural history of hemorrhagic stroke in SCD has been described in several case reports and cohort studies (Table 1). Typical presenting symptoms and signs include severe headache, nuchal rigidity, coma, and focal neurologic deficits. The cerebral spinal fluid is often bloody and xanthochromic.2 However, the availability of computed tomography in the United States may have increased the diagnosis of hemorrhagic stroke in patients with less severe symptoms and signs. The most commonly identified cause of hemorrhagic stroke in adults with SCD is a ruptured aneurysm causing subarachnoid hemorrhage; however, no explanation is identified in >50% of cases.2 Better characterization of the natural history of hemorrhagic stroke in SCD will facilitate the diagnostic evaluation and definitive therapy of this disease process.
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There are many proposed risk factors for hemorrhagic stroke, but only a few have been rigorously evaluated and none exclusively in children. The Cooperative Study of Sickle Cell Disease identified 3 significant risk factors for first hemorrhagic stroke in a cohort study of children and adults with SCD: age, low steady-state hemoglobin concentration, and high steady-state leukocyte count.1 Other proposed risk factors include previous ischemic stroke, moyamoya, cerebral aneurysms, acute chest syndrome (ACS), acute hypertension, and hypertransfusion.4–9 However, the evidence supporting these risk factors is limited to case reports and small series with obvious selection bias.
Based on our anecdotal experience, we hypothesized that either SCD-related comorbidity or treatment for acute comorbidities was associated with hemorrhagic stroke. To test this hypothesis, we performed a multicenter retrospective case-control study.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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We designed a retrospective case-control study to compare the natural history of ischemic and hemorrhagic stroke and evaluate risk factors for hemorrhagic stroke among children with SCD. Institutional review board approval was obtained according to guidelines at the participating centers. Eligibility criteria were age <19 years and hospitalization at Johns Hopkins Children’s Center from January 1979 and St Louis Children Hospital from January 1990 to December 2004. Case subjects had SCD and intraparenchymal, subarachnoid, or intraventricular hemorrhage confirmed by neuroimaging, autopsy, or analysis of cerebrospinal fluid.10 Exclusion criteria were traumatic hemorrhages, isolated subdural or epidural hemorrhage (usually associated with trauma or infarct of the overlying bone),11,12 or hemorrhagic conversion of ischemic stroke or cerebral venous sinus thrombosis. Control subjects had SCD and ischemic stroke (focal neurologic deficit lasting >24 hours with medical documentation or deficit lasting <24 hours with evidence of acute infarction by neuroimaging). We frequency-matched case subjects by year of diagnosis (or as close as possible) with
2 control subjects. Potential case and control subjects were identified by searching the hospital discharge database using International Classification of Disease, Ninth Revision, codes for acute stroke and SCD and reviewing the records, as well as interviewing the staff and providers, at the 2 institutions.
Definitions
ACS was defined as a new pulmonary infiltrate and 
2 of the following: chest, upper abdominal, or rib pain; dyspnea; fever; tachypnea; grunting; nasal flaring; or retractions.13 Blood pressure was standardized (z score) for age and gender, using reference ranges for HbSS.14 A history of hypertension was defined as previous treatment with an antihypertensive agent or a diagnosis of hypertension listed in the admission or clinic note. Fever was defined as a temperature 38.3°C. Bradycardia was defined as a heart rate <60 beats per minute.
Glasgow coma scores were obtained from the medical record for some patients and were retrospectively assigned based on the examinations documented in the record for others.15,16 Silent infarct was defined as a cerebral infarct seen on computed tomography or MRI without corresponding deficits by history or physical examination. Transient ischemic attack (TIA) was defined as a neurologic deficit lasting <24 hours without evidence of acute infarction by neuroimaging. Coagulopathy was defined as a prothrombin or activated partial thromboplastin time above the reference range without evidence for heparin contamination or a lupus anticoagulant. Outcomes were retrospectively classified using the Glasgow Outcomes Scale for the visit closest to 6 months after the initial stroke.17
Method of Medical Record Extraction
A single reviewer collected data from the article, microfiche, and electronic records using a data extraction form. These data included baseline characteristics from well visits, type and frequency of complications of SCD, medical events within the 2 weeks preceding the neurologic event, presenting signs and symptoms, laboratory and radiographic evaluation, treatment, and short- and long-term outcomes.
