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S. Allali et al.
Ophthalmic disease
Patients affected with SCD are at risk of retinopathy, which may result in sight-threatening complications, such as vitreous hemorrhage and retinal detachment. Ocular manifestations of SCD differ from previously described complications as peripheral retinopathy is more frequent in patients with HbSC than in patients with HbSS.97,98 The reasons for this finding are not fully understood although the blood hyperviscosity commonly observed in HbSC patients (who display higher hemoglobin levels than HbSS patients) could contribute to retinal ischemia. On the other hand, it has been hypothesized that increased vascular endothelial growth factor (VEGF) and angiopoi- etin production in response to chronic anemia could play a role by promoting angiogenesis.99
The prevalence of retinopathy has been estimated at 24% in HbSS and HbS/b0 adult patients versus 61% in HbSC and HbS/b+ patients.97 Non-proliferative retinopa- thy includes salmon-patch hemorrhages, iridescent spots, black sunbursts, and arteriovenous anastomoses. Patients are usually asymptomatic as long as the retinopathy is non-proliferative but secondary development of neovas- cularization, presenting as sea fans, bears the risk of vision loss due to vitreous hemorrhage or retinal detachment. A retrospective review of 263 children with SCD found pro- liferative retinopathy in seven cases (2.7%), including six with HbSC (occurring at a median age of 13.7 years; range: 9-18), one with HbSS (occurring at 16 years of age), and none with HbS/b-thalassemia.98 More recently, a high prevalence of temporal macular retinal atrophy diagnosed by optical coherence tomography (OCT) has been report- ed in SCD patients, including children, which may have direct consequences on visual function with impaired color vision ability and contrast sensitivity, even when visual acuity is preserved.100 In a retrospective series of 81 children (mean age 12 years; standard deviation [SD]: 3.5 years) with SCD (64 HbSS, 7 HbS/b0-thalassemia, 10 HbSC), temporal macular retinal atrophy was observed in 64% of cases with no significant difference in prevalence between HbSS and HbSC genotype.101 In this series, peripheral retinopathy was observed in 11% of patients and was more severe in children with HbSC.
Recent multimodal MRI evaluation of the visual cortex in 25 SCD children (mean age: 12.3 years; SD: 1.9 years) compared to 31 controls, found increased posterior peri- calcarine cortical thickness, with different trajectory of cortical maturation and decreased connectivity within visual neural networks.102 Whether these changes may rep- resent useful predictors of visual impairment in adulthood needs to be assessed by further studies.
Screening and prevention
There is universal consensus on the recommendation that children with SCD should be screened regularly for retinopathy with a dilated fundoscopic examination, starting earlier in children with HbSC than in children with HbSS genotypes.37,38,98 Nine and 13 years of age have been proposed as appropriate time points to start sys- tematic controls in HbSC and HbSS children, respective- ly.97 However, since temporal macular retinal atrophy seems to occur early in the course of SCD, especially for patients with HbSS,100 we personally recommend annual controls, including OCT, starting at six years of age. A simple annual survey is recommended for children with non-proliferative retinopathy and laser photocoagulation
is generally proposed to children with severe prolifera- tive retinopathy.
Hip abnormalities
Osteonecrosis of the femoral head (ONFH) is the main osteoarticular complication of SCD with an estimated prevalence ranging from 10% to 30% in adults.103 This rel- atively high frequency may be explained by several fac- tors. Firstly, vascularization of superior femoral epiphysis depends on the retinacular vessels, which originate from branches of the medial circumflex arteries in a terminal vascularization model, with limited possibilities of reper- fusion when these vessels are occluded by sickling red blood cells. In addition, the balance between osteoblasto- genesis and osteoclastogenesis is most likely modified in patients with SCD during hypoxia-reperfusion cycles.104 Lastly, vitamin D deficiency is frequent in patients with SCD and may contribute to bone fragility.105
In a study of 2,590 SCD children and adults followed-up in the 1980s for an average of 6 years, 10% of patients had ONFH at study inclusion.106 The prevalence of ONFH for patients aged 5-9 years, 10-14 years, and 15-24 years was 1.3%, 4.6%, and 8.2%, respectively. At follow-up, chil- dren with HbSS and α-thalassemia were at the greatest risk for osteonecrosis. The frequency of painful crises, age, and hematocrit were positively associated with osteonecrosis.106 The influence of hydroxyurea on the inci- dence of OFNH is much debated, although the interpreta- tion of most studies is limited by the fact that they are cross-sectional and retrospective, including only a limited number of patients.103
Screening and prevention
It has been shown that early treatment of ONFH, either conservative or operative, can lead to good functional out- comes with 75% of congruent hips at skeletal maturity.107 Early diagnosis is therefore mandatory. There is agreement on the need to investigate all children with SCD presenting intermittent or chronic hip pain for avascular necrosis by means of a full history and physical examination, X-ray, and MRI, as needed. Advice from an orthopedic department should be requested.37 At a pre-collapse stage, ONFH is, however, asymptomatic, and this observation has led a French panel of experts to recommend systematic hip X-ray after the age of 6 years with a checkup every 1-3 years.38
Conclusion
The median life expectancy of patients with SCD has increased to up to 55 years, which can be considered a sig- nificant achievement with regard to the natural history of the disease.3 However, detection and management of chronic organ failure still need to be improved in order to reach the life expectancy of the general population with- out major disabilities. Detecting and preventing early organ injury would not only reduce early mortality but may also improve quality of life. There is still no consen- sus on the best strategies for detecting and preventing chronic organ dysfunction in SCD patients. For these rea- sons, we propose a summary of the main recommenda- tions from both a US and a European panel of experts on SCD in Table 1.37,108
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haematologica | 2021; 106(6)