A 14-month-old boy was referred by his pediatrician because a whitish reflex from his left pupil (Figure 16-1) was noticed by his parents in certain directions of gaze. It was also noted on a few recent photographs. His pediatrician had checked the pupillary light reflex and indeed noted a dimmer and tan-colored reflex from the left pupil as opposed to a brighter and more reddish reflex in the left eye. She referred the child for further evaluation and management. Dilated fundus examination revealed a single large tumor in the left eye, occupying more than 50 percent of the globe. Ultrasonography showed a pattern consistent with calcifications within the tumor, and suggestive of retinoblastoma. A magnetic resonance imaging (MRI) scan showed no evidence of optic nerve or intracranial involvement. There were no other tumors in either eye. There was no family history of retinoblastoma. A decision was made to enucleate the eye because of the size of the tumor.
Leukocoria means a white (leuko) reflex from the pupil (coria). Leukocoria is a sign observed by the naked eye or with a scope, often detected incidentally on routine eye examination, or in photographs; it is not a diagnosis. The most feared cause of a white reflex in the pupil is retinoblastoma, the most common intraocular tumor of childhood. Other conditions can manifest themselves initially with leukocoria. Precise diagnosis ensures appropriate and early treatment to prevent irreversible blindness from primary pathology, secondary amblyopia, or life-threatening malignancies.
Retinoblastoma is diagnosed in 47 percent of children who are referred with leukocoria to tertiary centers.1
The majority (32 to 73%) of children with retinoblastoma present with leukocoria.2,3
Retinoblastoma occurs as rarely as in 1:13,000 to 1:20,000 live births, with an annual incidence of 11.8 per million children between zero and four years of age in the US and similar statistics in Europe.4
Other causes of leukocoria are slightly more common but exact estimates of their incidence are not available.
The direct cause underlying leukocoria that is common to the different conditions that cause it is an interference with the normal red reflex from opacities or abnormalities that occur strictly anywhere from the crystalline lens and posteriorly, hence excluding corneal opacities.
Leukocoria from retinoblastoma is caused by the whitish well-circumscribed retinal mass.
The tumor develops when a negative regulator of the cell cycle (pRB) is inactive or absent secondary to mutations in both alleles of the tumor suppressor gene RB1 in a retinal progenitor cell.5
The “two-hit” theory (first germline, second somatic; or both somatic) explains both heritable and non-heritable forms of retinoblastoma.
Other conditions are listed in the differential diagnosis (see Table 16-1).
TABLE 16-1Differential Diagnosis and Features of Entities that Can Simulate Retinoblastoma or Cause a Whitish Reflex from the Pupil
| Entity | Definition & Epidemiology | Leukocoria | Causes and Risk Factors | Clinical Features | Management | Prognosis | Prevention, Screening, & Education |
| Cataract | Progressive opacification of the lens. Congenital:~2 per 10,000. Infantile:1 to 15 per 10,000. | Opacity in the lens. Noticed by primary carephysician or parents, by naked eye, on red reflex evaluation or in photos. | Genetically determined in 50 percent of cases; mostly autosomal dominant. Could be a sign of systemic or infectious process, or the result of an injury. | Decreased visual acuity. Nystagmus. Strabismus. Photophobia. Family history of hereditary cataract. Features of genetic disorders associated with cataract (galactosemia, Down’s, etc). Labs for infections or metabolic causes. Genetic testing and/or karyotype. | If extra-axial or small & good vision, conservative: close follow up during age of visual development (until 8 to 9 years). Otherwise, prompt surgical extraction with optical rehabilitation (intraocular lens or postoperative contact lens) + near vision glasses + frequent adjustment of prescription with growth. Occlusion therapy (patching) if amblyopia ensues. | Untreated, amblyogenic and causing partial or total blindness. With early diagnosis and treatment, visual acuities of 20/40 to 20/20 can be achieved in many cases. Poor prognostic factors: nystagmus, strabismus, and unilateral infantile or congenital cataract. | Red reflex screening for all children in every exam. Regardless of leukocoria, all high risk children (positive family history, personal history of ionizing radiation exposure, long-term use of systemic steroids, or a systemic disorder associated with cataracts) require referral and yearly ophthamologic follow-up. |
