PEDIATRICS OPHTHALMIC PEARLS

A Stepwise Approach to

eukocoria, or “white ,” is one to the ophthalmologist. 1A 1B of the primary signs of retino- However, red removal Lblastoma. However, a number software in modern cameras of other conditions may also present may confound the detec- with leukocoria, and it is critical to tion of leukocoria. Also, if differentiate from the subject in the photo is these so-called pseudoretinoblastomas looking approximately 15° for proper management.1 Shields and off axis nasally, the coworkers have reported 27 different shadow can fill the pupil, 1C 1D pseudoretinoblastoma conditions.2 giving a white reflex. Some of the most common include Any patient with an • Coats disease abnormal should • Persistent fetal vasculature (PFV) be evaluated promptly by • Ocular an ophthalmologist. A red • Familial exudative vitreoretinopathy reflex exam is also warranted (FEVR) at every pediatric visit from RETINOBLASTOMA VS. COATS. (1A) • of prematurity (ROP) birth to 3 years and, later, as part of Leukocoria in retinoblastoma; promi- • Astrocytic hamartoma vision screening. nent vessels dip into the retinal detach- • Vitreous hemorrhage A detailed history, a good ophthal- ment. (1B) Xanthocoria (yellow pupil) in • Coloboma mic exam, and ancillary tests are essen- Coats disease due to retinal exudation. • Endogenous tial in evaluating patients with leuko- (1C) FA in retinoblastoma shows dilated • Rhegmatogenous coria. This article outlines a practical, and tortuous vessels feeding the hyper- Leukocoria is often first noticed by stepwise approach to identifying key fluorescent tumor compared with (1D) family members or on flash photog- diagnostic findings in retinoblastoma peripheral telangiectasia and capillary raphy, and such images can be helpful and pseudoretinoblastomas. nonperfusion in Coats disease.

History at diagnosis of retinoblastoma is quired etiology. Although a detailed history is import- 18 months, and the average age for C. Other symptoms, including pain, ant to provide diagnostic clues, it is Coats disease is 5 years. redness, , , not reliable in isolation and must be B. Duration of the abnormal white and blurred vision, should be noted. correlated with findings from the clin- reflex:A review of family photo- II. Past Ocular History ical examination. The following topics graphs can help ascertain if and A. History of retinopathy of prema- should be explored. when the reflex changed. A previ- turity: ROP can present as a white ously normal red reflex decreases pupil due to retrolental fibrous I. History of Present Illness the likelihood of a congenital disease tissue and total retinal detachment. A. Age at onset: The average age such as PFV and suggests an ac- B. Trauma: Ocular trauma can lead to , retinal detachment, or vitreous hemorrhage, any of BY REEMA SYED, MD, AND APARNA RAMASUBRAMANIAN, MD. EDITED BY which can produce an abnormal

Aparna Ramasubramanian, MD Aparna Ramasubramanian, SHARON FEKRAT, MD, AND INGRID U. SCOTT, MD, MPH. red reflex.

EYENET MAGAZINE • 35 III. Medical History toxocariasis (if child is exposed to tary component. A. Prematurity puppies) or toxoplasmosis (cats). A. Retinoblastoma: Autosomal B. Arthritis: Juvenile inflammato- F. Presence of skin lesions: In- dominant with incomplete pen- ry arthritis (JIA) can cause dense continentia pigmenti can cause etrance (approximately 90%), that mimics retinoblastoma, skin lesions ranging from vesicles although only 10% of patients with especially diffuse infiltrating retino- to hyperpigmentation to atrophy. retinoblastoma have a family history. blastoma. It may be associated with retinal B. Familial exudative vitreoretinop- C. Prenatal infections: TORCH detachment resulting in leukocoria. athy: FEVR has an autosomal dom- syndrome (which may include G. Other systemic diseases: Tuber- inant inheritance pattern, though toxoplasmosis, other agents, rubella, ous sclerosis (associated with retinal many patients may be asymptomatic. cytomegalovirus, and herpes sim- astrocytomas), endogenous endoph- C. Coloboma: Autosomal dominant plex) may show a white reflex. thalmitis. inheritance of mutation in PAX6 D. Birth trauma IV. Family History. Several conditions gene on chromosome 11 has been E. Exposure to pets: Consider that produce leukocoria have a heredi- noted.

