|Year : 2020 | Volume
| Issue : 3 | Page : 142-147
Ocular manifestations in SCD patients: role of fundus fluorescein angiography in the detection of sickle retinopathy
Nayera H Elsherif1, Mahmoud A Kenny1, Mohamed I Saleh2, Waheed S Elhalfawy1
1 Department of Pediatric Hematology Oncology Unit, Ain Shams University, Cairo, Egypt
2 Department of Ophthalmology, Ain Shams University, Cairo, Egypt
|Date of Submission||10-Jan-2020|
|Date of Acceptance||30-Mar-2020|
|Date of Web Publication||23-Jun-2021|
Nayera H Elsherif
Department of Pediatrics, Abbaseya square, Eldemerdash Hospital, Cairo, 11588
Source of Support: None, Conflict of Interest: None
Background Sickle cell retinopathy comprises a constellation of abnormal signs in the retinas of patients with sickle cell disease (SCD). The aim was to detect ophthalmological complications in patients with SCD, particularly macular microvascular alteration, using fundus fluorescein angiography (FFA), and to assess the role of potentially contributory clinicopathological factors including transcranial Doppler, genotypes, hydroxyurea, transfusion therapy, and finally, iron overload state on the development of sickle eye.
Patients and methods This cross-sectional study included 30 patients with SCD randomly recruited from the Paediatric Haematology Clinic of Ain Shams University Children’s Hospital, Cairo, Egypt. Complete blood count, transcranial Doppler, and FFA were done.
Results Of 30 patients, five had abnormal/conditional transcranial results. The FFA finding was normal in 60 eyes (all 30 SCD patients), and only one patient had abnormal visual acuity. This was a 29-year-old girl who was on simple blood transfusion and hydroxyurea treatment for recurrent cerebral strokes and vaso-occlusive crises, yet her FFA finding was normal.
Conclusion The authors could not demonstrate any retinal microvascular alternations using FFA among patients with SCD. The authors related the results to their young age and the fact that all were on hydroxyurea therapy with fair compliance. Further studies using a large sample size are warranted to illustrate the utility of FFA as a tool for early detection of sickle retinopathy.
Keywords: fundus fluorescein angiography, sickle cell disease, sickle retinopathy
|How to cite this article:|
Elsherif NH, Kenny MA, Saleh MI, Elhalfawy WS. Ocular manifestations in SCD patients: role of fundus fluorescein angiography in the detection of sickle retinopathy. Egypt J Haematol 2020;45:142-7
|How to cite this URL:|
Elsherif NH, Kenny MA, Saleh MI, Elhalfawy WS. Ocular manifestations in SCD patients: role of fundus fluorescein angiography in the detection of sickle retinopathy. Egypt J Haematol [serial online] 2020 [cited 2021 Sep 23];45:142-7. Available from: http://www.ehj.eg.net/text.asp?2020/45/3/142/319158
| Introduction|| |
Sickle cell disease (SCD) is a group of inherited blood disorders characterized by abnormality in the adult hemoglobin found in red blood cells, resulting in severe chronic hemolytic anemia and the occurrence of painful vaso-occlusive crises ,,. Ocular manifestations of SCD include retinal and macular vascular occlusions, sickle cell retinopathy (SCR), and finally, anterior segment abnormalities. Functional consequences are variable and range from decreased visual acuity to abnormal color vision and central scotomas . SCR is classified as nonproliferative sickle cell retinopathy (NPSCR) or proliferative sickle cell retinopathy (PSCR) . NPSCR is frequently characterized by precocious bilateral changes, peripheral closure/anastomoses, salmon-patch hemorrhages, iridescent spots, and black sunburst, whereas PSCR is generally associated with thinning of macular inner retinal layers and ganglion cell complex focal loss, as well as thickening of the central fovea ,. Screening for SCR starts at the age of 10 years, and then every 1-2 years if no clinically apparent SCR was detected . However, peripheral retinal vascular occlusions have been identified in sickle cell patients as young as 20 months old . Although carrying risks and requiring intravenous access and general anesthesia, fluorescein angiography (FA) is the current gold standard for evaluation of retinal vascular abnormalities .
