Sickle Cell Disease and the Eye

Sickle haemoglobin polymerises when deoxygenated, producing rigid sickled red cells that occlude small vessels. Ocular disease results from retinal vascular occlusion, ischaemia and neovascularisation, and from the unusual danger of hyphaema in carriers of sickle haemoglobin.

• Proliferative sickle retinopathy is most frequent in HbSC disease (30 to 40 percent by adulthood) and HbS-beta thalassaemia, and less frequent in HbSS despite the more severe anaemia. Onset is usually in the second to fourth decades, and it can begin in childhood.
• Sickling is promoted by hypoxia, acidosis, dehydration, haemoconcentration and cold. The peripheral temporal retina is a watershed zone and infarcts first, leaving a nonperfused periphery, arteriovenous anastomoses at the border and sea fan neovascularisation.
• Hyphaema in any patient with sickle haemoglobin, including sickle trait (HbAS), is a threat to vision. Sickled cells obstruct the trabecular meshwork and raise the intraocular pressure, and the low oxygen, acidic, ascorbate poor aqueous promotes further sickling. Pressures that a healthy optic nerve tolerates can cause central retinal artery occlusion and optic neuropathy in these patients.

• Conjunctival sign: comma shaped or corkscrew vessel segments in the bulbar conjunctiva (the commonest ocular sign, best seen in the inferior bulbar conjunctiva).
• Nonproliferative changes: salmon patch haemorrhage (pink red intraretinal or preretinal haemorrhage that fades over weeks), iridescent spots (refractile deposits within a resolved haemorrhage cavity), black sunburst (round or oval pigmented chorioretinal scar with spiculated edge), angioid streaks, vessel tortuosity, macular arteriolar occlusion with enlargement of the foveal avascular zone and temporal macular thinning.
• Proliferative stages: stage 1 peripheral arteriolar occlusion; stage 2 peripheral arteriovenous anastomoses; stage 3 sea fan neovascularisation; stage 4 vitreous haemorrhage; stage 5 tractional or combined detachment. Sea fans autoinfarct and regress in about 30 percent of eyes.
• Presentations: sudden floaters or painless visual loss (vitreous haemorrhage), curtain or field loss (detachment), sudden profound visual loss (central retinal artery occlusion, with high IOP or in crisis), unexplained field loss from macular or peripheral ischaemia.
• Hyphaema: pain, blurred vision and raised IOP out of proportion to the size of the bleed.
• Orbital: bone infarction of the orbital wall during crisis with periorbital swelling, pain, proptosis and sometimes ptosis or ophthalmoplegia, clinically resembling orbital cellulitis but with no fever response to antibiotics.

• Genotype: haemoglobin electrophoresis or HPLC to define HbSS, HbSC, HbS-beta thalassaemia or HbAS (HbAS carries about 35 to 45 percent HbS). A sickling solubility test alone cannot distinguish trait from disease and must not be the only test.
• Dilated fundus examination with scleral depression, widefield fundus photography, and widefield fluorescein angiography to show peripheral nonperfusion, neovascular leakage and the stage of disease.
• Macular OCT (temporal thinning, inner retinal atrophy) and OCT angiography (enlarged foveal avascular zone, parafoveal capillary dropout).
• B-scan ultrasound when the view is lost to vitreous haemorrhage, to exclude detachment.
• In hyphaema: slit lamp measurement of height of the blood, gonioscopy only after the eye has quietened, and IOP measured at least every 4 to 6 hours in the first days.
• Full blood count, reticulocytes, haemoglobin level and a record of the patient's baseline haemoglobin, since transfusion decisions depend on it.
• Screening: dilated examination every year from about 10 years of age in HbSC and HbS-beta thalassaemia, and every 1 to 2 years in HbSS.

• Nonproliferative disease: no ocular treatment. Maintain hydration, avoid hypoxia and cold, and keep the systemic disease controlled. Hydroxycarbamide 15 mg/kg once daily, increased by 5 mg/kg every 8 to 12 weeks up to 35 mg/kg/day, guided by neutrophil and platelet counts and tolerance, reduces crises and may reduce ocular complications.
• Proliferative retinopathy: scatter laser photocoagulation to the nonperfused peripheral retina (spots 200 to 500 micrometres, 0.1 s, power titrated to a moderate white burn), placed in the ischaemic retina at the border of the sea fan and not directly on the feeder vessels, which carries a risk of haemorrhage and retinal break. Repeat sessions until the sea fans regress. Intravitreal anti-VEGF (bevacizumab 1.25 mg/0.05 mL, ranibizumab 0.5 mg, or aflibercept 2 mg) may be used as an adjunct or to clear vitreous haemorrhage but can induce fibrovascular contraction and tractional detachment, so the eye is reviewed within 1 to 2 weeks.
• Vitreous haemorrhage: sit upright (head raised 30 to 45 degrees), avoid anticoagulants and aspirin, observe for 4 to 6 weeks if there is no detachment on B-scan. Vitrectomy for haemorrhage not clearing by 3 months, earlier when there is macular involving traction or rhegmatogenous detachment.
• Surgery (vitrectomy, buckling, anterior chamber washout) carries a high risk of anterior segment ischaemia and bleeding. Precautions: preoperative haematology involvement, consideration of simple transfusion (aiming for a HbS below 40 to 50 percent and a haemoglobin about 10 g/dL, avoiding overtransfusion because of hyperviscosity), full hydration, warmed fluids, supplemental oxygen, local anaesthesia without adrenaline containing mixtures, avoidance of hypotension and of tight or encircling scleral bands, and gas tamponade only with careful pressure monitoring.
• Hyphaema in sickle haemoglobin (including trait): treat IOP above 24 mmHg promptly. Topical timolol 0.5% twice daily and brimonidine 0.2% three times daily (not in young children). Topical dorzolamide 2% three times daily only with caution. Avoid oral and intravenous acetazolamide and methazolamide (they cause systemic acidosis and haemoconcentration, and lower aqueous ascorbate and pH, all of which promote sickling in the anterior chamber) and avoid mannitol (dehydration and haemoconcentration). Atropine 1% once daily, prednisolone acetate 1% four times daily, head elevation to 30 to 45 degrees, no aspirin or NSAIDs, analgesia with paracetamol.
• Surgical washout of the anterior chamber (paracentesis with irrigation, or anterior chamber washout through two ports) is indicated if the IOP stays above 24 mmHg despite maximal topical therapy for 24 hours, or at any time when central retinal artery pulsation is visible or optic disc pallor develops. In a patient without sickle haemoglobin, washout is considered at 35 mmHg or above for 7 days, 50 mmHg or above for 5 days, or 60 mmHg or above for 2 days.
• Central retinal artery occlusion in crisis: immediate IOP reduction by paracentesis, ocular massage, supplemental oxygen, hydration and urgent exchange transfusion in consultation with the haematology team.
• Orbital infarction: hydration, oxygen, analgesia (IV opioids as required), MRI orbit with contrast. Antibiotics are added only when infection cannot be excluded, since both conditions can coexist in febrile patients.
• Patients with a known haemoglobinopathy are counselled to report any sudden visual change, injury or blow to the eye immediately.