Management Of Cerebral Vasculopathy In Children With Sickle Cell Anaemia

Ischaemic brain injury is the most disabling complication of sickle cell anaemia (SS). The prevalence of symptomatic infarction with paresis nears 10% in North America, 8% in Jamaica and Nigeria, 8% in Turkey, 10±18% in Brazil and 1% in Eastern Saudi Arabia (Ozsoylu & Altinoz, 1977; Perrine et al, 1978; Powars et al, 1978; Annobil et al 1990; Balkaran et al, 1992; Goncalves et al, 1994; OheneFrempong et al, 1998). In untreated children, repeat clinical strokes occur in two-thirds of the subjects (Powars et al, 1978). If maintained on red cell transfusion, the majority with hemiparetic strokes have few recurrent clinical episodes and most survive childhood. The cerebral vasculopathy during the ®rst decade is not a static process; on transfusion, some will show improvement in functional neuroimaging (positron emission tomography; PET) (Powars et al, 1999) during the ®rst year of therapy, whereas others develop new asymptomatic penumbral lesions (unpublished observations). Functional neurological de®cits persist and become more obvious as the child matures (Hariman et al, 1991; Craft et al, 1993; Bernaudin et al, 1998; Wang et al, 1998a). As young adults, they often die of massive intracranial haemorrhage, adult respiratory distress syndrome (ARDS) or complications of transfusion-induced haemochromatosis (Powars et al, 1990a; Cohen et al, 1992; Miller et al, 1992; Platt et al, 1994). Modern neuroimaging techniques demonstrate `silent' infarction (incomplete infarction) in twice as many North American SS children as those who experience overt stroke (Moser et al, 1996; Kinney et al, 1999; Powars et al, 1999; Steen et al, 1999; Verlhac, 1999). Incomplete (cystic) infarction represents selective neuronal loss with preservation of some neurones, glia and microvessels and is often not visible as a hypodense region on computerized tomography (CT) (Garcia et al, 1996). Detailed follow-up evaluation by Kugler et al (1993) of untreated `asymptomatic' infarction demonstrated that 50% had progression of conventional magnetic resonance imaging (cMRI) abnormalities and 38% became clinically symptomatic. A high frequency of unexpected ischaemic brain injuries and atrophy has been observed at autopsy in adults (Koshy et al, 1990). Although there may be no focal de®cits (hemiparesis or hemisensory loss), there is a progressive decline in cognitive function, as measured by mathematics, vocabulary, visual motor speed and co-ordination (Swift et al, 1989; Wasserman et al, 1991; Armstrong et al, 1996; Watkins et al, 1998). These `asymptomatic' patients have never been consistently identi®ed or treated. This review will (i) focus on the identi®cation of predictive risk factors for cerebral ischaemia in young children; (ii) describe the utility of several neuroimaging modalities; (iii) summarize available clinical trials; and (iv) make recommendations for management using an intention-to-treat strategy. An algorithm has been developed as a clinical guide for management decisions (Fig 1). Unfortunately, the evidence base for clinical decision-making remains limited, and no sensitivity or speci®city analyses regarding treatment options for cerebrovascular disease in SS children have been reported. There has been one evidence-based controlled clinical trial for prevention of ®rst stroke (Adams et al, 1998). The ultimate goal is to preserve normal brain function in SS children. A secondary goal is to prevent the progression of preclinical ischaemia to permanent neuronal loss with disability. The ®rst step is to identify young children at high risk for large and small arterial cerebral vasculopathy before the development of focal neurological de®cits (Powars et al, 1984, 1990; Balkaran et al, 1992; Bernaudin et al, 1998; Liesner et al, 1998; Miller et al, 2000). To achieve these goals in neurologically asymptomatic high-risk young SS children, neuroimaging studies are required (Verlhac, 1999). The technology of neuroimaging is in a rapid phase of development and the choice of preferred methodology is dependent upon the neuroradiologist and the institution (Steen et al, 1998, 1999; Verlhac, 1999). We recommend the combination of physiological large-vessel velocity measurement (Doppler) (Adams et al, 1992, 1997; Seibert et al, 1998) with neurofunctional studies [PET or single photon emission computerized tomography (SPECT)] (Powars et al, 1999) con®rmed by cMRI or quantitative (q)MRI and magnetic resonance angiography (MRA) (Kandeel et al, 1996; Gillams et al, 1998; Steen et al, 1999). This should be followed by preventative therapy in those with evidence of `silent' or incomplete infarction (Adams et al, 1998; Garcia et al, 1996; unpublished observations).