Our goal was to detect ophthalmological complications in patients with SCD particularly macular microvascular alteration using fundus fluorescein angiography (FFA) and to assess the role of potentially contributory clinicopathological factors including transcranial Doppler (TCD), genotypes, hydroxyurea, transfusion therapy, and finally, iron overload state on the development of sickle eye.
| Patients and methods|| |
This cross-sectional study included 30 patients with SCD (16 males and 14 females), aged greater than or equal to 10 years, and randomly recruited from the Pediatric Hematology clinic of Ain Shams University Children’s Hospital, Cairo, Egypt, in the period from January 2018 to June 2019. An informed consent was obtained from the guardian of each patient before participation. The procedures applied in this study were approved by the Ethical Committee of Human Experimentation of Ain Shams University and were in accordance with the Helsinki Declaration. Other types of chronic hemolytic anemia, patients with SCD with congenital ocular affection, diabetes mellitus, or thyroid affection were excluded.
Data collected from the files of the patients included the age of onset, the duration of the disease, the transfusion history including the type (simple/exchange) and cause, history of viral hepatitis (hepatitis B and or C virus) infection, hydroxyurea and chelation therapies, and the assessed compliance using the patient self-report of dose taking and by checking the prescription refill and pill count; a cutoff point below 80% was considered as poor compliance . History of vaso-occlusive crises, avascular necrosis of bones, acute chest syndrome, and cerebral stroke (occult or overt) was collected. A sickling scoring system was used for clinical assessment of the disease severity .
Complete blood count was assessed using Sysmex XT-1800i (Sysmex, Kobe, Japan) and markers of hemolysis (lactate dehydrogenase and indirect bilirubin) were assessed using Cobas Integra 800 (Roche Diagnostics, Mannheim, Germany). The mean pretransfusion hemoglobin was calculated, as well as the mean serum ferritin in the last 2 years before the study.
Liver iron concentration
All patients underwent MRI examination using a 1.5-T MRI scanner (Achieva, Philips-Intera, Holland, Hollandm Netherlands) and a 12-element phased array coil at the MR Unit, Radiology Center, Ain Shams Hospital. Liver iron concentration (LIC) measurements were conducted by acquiring eight consequent T2* values and assessing T2* decay. Liver T2* values were converted into LIC values using the calibration curve. LIC values were expressed as mg/g dry weight .
TCD evaluations were performed using the same device (M7MINDRAY, TCD transducer 11–12 MHz), by the same radiologist and using the same technique. The middle cerebral artery (MCA), anterior cerebral artery (ACA), posterior cerebral artery (PCA), vertebral (AV). and basilar were evaluated. Each vessel was examined through its proper bone window (MCA, ACA, and PCA via temporal window e VA e basilar via occipital windows) according to Aaslid technique . Ultrasound signal was deepened by 2 mm each time, and the highest speed was chosen, in accordance with STOP study 
Complete ophthalmological examination
Slit lamp, fundus examination, and visual acuity were done for all patients by an experienced ophthalmologist who was unaware of the patient’s clinical data.
Fundus fluorescein angiography
FFA was performed using Kowa VX-20 Fluorescein Angiography Retinal Camera (Kowa, Hamburg, Germany) to take color photographs after injecting a 10% fluorescein solution intravenously. A ‘red-free’ image is captured. If indicated, a preinjection study is performed to detect autofluorescence, with both the excitation and barrier filters in place. Images are taken at approximately 1 s intervals, beginning 5–10 s after injection and continuing through the desired phases. If the pathology is monocular, control pictures of the opposite eye should still be taken, usually after the transit phase has been photographed in one eye. If appropriate, late photographs may be taken after 10 min to show leakage, and occasionally after 20 min . Cautions against adverse reactions (gastrointestinal manifestations, vasovagal disorders, local reactions, and severe anaphylaxis) were taken .
