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Risk of cerebral haemorrhage in children with sickle cell disease

Ischaemic stroke occurs in about 11% of patients with sickle cell disease (SCD) before the age of 20 years, with a peak incidence between 2 years and 5 years. It usually follows the occlusion of the big vessels of the Circle of Willis, hence the usefulness of transcranial doppler (TCD) in identifying patients at risk. Guidelines call for chronic transfusion therapy to keep the HbS concentration at <30% for the primary and secondary prevention of stroke. 1 In young adult patients (with a peak between 20y and 29y), stroke is usually haemorrhagic, related mainly to aneurysmal rupture, or moyamoya syndrome. The conundrum, however, is: at what age does the transition from ischaemic to haemorrhagic risk take place? Could the risk for both coexist or overlap? Are they part of a continuum, occurring sequentially? It is pertinent to unravel these issues because, while the incidence of ischaemic stroke in SCD has been falling steadily in countries where TCD screening, followed by transfusion therapy, is practised, the rate of haemorrhagic stroke has remained constant. Identification of its risk factors would, therefore, provide an opportunity of designing appropriate screening and preventive measures. The underlying pathophysiology of stroke in SCD is related to chronic vasculopathy. 2 Several mechanisms contribute to this but the central paradigm is nitric oxide resistance, inactivation and impaired availability, triggered by circulating free heme. Nitric oxide is a critical endogenous vasodilator synthesized by endothelial cells and its depletion produces extensive oxidative stress, mediated by a cascade of inflammatory and signalling agents. There is consequent vasoconstriction, platelet activation, thrombin generation and up-regulation of adhesion molecules. This leads to endothelial intimal proliferation culminating in arterial stenosis and eventual occlusion. However, within areas of the hypertrophied smooth muscle of cerebral arteries, foci of atrophy and fibrosis of the media have been described. It has been hypothesized that these weakened areas are prone to aneurysms. Indeed, several reports have confirmed the presence of multiple aneurysms in patients with SCD, with a predilection for the posterior cerebral and the basilo-vertebral arteries. 3 While there have been several anecdotal reports of haemorrhagic stroke in children, detailed studies have been few. Strouse et al. 4 identified 15 children with SCD who had