Clinical Examination which may be a poor prognostic sign. retinoblastoma. There may be vit- A thorough clinical examination is VI. Strabismus. In about 20% of ritis in toxocariasis and a persistent pivotal to the diagnosis of leukocoria. retinoblastoma cases, strabismus is the hyaloid canal in PFV. Following are important clues for dis- presenting feature. It may also be asso- B. Optic disc: The funnel-shaped tinguishing among conditions. ciated with other diseases that decrease excavated head of morn- vision, leading to interruption of the ing glory disc or coloboma (Fig. 2E) I. Laterality fusional mechanism. may cause leukocoria. In PFV, fun- A. Unilateral disease: Retinoblas- VII. Anterior Segment dus findings may include Bergmeis- toma (60%), Coats disease, PFV, A. PFV: Associated findings include ter papilla, a retinal fold from the toxocariasis, vitreous hemorrhage, microphthalmia, microcornea, disc to the periphery, hypoplastic or retinal detachment. shallow anterior chamber, persistent dragged macula, hypoplastic optic B. Bilateral disease: Retinoblastoma tunica vasculosa lentis, cataract, fine nerve, or tractional retinal detach- (40%), FEVR, ROP, astrocytic ham- vessels coursing over the to the ment with a stalk to the optic disc. artoma, endogenous endophthalmi- anterior surface, and retrolental C. Retinal vessels: In retinoblasto- tis. However, Coats disease may be fibrovascular membrane. ma, the vessels are uniformly dilated bilateral in patients with facioscapu- B. Anterior chamber retinoblastoma: and tortuous (Fig. 1C), but in Coats lohumeral dystrophy, and there have May appear as white, fluffy seeds on disease, the vascular dilation is irreg- been rare reports of bilateral PFV. the iris stroma or layered as pseudo- ular with saccular enlargement (Fig. II. Color of the Reflex hypopyon. 1D), and there may be peripheral A. White pupillary reflex is typical C. medulloepithelioma: telangiectasia. In retinoblastoma, of retinoblastoma (Fig. 1A). Signs include lens coloboma, cata- retinal vessels dip into the detach- B. Yellow pupillary reflex,or xan- ract, , and retrolental mass. ment (1A), unlike Coats disease, in thocoria, from exudates and exuda- D. Coats disease: Anterior chamber which they course over the detach- tive retinal detachment is indicative cholesterolosis with free-floating ment (2B). Also, peripheral dragging of advanced stages of Coats disease yellow crystalline cholesterol depos- from fibrovascular proliferation is (Fig. 1B). its in the aqueous. seen in FEVR. C. Blue-gray pupil is commonly E. Iris coloboma: Can be associated D. : seen in congenital . with choroidal coloboma. 1. Retinoblastoma can present III. Visual Acuity. It is useful to doc- F. Anterior chamber inflammation: in 3 growth patterns: exophytic, ument the visual acuity in verbal chil- Consider JIA uveitis and endoge- which leads to retinal detach- dren. In preverbal children, Teller visual nous endophthalmitis. ment (Fig. 1A); endophytic (Fig. acuity measurements can be obtained. G. Neovascularization of iris and 2A) with vitreous seeding; and IV. Intraocular Pressure. IOP may glaucoma: Can be seen in both the rare diffuse infiltrating type, be elevated in both retinoblastoma and retinoblastoma and Coats disease which grows along the retinal Coats disease secondary to anterior and can also be associated with any layers, without causing retinal segment neovascularization. The IOP long-standing retinal detachment. elevation, and mimics uveitis. can also be elevated in JIA uveitis due VIII. 2. Coats disease presents as to trabeculitis. A. Vitreous: In Coats disease, the retinal exudation and exudative V. Pupil. It is important to note the vitreous remains clear; while vitre- retinal detachment (Fig. 2B). presence of afferent pupillary defect, ous seeds are present in endophytic Macular exudation may mimic

36 • JULY 2016 retinoblastoma—dif- fibrosis and retinal detachment. 2A 2B ferentiating features 7. Astrocytic hamartoma in include irregular light- tuberous sclerosis presents bulb telangiectasia in the as a flat (Fig. 2F) or elevated peripheral fundus and lesion. It can be differentiated yellow subretinal and from retinoblastoma by its lack intraretinal exudation. A of retinal detachment, lack subretinal gliotic nodule 2C 2D of growth, and the course of in Coats disease can be retinal blood vessels under or mistaken for a solitary around the astrocytic tumor. retinoblastoma lesion. 8. Vitreous hemorrhage can be However, there is no secondary to trauma, posterior feeder vessel or tortu- uveitis, or any of the vascular ous draining vein as in abnormalities noted above. retinoblastoma. Careful examination of the 3. PFV is usually unilat- 2E 2F underlying retina will point eral with a central fibro- toward the diagnosis. vascular stalk emanating 9. Uveal coloboma appears as a from the disc, often with sharply demarcated, glistening retinal detachment (Fig. white, bowl-shaped excavation 2C). in the fundus (Fig. 2E). Unlike 4. Ocular toxocaria- retinoblastoma, no elevated sis causes a retinal or FUNDUS APPEARANCE. (2A) Endophytic retinoblasto- mass is seen. subretinal granuloma ma with vitreous seeds can be differentiated clinically 10. Endogenous endophthal- that can mimic exophytic from (2B) Coats disease, showing exudation, telangiecta- mitis presents as anterior and retinoblastoma. Chronic sia, retinal detachment, and macrocyst. (2C) Total retinal posterior segment inflamma- toxocariasis endophthal- detachment with prominent vasculature in PFV can be tion and there may be signs of mitis presents as severe differentiated from other causes of retinal detachment, systemic sepsis. Cultures may granulomatous vitritis of which trauma (2D) is the most common. (2E) Large be confirmatory. with cyclitic membrane, optic disc and chorioretinal coloboma can cause leuko- 11. Retinal detachment from retinal detachment, leu- coria. (2F) Astrocytic hamartoma in tuberous sclerosis. any other etiology (e.g., trau- kocoria, and hypopyon. ma, Fig. 2D) needs to be differ- 5. FEVR is characterized and fibrovascular proliferation entiated from retinoblastoma.­ by peripheral retinal nonper- leading to retinal detachment. Thorough fundus examination fusion with resultant neovas- 6. ROP also presents with ab- evaluating for a mass lesion or ret- cularization, retinal traction, normal vascularization leading to inal or vitreous seeds is critical.

