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Journal Français d'Ophtalmologie
Volume 41, n° 1
pages 50-56 (janvier 2018)
Doi : 10.1016/j.jfo.2017.07.005
Received : 6 June 2017 ;  accepted : 10 July 2017
Communications de la SFO

Sickle cell retinopathy and other chronic complications of sickle cell anemia: A clinical study of 84 Sub-Saharan African cases (Cameroon)
La rétinopathie drépanocytaire et les complications non ophtalmologiques de la drépanocytose : étude clinique de 84 cas en Afrique sub-saharienne (Cameroun)
 

Y. Bilong a, , M. Dubert b, c, 1, G. Koki a, 1, J.J. Noubiap d, e, H.N. Pangetna f, A. Menet c, g, D. Chelo h, L. Offredo c, S. Jacob c, S. Belinga i, A.N.A. Yanda j, S. Kingue k, X. Jouven b, l, B. Ranque b, c, L.A. Bella a
a Ophthalmology, faculty of medicine and biomedical sciences, university of Yaoundé I, 6066 Yaoundé, Cameroon 
b Internal medicine, hôpital européen Georges-Pompidou, Assistance publique–Hôpitaux de Paris, 75015 Paris, France 
c UMR_S970, Inserm, Paris-Descartes university, 75908 Paris, France 
d Medicine, Groote Schuur hospital, university of Cape Town, 7925 Cape Town, South Africa 
e Medical diagnostic center, Yaoundé, Cameroon 
f Clinical biology, faculty of medicine and biomedical sciences, university of Yaoundé I, Yaoundé, Cameroon 
g Cardiology, groupement des hôpitaux, université catholique de Lille, Lille, France 
h Cardiology, mother and child center of the Chantal Biya foundation, 6066 Yaoundé, Cameroon 
i Medical biology vaccination and training unit, Pasteur Center, Yaoundé, Cameroon 
j Sickle cell unit, mother and child center of the Chantal Biya foundation, Yaoundé, Cameroon 
k Internal medicine, faculty of medicine and biomedical sciences, university of Yaoundé I, 6066 Yaoundé, Cameroon 
l Cardiology, hôpital européen Georges-Pompidou, Assistance publique–Hôpitaux de Paris, Paris, France 

Corresponding author.
Summary
Objective

Sickle retinopathy is a severe complication of sickle cell disease than can lead to blindness. We aim to describe the epidemiology of sickle retinopathy in homozygous sickle cell (SS) African patients and to analyze its association with non-ophthalmologic disease complications of sickle cell anemia.

Methods

We conducted a nested study within the CADRE cohort in Cameroon. Eighty-four consecutive SS outpatients, aged 10 years and older, with no visual symptoms, underwent an ophthalmologic examination. Mean age was 23±10 years. Clinical and biological features were compared between patients with and without sickle retinopathy. We compared the prevalence of the clinical complications and main biological characteristics in patients with and without sickle retinopathy using a univariate logistic regression. The same analysis was used to compare the patients with non-proliferative sickle retinopathy to those with proliferative sickle retinopathy. Statistical analyses were done using the R software (version 3.1.2).

Results

Fifty-two patients (62%) displayed sickle retinopathy, among them 23 (27%) had a non-proliferative sickle retinopathy, and 29 (35%) had proliferative sickle retinopathy. Patients with proliferative sickle cell retinopathy had a mean age of 28±11 years. Sickle retinopathy was associated with higher hemoglobin level (P =0.047) and fewer leg ulcers (P =0.018). Proliferative SR was associated with increasing age (P =0.008) and male sex (P =0.025) independently of the hemoglobin level.

Conclusions

Sickle retinopathy is particularly frequent in sub-Saharan sickle cell SS patients, which advocates for early systematic screening.

The full text of this article is available in PDF format.
Résumé
Objectif

La rétinopathie du drépanocytaire est une complication sévère de la drépanocytose pouvant conduire à la cécité. Le but de cette étude est de décrire l’épidémiologie de la rétinopathie drépanocytaire chez le patient drépanocytaire homozygote (SS) africain et de rechercher les corrélations de cette rétinopathie avec les complications non ophtalmologiques de la drépanocytose.

Méthode

Nous avons conduit une étude prospective au sein de l’étude CADRE. Quatre vingt quatre patients SS, de plus de 10 ans et asymptomatiques, ont été examinés. L’âge moyen était de 23±10ans. Les données cliniques et biologiques obtenues entre les patients porteurs ou non de rétinopathie drépanocytaire ont été comparées. Ainsi nous avons comparé, entre ces deux groupes, les prévalences des complications cliniques non ophtalmologiques et les paramètres biologiques, à l’aide d’un modèle de régression logistique. Et, nous en avons fait de même, entre les patients porteurs d’une rétinopathie proliférante et ceux ayant la rétinopathie non proliférante. L’analyse statistique s’est effectuée grâce au R software (version 3.1.2).