Data was collected, revised, coded and entered to the Statistical Program for the Social Sciences version 21 (SPSS Inc., Chicago, Illinois, USA). The qualitative data were described as number and percentages. The quantitative data were described as mean, SD, median, and interquartile range. The comparison between two groups with parametric qualitative data was done by using χ2-test or Fisher’s exact test when the frequencies were below five. To compare between two groups with parametric quantitative data, Student’s t-test was applied. To compare between two groups with nonparametric quantitative data, Mann–Whitney test was used. Pearson’s correlation test was used to assess associations between Doppler parameters and other data. P value less than 0.05 was considered statistically significant.
| Results|| |
The clinical and demographic, laboratory, and radiological data of the studied patients with SCD are illustrated in [Table 1].
|Table 1 Clinical, demographic, laboratory &radiological data of the studied sickle cell disease patients|
Click here to view
Relation of genotype to the clinical, laboratory, and radiological data
A total of 15 patients with SCD (50%) had vaso-occlusive crisis, five (16%) had avascular necrosis, two (6.7%) patients had acute chest syndrome, and two (6.7%) patients had cerebral stroke. Fourteen of our patients with SCD (46.7%) were on regular blood transfusion, for strokes (14.3%), avascular necrosis (57.1%), acute chest syndrome (7.1%), and anemia (21.4%). There were no significant differences between the different SCD genotypes regarding the disease duration, the transfusion history, hydroxyurea, and chelation history (P=0.288, 0.204, 0.117, and 0.236, respectively). Different SCD genotypes had comparable frequency of vaso-occlusive crises, sickling score, liver iron content (LIC), and TCD (P=0.72, 0.056, 0.651, and 0.44, respectively). However, patients with HbSS had significantly higher HBS compared with the other genotypes (P=0.000).
Relation of transcranial Doppler results to the clinical, laboratory, and radiological data
There were no significant differences between patients with normal TCD finding and those with abnormal/conditional TCD finding regarding the duration of disease, the transfusion history, hydroxyurea, and chelation history (P=0.073, 0.317, 0.513, and 0.847, respectively). The dose of hydroxyurea was significantly higher among patients with abnormal/conditional TCD (P=0.011). There were no significant differences between patients with SCD with normal TCD finding and those with abnormal/conditional TCD finding regarding the frequency of vaso-occlusive crisis, stroke, and sickling score (P=0.847, 0.190, and 0.765, respectively). No significant differences were found between patients with normal TCD finding and those with abnormal/conditional TCD finding regarding the mean serum ferritin, mean Hb in the last 2 years, initial HbS, initial HbF, and LIC (P=0.636, 0.170, 0.356, 0.452, and 0.470, respectively).
Ocular examination and FFA assessment
All studied patients had normal FFA examination with normal slit lamp, and only one (3.3%) patient had abnormal visual acuity. The descriptive data of the patient with abnormal ocular examination are shown in [Table 2]. She was a 29-year-old woman who had five attacks of cerebral stroke. Although she had limited visual acuity, yet FFA finding was normal ([Figure 1]). She was on regular simple blood transfusion and hydroxyurea treatment.
|Table 2 Descriptive data of sickle cell disease patient with abnormal ocular examination|
Click here to view
|Figure 1 Fundus fluorescein angiography of sickle cell disease patient with visual loss showing normal retinal circulation: (a) red-free photo, (b) late venous phase of fundus fluorescein angiography and (c) fundus fluorescein angiography of retinal periphery.|
Click here to view
| Discussion|| |
SCD is a severe chronic hemolytic disorder characterized by hemolysis, vascular injury, and tissue ischemia affecting multiple organs . The pathophysiology of SCD is based on the polymerization of hemoglobin S, leading to hemodynamic abnormalities, such as sludging, and vascular occlusion in the microvasculature, including that of the retina . Vaso-occlusive disease of the retina can be either proliferative or nonproliferative .
Our aim was to detect ophthalmological complications in patients with SCD particularly macular microvascular alteration using FFA and to assess the role of potentially contributory clinicopathological factors, including TCD, genotypes, hydroxyurea, transfusion therapy, and finally, iron overload state on the development of sickle eye, highlighting the importance of regular ocular examination of patients with SCD.
