A 45 year old Black male was referred by his sickle cell specialist for a sickle cell retinopathy screening. He denied any ocular complaints or any issues noted at his last eye exam two or three years ago with a different provider. Aside from a diagnosis of HbSS disease, the patient did not have any other medical issues. His last sickle cell crisis was one year prior. He was taking hydroxyurea 500mg QID and L-glutamine 10mg BID to prevent sickle cell complications.
Pertinent findings
Entering distance acuities were 20/20 in each eye without a correction. External examination was unremarkable. No significant anterior segment findings were noted. Dilated fundus examination revealed inactive black sunburst lesions temporally and inferiorly in the right eye and inferiorly in the left eye. No active neovascularization was noted. His optic nerves were distinct with 0.45 cupping in the right eye and 0.35 cupping in the left.
OCT imaging of the macula was performed to check for sickle cell maculopathy, which is often invisible to ophthalmoscopy but easily discernible with OCT imaging. Because sickle cell maculopathy is thought to stem from a vascular issue, optical coherence tomography angiography (OCTA) was also completed. The macular OCT images revealed inner retinal atrophy mostly isolated to the temporal half of the macula in both eyes. The temporal inner retinal atrophy created a “splaying” pattern, which is characteristic of sickle cell maculopathy and is the key sign in the diagnosis of this condition. The Ganglion Cell Analysis (GCA) mirrored the full thickness retinal thinning, confirming that much, if not all, of the retinal atrophy was of the inner layers. Due to the mild asymmetry in cupping, OCT imaging of the optic nerve and RNFL was also performed. Almost 360° RNFL thinning was noted in the right eye worse than in the left eye. Of note, the non-nasal RNFL thinning seemed to correspond to the areas of macular atrophy.
1A/2A: OD macular thickness images reveal significant thinning, mostly confined to the temporal macula.
3A/4A: OD RNFL thickness images reveal diffuse thinning.
5A/6A: OD GCA thickness images reveal significant thinning, mostly confined to the temporal macula.
7A: OD macular scan reveals temporal splaying characterized by inner retinal atrophy of the temporal macula.
8A: OD OCT angiography 8x8mm scan reveals nonperfusion of the temporal macula.
9A: OD OCT angiography 3x3mm scan reveals nonperfusion of the temporal macula.
1B/2B: OS macular thickness images reveal significant thinning, mostly confined to the temporal macula.
3B/4B: OS RNFL thickness images reveal diffuse thinning.
5B/6B: OS GCA thickness images reveal significant thinning, mostly confined to the temporal macula.
7B: OS macular scan reveals temporal splaying characterized by inner retinal atrophy of the temporal macula.
8B: OS OCT angiography 8x8mm scan reveals nonperfusion of the temporal macula.
9B: OS OCT angiography 3x3mm scan reveals nonperfusion of the temporal macula.
Diagnosis and treatment
The leading differential diagnosis for this case was sickle cell maculopathy due to the bilateral inner retinal atrophy noted on macular OCT imaging and history of sickle cell disease. Other diagnoses considered in this case were bilateral artery occlusions, macular ischemia from diabetic retinopathy, and retinal atrophy after neuroretinitis. The additional differentials were easily excluded because the patient was asymptomatic, had 20/20 vision in each eye, and had no history of diabetes or signs of diabetic retinopathy.
The patient was appraised of all findings and educated that though there is no treatment for sickle cell maculopathy, most patients remain asymptomatic and retain vision in the 20/20-20/25 range. An appointment for a six month follow up was scheduled and the patient instructed to return to clinic ASAP if he noticed any changes in vision, floaters, flashes of lights, or peripheral blur/curtain/veil; these could be signs of proliferative sickle cell retinopathy which could require treatment.