Résultats

Cinquante deux patients (62 %) avaient la rétinopathie drépanocytaire. Vingt trois (27 %) avaient la rétinopathie drépanocytaire non proliférante, tandis que 29 (35 %) avaient la rétinopathie proliferante. L’âge moyen des patients ayant une prolifération rétinienne était de 28±11ans. La rétinopathie drépanocytaire était associé à un taux élevée d’hémoglobine (p =0,047) et un taux bas d’ulcère de jambe (p =0,018). La rétinopathie drépanocytaire proliférante était associé à l’âge avancé (p =0,008) et le sexe masculin (p =0,025) indépendamment du taux d’hémoglobine.

Conclusion

La rétinopathie drépanocytaire est particulièrement fréquente chez le patient SS en Afrique sub-saharienne, d’où l’importance de la recommandation d’un dépistage précoce systématique.

The full text of this article is available in PDF format.

Keywords : Sickle cell retinopathy, Epidemiology, Vascular complications

Mots clés : Rétinopathie drépanocytaire, Épidémiologie, Complications vasculaires


Introduction

Sickle cell disease (SCD) main chronic complications result from the development of a vasculopathy: stroke, pulmonary arterial hypertension (PAH), kidney disease, osteonecrosis, leg ulcers, priapism and sickle retinopathy (SR). SR can be classified into non-proliferative (npSR) or proliferative (pSR), depending on whether the retinal ischemia is minimal or large [1]. The prevalence of SR has mostly been evaluated in Europe and America and is believed to concern mainly patients with the SC phenotype [2, 3]. Moreover, very few studies have assessed the association between SR and other vascular SCD complications especially in sub-Saharan Africa [4, 5]. The aim of the study was to describe the prevalence of SR in outpatients with the SS phenotype in Cameroon and to assess its association with the other SCD complications.

Methods

We performed a prospective study nested in the multinational CADRE (coeur, artères et drépanocytose ) cohort [6]. SCD patients were recruited through outpatient clinics and media in Yaoundé and Douala (Cameroon). From January 2012 to August 2013, SS patients, aged 10 year and older were consecutively enrolled to visit the ophthalmologic unit of the Central Hospital of Yaoundé, at a steady state. During the first visit, medical history of infectious diseases and vascular complications (stroke, leg ulcers, priapism and symptomatic osteonecrosis), frequency of vaso-occlusive crises and clinical parameters, urine and blood tests results were recorded. The SS phenotype was confirmed by haemoglobin electrophoresis and/or high-performance liquid chromatography. Renal disease was defined as a urine albumin/creatinine ratio >30mg/g. Estimated glomerular filtration rate (eGFR) was calculated using the CKD-EPI formula for adults and the Schwartz formula for children younger than 20 years old. Patients underwent an echocardiography and tricuspid regurgitation jet velocity (TRV) greater than 2.5m/s defined pulmonary arterial hypertension (PAH). During the second visit, the patients underwent an ophthalmologic examination by a general ophthalmologist, under the permanent supervision of two experienced and trained retina specialists. Visual acuity was checked using the E. Snellen chart and a dilated indirect fundoscopic examination was performed. According to the most affected eye, each patient was classified as follow: no SR, npSR or pSR. NpSR was defined by the presence of white-without-pressure, salmon-patch haemorrhages, iridescent spots or black sunbursts (Figure 1A–D). Proliferative SR was classified in 5 stages according to the level of ischemia and the presence of neovascularization complication (Figure 1E–G and Appendix A) [1].



Figure 1


Figure 1. 

Ophthalmologic findings in patients with sickle cell retinopathy during the study. A. White-without pressure. B. Salmon-patch hemorrhages. C. Iridescent spots. D. Black sun-bursts. E. Peripheral arterial occlusion (pSR class I). F. Peripheral arteriovenous anastomoses (pSR class II). G. Neovascular and fibrous proliferations (pSR class III). H. Tortuosity of vessels and angioid streaks.

Zoom

The CADRE protocol was approved by the national ethic committee (N016-CNE-SE-2011).

The prevalence of the clinical complications and the main biological characteristics were compared between the patients with and without SR using a univariate logistic regression. The same analysis was performed to compare the patients with npSR and pSR, with a subsequent adjustment for age and sex. Statistical analyses were done using the R software (version 3.1.2).

Results

Eighty-four patients with the SS phenotype and a mean age of 23±10 years (range 10–54years) were enrolled in the study. Forty patients (48%) were males. Sex ratio and age was not different between patients with and without SR (Table 1). Fifty-two patients (62%) presented a SR in at least one eye including 23 (44%) with npSR and 29 (56%) with pSR (Table 2). Noteworthy, among the 12 patients aged 10 to 13 years old, 6 (50%) presented a SR. Retinal lesions were mainly localized in the upper (83%) and lower (73%) temporal retina. In patients with npSR, the most common retinal lesion was white-without pressure (52%) (Figure 1A and Table 2). In patients with pSR, 19 (66%) were classified in class I, 8 (28%) in class II and 6 (12%) were class III (Figure 1E–G and Table 2). Noteworthy, 21 (41%) patients also presented a posterior pole abnormality (tortuosity of major vessels or angioid streaks) for at least one eye (Figure 1H). Among patients with SR, 41 (79%) had a 10/10 visual acuity for both eyes and only one patient had a less than 3/10 visual acuity for one eye.