El-Ghamrawy et al.  in their cohort study reported an overall frequency of 47.5% ocular lesions, which was in concordance with the published data. PSCR and NPSCR were evident in 32.5 and 27.5% of all their patients, respectively (five patients having both).
Genotype is the most important risk factor for disease severity. Individuals with HbSS are most severely affected, followed by individuals with HbS/β0 thalassemia. Individuals with HbS/β0 thalassemia tend to have mild-to-moderate phenotype . Overall, 16 of our patients with SCD (53.3%) were HbSS, 10 (33.3%) were HbS/B0, and four (13.3%) were HbS/B+, but all had normal FFA finding and slit lamp examination. Only one (HbSS) had visual affection that was related to recurrent attacks of strokes in the last year before the study. On the contrary, two (6.7%) patients had cerebral stroke (both were HbSS) yet their ocular examinations were normal. Bottin et al.  stated the early involvement of the inner retina in patients with HbSS, and El-Ghamrawy et al.  found that of 13 patients showing PR, six had S/β thalassemia, confirming what was previously mentioned about the occurrence of serious ischemic retinopathy among patients with S/β thalassemia . However, Rosenberg and Hutcheson  reported that pain crisis and male sex are clinical risk factors for sickle retinopathy. We related the normal FFA of our patients with SCD to the fact that our patients were young (mean age=14.1±4.02 years), with a mean disease duration of 148.60±52.1 months. Indeed, Leveziel et al.  reported that sickle retinopathy is an age-dependent process, with older people being at substantially higher risk. Moreover, El-Ghamrawy et al.  found that older age and longer disease duration were the only determinants for development of retinal changes. In addition, in a London cohort of 189 patients with SCD , the investigators reported that proliferative sickle retinopathy (PSR) was associated with older age (> 35 years) and that visual impairment was related to the presence of PSR but not to the disease genotype . The association between age and progression toward PSR was further corroborated in a recent retrospective study of 296 patients with SCD, where male sex and older age were associated with PSR . Another argument would be that all our patients were in HU treatment. The beneficial effect of HU in preventing SCR is demonstrated by Estepp et al.  and Dell’Arti et al.  and was probably attribute to the induction of HbF with hydroxyurea, which prevents macular and peripheral ischemia, and therefore potentially reduces the occurrence of sickle cell maculopathy.
TCD is an important screening test in patients with SCD. Bernaudin et al.  showed that early TCD screening and initiation of chronic transfusions has reduced the risk of overt stroke. VAN den Tweel et al.  found that central nervous system abnormalities occurred only in patients with HbSS/HbS/β0 thalassemia and not in those with HbS/β+ thalassemia. Moreover, Lagunju and his colleagues  illustrated a significant correlation between conditional and abnormal TCD values and the age. In our study, five patients had abnormal/conditional TCD, so there were no significant differences between patients with normal TCD and those with abnormal/conditional TCD regarding the disease duration, the frequency of vaso-occlusive crises, or stroke. Our patient with HBSS with lost vision had 5 attacks of strokes in the last year, although being on HU treatment and regular transfusion regimen. In contrast, El-Ghamrawy et al.  stated that the changes in visual acuity among their patients with SCD were attributed to refractive errors rather than optic atrophy or central retinal occlusion.
Blood transfusion may be needed in the emergency situation for patients with SCD such as acute anemia, acute ischemic stroke, multiorgan failure, acute sickle hepatopathy, severe sepsis, and acute priapism, both to increase the oxygen-carrying capacity and to decrease vaso-occlusive complications . Although blood transfusion plays a prominent role in the management of patients with SCD yet causes significant iron overload . Karam et al.  determined serum ferritin cutoff point as 2500 g/l and used this cutoff point in their study, with a sensitivity of 62.5% and specificity of 77.8%. LIC accurately reflects total body iron loading and is best measured by MRI . A striking finding from their analysis, DellArti et al.  illustrated the importance of chelation therapy as the most protective factor against occurrence of sickle cell maculopathy. In our series, 14 (46.7%) of our patients with SCD were on regular blood transfusion, for strokes (14.3%), avascular necrosis (57.1%), acute chest syndrome (7.1%) and anemia (21.4%); all had normal ocular examination and FFA. In addition, there were no significant differences between different SCD genotypes nor between patients with SCD with normal and those with abnormal/conditional TCD regarding LIC and mean serum ferritin. Nevertheless, our patient with SCD with abnormal visual acuity was on regular transfusion for cerebral strokes and had high serum ferritin level and LIC, a contributing factor for her ocular affection, as it has been reported that iron overload can cause neurological complications such as optic atrophy or retinal degeneration .