| Persistent fetal vasculature (PFV) or Persistent hyperplastic vitreous (PHPV). | Congenital malformation resulting from failure of regression of the primary vitreous and hyaloid vascular system. Rare in the population. PFV is in up to 63 percent of children presenting with leukocoria. | Rudimentary vascular stalk in vitreous associated to plaque-like opacity retrolental fibrovascular tissue. Usually unilateral (Figure 16-4). | Arrest of normal involution of the embryonic vascular connective tissue that normally occurs after 4 months gestation. Non hereditary. | Microphthalmia. Strabismus. Cataract. Vascularized white retrolental tissue. Prominent iridial vessels. Elongated ciliary processes Glaucoma. Other malformations (intralenticular hemorrhage, uveal coloboma, etc) Posterior features (retinal fold, hypoplastic macula &/or optic nerve, traction retinal detachment + stalk to optic disc) | Ocular ultrasound: persistent hyaloid remnants with hyaloid artery or canal from disc into vitreous towards lens + confirmation of other clinical findings. CT or MRI: same as ultrasound. With contrast: hypervascular vitreous. Treatment: Lens extraction and anterior vitrectomy; can be complex. Enucleation in severe cases with no vision and malformed small globe. | High risk of: glaucoma, cataract, intraocular hemorrhage, and retinal detachment. Visual prognosis limited by associated optic nerve or macular disease. Long term: enucleation for terminal glaucoma, intra-ocular hemorrhage, retinal detachment, phthisis bulbi. | Red reflex screening for all children in every exam. No preventive measures available due to sporadic nature of the abnormality. Has been diagnosed on fetal ultrasound. |
| Extensive myelination of the nerve fiber layer | Abnormal myelination of nerve fibers of the retina. Almost in 1 percent of the population. | Lesion follows distribution of nerve fibers, typically striated white or gray myelinated nerve fibers patches with feathery borders (Figure 16-5). | Most cases are sporadic. Can occur in the context of some syndromes such as Gorlin syndrome (basal cell nevus syndrome). | Mostly asymptomatic. Usually normal vision (scotomas or enlarged blind spots may occur). In extensive cases has been associated with a higher incidence of amblyopia, myopia, and strabismus. Optic nerve may also be hypoplastic. | Visual field test. Asymptomatic cases: no treatment required. Symptomatic cases: prompt treatment of coexisting conditions that are associated with negative prognosi such as high myopia and amblyopia. | Generally stable. Poor vision from amblyopia in some cases. | Typically stable and benign disease. No preventive measures available. |
| Retinopathy of prematurity (ROP). | Developmental vascular disorder with uncontrolled vasoproliferation of incompletely vascularized retinas of premature infants. Affects around 21 percent to 36 percent of preterm infants. | Opaque mass behind lens (retrolental fibroplasia) in advanced and untreated cases of ROP and retinal detachment. | Prematurity <32 weeks Decreasing gestational age and birth weight. Assisted ventilation (>1 week). Surfactant therapy. Blood transfusions. Severity of illness. Hyperglycemia and insulin therapy. Sepsis. Elevated arterial oxygen tension. Fluctuations in blood gas measurements. Intraventricular hemorrhage. Bronchopulmonary dysplasia. | Detected on screening by an experienced ophthalmologist: location and retinal changes noted. The AAP/AAO/AAPOS 2006 recommendations for screening: 1- all infants with a birth weight <1500 g or gestational age ≤32 weeks 2- selected infants weighing: 1500 to 2000 g or gestational age >32 weeks with an unstable clinical course 3- infants at high risk according to their attending pediatrician or neonatologist. | Prethreshold ROP: elective treatment for prevention of progression. Threshold ROP: ablation of peripheral abnormal retina with laser photocoagulation (better than cryotherapy). Severe ROP without retinal detachment + ocular opacities (photocoagulation not possible): Bevacizumab (anti-VEGF) off-label (optimal timing and dose unknown). Retinal detachment: urgent surgical treatment. Post-treatment follow-up exam: weekly or biweekly for 1 to 2 months then less frequently depending on clinical course. | Irregular progression. Spontaneous regression in vast majority in 4 months. Poor visual acuity or fundus structural abnormalities in 5.1 percent. Blindness in children <1000 g birth weight. Poor visual prognosis in untreated severe ROP. High risk for: vitreous hemorrhages, preretinal membrane, tractional retinal detachment, strabismus, anisometropia, future myopia. | First screening examination: sufficient if both retinas fully vascularized. Screening examinations should continue until ROP regresses and the vessels mature, or until treatment is needed. Prevention targeted at oxidant injury (vitamins, penicillamine, and limiting light exposure): tested but not supported by evidence. Recommendations: avoiding episodes of physiologic instability. |
