Interactive Clinical Case 6 December 2017

Mr E. D. 35







OD Temporal Periphery
OD Temporal Periphery
FA 1:57s / ICG 3:30s


OS Temporal Periphery
OS Temporal Periphery
FA 4:09s / ICG 5:49s


Epidemiology

As of 2015, about 4.4 million people have sickle-cell disease (SCD), while an additional 43 million have sickle-cell trait. About 80% of sickle-cell disease cases are believed to occur in sub-Saharan populations. It affects mostly patients with SC (33%) or S-Thal (14%). Patients with SS have a 3% incidence of proliferative retinopathy.3

Physiopathology

SCD is inherited through an autosomal recessive pattern with mutations in the normal β-globin gene. The most frequent variant is HbS followed by HbC.1
Different pathways are involved such as inflammation, endothelial activation, blood cells adhesiveness and oxidative stress that lead to stasis and occlusion of small vessels by sickled erythrocytes.2,3

Sickle cell retinopathy (SCR)

Occlusions of small eye vessels can lead to proliferative sickle cell retinopathy (PSCR) with vascular proliferation, vitreous hemorrhage and retinal detachment.2 Every vascular bed can be affected.
This retinal neovascularization grows anteriorly from the perfused to non-perfused retina. It is denominated sea fan and is a pre-retinal fibrovascular membrane. Figure 1 and 2: Sea fan can cause hemorrhage and tractional retinal detachment.6 20%-60% of them can spontaneously regress.7
The phenotype is variable, even among individuals with the same genotype.8

Figure 1: Sea fan
Figure 1: Sea fan
Figure 2: Areas of non-perfusion with sea fans peripheral arteriovenous anastomosis
Figure 2: Areas of non-perfusion with sea fans peripheral arteriovenous anastomosis

Other affections can be found during the fundus exam such as:

  • salmon patch hemorrhages: retinal hemorrhage that become salmon-colored due to the hemolysis (Figure 3),
  • black sunburst: migration and proliferation of retinal pigment epithelium in response to hemorrhage (Figure 3),
  • iridescent spots (Figure 4),
  • angioïd streaks Figure 5),
  • iridal atrophy (Figure 6).

Figure 3: Salmon-patch hemorrhage and a black sunburst in sickle cell retinopathy
Figure 3: Salmon-patch hemorrhage and a black sunburst in sickle cell retinopathy
Figure 4: Iridescent spots
Figure 4: Iridescent spots
Figure 5: Angioid Streaks
Figure 5: Angioid Streaks
Figure 6: Iridal atrophy in sickle cell retinopathy (thanks to Dr Kamami)
Figure 6: Iridal atrophy in sickle cell retinopathy (thanks to Dr Kamami)

Risk factors

Proliferative sickle cell retinopathy is associated with high levels of Hb, history of pulmonary disease, deafness and older age (> 35 years) in SC patients.4 In SS patients, male gender, older age and history of acute pyelonephritis are associated with the development of PSCR.2 Low HbF level (<15%) is also associated with PSCR, independently of the SCD genotype.5

Goldberg classification is used to grade SCR:9
Stage Name
Stage I Peripheral arterial occlusion
Stage II Peripheral arteriovenous anastomoses
Stage III Sea fan
Stage IV Vitreous hemorrhage
Stage V Tractional retinal detachment

The gold standard exam to analyze it is fluorescein angiography, using a wide field if possible.

The central part of the retinal can also be affected and reveals enlargement of the foveal avascular zone, arteriovenous tortuosity, perimacular and peripapillary arterial occlusions. 10

Optical coherence tomography (OCT) can reveal thinning of macular inner retinal layer and ganglion cell complex loss secondary to non-perfusion. 11

OCT angiography (OCTA) identifies retinal ischemia in the posterior pole and is more sensitive than FA. It detects macular microangiopathy.12 However, FA remains more sensitive to detect peripheral lesions (Figure 7).

Figure 7: Microangiopathy in sicle cell disease using OCTA. OCT reveals thinning of macular inner retinal layer and ganglion cell complex.
Figure 7: Microangiopathy in sicle cell disease using OCTA. OCT reveals thinning of macular inner retinal layer and ganglion cell complex.

