Leukocoria means ‘white pupil’ or ‘cat’s eye pupil.’ Leukocoria is an abnormal pupillary reflex more clearly seen on mydriasis or photography. It is often the first sign of a range of serious intraocular disorders. Leukocoria is commonly seen in congenital cataract, Coats disease, retinoblastoma, retinopathy of prematurity, toxocariasis, Norrie disease, retrolental fibroplasia, and other disorders. Immediate diagnosis and management are mandatory as most conditions are vision-threatening, and retinoblastoma may be life-threatening. Immediate referral to an ophthalmologist, an interdisciplinary liaison with a pediatric ophthalmologist, retina specialist, and ocular oncologist will help in the management of eyes with leukocoria in an appropriate manner.
The normal red reflex of the human eye is due to the retro-illumination of normal choroidal vasculature reflecting thorough the retina, vitreous, lens, pupil, and cornea. Any interference in any of these structures would give an altered red reflex or Leukocoria. Some of the common causes of Leukocoria are:
In a retrospective study spanning ten years, the mean age of children presenting with leukocoria was 42.5 months. Bilateral involvement was seen in 54% with a male-female sex ratio of 1.5. 76% of children were under six years of age. 75% of the cases were caused by cataracts, and 21% were retinoblastoma. Other causes of leukocoria included retinal detachment (1%), retinopathy of prematurity (1%), persistent pupillary membrane (1%), persistent hyperplastic primary vitreous (0.6%), endophthalmitis (0.64%), optic nerve coloboma (0.3%), iris heterochromia (0.3%), and ametropia (0.3%).
The Third National Cancer survey data indicates an annual incidence of 11 new cases of retinoblastoma per million children under the age of 5 years. Retinoblastoma is the most common intraocular malignancy in children and accounts for 2% of all childhood cancers. The estimated incidence ranges from 3 to 42 cases per million live births. In the United States, the incidence is 12 cases per million live births in children less than five years of age, with a prevalence of 6 % of all cancers in this age group. Retinoblastoma affects both sexes equally. Retinoblastoma shows the highest incidence in children less than four years of age. Coats disease has an incidence of 0.09 per 100,000 population, with 85% of cases affecting the males.
The global prevalence of childhood cataract ranges from 0.3% to 23% per 10,000, with a median of 1 per 10,000 and 0.6% to 9.8% per 10,000 for congenital cataract with a median of 1.7 per 10,000 based on many studies that reported congenital cataract. In a study involving 602 newborns, the incidence of retinopathy of prematurity (ROP) at any stage was 34%, and Type 1 pre threshold ROP was 5% with a mean gestational age of 31 weeks. The incidence of neonatal endophthalmitis in the United States is 4.2 cases/1000000 live births.
Leukocoria is a whitish or altered pupillary reflex that appears due to obstruction of the normal retinochoroidal vasculature, which reflects through the pupil. The various causes of leukocoria, their etiopathogenesis, and clinical features are as follows:
A thorough medical history of present illness, past ocular history, medical history, and family history should be elicited. A family photograph would help know if the leukocoria was present from birth or later in childhood. Persistent fetal vasculature is most often present at birth. A history of prematurity would lead us to investigate in line with retinopathy of prematurity, which presents as leukocoria due to retinal detachment and retrolental fibroplasia. Birth trauma can lead to hyphema or vitreous hemorrhage, which presents as an altered pupillary reflex. Family history is essential in retinoblastoma, FEVR, and coloboma.
The color of the pupillary reflex also gives a hint of the diagnosis. Retinoblastoma presents as a whitish pupillary reflex, while congenital cataracts show a blue-grey reflex. Coats disease and retinal detachment show a yellowish reflex. In 20% of cases, retinoblastoma presents as strabismus. Retinal detachments, vitreous hemorrhage, Coats disease, and retinoblastoma (60%) usually presents as unilateral disease, while FEVR, endogenous endophthalmitis, astrocytic hamartomas, and 40% of retinoblastomas are bilateral.
Any child presenting with leukocoria should be evaluated for vision, pupillary reflexes, slit-lamp examination of both anterior segment and fundus, indirect ophthalmoscopy, FFA, OCT of the retina, and B scan ultrasonography. Neuroimaging, blood workup, genetic testing, and fine-needle aspiration cytology are other ancillary tests done to confirm the diagnosis.
