A Girl Whose Eyes Appear White in Photos

Leah M. Douglas, BS; Kimberly G. Yen, MD; Madhuri Chilakapati, MD

Disclosures

December 12, 2018

Case Diagnosis

High refractive error is the correct diagnosis, given the normal dilated fundus exam and astigmatism found with the cycloplegic refraction. Pseudoleukocoria, a transient artefactual white pupillary reflex seen on flash-illuminated photography in a clinically normal eye, is seen in the photographs of the patient, owing to this uncorrected high refractive error.

The diagnoses of retinoblastoma, FEVR, Coats disease, and ocular toxocariasis are not supported by this patient's normal dilated fundus exam.

Clinical Course

The patient was prescribed glasses for her refractive error and was asked to wear them full-time. On follow-up exam, the parents noted that the white reflex was no longer seen in photographs when the patient wore the glasses. The patient's vision improved to 20/25 in each eye.

The patient was also subsequently diagnosed with mild bilateral ametropic amblyopia that improved with glasses wear alone. The parents were instructed to have her continue to wear her glasses full time and to have her be monitored for her amblyopia.

Discussion

Leukocoria (from the Greek meaning "white eye") is a finding with expansive differential diagnoses. Etiologies of true (pathologic) leukocoria include malignant, inflammatory, vascular, infectious, and embryologic, and nearly any ocular structure may be implicated. The finding of leukocoria demands prompt ophthalmologic referral and evaluation for vision- or life-threatening conditions.

Some patients with observed leukocoria in photographs are found to have an unremarkable dilated funduscopic exam. As such, pseudoleukocoria is yet another entity to consider on the differential diagnosis of leukocoria.

Differential Diagnoses of Leukocoria

In the pediatric population, the discovery of a white pupillary reflex on physical exam or in photographs immediately evokes concern for retinoblastoma. Up to one half of patients referred to tertiary care centers for leukocoria are diagnosed with retinoblastoma.[1] Several studies examining the accuracy of referrals for retinoblastoma to large tertiary care centers found misdiagnosis rates between 16% and 40%. Coats disease, persistent hyperplastic primary vitreous, FEVR, and ocular toxocariasis are the most common mimicking pathologic conditions and should be considered in the differential diagnosis of leukocoria; the proportions of these simulating lesions vary by age of presentation.[2,3,4]

Retinoblastoma is the most common primary intraocular cancer of childhood. It may be inherited or sporadic. It is an embryonic malignant neoplasm of the retina.

Retinoblastoma can be unilateral (three fourths of cases) or bilateral (one fourth of cases), with 95% of cases presenting in patients younger than 5 years[5] and 10% having a positive family history.[4] The most common presenting sign of retinoblastoma is leukocoria (about 60% of patients), followed by strabismus (about 20%).[6,7] For the majority of children diagnosed with retinoblastoma in the United States, the initial presenting sign is detected by family or friends, rather than a primary care provider or an ophthalmologist.[8,9]

Retinoblastoma is fatal if untreated, and earlier diagnosis and treatment of retinoblastoma correspond to lower mortality rates and better visual outcomes.[10] Longer duration of presenting symptoms and older age at diagnosis are each independently correlated with greater risk for extraocular invasion.[11,12]

Coats disease is almost exclusively unilateral, has an age of presentation usually between 5 and 10 years, involves a male predominance of 3:1,[13,14] and is often characterized by a pale-yellow light reflex.

Persistent hyperplastic primary vitreous is nearly always unilateral.[15,16] Commonly associated features include microphthalmia and cataract in the same eye.[15]

FEVR is an inherited, bilateral disorder of aberrant retinal angiogenesis and incomplete vascularization of the peripheral retina. Retinal ischemia may lead to neovascularization, retinal exudates, tractional detachments, and retinal folds.

Although FEVR is bilateral, it may present asymmetrically. Patients may present with decreased vision due to retinal pathology and cataracts. FEVR has a wide range of presenting ages, and can have variable expressivity between eyes and among affected family members.[17,18,19,20] Patients often have a positive family history of FEVR or of ocular diseases consistent with but undiagnosed as FEVR; however, negative family history does not rule out FEVR, because sporadic mutations are common.[18]

Ocular toxocariasis is generally unilateral and can have a variable age of presentation. Dog or cat exposure is an important clue in the history.[21]

Anterior segment pathology can also be a cause of leukocoria, and it is important to assess the patient for such conditions as corneal opacities, pupillary/prelenticular membranes, and cataract. The most prevalent anterior segment mimic of retinoblastoma is a posterior cataract,[6] and can often be associated with persistent fetal vasculature.[15] A pediatric patient with a cataract obstructing the view of the fundus should have ocular ultrasound to evaluate for posterior segment pathology.[22]

Pseudoleukocoria

With so many patients seeking medical attention because of photographic leukocoria, the mechanisms of pseudoleukocoria have garnered much interest and investigation. Uncorrected refractive errors can produce the impression of leukocoria on flash photography, a phenomenon explained by the principle of eccentric photorefraction.

When a subject fixates on the camera, light from the flash focuses on the fundus and produces the "red eye" effect. In a subject with refractive error exceeding a certain threshold, a crescent of light can be observed in the pupil on flash photography. If the flash source is positioned above the aperture of the lens (as in most cameras), the crescent of light will be observed in the superior pupil margin of a myopic eye and in the inferior pupil margin of a hyperopic eye.[23] Significant astigmatic error produces an oblique, tilted crescent of light.[24] The size of the crescent increases with the magnitude of the refractive error[23]; thus, a sufficiently large refractive error can illuminate the entire pupil and give the illusion of leukocoria. Unilateral leukocoria can also suggest the presence of significant anisometropia, a potential cause of refractive amblyopia.

If the subject fixates approximately 15° off-axis from the camera, unilateral leukocoria can be observed in the eye where the nasal retina is illuminated. It is theorized that the optic nerve head acts as a mirror and reflects enough light to illuminate the entire pupil. Owing to the nasal anatomical positioning of the optic disc on the retina and the angled exit of the optic nerve, this direct reflection of light off the optic nerve head only occurs when the subject fixates off-axis.[25] By the same mechanism, this photographic phenomenon may also be observed in patients with isolated strabismus (eg, in a patient with unilateral esotropia, where the normal eye is fixated on the camera).

Patients with pseudoleukocoria from refractive error may need refractive correction or evaluation for amblyopia.

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