retinal thinning

Sickle Cell Anemia

Clinical Characteristics

Ocular Features

The majority of serious ocular manifestations in sickle cell anemia are secondary to red blood cell sickling under conditions of relative hypoxia or dehydration resulting in thrombosis of retinal vessels with secondary ischemia.  Thrombosis of the central retinal artery and vein may also occur.  Other vessels of the orbit tissue and orbital walls when involved can result in acute proptosis with restrictions to globe motion and severe vascular congestion.

The conjunctival vessels are often comma-shaped and sludging or boxcaring of vascular flow is evident in a majority (70-90%) of patients.  Anterior uveitis of a granulomatous nature and frank anterior segment ischemia may occur.  Hyphemas are sometimes seen and an associated elevated intraocular pressure is a major risk.

The retina and its responses to small vessel occlusive disease constitute a major threat to vision and the risk is higher in patients with SC disease.  In early disease only arteriolar occlusions are seen but the localized ischemia stimulates the formation of arteriovenous anastomoses.  The involvement of larger areas of ischemia results in frank neovascularization, often in a formation known as retinal sea fans.  Intravitreal bleeding results in vitreal fibrosis with retinal traction that may result in a detachment.

Retinal imaging reveals general thinning.  SD-OCT imaging shows this to be especially visible in the macula and is present early in the disease.  The temporal retina likewise has significant thinning and microperimetry may demonstrate decreased function in these areas.

Systemic Features

The term sickle cell anemia as generally used refers to the disease caused by homozygous mutations in the HBB gene in which both beta chains contain a change in the 6th position from glutamic acid to valine yielding hemoglobin S.  These cells are susceptible to distortion into a sickle shape under certain conditions such as relative dehydration or anoxia and, as a result, form microthrombi with downstream ischemia.

The term sickle cell disease is commonly used to refer to sickling disorders in which only one beta chain contains the S change and the other chain has another variant such as Hb C (Hb SC disease), beta thalassemia (Hb S beta thalassemia) or some other more rare change in the beta chain.  Symptoms of the variant diseases generally have a later onset and cause a less severe disease.

Hb SS disease accounts for 60-70% of sickle cell disease and often leads to symptoms in the first month of life.  The diagnosis is usually made through newborn screening programs and should be followed by confirmatory testing using genotyping within 6 weeks.

The major early symptom is intermittent pain which can be incapacitating.  This can occur in virtually any organ and results from vascular occlusion, especially in small vessels such as arterioles and capillaries with downstream microinfarctions and hemolysis.  These vasoocclusive episodes can eventually lead to organ failure, especially in adults in which the major causes of death by midlife are pulmonary hypertension, cerebrovascular events, and acute chest syndrome.  Children are more likely to die of infections and organ sequestration.  In particular, the spleen is damaged as early as 3 months of age leaving infants vulnerable to recurrent septicemia and meningitis.  Severe bone pain with osteomyelitis can be debilitating.  Priapism, anemia, and ischemic strokes can occur at any age but are especially worrisome in young children.

Sickle cell disease can damage any part of the body and global evaluations are recommended when the diagnosis is under consideration. 

Genetics

Sickle cell disease and sickle cell anemia are autosomal recessive disorders resulting from homozygous or compound heterozygous mutations in the genes that code for hemoglobin molecules.  Usually at least one beta chain contains the amino acid substitution of valine for glutamic acid at the 6 position.  The HBB gene is located at 11p15.4.

Treatment Options

In general, patients with SS and S-variant disease should avoid strenuous exercise, low oxygen environments, extreme cold, and dehydration. Avoidance of contact with others who may have infectious disease is always recommended.  Hydroxyurea therapy may lessen or prevent chronic pain but it has little value in the treatment of acute painful crises.  Specific organ treatment should be applied as indicated for acute episodes.  All patients with sickle disease need to be under lifelong surveillance.

Epsilon aminocaproic acid is especially useful in the management of hyphemas and reduces the risk of recurrence.  The usual treatment for subretinal neovascularization and retinal detachment may be applied.  Anterior segment disease must be appropriately treated.

More recent approaches that show some promise include stem-cell transplantation.

