Silent Stroke a Major Problem in Children
with Sickle Cell Disease

Silent cerebral infarcts (SCI) are increasingly recognized as a major cause of school problems, performance on tests measuring intelligence quotients (IQ), and other neurological defects, stated Dr. Michael DeBaun and his colleagues in the Education Program on Sickle Cell Disease on Saturday and Sunday.

Nearly half of all patients with sickle-cell anemia suffer brain injury. New understanding of risk factors, associated clinical findings, and imaging technologies are impacting substantially on identifying patients and highlighting the need for additional, more effective treatment options and prevention strategies.

Currently, blood transfusion therapy is the mainstay for primary and secondary stroke prevention in children, based on results from the Stroke Prevention Trial in Sickle Cell Anemia (STOP 1) study in 1997. The relative risk reduction is approximately 85 percent, but at a cost of at least monthly transfusion therapy (and its attendant risks such as potential infectious disease transmission, transfusion reactions, alloimmunization, and iron overload). As was reported yesterday, the Stop II trial (which was studying the feasibility of cessation of transfusion therapy to prevent strokes after a minimum of 30 months) was halted because radiographic imaging indicated that patients assigned to the stop transfusion cohort reverted to a high risk of stroke, along with the occurrence of stroke in two of the patients. Recent results from an NHLBI-supported clinical trial also suggest that the use of blood transfusion therapy provides benefit to children with SCI and elevated Transcranial Doppler (TCD) measurements, with a 100 percent relative risk reduction for the incidence of new, overt strokes or subsequent SCI.

New strategies to reduce the adverse consequences of long-term transfusion support need to be pursued. One method to prevent excessive iron accumulation is red cell apheresis (in which aging red cells received by the patient from the previous transfusion visit are removed by apheresis and replaced during the procedure with younger red blood cells). This technique is most suitable in older children who have adequate venous access and/or can help maintain a central venous catheter for vascular access. Another method is the therapeutic administration of an iron chelation agent for five to seven nights or more, monthly.

The likelihood of developing red cell alloimmunization can be reduced by providing blood from donors who are phenotypically matched to an individual patient for selected minor red cell antigens, such as the rh antigens as well as others such as the Kidd, Kell, and Duffy antigens. This strategy requires close cooperation between transfusion services and regional blood centers, since many units of blood need to be screened in order to provide such a specialized product. To make this approach feasible for his patients, Dr. Debaun and his associates at Children’s Hospital in St. Louis initiated a pioneering approach called the Charles Drew Program. Working closely with community leaders and the American Red Cross Regional Blood Center in Missouri, African- American blood donors have been recruited and pheno-typed, so that they can now serve as designated donors matched to individual patients for long-term transfusion support. Additional and novel strategies to eliminate the risks of infectious disease transmission, such as pathogen inactivation techniques, remain investigational.

Alternative treatment options for SCI include therapy with hydroxyurea or allogeneic stem cell transplantation. Future studies using alternative stem cell sources, such as cord blood from unrelated donors, may make allogeneic transplant a potential option for the majority of children with sickle-cell anemia.

Dr. Mark Walter from Oakland Children’s Hospital and his colleagues provided an update (abstract #4667) on the results of a multicenter trial in hematopoietic cell transplantation for sickle-cell disease. Of 59 children enrolled between 1991 and 2000, 55 patients survive and 50 survive free of sickle-cell disease. Engrafted patients with history of stroke had no subsequent stroke events after transplantation, and cerebral MRI and MRA exams demonstrated stable or improved appearance. When other evaluations of pulmonary function and gonadal function were performed, the results indicate that stem cell transplantation is a suitable intervention for patients with severe sickle cell disease.

Dr. Paola Sebastiani and her colleagues from Boston University reported in their abstract (#2391) a novel model for identifying patients with sickle-cell anemia at risk for stroke. They utilized Bayesian networks to integrate multiple variables and analyzed 235 single nucleotide polymorphisms (SNPs) in 80 candidate genes in 1398 unrelated subjects enrolled in the Cooperative Study of Sickle Cell Disease. In a prospective study of 114 subjects in the general population, their model predicted the correct outcomes for all seven stroke patients and for 105 of 107 nonstroke patients. The authors conclude that some genetic factors predisposing to stroke are shared both by sicklecell anemia patients and stroke victims in the general population, providing an opportunity for further insights into the genetic basis for stroke.