The small sample size is one limitation that might affect the validation of the utility of the FFA. As many variables were addressed, a larger sample would have been more convenient.
| Conclusion|| |
We could not demonstrate retinal microvascular alternation in our studied patients with SCD using FFA. Further studies are required to compare FFA with optical coherence tomography angiography to identify the best and safest method to detect early macular microvascular affection among patients with SCD.
All the authors contributed equally in this article.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Strouse J. Sickle cell disease. Handb Clin Neurol
El-Beshlawy A, Youssry I. Prevention of hemoglobinopathies in Egypt. Hemoglobin
Ballas SK, Gupta K, Adams-Graves P. Sickle cell pain: a critical reappraisal. Blood
Chow CC, Genead MA, Anastasakis A, Chau FY, Fishman GA, Lim JI. Structural and functional correlation in sickle cell retinopathy using spectral-domain optical coherence tomography and scanning laser ophthalmoscope microperimetry. Am J Ophthalmol
El-Ghamrawy MK, El Behairy HF, El Menshawy A, Awad SA, Ismail A, Gabal MS. Ocular manifestations in Egyptian children and young adults with sickle cell disease. Indian J Hematol Blood Transfus
Santos AM, Faro GB, Amaral MV, Mendonça Cde Q, Leal BC, Cipolotti R. Retinal impairment in young individuals with sickle cell anemia (hemoglobin SS disease) in university hospital in Northeastern of Brazil. Arq Bras Oftalmol
Brasileiro F, Martins TT, Campos SB, Andrade Neto JL, Bravo-Filho VT, Araújo AS, Arantes TE. Macular and peripapillary spectral domain optical coherence tomography changes in sickle cell retinopathy. Retina
Yawn BP, Buchanan GR, Afenyi-Annan AN et al.
Management of sickle cell disease: summary of the2014 evidence-based report by expert panel members. JAMA
McLeod DS, Goldberg MF, Lutty GA. Dual-perspective analysis of vascular formations in sickle cell retinopathy. Arch Ophthalmol
Ong SS, Linz MO, Li X, Liu TYA, Han IC, Scott AW. Retinal thickness and microvascular changes in children with sickle cell disease evaluated by optical coherence tomography (OCT) and OCT angiography. Am J Ophthalmol
Claxton AJ, Cramer J, Pierce C. Systematic review of the associations between dose regimens and medication compliance. Clin Ther
Al-Saqladi AM, Delpisheh A, Bin-Gadeem HA, Brabin BJ. Severity of sickle cell disease in Yemeni children. J Trop Pediatr
Elalfy MS, Esmat G, Matter RM, Abdel Aziz HE, Massoud WA. Liver fibrosis in young egyptian Beta-thalassemia major patient:relation to hepatitis C virus and compliance to chelation. Ann Hepatol
Newell DW, Aaslid R. Transcranial Doppler
. New York, NY: Raven Press 1992.
Nicchols FT, Jones AM, Adams RJ. Stroke prevention in sickle cell disease (STOP) study guidelines for transcranial Doppler testing. J Neuroimaging
Carl R. Basic and Clinical Science Course (BCSC): Section 12: Retina and Vitreous
. 2008; PP. 1–424.
Yanoff M, Duker J. Fluorescein angiography, indocyanine green angiography, and optical coherence tomography (Chapter 6). In: Am J Ophthalmology. 3 rd edition (by Richard K Parrish II). Elsevier Mosby (Maryland Heights, Missouri, Colombia, USA); 8:536–541.