Statistical Analysis
We calculated odds ratios (ORs) and confidence intervals (CIs) by exact methods. Some ORs could not be calculated, because there were no events in the control group (denominator of 0). We compared continuous variables by Student’s t test or the Wilcoxon rank-sum test for nonnormal data and categorical variables by Fisher’s exact methods. We used Kaplan-Meier estimates and the log-rank test to determine and compare survival curves. We evaluated associations between patient characteristics and survival by Cox proportional hazard analysis. Statistical analyses were performed with Stata 9.2 (Stata Corp, College Station, TX).
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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Demographics
We identified 15 case subjects (Table 2) and 29 control subjects. We excluded 2 children with isolated epidural or traumatic subdural hemorrhage. Most children had homozygous SCD (HbSS), but 2 of the 15 children with hemorrhagic stroke had sickle-ß0 thalassemia, and 1 of 29 children with ischemic stroke had sickle-ß+ thalassemia. No children were receiving hydroxyurea at the time of their stroke. Case and control subjects had similar steady-state hemoglobin, platelet, and leukocyte counts (Table 3). Premorbid blood pressures at well visits (systolic: 106 ± 4 vs 101 ± 4 mmHg; diastolic: 61 ± 4 mmHg vs 57 ± 2 mmHg) were higher in case than control subjects but were nearly identical after adjustment for age and gender (Table 3). None of these differences were statistically significant. However, a history of hypertension was more common in case (20%) than control subjects (0%; P < .05), and the frequency of hospitalization for painful crisis over the last year was greater (median: 1; interquartile range: 0–3 for case subjects; median: 0; interquartile range: 0–1 for control subjects; P < .05).
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Clinical Presentation of Primary Hemorrhagic Stroke Is Different From Ischemic Stroke
The presentation and natural history of primary hemorrhagic stroke differed from that of ischemic stroke in our study (Table 4). Case subjects were significantly older than control subjects (10.4 ± 1.3 vs 5.2 ± 0.4 years; P < .0001) and frequently presented with symptoms of increased intracranial pressure (impaired mental status [86%], headache [67%], bradycardia [33%], and emesis [42%]). Control subjects more frequently presented with focal weakness (90%), dysarthria (31%), or aphasia (28%). The Glasgow Coma Score was significantly lower in case subjects (9.1 ± 1.4) than control subjects (14.3 ± 1.4; P < .0001). Approximately 30% of both case and control subjects had seizures, and about half had elevated systolic blood pressure at the time of stroke (43% of case subjects and 60% of control subjects; Table 4). Mean hemoglobin concentration increased by 29 g/L (41%) from steady state to 97 ± 7 g/L at the time of hemorrhagic stroke; a decrease of 1 g/L (1%) was seen in control subjects (P < .0005, by t test). Case subjects were significantly more likely to have coagulopathy at the time of diagnosis than control subjects (6 of 11 case subjects vs 0 of 15 control subjects for whom coagulation studies were available; P < .005). A single patient had an underlying aneurysm identified as the cause of hemorrhage, but only 9 patients had evaluations for this complication (conventional cerebral angiogram [3], magnetic resonance angiogram alone [2], magnetic resonance angiogram and venogram [1], or autopsy [3]).
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Selected Comorbid Conditions and Treatments Were Temporally Associated With Hemorrhagic Stroke
When compared with ischemic strokes, hemorrhagic strokes were associated with a history of hypertension (OR: not calculable; 95% CI: 1.7 to not calculable; P < .05; Table 5). Hemorrhagic strokes were also associated with selected treatments for comorbid conditions (within 14 days of the stroke) including transfusion of red blood cells (OR: 35; 95% CI: 4.9–289; P < .0001) or the use of corticosteroids (OR: 20; 95% CI: 2.9–217; P < .0005) and possibly nonsteroidal antiinflammatory drugs (NSAIDs) (OR: 4.4; 95% CI: 0.9–21; P < .05; Table 6). Three children were receiving chronic transfusions: 2 for previous ischemic stroke and 1 for osteomyelitis. Twelve children received transfusions for acute indications including ACS (9), surgery (1), sickle hepatopathy (1), and glomerulonephritis (1). None received corticosteroids to prevent transfusion reactions.
