Description of the condition
Sickle cell disease (SCD) is a recessive genetic disorder determined by a nucleotide substitution at the 17th position of the β-globin gene and, consequently, the sixth amino acid in the β-globin chain changes from glutamic acid to the hydrophobic amino acid, valine. The hemoglobin that results from this change is called hemoglobin S (HbS) and, when oxygen concentration is low, it polymerizes and the red blood cells change to a sickle shape. This process results in vaso-occlusion, tissue hypoxia, red blood cell destruction (hemolysis) and chronic inflammation. People with SCD have recurring episodes of pain (due to vaso-occlusion and hypoxia) and are at risk for organ damage over their lifetime (Powars 2005). In developed countries, the survival of children with SCD is no longer the major concern, since neonatal screening programs and the high standard of care provided have increased life expectancy (Almeida 2001; Quinn 2004). Morbidity has now become the greater concern.
Although ischemia reperfusion injury can occur in any organ, one of the most overwhelming is that of cerebral injury, such as silent cerebral infarct (SCI) and overt stroke. Stroke is an acute event expressed by neurological symptoms, which are caused by the restriction of cerebral blood flow, resulting in ischemia (Wang 2007). The Cooperative Study of Sickle Cell Disease (CSSCD) defined SCI in children as lesions of abnormal hyperintensity on cerebral T2-weighted magnetic resonance imaging (MRI) in patients without any history of focal neurological symptoms, or abnormalities on neurologic examination in that particular vascular territory (Moser 1996). Recently, the definition became more precise, considering lesions that are greater than 3 mm in diameter and that appear in at least two views of T2-weighted MRI images (Casella 2010). In the adult population, the definition of SCI must be more restrictive, as adults accumulate T2 hyperintensities with time. The definition in adults considers lesions of abnormal hyperintensity on cerebral T2 weighted MRI that are greater than 5 mm and that show a corresponding hypointensity on the T1-weighted image (Vichinsky 2010).
In people with SCD, SCI is the most common form of neurologic disorder, occurring in 27% of children before six years of age (Kwiatkowski 2009) and in 37% by the time they reach 14 years old (Bernaudin 2011). Males with SCD are more likely to experience SCI, other risk factors include lower baseline hemoglobin concentration and higher baseline systolic blood pressure (DeBaun 2012a). The pathophysiology of stroke in SCD is characterized by the co-existence of macro- and microvascular abnormalities. Multiple mechanisms are thought to be involved, such as proliferation of intima and fibrosis that is amplified by inflammation associated with a hypercoagulable state and vascular tone dysregulation. Although evidence about the pathophysiology of SCI is still lacking, it is thought to be a small vessel disease, since it is not associated with large vessels stenosis (Wang 2007). A SCI occurs preferentially in the border zones of the brain, suggesting the participation of hemodynamic factors in its pathogenesis (DeBaun 2012b).
Patients with SCI do not have any obvious symptoms, but they show significant cognitive deficits when compared with people who have a normal brain MRI scan (Armstrong 1996). Identifying patients with SCI is an important issue, given that the cost of routine cerebral MRI scans means this option is not feasible for most healthcare services and there is an additional risk for children who require sedation. Neuropsycologic testing, especially those tests focused on attention and executive functions, may be useful as a screening tool to identify people with SCI (DeBaun 1998). Patients with altered tests should then undergo an MRI scan of the brain to confirm the diagnosis.
The occurrence of SCI leads to an increased risk for further progression of neurological disease, including new or progressive SCI lesions on MRI scans and a 14-fold increase in the incidence of overt strokes (Miller 2001). Despite the high prevalence, little is known about the causes of SCI and the effectiveness of therapies for its prevention.
Description of the intervention
At present, no standard intervention is available for the primary or secondary prevention of SCI.
In chronic blood transfusion therapy 10 mL to 15 mL per kg or one international unit of packed red blood cells are given per transfusion, to maintain the hemoglobin S at < 30%. Depending on the evaluation of the pre-transfusional hemoglobin, simple transfusion or partial exchange transfusions can be performed.