Discussion
Sickle cell disease is a group of inherited disorders characterized by abnormal erythrocytes (red blood cells). Sickle cell disease is most common in descendants of people from Sub-Saharan Africa, Spanish speaking regions in Central and Southern America, Greece, Italy, Turkey, India, and Saudi Arabia (CDC).1 The abnormal erythrocytes take on a sickle shape and can lead to multiorgan injury via vaso-occlusive, anemic, and ischemic injury. The various sickle cell genotypes manifest a broad range of clinical complications such as stroke, acute pain crisis/sickle cell crisis/vaso-occlusive crisis, chronic kidney disease, infection, chronic pain, and both acute and chronic ocular conditions.2 Generally, patients with the most severe forms of systemic sickle cell disease will have lower incidence of ocular complications.2
| Disease | Genotype | Risk of Ocular Complication | Risk of Systemic Complication |
|---|---|---|---|
| HbSS | 2 sickle cell genes (S) | Low | High |
| HbSC | 1 sickle cell gene (S) and 1 abnormal hemoglobin gene (C) | High | Low/Medium |
| HbS β0 thalassemia | 1 sickle cell gene (S) and 1 β0 thalassemia gene (β) | Medium | High |
| HbS β+ thalassemia | 1 sickle cell gene (S) and 1 β+ thalassemia gene (β) | Medium | Low/Medium |
| HbAS (Sickle Cell Trait) | 1 normal hemoglobin gene (A) and 1 sickle cell gene (S) | Rarely under abnormal physiological conditions | Rarely under abnormal physiological conditions |
Sickle cell disease has many ocular manifestations; the most well-known are the peripheral findings secondary to vaso-occlusive disease. Other ocular manifestations of sickle cell disease include hyphema, central retinal artery occlusion, venous dilation and tortuosity, angioid streaks, and orbital disease.
Peripheral hemorrhaging known as salmon patches progress to iridescent spots and eventually to black sunbursts; these findings are not visually significant and do not require treatment. Peripheral arterial occlusion with subsequent arteriolar-venular anastomosis can progress to sea fan neovascularization and then vitreous hemorrhage and/or tractional retinal detachments. These proliferative forms of sickle cell retinopathy can be treated with anti-VEGF therapy or laser photocoagulation to prevent vision loss.
Sickle cell maculopathy is a less well-known condition that is also likely caused by vaso-occlusive disease. It is thought that the vessels temporal to the macula at the horizontal raphe represent a watershed zone and are therefore more susceptible to ischemia.3 OCTA studies in sickle cell maculopathy have demonstrated that the deep capillary plexus tends to be more affected than the superficial capillary plexus, findings which are consistent with the watershed zone theory.4 The “splaying” of the temporal macula, caused by inner retinal atrophy, is easily identifiable with macular OCT imaging and correlates well with OCTA nonperfusion. Secondary retinal nerve fiber layer defects/optic nerve head atrophy likely develop due to corresponding inner retinal degeneration, in much the same way that a branch retinal artery occlusion results in inner retinal atrophy and eventual retinal nerve fiber layer defects/optic nerve head atrophy.
It is important to recognize the correlation between macular atrophy and retinal nerve fiber layer defects/optic nerve atrophy in sickle cell maculopathy because many patients in the USA with sickle cell disease are African American, which is a known risk factor for glaucoma. The diagnostic work up for glaucoma often includes retinal nerve fiber layer measurements and measurement of the ganglion cells within the inner retina. Atrophy from sickle cell maculopathy may confound the glaucoma evaluation, complicating management of these patients.
Though easily identifiable with OCT and rarely affecting vision, sickle cell maculopathy is a lesser-known manifestation of sickle cell disease that clinicians must be aware of in order to ensure accurate diagnosis and management.
In a nutshell:
- Sickle cell disease has many ocular manifestations.
- Sickle cell maculopathy is easily detected and diagnosed with OCT imaging but is poorly visualized with ophthalmoscopy.
- No treatment for sickle cell maculopathy currently exists.
- It is important to distinguish macular and optic nerve changes secondary to sickle cell maculopathy from other treatable conditions such as glaucoma.