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Hemorrhagic Strokes Were Associated With High Mortality Rate
The presence of hemorrhagic stroke was associated with an increased rate of death when compared with ischemic stroke. Survival was significantly worse for case subjects with 6 (40%) of 15 dying within a week of diagnosis compared with 0 of 29 control subjects. There were no additional deaths in the case subjects (mean follow-up: 4.0 ± 3.0 years for the 9 case subjects surviving the first week), but 2 control subjects died of primary hemorrhagic stroke (7.5 years) and candidal sepsis (13.3 years) after their ischemic stroke (mean follow-up: 9.0 ± 5.9 years; 0.7 [95% CI: 0.08–2.4] deaths per 100 person-years). The Kaplan-Meier estimates of survival for the case and the control subjects were significantly different (P < .0005; Fig 1). Only systolic blood pressure at the time of diagnosis was significantly associated with risk of death after primary hemorrhagic stroke (hazard ratio: 1.6; 95% CI: 1.1–2.3 per 10-mm increase; P < .01).
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Treatment and Outcomes of Patients With Stroke
Of the 35 surviving patients with complete information, 7 of 9 with hemorrhagic stroke and 25 of 26 with ischemic stroke began treatment with transfusions at least every 4 weeks. After ischemic stroke, the rate of hemorrhagic stroke was 0.5 per 100 person-years (95% CI: 0.01–2.7), and the rate of recurrent ischemic stroke was 2.4 per 100 person-years (95% CI: 0.7–5.6). The rate of a composite end point, including recurrent neurologic events (TIA or stroke) and death, was higher for patients with ischemic stroke (8.1 per 100 person-years; 95% CI: 4.8–13.1), because there were no recurrent neurologic events or late deaths in the patients who survived a hemorrhagic stroke (0 per 100 person-years; 95% CI: 0–12.7; P = .11). This included 3 patients with a total of 8 (6.75, 1.33, and 0.17) years of follow-up without treatment with transfusions or hydroxyurea. The Glasgow Outcome Scale was lower for case subjects (3.1 ± 0.5) than control subjects (4.6 ± 0.1; P < .0005), but this difference was not significant after early deaths were excluded (4.4 ± 0.2 vs 4.6 ± 0.1; P > .5). Most of the survivors had a score of 4 (moderate disability defined as disabled but independent) or 5 (good recovery).
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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The risk factors, natural history, and long-term management of primary hemorrhagic stroke are unclear. We identified a very strong association among recent blood transfusion, treatment with corticosteroids, and hemorrhagic stroke. Although the mechanism associated with these treatments and subsequent hemorrhagic stroke is unclear, each treatment was associated with moderately ill patients. The relationship with transfusion may reflect a deleterious effect of transfusion on the viscosity of blood18 or the regulation of cerebral blood flow. Several investigators have postulated an effect of transfusion on blood pressure and other hemodynamic parameters through vasoactive substances in stored blood.7,19 Patients with SCD have increased cerebral blood flow and may be unable to fully compensate for changes in blood volume or increased viscosity via autoregulation.20 Transfusion and excessive blood volume may also lead to systemic hypertension and subsequent dysregulation of cerebral blood flow. This may be a mechanism of hemorrhagic stroke in children with SCD and reversible posterior leukoencephalopathy syndrome.9
The basis for the association between corticosteroids and hemorrhagic strokes is speculative. Corticosteroids often increase blood pressure,21 and possibly an increase in blood pressure is less well tolerated in patients with SCD. The higher systolic blood pressure at presentation in patients with primary hemorrhagic stroke supports a contribution of elevated blood pressure to risk of hemorrhagic stroke. Similarly, the mechanism for the possible association between NSAIDs and hemorrhagic strokes is unclear. This association may reflect the impaired platelet function seen with these agents even after short-term use.22 Quite possibly the administration of corticosteroids or NSAIDs is a proxy for more severe disease that is the root cause of hemorrhagic stroke in SCD.
We did not identify a statistically significant association between previous ischemic stroke, elevated steady-state blood pressure, aneurysms, moyamoya, low steady-state hemoglobin, high steady-state leukocyte count, or ACS and hemorrhagic stroke. These associations, if true, were likely not as strong or also associated with our control group (previous ischemic stroke, elevated steady-state blood pressure, low steady-state hemoglobin, and recent or frequent ACS are risk factors for ischemic stroke).1,14 The association with a history of hypertension but not baseline blood pressure suggests that the case subjects may have intermittent hypertension. Of interest, the 3 patients with moyamoya had hemorrhagic stroke in the second decade of life, the classic timing for hemorrhage secondary to this disease. Notably, our analysis did not identify any single antecedent medical event associated with hemorrhagic strokes.