Downes SM, Hambleton IR, Chuang EL, Lois N, Serjeant GR, Bird AC. Incidence and natural history of proliferative sickle cell retinopathy: observations from a cohort study. Ophthalmology
Emerson GG, Harlan JB, Fekrat S, Lutty GA, Goldberg MF. Hemoglobinopathies. Med Retina
Fadugbagbe AO, Gurgel KQ, Mendonca CQ, Cipolotti R, dos Santos AM, Cuevas LE. Ocular manifestations of sickle cell disease. Ann Trop Pediatr
Kanter J, Kruse-Jarres R. Management of sickle cell disease from childhood through adulthood. Blood Rev
Bottin C, Julie R, Matthieu PR, Salomon-Yves C, Benedicte MJ, Camille J et al.
Electroretinogram findings in early-stage sickle cell retinopathy according to hemoglobin type. Invest Ophthalmol Vis Sci
Fanny A, Coulibaly F, Gbe K, Meite M, Adjorlolo C, Konan Toure ML et al.
Sickle cell beta thalassemia leading to serious ischemic retinopathy: a study of 18 patients in Abidjan. J Fr Ophthalmol
Rosenberg JB, Hutcheson KA. Pediatric sickle cell retinopathy: correlation with clinical factors. J AAPOS
Leveziel N, Bastuji-Garin S, Lalloum F, Querques G, Benlian P, Binaghi M et al.
Clinical and laboratory factors associated with the severity of proliferative sickle cell retinopathy in patients with sickle cell hemoglobin C (SC) and homozygous sickle cell (SS) disease. Medicine (Baltimore)
Gregory A, Hayflick S, Adam MP, Ardinger HH, Pagon RA, Wallace SE et al.
Neurodegeneration with brain iron accumulation disorders overview. GeneReviews
Duan XJ, Lanzkron S, Linz MO, Ewing C, Wang J, Scott AW. Clinical and ophthalmic factors associated with the severity of sickle cell retinopathy. Am J Ophthalmol
Estepp JH, Smeltzer MP, Wang WC, Hoehn ME, Hankins JS, Aygun B. Protection from sickle cell retinopathy is associated with elevated HbF levels and hydroxycarbamide use in children. Br J Haematol
Dell’Arti L, Barteselli G, Riva L, Carini E, Graziadei G et al.
Sickle cell maculopathy: Identification of systemic risk factors, and microstructural analysis of individual retinal layers of the macula. PLoS One
Bernaudin F, Verlhac S, Arnaud C, Kamdem A, Chevret S, Hau I et al.
Impact of early transcranial Doppler screening and intensive therapy on cerebral vasculopathy outcome in a newborn sickle cell anemia cohort. Blood
van den Tweel XW, van der Lee JH, Heijboer H, Peters M, Fijnvandraat K. Development and validation of a pediatric severity index for sickle cell patients. Am J Hematol
Lagunju I, Sodeinde O, Telfer P. Prevalence of transcranial Doppler abnormalities in Nigerian children with sickle cell disease. Am J Hematol
Vitrano A, Calvaruso G, Tese L, Gioia F, Cassara F, Campisi S et al.
Real-life experience with liver iron concentration R2 MRI measurement in patients with hemoglobinopathies: baseline data from LICNET. Eur J Haematol
Coates TD, Wood JC. How we manage iron overload in sickle cell patients. Br J Hematol
Karam LB, Disco D, Jackson SM, Lewin D, McKie V, Baker RD et al.
Liverbiopsy results in patients with sickle cell disease on chronic transfusions: poor correlation with ferritin levels. Pediatr Blood Cancer
Wood JC, Pressel S, Rogers ZR, Odame I, Kwiatkowski JL, Lee MT et al.
for the TWiTCH Investigators. Liver iron concentration measurements by MRI in chronically transfused children with sickle cell anemia: baseline results from the TWiTCH trial. Am J Hematol
[Table 1], [Table 2]