Ancillary Tests and Imaging may be linear dystrophic retinal useful to evaluate for the presence of I. Ultrasonography. We recom- calcifications from chronic retinal a mass. mend performing ultrasonography detachment at the level of RPE, G. Astrocytic hamartoma: Calcifi- in all patients with leukocoria, as it is unlike retinoblastoma, where the cations may be present in astrocytic inexpensive, noninvasive, and highly calcification is within the intraocular hamartoma, but they are glistening specific for detecting the calcifications tumor. yellow rather than the dull, chalky distinctive of retinoblastoma (seen in C. PFV: Persistent hyaloid remnants white seen in retinoblasto­ma. 90% of cases). Following are character- in PFV (Fig. 3C, Web Extra). II. Fluorescein Angiography. FA istic findings. D. Ocular toxocariasis: Absence of with Retcam photography is useful in A. Retinoblastoma: A solid retinal calcification in the elevated granulo- evaluating children with leukocoria. mass with high-intensity internal mas. In Coats disease, FA shows retinal tel- echoes due to intratumoral calcifica- E. Medulloepithelioma: Ultrasound angiectasia manifesting as “lightbulbs” tion (Fig. 3A, Web Extra). biomicroscopy is useful to demon- with late leakage from abnormal vessels B. Coats disease: Subretinal fluid strate multicystic irregular internal and peripheral nonperfusion (Fig. 1D). and retinal detachment without reflectivity of the ciliary body. Retinoblastoma is associated with a a solid retinal mass (Fig. 3B, Web F. Retinal detachment: In patients relatively rapid homogeneous hyperflu- Extra). Occasionally, a retinal with retinal detachment (Fig. 3D, orescence without retinal dragging (Fig.

Aparna Ramasubramanian, MD Aparna Ramasubramanian, macrocyst may be seen. Rarely, there Web Extra), ultrasonography can be 1C), while granulomas due to toxoca-

EYENET MAGAZINE • 37 riasis demonstrate reticular hyperfluo- Coats disease appears as a hyperintense endophthalmitis to make the diagnosis rescence and are commonly associated subretinal exudate. Ocular toxocariasis or in patients with chronic endoph- with retinal traction. A peripheral avas- appears as an isointense granuloma on thalmitis due to toxocariasis in which cular zone is seen in ROP and FEVR. T1 and hyperintense on T2. aqueous humor cytology will reveal III. Optical Coherence Tomography. VI. Blood Work. Toxocara exposure eosinophils. OCT is increasingly used to evaluate is common, so a positive serologic test macular tumors or simulating lesions. is supportive but not diagnostic. Blood 1 Kaliki S, Shields CL. Differential diagnosis of Noninvasive and well tolerated, it work is also useful to diagnose TORCH retinoblastoma. In: Ramasubramanian A, Shields provides invaluable information on infections and to identify the underly- CL, eds. Retinoblastoma. New Delhi, India: Jaypee the presence of fibrosis, edema, or ing disease in patients with endogenous Brothers Medical Publishers; 2012;46-60. subretinal fluid in the macula. endophthalmitis. 2 Shields CL et al. . 2013;120(2): IV. Computerized Tomography. CT VII. Genetic Testing. This is import- 311-316. is generally avoided in children because ant in diseases such as retinoblastoma, of radiation risks but can be considered FEVR, and astrocytic hamartoma, both Dr. Syed is an ophthalmology resident, and Dr. if the presence of calcification is ques- for confirming the diagnosis and for Ramasubramanian is a pediatric ophthalmologist tionable. Ultrasonography has good genetic counseling. Newer studies have and an ocular oncologist; both are at Univer- sensitivity to detect calcification; thus, indicated a somatic mutation in the sity of Louisville, Kentucky. Relevant financial CT is very rarely required. NDP gene (mutant in ) disclosures: This work was supported in part by an V. Magnetic Resonance Imaging. in Coats disease. unrestricted educational grant from Research to MRI is performed to evaluate the pine- VIII. Fine-Needle Aspiration Prevent Blindness, New York. al gland and to visualize the optic nerve Biopsy. FNAB is avoided in patients and to detect infiltration in suspected of having retinoblastoma MORE ONLINE. See this article patients with retinoblastoma. Retino- due to the risk of metastasis. If retino- at www.aao.org/eyenet for blastoma appears isointense to hyper- blastoma is ruled out, intravitreal tap ultrasound images of characteristic intense on T1 and hypointense on T2. may be useful in with endogenous findings in leukocoria.

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38 • JULY 2016