In this article, the author reviews the risk of stroke in children with sickle cell anemia (HbSS). Stroke occurs in 11% of children with the disease by 20 years of age. The author reviews the pathophysiology of stroke in sickle cell disease and discusses ways to identify those at high risk for stroke. Transcranial Doppler (TCD) measurement of the time-averaged mean of the maximum (TAMM) blood flow velocities in the distal internal carotid (ICA) and proximal middle cerebral artery (MCA) has proven to be the best predictor of stroke risk in this population. The author discusses the TCD technique used in the examination of children with sickle cell disease for both initial examination as well as follow-up examinations. He also reviews the effectiveness of transfusion therapy for prevention of stroke in this population and discusses possible alternative therapies, including hydroxyurea and bone marrow transplantation, for stroke prevention in this high-risk population. Finally, the author reviews publications on the risk associated with elevated anterior cerebral artery velocities, reports on encephalo-arterio-duro-synangiosis (EDAS) in patients with homozygous sickle cell anemia with moyamoya, and reviews the parameters that affect TCD velocity and potentially impact stroke risk in this population. He reviews recent trials in HbSS, including SWITCH, TWITCH, and a controlled trial of transfusions for silent cerebral infarcts in sickle cell anemia. He cites the development of different gene therapies that can silence BCL11a, resulting in increased HbF levels.
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• Children with sickle cell disease have an 11% risk of developing stroke by age 20 years. Of these strokes, 75% are ischemic and occur in patients with severe stenosis of the terminal internal carotid artery or proximal middle and anterior carotid arteries.
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• Transcranial Doppler can identify those children at highest risk of developing stroke.
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• Prophylactic chronic transfusion to maintain HbS levels of less than 30% decreases stroke risk by 90%.
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• Because of the potential complications of long-term transfusion (risk of infection, alloimmunization, and iron overload), other therapies, including hydroxyurea and bone marrow transplantation, are currently being evaluated, but to date none have been as effective as transfusion.
Historical note and terminology
In this article, the term “sickle cell anemia” will refer to those cases homozygous for hemoglobin S. Other sickle hemoglobinopathies will be referred to by specifying the abnormality as appropriate (eg, HbSA (sickle cell trait), HbSC, HbSD, HbSE, etc.).
Sickle cell disease was first reported in 1910 by Herrick (93). In 1923, a young patient with sickle cell disease who suffered a stroke was reported by Sydenstricker and colleagues (206). Since those early observations, much has been learned about sickle cell disease through laboratory and clinical studies. These studies have established it as a genetic disease with autosomal dominant inheritance in which the abnormal gene product is an altered beta chain in the structure of hemoglobin (190). Most of the hemoglobin in the red cells in adults exists as a tetramer of 2 alpha and 2 beta chains. A change in the amino acid sequence of 1 of the globin chains gives rise to hemoglobinopathies, whereas decrease in quantity of globin chains causes the thalassemias. The major sickle hemoglobinopathies are categorized as sickle cell trait (Hb SA) (one normal beta-globin and the other a sickle beta-globin), sickle cell (Hb SS) (both beta-globins are sickle beta-globins), and sickle C hemoglobin (Hb SC) (one sickle beta-globin and the other C beta-globin).
In their 1949 article entitled “Sickle Cell Anemia, a Molecular Disease,” Pauling and colleagues demonstrated the significant differences in the electrophoretic mobility between sickle cell hemoglobin and normal hemoglobin, which was an observation that was important in the development of the concept of the molecular basis of disease (160). In 1956, Ingram demonstrated that patients with HbSS had a substitution of glutamic acid for valine at position 6 of the beta globin chain (108). This was found to be the result of an A to T transversion in the codon for amino acid 6 in the Beat-hemoglobin gene (Ingram). Deoxygenation of HbS may cause a transformation from a soluble compound to a densely packed polymer; this polymer is a series of parallel bundles of long fibers that align with other fibers, distorting the red cell shape from a biconcave disc to the crescentic or sickle shape. Depolymerization usually occurs with reoxygenation (51). Patients with HbSS have an ongoing hemolytic anemia, with average red blood cell life span of 10 to 20 days. Most patients maintain a hematocrit of 20 to 25.
Stroke was recognized early on as an important complication of sickle cell disease (102). The series of Greer and Scotland, as well as that of Portnoy and Herion, were the first to emphasize the high prevalence of cerebrovascular disease in sickle cell disease (81; 169). The most comprehensive study of stroke comes from the Cooperative Study of Sickle Cell Disease (CSSCD), which reported the prevalence of stroke in children to be 0.5% to 1% per year, for a total of 11% by 20 years of age (155). Other studies have confirmed this high incidence of stroke in children with sickle cell (176). This rate of stroke is extremely high, particularly when compared to the 2.5/100,000 yearly incidence of stroke in children without sickle cell disease (67), and is comparable to that of moderately high-risk elderly adults.
It has been estimated that in 2005 the United States HbSS population was over 89,000 people, with a total estimate of 89,079 (95% CI: 88,494 - 89,664) people with sickle cell anemia in the United States, of which 80,151 were black and 8928 Hispanic (32). Sickle cell disease has a high morbidity and mortality. There has been a significant increase in life expectancy for patients with HbSS over the last 50 years. Platt and colleagues reported that based on Cooperative Study of Sickle Cell Disease (CSSCD) data for 1313 females and 1229 males with HbSS followed from 1978 to 1988, the average life expectancy for males was 42 years, and for females 48 years (168). They cited Diggs, who estimated, based on an autopsy review, that patients with HbSS had a median survival of 14.3 years, with 20% of deaths occurring in the first 2 years of life, one third before the fifth year of life, half between 5 to 30 years, and one sixth after 30 years of age (48).
It has been reported that during the study period from 1999 to 2009, the greatest decline in sickle cell disease-related mortality rates occurred in children in the 1 to 4 year age group when compared to years 1979 to 1998 (decrease of 67% from 1.3/100,000 in 1979-1998 to 0.4/100,000 in 1999-2009). Significant declines in sickle cell-related mortality occurred in all pediatric groups up to age 19, with decreases of 61% for children age 0 to 1 year, 35% for children age 5 to 9 years, 33%for children age 10 to 14 years, and 22%for those age 15 to 19 years. This improved survival has been attributed to neonatal screening, early initiation of penicillin prophylaxis, and pneumococcal vaccinations, especially the current ones for invasive pneumococci. TCD screening was also thought to have perhaps contributed to the decline (83). Quinn and colleagues have reported similar findings for the Dallas Newborn Cohort, where 93.4% of children with HbSS survived to 18 years of age (177).