References

King A, Shenoy S. Evidence-based focused review of the status of hematopoietic stem cell transplantation as treatment of sickle cell disease and thalassemia. Blood. 2014 May 15;123(20):3089-94. Review.

PubMed ID: 
24511087

Lim JI. Ophthalmic manifestations of sickle cell disease: update of the latest findings. Curr Opin Ophthalmol. 2012 Nov;23(6):533-6. Review.

PubMed ID: 
23047170

McGann PT, Ware RE. Hydroxyurea for sickle cell anemia: what have we learned and what questions still remain? Curr Opin Hematol. 2011 May;18(3):158-65. Review.

PubMed ID: 
21372708

Pierson Syndrome

Clinical Characteristics

Ocular Features

Microcoria is the most consistent ocular feature but is not present in some families.  It is congenital and sometimes seen with iris hypoplasia.  Glaucoma and lens opacities (including posterior lenticonus sometimes) are present in one-fourth of patients.  Corneal size varies with some patients having apparent macrocornea which can lead to the mistaken diagnosis of buphthalmos.  Pigment mottling and clumping is common in the retina and the ERG can show changes characteristic of cone-rod dystrophy.  Retinal thinning is often present as well.  Non-rhegmatogenous retinal detachments occur in 24% of patients and optic atrophy is seen in some patients.  There is considerable interocular, intrafamilial, and interfamilial variability in these signs. 

Systemic Features

The primary and most consistent systemic problem is progressive renal disease. Congenital nephrotic syndrome with proteinuria, hypoalbuminemia and hypertension is characteristic.  Renal failure eventually occurs although the rate of progression varies. Most patients require a renal transplant for end-stage kidney disease in the first decade of life.  Kidney histology shows glomerulosclerosis, peritubular scarring, and diffuse mesangial sclerosis.  Hypotonia and muscle weakness are sometimes present and congenital myasthenia has been reported.  Severe global psychomotor retardation is common and many infants never achieve normal milestones. 

Genetics

This is an autosomal recessive disorder resulting from homozygous mutations in the LAMB2 gene located at 3p21.  The normal gene encodes laminin beta-2 that is strongly expressed in intraocular muscles which may explain the hypoplasia of ciliary and pupillary muscles in Pierson syndrome.  Mutations in this gene are often associated with nephronophthisis but ocular abnormalities are not always present. 

Microcoria is also a feature of the autosomal dominant ocular condition known as congenital microcoria (156600).

Treatment Options

Kidney replacement can restore renal function.  Glaucoma, cataracts, and retinal detachments require the usual treatment but patient selection is important due to the neurological deficits.  Lifelong monitoring is essential. 

References

Mohney BG, Pulido JS, Lindor NM, Hogan MC, Consugar MB, Peters J, Pankratz VS, Nasr SH, Smith SJ, Gloor J, Kubly V, Spencer D, Nielson R, Puffenberger EG, Strauss KA, Morton DH, Eldahdah L, Harris PC. A Novel Mutation of LAMB2 in a Multigenerational Mennonite Family Reveals a New Phenotypic Variant of Pierson Syndrome. Ophthalmology. 2011 Jan 12.

PubMed ID: 
21236492

Bredrup C, Matejas V, Barrow M, Bl?deghov?deg K, Bockenhauer D, Fowler DJ, Gregson RM, Maruniak-Chudek I, Medeira A, Mendon?ssa EL, Kagan M, Koenig J, Krastel H, Kroes HY, Saggar A, Sawyer T, Schittkowski M, Swietli?Nski J, Thompson D, VanDeVoorde RG, Wittebol-Post D, Woodruff G, Zurowska A, Hennekam RC, Zenker M, Russell-Eggitt I. Ophthalmological aspects of Pierson syndrome. Am J Ophthalmol. 2008 Oct;146(4):602-611.

PubMed ID: 
18672223

Zenker M, Tralau T, Lennert T, Pitz S, Mark K, Madlon H, D??tsch J, Reis A, M?ontefering H, Neumann LM. Congenital nephrosis, mesangial sclerosis, and distinct eye abnormalities with microcoria: an autosomal recessive syndrome. Am J Med Genet A. 2004 Oct 1;130A(2):138-45. Review.

PubMed ID: 
15372515