| Toxocariasis | Ocular infection caused by a zoonotic parasite: the dog or cat ascarid Toxocara (canis or catis). Most common in children aged 1 to 5 years. Leukocoria is the presenting sign in 15 percent of the cases. 98 percent of the cases have a history negative for visceral larva migrans syndrome. | Subretinal granuloma: whitish, 1 to 2 disc diameters, located anywhere in the retina. Nematode endophthalmitis: large inflammatory mass (with prominent vitreous inflammation). Both lesions may have calcification & be confused with retinoblastoma. | Ocular lesion: caused by inflammatory response to the second-stage larva. Human infection: due to accidental ingestion of infective eggs and tissue invasion of second stage larvae. Transmission: by con- taminated food or geophagia. Factors influencing onset of ocular disease are unknown, but the inflammatory reaction is mainly associated with larval death. | The only manifestation of the disease may be ocular. Unilateral. Subretinal granuloma (alone, in a quiet eye). Retinal damage: folds, elevation, detachment. Strabismus. Decreased vision. Chronic endophthalmitis. Uveitis (posterior). Macular and optic nerve disversion. Positive serum IgG (ELISA): confirmatory. Negative serum IgG: does not rule Toxocariasis out. Aqueous humor antibodies demonstrate intraocular production. | Peripheral granuloma (silent, minimal inflammation) does not require treatment. Anthelmintics (tiabendazole or diethylcarbamazepine) are controversial: larvae death may increase inflammation. Steroid umbrella (systemic or periocular) with anhelmintics to reduce inflammation, or alone to control vitreoretinal tractional membranes. Vitreoretinal surgery: for vitreous opacities, epiretinal membranes, and retinal detachment. Laser photocoagulation: to kill mobile visible larva, under “steroid umbrella.” Other ophthalmologic procedures to improve vision. | 56 percent suffer permanent vision loss. Poor visual prognostic factors are: Severe vitreitis. Cystoid macular edema. Tractional retinal detachment. | No screening (no need for treatment if silent). Prevention by reducing oral transmission to humans: periodic deworming treatment of pets (especially lactating females), timely disposal of pet feces, and good hygiene practices. Education to patients at risk: to prevent infection in pets, and to avoid exposure to potentially contaminated soil. |
| Optic disc and uveal coloboma. | Cleft of the optic disc secondary to failure of the fetal fissure to close inferiorly. Rare. | White sharp decentered excavation in the optic disk. May extend inferiorly to retina and choroid (rarely affects the entire disc; Figure 16-6). | Sporadic or inherited. Isolated or part of a syndrome: Renal coloboma syndrome (autosomal dominant, PAX2 gene on 10q). CHARGE syndrome. Other syndromes (Walker-Warburg, Aicardi, Goldenhar, linear sebaceous nevus, Noonan, focal dermal hypoplasia). | Unilateral or bilateral. Thin neuroretinal rim. Iris & ciliary coloboma. Orbital cyst. Iris heterochromia. Retinal venous malformations. Renal coloboma findings (VU reflux, renal hypoplasia, renal failure, chronic nephritis). CHARGE syndrome (+PHPV, microphthalmos, facial palsy, facial dysmorphism, TE fistula, renal, cardiovascular and CNS abnormalities.) | Renal ultrasound to rule out significant renal disease. Rule out CHARGE syndrome (Colobomas, Heart defects, Choanal Atresia, Retarded growth, Genital abnormalities, Ear abnormalities) with echocardiography, nasal catheter (or CT sinuses) and hearing test. | Visual acuity ranges form normal to complete visual loss (not predictable by appearance of the lesion). Best visual prognostic factor: sparing of the fovea by associated chorioretinal coloboma. | Red reflex screening for all children in every exam. No preventive measures available due to nature of the abnormality. |