In children with SCD, subarachnoid and intraventricular hemorrhage are responsible for more than half of the hemorrhagic strokes compared with about a third in the general pediatric population.23 This may reflect differences in the pathophysiology of hemorrhagic stroke in SCD.
Death in patients with hemorrhagic stroke usually occurs within days of diagnosis, because of the mass effect of the hemorrhage, with tonsillar herniation or vasospasm from subarachnoid blood. There is no established specific therapy for acute hemorrhagic stroke in SCD. Simple or exchange blood transfusion is often considered but without clear evidence of its efficacy. However, there are recommendations for the management of both subarachnoid and intraparenchymal hemorrhage in the general population.24,25 Patients with either condition should be monitored in an intensive care unit with aggressive treatment of moderate or severe hypertension and rapid correction of coagulopathy or thrombocytopenia. Surprisingly, only 73% of children with hemorrhagic stroke had basic screening studies for coagulopathy. Invasive monitoring and treatment of increased intracranial pressure may be necessary, including emergent ventriculostomy for obstructive hydrocephalus or evacuation of intraparenchymal hemorrhage. Aneurysms are the most common cause of subarachnoid hemorrhage in adults with SCD and can be managed by surgery with favorable outcomes.26 However, only 1 child in our study had an aneurysm identified; it was occluded by the placement of clips via a stereotactic craniotomy with an excellent outcome. To our knowledge, the use of promising new therapies for intraparenchymal hemorrhage, such as recombinant activated Factor VII,27 has not been reported in SCD.
None of the 9 patients who survived a primary hemorrhagic stroke had a recurrent neurologic event or died during nearly 30 person-years of follow-up. This suggests that this group may be at lower risk for recurrent events or death than patients with a history of ischemic stroke, a group with significant risk of recurrent events even with regular transfusions. Our rate of recurrent ischemic stroke was similar to that reported by Scothorn et al28 for patients with SCD and ischemic stroke (2.2 per 100 person-years; 95% CI: 1.5–3.2). Additional data are necessary to guide treatment after primary hemorrhagic stroke, in particular, the role of chronic transfusion.
Our study has several limitations. We collected information retrospectively and were unable to obtain hemoglobin or blood pressure in steady state for about a third of the patients. Case subjects were compared with a control group of children with ischemic stroke; this may not be representative of the overall population of children with SCD. However, it assured that similar information was available in the medical record to assess differences in the natural history and risk factors of hemorrhagic and ischemic stroke. In addition, the treatments associated with hemorrhagic stroke (transfusions, corticosteroids, and possibly NSAIDs) may reflect concurrent illness (severe anemia, pulmonary, or renal disease), contributing to hemorrhagic stroke. However, the strength of these associations and the occurrence of primary hemorrhagic stroke in some children with transfusion and no other acute illness argue against concurrent illness being the primary factor. As expected, a cause-and-effect relationship between elevated blood pressure and coagulopathy and hemorrhagic stroke could not be established, because these findings can occur secondary to increased intracranial pressure and activation of the coagulation system from the stroke.29
We provide here a systematic report of primary hemorrhagic stroke in children with SCD and, for the first time, describe the association of hemorrhagic stroke with: a history of hypertension; recent transfusion of packed red blood cells or treatment with corticosteroids; and, at the time of diagnosis, coagulopathy, increases in hemoglobin, or elevated systolic blood pressure. The identification of risk factors for this devastating complication of SCD will permit the evaluation of strategies for its prevention and treatment. These strategies include partial volume exchange transfusion to avoid acute increases in hemoglobin and viscosity, the judicious use of corticosteroids, and the reduction of blood pressure, correction of coagulopathy, and, when indicated, surgery.
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ACKNOWLEDGMENTS |
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Dr Strouse was supported by the National Institutes of Health (clinical research scholar; grant K12RR01627) and the Doris Duke Charitable Foundation; and Dr Hulbert (grant 5T32HD4301003) and Dr Jordan (clinical research scholar; grant K12RR01627) were supported by the National Institutes of Health.
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FOOTNOTES |
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Accepted Jun 20, 2006.
Address correspondence to John Strouse, MD, Division of Pediatric Hematology, 720 Rutland Ave, Ross 1125, Baltimore, MD 21205. E-mail: jstrous1{at}jhmi.edu
The authors have indicated they have no financial relationships relevant to this article to disclose.
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