Sickle cell disease: The neurological complications

Abstract

The genetic cause of sickle cell disease has been known for decades, yet the reasons for its clinical variability are not fully understood. The neurological complications result from one point mutation that causes vasculopathy of both large and small vessels. Anemia and the resultant cerebral hyperemia produce conditions of hemodynamic insufficiency. Sickled cells adhere to the endothelium, contributing to a cascade of activated inflammatory cells and clotting factors, which result in a nidus for thrombus formation. Because the cerebrovascular reserve becomes exhausted, the capacity for compensatory cerebral mechanisms is severely limited. There is evidence of small-vessel sludging, and a relative deficiency of nitric oxide in these vessels further reduces compensatory vasodilatation. Both clinical strokes and silent infarcts occur, affecting motor and cognitive function. New data suggest that, in addition to sickle cell disease, other factors, both environmental (eg, hypoxia and inflammation) and genetic (eg, mutations resulting in thrombogenesis), may contribute to a patient's stroke risk. The stroke risk is polygenic, and sickle cell disease can be considered a model for all cerebrovascular disease. This complex disease underscores the potential intellectual and practical distance between the determination of molecular genetics and effective clinical application and therapeutics.

Neurocognitive deficits in children with sickle cell disease: a comprehensive profile

“…Deficits in these two areas are expected, given that silent infarcts commonly occur in frontal lobe white matter, within the border zone between the middle and anterior cerebral artery distribution [17,18]. The frontal lobes play a major role in executive functions, which are higher order cognitive functions including abilities such as response inhibition, planning, working memory, and attention [19].…”

Hemodynamic Etiology of Elevated Flow Velocity and Stroke in Sickle-Cell Disease

“…More than 10% of SCD patients will have a clinical first stroke by age 20, and another 20 to 30% will have a silent infarction (Switzer et al, 2006). The pathophysiology of stroke in SCD has been a subject of intense research for decades, and it is known to involve several interacting mechanisms at the molecular and vascular levels (Kirkham and Datta, 2006;Prengler et al, 2002).…”

Endothelial nitric oxide synthase and nitric oxide regulate endothelial tissue factor expression in vivo in the sickle transgenic mouse

“…Whether this, in turn, actually contributes to clinical thrombotic events has not been proven, but it certainly is a reasonable inference. In the case of ischemic stroke in the Circle of Willis, for example, children apparently have been in a state of being at risk for stroke by virtue of their vascular occlusive process in the Circle of Willis [15]. But the actual event of stroke completion commonly involves additional development of a thrombosis in that location of vascular anomaly.…”