Differential diagnosis

  • Retinal vascular occlusion
  • Diabetic retinopathy
  • Hypertensive retinopathy
  • Eale’s disease
  • Sarcoidosis
  • Ocular ischemic syndrome
  • Retinopathy or prematurity
  • Hyperviscosity syndrome
  • Familial exudative vitreoretinopathy

Treatment of proliferative sickle cell retinopathy

At first, a multidisciplinary approach is essential to stabilize the disease.
The treatment for SCR can be discussed since lesions can be stable or regress spontaneously.
However, it is well admitted to treat proliferative SCR when:

  • lesions are bilateral, have already bled or progress rapidly
  • the patient is monophtalmic
  • large sea-fans exist (larger than one-disc diameter)

The treatment can be multimodal, including pan photocoagulation of the ischemic areas closed to the sea fan and intravitreal injections of anti-VEGF.13 Figure 8: Retinal tear and rhegmatogenous retinal detachments may occur after pan photocoagulation.
Eventually, vitrectomy can be performed for the stages 4 and 5 of the Goldberg classification.14

Figure 8: Pan photocoagulation of the ischemic areas
Figure 8: Pan photocoagulation of the ischemic areas

  1. Rheology of red blood cells in patients with HbC disease.
    Lemonne N, Billaud M, Waltz X, et al.
    Clin Hemorheol Microcirc. 2016;61(4):571-577. doi:10.3233/CH-141906
  2. Ocular Manifestations in Egyptian Children and Young Adults with Sickle Cell Disease.
    El-Ghamrawy MK, El Behairy HF, El Menshawy A, Awad SA, Ismail A, Gabal MS.
    Indian J Hematol Blood Transfus. 2014;30(4):275-280. doi:10.1007/s12288-014-0333-0
  3. Sickle cell retinopathy: improving care with a multidisciplinary approach.
    Menaa F, Khan BA, Uzair B, Menaa A.
    J Multidiscip Healthc. 2017;Volume 10:335-346. doi:10.2147/JMDH.S90630
  4. Risk Factors for Visual Impairment in Patients with Sickle Cell Disease in London.
    Saidkasimova S, Shalchi Z, Mahroo OA, et al.
    Eur J Ophthalmol. 2016;26(5):431-435. doi:10.5301/ejo.5000767
  5. Protection from sickle cell retinopathy is associated with elevated HbF levels and hydroxycarbamide use in children.
    Estepp JH, Smeltzer MP, Wang WC, Hoehn ME, Hankins JS, Aygun B.
    Br J Haematol. 2013;161(3):402-405. doi:10.1111/bjh.12238
  6. Retinal photocoagulation for proliferative sickle cell retinopathy: a prospective clinical trial with new sea fan classification.
    Sayag D, Binaghi M, Souied EH, et al.
    Eur J Ophthalmol. 2008;18(2):248-254
  7. Incidence and Natural History of Proliferative Sickle Cell Retinopathy.
    Downes SM, Hambleton IR, Chuang EL, Lois N, Serjeant GR, Bird AC.
    Ophthalmology. 2005;112(11):1869-1875. doi:10.1016/j.ophtha.2005.05.026
  8. Ophthalmic Manifestations of Sickle Cell Disease.
    Scott AW.
    South Med J. 2016;109(9):542-548. doi:10.14423/SMJ.0000000000000525
  9. Classification and pathogenesis of proliferative sickle retinopathy.
    Goldberg MF.
    Am J Ophthalmol. 1971;71(3):649-665
  10. Alterações retinianas em jovens portadores de anemia falciforme (hemoglobinopatias) em hospital universitário no nordeste do Brasil.
    Santos AM dos, Faro GB de A, Amaral MVM do, Mendonça C de Q, Leal BC, Cipolotti R.
    Arq Bras Oftalmol. 2012;75(5):313-315. doi:10.1590/S0004-27492012000500003
  11. Macular and Peripapillary Spectral Domain Optical Coherence Tomography Changes in Sickle Cell Retinopathy.
    Brasileiro F, Martins TT, Campos SB, et al.
    Retina. 2015;35(2):257-263. doi:10.1097/IAE.0000000000000309
  12. Macular Microangiopathy in Sickle Cell Disease Using Optical Coherence Tomography Angiography.
    Minvielle W, Caillaux V, Cohen SY, et al.
    Am J Ophthalmol. 2016;164:137-144.e1. doi:10.1016/j.ajo.2015.12.023
  13. Intravitreal Ranibizumab for Stage IV Proliferative Sickle Cell Retinopathy: A First Case Report.
    Mitropoulos PG, Chatziralli IP, Parikakis EA, Peponis VG, Amariotakis GA, Moschos MM.
    Case Rep Ophthalmol Med. 2014;2014:1-6. doi:10.1155/2014/682583
  14. Red cell exchange transfusion halts progressive proliferative sickle cell retinopathy in a teenaged patient with hemoglobin SC disease: Exchange Transfusion for Sickle Cell Retinopathy.
    McKinney CM, Siringo F, Olson JL, Capocelli KE, Ambruso DR, Nuss R.
    Pediatr Blood Cancer. 2015;62(4):721-723. doi:10.1002/pbc.25397
  15. Increased circulating PEDF and low sICAM-1 are associated with sickle cell retinopathy.
    Cruz PRS, Lira RPC, Pereira Filho SAC, et al.
    Blood Cells Mol Dis. 2015;54(1):33-37. doi:10.1016/j.bcmd.2014.08.003