Prevention of Strokes in Sickle Cell Disease
Prevention of Strokes in Sickle Cell Disease
ABSTRACT & COMMENTARY
Synopsis: Children with sickle cell anemia who were believed to be at high risk of developing stroke were identified by abnormal transcranial Doppler ultrasonography. One hundred thirty of these children were randomized to receive chronic RBC transfusions or standard management. There were 11 strokes in the control group compared to only one in the transfusion group, a 92% reduction (P < 0.001).
Source: Adams RJ, et al. Prevention of a first stroke by transfusions in children with sickle cell anemia and abnormal results on transcranial Doppler ultrasonography. N Engl J Med 1998;339:5-11.
Strokes occur in about 10% of children with sickle cell anemia in the first two decades of life. Strokes are usually caused by blockage of the large intracranial arteries, especially the internal carotid and middle cerebral arteries. Obstructive lesions in these large arteries can be detected by transcranial Doppler ultrasonography which demonstrates high blood flow velocity through the constricted artery. Children with such obstruction are at risk of having a stroke, estimated to be as high as 40% in the subsequent three years. Because regular blood transfusions are highly effective in reducing the risk of recurrent stroke in children with sickle cell, this study was designed to see whether they also could reduce the frequency of initial stroke in children at high risk.
One hundred thirty children in the abnormal doppler study who had a mean age of 8.3 ± 3.3 years and no history of stroke were randomly assigned to receive either regular RBC transfusions to keep the proportion of circulating Hb S < 30% or to receive standard care, not involving regular transfusions. Baseline studies included a cranial MRI.
Strokes were diagnosed by an external panel of experts on the basis of clinical focal and neurological symptoms and post event MRIs. Post event MRI showed new or worsened cerebral lesion in 10 of 11 cases.
The study was scheduled to continue for 36 months but was terminated 16 months early, because there were 11 strokes in the control group, compared to only one in the transfusion group, a 90% reduction. Ten patients dropped out of the transfusion group; alloimmunization to RBC antigens occurred in 10 transfused patients. The mean serum ferritin increased from 164 ± 155 ng/mL at baseline to 1804 ± 773 ng/mL at 12 months. Central venous lines were placed in five children to facilitate transfusions.
COMMENT BY HOWARD A. PEARSON, MD, FAAP
With the virtual elimination of severe pneumococcal infection in young children with sickle cell disease made possible by neonatal diagnosis and penicillin prophylaxis, stroke remains the most important serious complication in the first decade of life for these children. As many as 10% of children have overt strokes, and many more have asymptomatic cerebral infarction demonstrable by MRI. Strokes tend to be repetitive without interventions and may cause significant mortality and morbidity such as hemiplegia. Adams and associates in a large cooperative study have convincingly demonstrated the effectiveness of transfusion therapy in preventing first clinical strokes in a group of children with cerebral large blood vessel obstruction demonstrated by transcranial Doppler ultrasonographic measurements of cerebral blood velocity.
These results are convincing and conclusive. Transcranial Doppler studies should become part of the management of these children beginning at age 3-4 years. Institution of a chronic transfusion program will certainly reduce the 40% expected incidence of overt stroke in children who have blood flow velocities ³ 200 cm/sec in either carotid or the middle cerebral artery (normal < 170 cm/sec). However, as pointed out by Cohen in an accompanying editorial, there are significant problems.1 The transcranial Doppler measurements require instrumentation comparable to that of Adams et al in order to use the same definition of increased blood flow velocity. Monthly blood transfusions are significantly expensive and inconvenient. (At my hospital, an outpatient transfusion costs $800-$1200.) Acceptance of transfusion by families may also be a problem. About 25% of eligible patients were not randomized in the Adams et al study because of the families' unwillingness to accept possible transfusions or their physician's opinion that compliance with a transfusion regimen was unlikely. Venous access may be a significant problem in small children, and, not surprisingly, central venous lines were placed in several children. Transfusional hemosiderosis, an expected complication of chronic transfusion, was just developing in these children when the study was stopped. High levels of serum ferritin indicate that chelation therapy should be considered. Present chelation therapy with nightly, prolonged desferrioxamine (DF) infusions is complicated, expensive, and uncomfortable. The inevitable need to start DF in patients who are chronically transfused adds another problem and will doubtless reduce physician and family acceptance.
Unfortunately, at present there is no proven alternative therapy to transfusions for stroke-either actual or potential-in children with sickle cell disease. Bone marrow transplantation can cure sickle cell anemia but it is risky, expensive, and possible in only a small percentage of patients. Hydroxyurea (HU) therapy has been shown to reduce vasooclusive painful episodes and acute chest syndrome in adults.2 HU might be of value in reducing the risk of stroke, and the drug appears to be safe in children, at least in the short run.3 A randomized, controlled study comparing HU with transfusion or perhaps with no therapy would be necessary. Hopefully, it will be as well designed and implemented as this excellent study by Adams et al.
References
1. Cohen AR. Sickle cell disease-New treatments, new questions. N Engl J Med 1998;339:42-43.
2. Charache S, et al. Effect of hydroxyurea on the frequency of painful crises in sickle cell disease. N Engl J Med 1995;382:1317-1322.
3. Jayabose S, et al. Clinical and hematologic effects of hydroxyurea in children with sickle cell anemia. J Pediatr 1996;129:559-565.
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