Patients with pSR were significantly older than those with npSR (23 [20–37] versus 19 years [16–22], univariate P =0.008). The age-adjusted analysis demonstrated a strong association between pSR and male sex (OR=4.70, 95% CI 1.28–19.80), that was unchanged after adjustment for haemoglobin level (OR=4.26, 95% CI 1.16–18.11) (Table 1).

Looking for an association with non ophtalmological SCD clinical complications (Table 1), we demonstrated a negative association between SR and leg ulcers (OR=0.27, 95% CI 0.09–0.78), and a trend to a positive association with osteonecrosis (OR=2.74, 95% CI 0.76–13.14). Regarding the biological findings, SR was associated with higher haemoglobin level (OR=2.88, 95% CI 1.03–8.45). However, among the six patients presenting the most severe fundoscopic findings (class III pSR), three (50%) had an haemoglobin level of less than 10g/dL.

Discussion

We observed a high prevalence of SR (62%) and pSR (35%) in patients with the SS phenotype in Cameroon. Diallo et al previously reported that the prevalence of SR in sickle cell patients varies greatly in the literature, from 17 to 64% [7]. In the other hand the prevalence of pSR varies from 0.5% to 64% [2, 3, 7, 8, 9, 10, 11]. Different population characteristics and type of recruitment may explain these discrepancies. First, because of the association between age and pSR, the pediatric cohorts usually demonstrate a lower prevalence of SR [3, 10, 11]. Whereas our patients were children aged more than 10 years old and young adults. Most authors recommend a systematic screening for SR after the age of 9 years in patients with the SC phenotype and after the age of 13 years in patients with the SS phenotype [10]. Noteworthy, we also observed a high prevalence of SR (50%) in the patients aged 10 to 13 years old. Second, most previous studies were conducted in ophthalmology clinics, targeting patients presenting a visual impairment which may lead to an overestimation of SR prevalence [2, 7]. In our study, the patients were consecutively recruited, independently of any visual symptoms. Therefore, the high frequency of SR we observed is likely to be a fair estimation of the prevalence of SR in the general population of SCD patients in Yaoundé, Cameroon.

In our study, only one patient, presenting class III pSR, had a severe impairment of visual acuity. Noteworthy, none of the patients displayed class IV or class V pSR (Table 2). This result confirms that SR is rarely responsible of blindness before the two last classes of Goldberg classification [8].

As demonstrated by previous studies, we observed a significant association between SR and the haemoglobin level [9, 12]. However, half the patients with class III pSR had an haemoglobin level of less than 10g/dL, suggesting that even patients with deep anemia can develop vaso-occlusion and neovascularization.

We also observed that pSR was strongly associated with male sex, as reported in other studies [2, 7, 8, 9]. Some authors presumed that this gender effect is attributable to the lower median haemoglobin rate observed in females but this hypothesis was contradicted in our study by the persistence of the male sex effect after adjustment for the haemoglobin level [2, 8, 9].

Regarding the association with other SCA complications, we found that SR was negatively associated with leg ulcers and positively associated with osteonecrosis. Although this latter association was not statistically significant, a similar trend has already been reported by Leveziel and colleagues in a previous study including SS patients in France [2]. The association with leg ulcers was not assessed in previous studies. Kato et al described a pathophysiological model that associated clinical SCD vascular complications to either blood viscosity or hyperhaemolysis mechanisms [13]. According to this dichotomization, SR should be classified as viscosity-related complication in SS patients because of higher haemoglobin level, more frequent osteonecrosis and less frequent leg ulcers. Nevertheless, the pathophysiology of SR in SS patients is probably more complex, since a previous study could not find any association between SR and hyperviscosity in 32 SS patients, conversely to the findings in SC patients [14]. To our knowledge, our study is the first to analyze SR in Central Africa where more than 90% of SCD patients display a SS phenotype [6]. However, we acknowledge on a series of limitations. First, the sample size is modest and potentially responsible for a lack of power. Second, non ophthalmologic SCD complications were clinically assessed (except for PAH) and subclinical phenotypes, such as early osteonecrosis, may have been underdiagnosed.

Conclusions

This study demonstrates that SR is a very common complication in SS patients in Cameroon, including the children aged 10 to 13 years old and those with a low haemoglobin level. These results support the generalization of an ophthalmologic screening for every SS patient aged 10 years and older, as currently recommended for patients with the SC phenotype [10]. Moreover, although the association between SR and higher haemoglobin level suggests a link with hyperviscosity, other pathophysiological mechanisms may be involved. Further studies are needed to better understand the underlying pathophysiological processes of SR in SS patients.

Disclosure of interest

The authors declare that they have no competing interest.


Appendix A. Supplementary data

(263 Ko)
  

 This work is issued from the oral presentation, which won the Francophonie award, during the 120th congress of the French Ophthalmic Society.

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1  These authors contributed equally to this work.


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