The Sickling Disorders

Two views of sea-fan neovascularization in sickle-cell disease.

Signs and Symptoms: Hemoglobinopathies are among the common inherited diseases in humans, and in the United States, blacks are most commonly afflicted. AA globin chains comprise normal hemoglobin. Variations in the alteration of the amino acid sequence on the globin chains produce differences in the expression of the disease. The four forms of the disease are often referred to by their genotype, sickle-cell trait (AS), classic sickle-cell anemia (SS), sickle-cell disease (SC) and sickle-cell thalassemia (S Thal).

Systemic signs and symptoms include chronic anemia, pallor of mucous membranes, fatigue, decreased exercise tolerance, grayish cast to skin, periods of jaundice, susceptibility to gall-stone formation, leg ulcers, chest pain secondary to pulmonary infarctions and crisis (characterized by skeletal pain for days to weeks).

In the early stages, the ocular symptoms are uncommon (see table).

Proliferative sickle-cell retinopathy is categorized into five stages:

• Stage 1. Peripheral retinal arteriolar occlusions.
• Stage 2. Peripheral arteriovenous anastamoses.
• Stage 3. Growth of neovascular fronds known as sea fans.
• Stage 4. Vitreous hemorrhage as tractional forces and vitreous collapse, tearing fragile neovascular membranes.
• Stage 5. Advanced disease, identifiable by severe vitreous traction and retinal detachment.

Pathophysiology: The sickling gene can be traced to the continent of Africa where, data suggests, the mutation of the hemoglobin chain protected individuals from malaria. Inheritance of the sickle-cell hemoglobinopathies is autosomal codominant, with each parent providing one gene for the abnormal hemoglobin.

Ocular Symptoms In the Sickling Disorders   Anterior Segment Comma-shaped vessels in the bulbar conjunctiva Iris atrophy and/or neovascularization Mild anterior chamber inflammation Posterior Segment Dull-gray fundus appearance Retinal venous tortuosity Subretinal, intraretinal or preretinal nonproliferative hemorrhages Black sun bursts (retinal pigment epithelial hypertrophy secondary to deep retinal vascular occlusions) Glistening refractile deposits in the retinal periphery (hemosiderin-laden macrophages) Salmon-patch hemorrhages (orange-pink colored intraretinal hemorrhage) Angioid streaks (breaks in Bruch's membrane radiating from the optic nerve) Venous occlusion Macular depression sign (oval reflex representing thinning of the neural macula) Macular ischemia Cotton-wool patches

Normal erythrocytes, containing normal hemoglobin, appear as flexible, pliable, biconcave discs. Erythrocytes affected by sickling disease lose their biconcave shape and their ability to efficiently move through the circulatory system. The "sickled" cells become rigid, restrict blood flow, produce clots and cause tissues to become hypoxic.

Systemically, the sickle cell anemia variation SS produces the most symptoms. With respect to the eye, the sickle cell disease mutations SC and S Thal produce the most effects. Even though anemia is worse in SS disease, the blood cells seem to be less disposed to "sludge" in the circulation. Overall, the sickle-cell trait expression AS produces the fewest complications.

Cross-sectional studies have approximated that up to 40% of SC patients and 20% of SS patients can develop proliferative retinopathy.^1-5 Because retinopathy can lead to vision-threatening sequelae, it receives the most attention. However, the sickling diseases can affect virtually all periocular structures.

Management: Systemic management includes analgesia for painful crisis, aggressive antibiosis at the first sign of infection, rehydration therapy, oxygen therapy and supportive instructions for avoiding crisis along with genetic counseling.

Your treatment goal for sickle-cell retinopathy is to prevent and/or eliminate retinal neovascularization. Follow patients with asymptomatic sickle-cell disease, free of ocular signs, biannually with ocular examinations and dilated retinal evaluation.

The treatment for proliferative disease includes argon laser panretinal photocoagulation. Cryotherapy has not been proven to be efficacious and is associated with high complication rates. Vitrectomy and scleral buckling may be indicated in cases progressing to retinal detachment.

Clinical Pearls:

• While single doses of oral carbonic anhydrase inhibitors or I.V. Mannitol can be used to lower IOP in patients with sickling disorders, they are contraindicated for chronic glaucoma therapy as they can produce metabolic acidosis encouraging systemic crisis.
• The laboratory testing for detecting sickle-cell disease in patients with suspicious findings includes the Sickledex, Sickle Prep and plasma hemoglobin electrophoresis.

1. Kaiser HM. Hematologic Disease. In: Blaustein BH. Ocular Manifestations of Neurologic Disease. Philadelphia: Mosby 1996:165-177.
2. Rogers-Philips E., Philips A. Hematology and Oncology. In: Muchnick BG. Clinical Medicine in Optometric Practice. Philadelphia: Mosby 1994:306-316.
3. Cullom RD, Chang B. Sickle Cell Disease. In: Cullom RD, Chang B. The Will's Eye Manual: Office and Emergency Room Diagnosis and Treatment of Eye Disease. Philadelphia: J.B. Lippincott Co. 1994:335-337.
4. Alexander LJ. Retinal Vascular Disorders. In: Alexander LJ. Primary Care of The Posterior Segment, 2nd ed. Norwalk, Conn: Appleton and Lange 1994:171-275
5. Beutler E. Hemoglobinopathies. In: Fauci A, Braunwald E., Isselbacher KJ, et al. eds. Harrison's Principles of Internal Medicine Companion Handbook, 14th ed. New York: McGraw-Hill 1998:645-652.