Treatment with hydroxyurea (hydroxicarbamide, an oral use of the chemotherapeutic agent) is administered once per day for at least four days each week. The dose ranges from 15 mg/kg of body weight per day until the maximal tolerated dose for each individual patient is reached.
Allogeneic hematopoietic stem-cell transplantation (HSCT) consists of the transplantation of a graft from a sibling or unrelated donor with stem cells derived from the bone marrow or umbilical cord blood, after any myeloablative conditioning regimen.
How the intervention might work
Chronic blood transfusion therapy is an attempt to dilute the sickled red blood cells, thus reducing the complications of the disease. The main objective of transfusion therapy is to keep the hemoglobin S at a low level. This in turn increases the oxygen carrying capacity and decreases the sickling of red blood cells, reducing the intravascular hemolysis and the free hemoglobin that consumes nitric oxide (Quattlebaum 1986). The transfusion also raises total hemoglobin levels, which leads to a lower flow velocity, an increase in red cell mass and the reduction of the adhesion to the endothelium. It has long been used to prevent strokes in patients with SCD (Sarnaik 1979). The 'Stroke Prevention Trial in Sickle Cell Anemia (STOP)' studying children with altered transcranial doppler (TCD) tests observed a significant reduction of stroke episodes in children maintained in chronic blood transfusion compared with children with no transfusion treatment. This study led to recommendations for TCD screening and prophylactic chronic blood transfusion therapy for children with abnormal TCD results (Adams 1998).
Data from the 'Optimizing Primary Stroke Prevention in Sickle Cell Anemia (STOP II) Trial' suggest that the discontinuation of transfusions in children who reverted to low risk on TCD after long-term transfusion would lead to progression or development of SCI. At the end of the study new brain MRI lesions were diagnosed in 8.1% of the patients who continued the transfusions versus 27.5% of the patients who stopped the therapy (P = 0.03). This result suggests that transfusion was protective for those patients, with an absolute SCI risk reduction of 19.4% (Abboud 2011). However, when studying a population of children receiving chronic blood transfusion therapy for secondary stroke prevention, new or enlarging cerebral infarcts occurred in 45% of patients and progressive cerebral vasculopathy in 38% (Hulbert 2011).
Although chronic blood transfusion is a potential therapy for preventing SCI, significant side effects must be considered, such as the risks of alloimmunization, the transmission of viral or bacterial infections, allergic reactions and iron overload.
Hydroxyurea is a cytostatic myelosuppressive drug initially used to treat cancer. Since the 1980s it has also been used to treat adult patients with SCD due to its ability to increase the fetal hemoglobin levels and decrease the reticulocyte, white blood cell and platelet count (Charache 1992; Platt 2008). In 1996 pediatric patients began to use this agent with similar laboratory results. The patients using hydroxyurea had a reduction in the number and duration of hospitalizations (Fester 1996). The treatment with hydroxyurea also led to fewer pain episodes and decreased episodes of acute chest syndrome (Charache 1995; Hankins 2005). The Belgian experience also suggests that hydroxyurea may be effective in primary or secondary stroke prevention (Gulbis 2005). Several studies have proven that this drug is safe and well-tolerated in adults and children (Jayabose 1996; Scott 1996; Zimmerman 2004). The most frequent adverse events are mild hematologic toxicities (thrombocytopenia, leukopenia (including neutropenia), reticulocytopenia and pancytopenia), which rarely lead to cessation of treatment (de Montalembert 2006).
Allogeneic HSCT is the only curative treatment for SCD, therefore it is a potential option for the primary or secondary prevention of SCI (Apperley 1993; Bernaudin 2007). It has ben reported that HSCT in SCD is successful in 85% to 90% of patients (Locatelli 2012).
Why it is important to do this review
It remains unclear whether chronic blood transfusion therapy, hydroxyurea or HSCT are effective in preventing primary or secondary SCI. This review aims to identify and appraise the best quality evidence on medical interventions for primary and secondary prevention of SCI.