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Quick Consult: Symptoms: Irregular Right Pupil Lacking Red Reflex

Wiler, Jennifer L. MD, MBA

doi: 10.1097/01.EEM.0000387714.87739.2c
Quick Consult
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A 6-week-old infant is brought to the ED for constipation. The child was a normal, full-term spontaneous vaginal delivery, and he has been followed appropriately by his pediatrician. No significant family medical problems were reported. During the physical examination, you note that the infant has an irregularly shaped right pupil that lacks a red reflex. Otherwise his physical examination is unremarkable.

What is the differential diagnosis of leukocoria?

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Diagnosis: Retinoblastoma

Retinoblastoma is a vision-threatening condition that can be life-threatening. Although a rare presentation to the ED, it is the most common intraocular malignancy of infancy and childhood (Int J Cancer 2007;121[11]:2501), and accounts for approximately four percent of all pediatric cancers. (Retinoblastoma. In Shields JA, Shields CL, editors. Atlas of Intraocular Tumors. Philadelphia: Lippincott Williams & Wilkins; 1999, p. 207.) Increased patient survival is strongly correlated with early recognition.

Retinoblastoma is caused by inactivation (the “two-hit” theory) of both retinoblastoma tumor suppressor gene copies (RB1) on chromosome 13q14, and does not appear to be influenced by race or gender. This disease is one of the classic genetic etiologies of cancer models. It is classified in three ways: sporadic (60%) or hereditary (40%); unilateral (60%) or bilateral (40%; Orphanet J Rare Dis 2006;25[1]:31); or the result of a somatic (inactivation in a single developing retinal progenitor cell, 66%) or germline mutation (mutation present in all cells of the body, 33%). (Curr Opin Ophthalmol 2006;17[3]: 228; Retina 2004;24[6]:828.)

Patients with the germline mutation form risk developing other types of cancers, including osteosarcomas, soft tissue sarcomas, primary intracranial neuroblastic tumors (trilateral retinoblastoma), and cutaneous melanomas (Int J Cancer 1996;67[4]: 515), with the risk increasing exponentially as the patient ages (10% at 10 years, 20% at 20 years, and so on), with half of patients developing a second nonocular cancer by age 50. (Retina 2004;24[6]:849; JAMA 1997;278[15]:1262.) As the cancer progresses, retinoblastoma lesions can invade the optic nerve, and extend through subarachnoid space into the choroid plexus. From there, it can metastasize to brain, bone, liver, kidney, lung, testes, and lymph nodes.

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The median age at diagnosis is 2 years in those with unilateral disease, 1 year in those with bilateral tumors. (Retinoblastoma. In Ries LA, ed. Cancer Incidence and Survival Among Children and Adolescents: United States SEER Program 1975-1995. Bethesda, MD: National Cancer Institute, 1999; http://seer.cancer.gov/publications/childhood/.) Patients may present with a red painful tearing eye, poor vision, orbital cellulitis (Am J Ophthalmol 1991;112[4]: 442; Arch Pediatr Adolesc Med 1996; 150[8]:873; J Pediatr Ophthalmol Strabismus 2004;41[3]:143), a dilated or irregular pupil, failure to thrive, corneal clouding, discoloration of the iris, atraumatic hyphema (Can J Ophthalmol 2007;42[3]:489), vitreous hemorrhage (Curr Opin Ophthalmol 2006; 17[3]:228), hypopyon, pseudouveitis, eye enlargement (buphthalmia), proptosis, or glaucoma. (J Pediatr 1998; 132[3 Pt 1]:505; Orphanet J Rare Dis 2006;25[1]:31.)

Patients with advanced disease and retinal detachment can present with neovascular glaucoma (17%). (Ophthalmology 1987;94[7]:839.) Those with trilateral retinoblastoma (bilateral or familial retinoblastoma and brain tumor (8% pinealoblastoma) may present with signs of increased intracranial pressure. (J Clin Oncol 1999;17[6]:1829; Am Fam Physician. 2006;73[6]:1039.)

The most common sign of retinoblastoma is a white light reflex, also known as leukocoria or “cat's eye reflex” (56%) and strabismus (24%). (J Pediatr 1998;132[3 Pt 1]:505; Orphanet J Rare Dis 2006;25[1]:31.) Parents may note a “sparkle” in the eye after flash photography. (J Pediatr 1998;132[3 Pt 1]:505.) It is unlikely that these findings would be the primary reason for the ED visit, and are more likely to be incidental findings in the ED. Leukocoria is concerning because it is often indicative of a large, advanced tumor. Classic findings are one or more white-yellow retinal tumors with prominent blood vessels on funduscopic examination. These may be difficult to appreciate through a non-dilated pupil.

The differential diagnosis includes retinopathy of prematurity, Coats' disease, toxocariasis, congenital cataract, retinal astrocytoma, retinochoroidal coloboma, uveitis, retinal detachment, and medulloepitheliomas.

Unless there is a concern for extensive local or metastatic disease, no ED testing is warranted. The EP's role is to suspect the diagnosis, and make a prompt referral to an ophthalmologist, preferably an ocular oncologist. CT scans are no longer routinely performed by ophthalmologists to evaluate a suspected retinoblastoma, secondary to the increased risk of cancer in children who have had CT scans. Magnetic resonance imaging is becoming the diagnostic imaging modality of choice. (Retina 2004; 24[6]:828.)

Cerebrospinal fluid evaluation, bone marrow biopsy, and genetic testing of the patient and parents are part of the routine retinoblastoma workup in the outpatient setting. Treatment depends on the extent of disease, among other factors, but can include intravenous chemoreduction, thermotherapy, cryotherapy, laser photocoagulation, plaque brachytherapy, external beam radiotherapy, and enucleation. (Curr Opin Ophthalmol 2006;17[3]:228.) Fortunately, the mortality for patients with retinoblastoma is good in the United States (less than 5%), but is still approximately 50 percent worldwide. (Curr Opin Ophthalmol 2006;17[3]:228.)

A large tumor, older age at diagnosis, evidence of optic nerve involvement, and extraocular extension are predictors of a poor prognosis. (Graefes Arch Clin Exp Ophthalmol 1990;228[5]:426.) Unfortunately, nearly 10 percent will develop a tumor in the contralateral eye (Acta Ophthalmol Scand 998;76[3]:334), and almost half of patients with globe-sparing treatment will need subsequent therapies. (Graefes Arch Clin Exp Ophthalmol 1990;228[5]:426.) Metastasis typically develops within one year of the initial diagnosis. (Curr Opin Ophthalmol 2006;17[3]:228.

Thank you to Carol Shields, MD, Department of Ophthalmology, Wills Eye Institute, Thomas Jefferson University in Philadelphia for the intraoperative photos.

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Dr. Wiler

Dr. Wiler

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