| Coats disease | Primary retinal telangiectasias, a rare exudative retinopathy usually affecting young males (80% are 5 to 10 years old). | Luminous leukocoria from massive yellow exudates on/in edematous retina (pseudo-tumor; Figure 16-7). | Idiopathic, congenital, and nonhereditary. Somatic mutation in NDP gene, causing deficiency of norrin (protein product) in the developing retina. No known associated systemic problems. | 90 percent unilateral. Decreased visual acuity. Strabismus. Retinal telangiectasia: usually peripheral strings of fusiform aneurysmal dilatations of the retinal vessels (tiny light bulbs). Pseudo-tumoral exudates, predilection for macula. Exudative (partial or total) retinal detachment. Iridis rubeosis. Neovascular glaucoma. Cataract. Uveitis. Phthisis bulbi. | Treatment goal: arresting vascular progression. Cryotherapy or laser photocoagulation: limited success. Avoided if lesions around optic nerve. Enucleation is an option for further complicated cases. | Variable evolution. Spontaneous stabilization or regression is occasional and may be temporary or permanent, but usually with loss of central vision (macular deposits). Retinal exudation can cause retinal detachment. Progressive retinal damage and eventual definitive blindness. | As precise origin is unknown, disease cannot be prevented. |
| Morning Glory syndrome | Congenital anomaly: funnel shaped excavation of the fundus and the optic nerve head with a ring of chorioretinal pigment around the disk. Uncommon, but more common in females. | Central white glialtuft of tissue at center of optic cup, surrounded by vessels radiating out like spikes from an enlarged optic nerve head. | Unknown. Sporadic occurrence in great majority of cases. Some underlying genetic defect must be present (see associated malformations). | Unilateral. Usually isolated. Retinal detachment up to 1/3 of cases. Association to midline cranial defects with symptoms of mouth-breathing, snoring, and rhinorrhea. Baasal cephaloceles Reported associations with capillary hemangiomas, carotid circulation abnormalities such as Moyamoya disease, and renal disease. | MRI: transsphenoidal encephalocele may be seen affecting the nasopharynx. MRAs are essential to rule out associated Moyamoya disease that could be treatable. | Serous retinal detachment retinal folds, and subretinal neovascularization may contribute to a poor visual prognosis. Usually severely reduced visual acuity (20/200 to finger counting). But occasionally better. | No preventive measures available for malformation itself. |
| Congenital Toxoplasmosis | Ocular infection with the protozoa Toxoplasma causing uveitis, vitritis, and focal necrotizing retinochoroiditis. Congenital cases show chorioretinal scars (Figure 16-8), may also have optic atrophy, cataract, and microphthalmos. | Fluffy whitish lesion + retinal edema: necrosis, usually involving inner layers of the retina where the primary site of multiplying parasites is. Possible sites of contiguous inflammation: choroid and sclera. | Transplacental transmission from infected mother to fetus, highest in 3rd semester. Maternal infection from ingestion of undercooked or contaminated dairy products and meat, or (directly or indirectly) cat feces. Immune deficient state primes for infection or reactivation of toxoplasmosis (HIV or medical immune suppression). | No clinical signs in 90 percent of congenital infections. Symptomatic infection: Chorioretinitis (in 80 percent of congenital cases, and usually bilateral), intracranial Calcification, convulsions, as well as cerebral palsy, mental retardation, microcephaly or hydrocephaly. Accounts for up to 50 percent of cases of posterior uveitis cases. Panuveitis, optic atrophy, microphthalmos, cataract. Retinal destruction & thickening from retinal vasculitis. Elevated IgM in neonate (ELISA). | Fluorescein angiography: hypofluorescence, followed by progressive leakage. Indocyanine angiography: dark small spots around the lesions implying retinal involvement is greater than initially seen. Useful for follow up after treatment. Pharmacologic therapies: Triple: pyrimethamine, sulfadiazine, & prednisone. Quadruple: add clindamycin. + folinic acid to avoid hematologic complications of pyrimethamine. Duration of therapy depends on clinical response: usually 4 to 6 weeks. Goals: to eradicate parasite and suppress inflammation. | Poor prognostic factor: earlier infection in pregnancy. Indications to treat: Lesions involvement of the optic disc, papillomacular bundle, or macula. Active large lesions. Immunocompromised patient. | Cooking food to safe temperatures and other habits that reduce risk from food, as well as keeping pregnant women away form litter boxes and other behaviors that reduce risk from the environment are recommended by the CDC and the USDA. |
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