Leukocoria is a sign of an underlying ocular disease. The management of common ocular conditions causing leukocoria is as follows:
Retinoblastoma: Chemoreduction followed by adjuvant consolidative treatment (laser photocoagulation, thermotherapy, cryotherapy, chemotherapy) has replaced external beam radiotherapy as the primary mode of treatment for intraocular retinoblastoma. The following are the various methods of treatment of retinoblastoma:
Coats disease: Mild cases may be observed. Other management options include laser treatment of telangiectatic vessels, microaneurysms, and capillary nonperfusion areas, cryotherapy for exudation with subretinal fluid, intravitreal anti-vascular endothelial growth factor (anti-VEGF) agents, and retinal surgery for retinal detachment are other available therapy.
PFV: The anterior PFV is treated with observation, cataract, and glaucoma management. Treatment is aimed at preventing amblyopia and correcting strabismus by treating cataracts and glaucoma. Severe intraoperative bleeding should be anticipated from persistent tunica vasculosa lentis. Retinal lesions of posterior PFV are managed by lensectomy, membranectomy, and vitrectomy through either anterior limbal or pars-plana approach.
Pediatric cataract: Cataracts operated between 2 months to 6 months yield good results. Emmetropization of an eye generally is achieved by nine years of age. Unilateral cataracts should be operated before six weeks and bilateral cataracts before eight weeks of age. Surgery is advised for visually significant cataracts (more than 3 mm of opacity).
Pediatric uveitis: Corticosteroids are the mainstay of treatment of noninfectious uveitis in children. Periocular or sub-tenons corticosteroid injections are used in pars planitis, especially in unilateral cases. Steroid-induced glaucoma and cataract are potential complications of corticosteroid therapy and should always be looked for. Methotrexate is the most commonly used first-line immunomodulatory drug in children with uveitis. Second-line agents are azathioprine, cyclosporine, and mycophenolate. Anti-TNF (tumor necrosis factor) agents like infliximab and adalimumab are successfully used in the treatment of resistant pediatric uveitis.
Toxocariasis: Topical or systemic corticosteroids are the mainstay of treatment in the control of the inflammation. The role of anti-helminthic therapy in ocular toxocariasis is controversial and should always accompany steroids. Pars plana Vitrectomy is the most common surgical treatment for ocular toxocariasis.
Astrocytic hamartoma should be observed. Glaucoma should be treated accordingly. Tuberous sclerosis should be ruled out.
Retinopathy of prematurity: Observation, retinal laser, cryotherapy, and retinal surgery are the different treatment modalities for ROP. Immature retinal vessels alone can be observed, and screening repeated. The cryo-ROP study showed positive results of cryotherapy for the entire avascular retina in the threshold ROP. Early treatment of the ROP study (ETROP) recommended the ablation of the peripheral avascular retina for type 1 ROP.
Endogenous endophthalmitis: Management depends on the causative organism and the severity of the infection. Empirical treatment includes intravitreal injection of vancomycin (1 mg/0.1 ml) plus either ceftazidime (2.25 mg/0.1 ml) or Amikacin (0.4 mg/0.1 ml). Vancomycin covers for gram-positive organisms while ceftazidime and amikacin cover for gram-negative organisms. For fungal vitritis, vitrectomy with intravitreal injection of amphotericin (5-10 mcg/0.1 ml) or voriconazole (100 to 200 mcg/0.1 ml) and systemic antifungal therapy are indicated. Pars plana vitrectomy is indicated for all severe sight-threatening endophthalmitis. Systemic antifungal or antibacterial therapy should be started depending on the blood and vitreous culture reports.
Retinochoroidal coloboma: Retinal detachment and cataract are the most common associations of retinochoroidal coloboma. Poor vision, amblyopia, and strabismus may be noted. Prophylactic barrage laser along the coloboma margin creates a strong chorioretinal adhesion and reinforces the margins, thereby may reduce the occurrence of extra-colobomatous retinal detachment. Pars-plana vitrectomy with or without scleral buckling, drainage of subretinal fluid, and endotamponade with long-acting gas or silicone oil is the treatment of choice for retinal detachment. The exact localization of the retinal breaks that cause the retinal detachment may be very difficult to localize because of the thin atrophic retina, transparent intercalary membrane, nystagmus, small cornea, and cataract.
Familial exudative vitreoretinopathy: Stage 1 FEVR without exudation can be observed. Stage 2 with exudation is treated with a laser to the avascular retina. Surgery is indicated for stages 3 to 5 and is aimed at relieving traction by excision or incising the scar tissue, thereby encouraging reattachment of the retina.
Retinal detachment: Two surgical options for pediatric rhegmatogenous retinal detachments are scleral buckle with or without encircling band and vitrectomy. This is the preferred surgery, even in Grade C proliferative vitreoretinopathy (PVR). Vitrectomy with or without encirclage is done in retinal detachment with more than PVR Grade C. In tractional retinal detachment, the scleral buckle may be sufficient if the break is in the periphery.
Medulloepithelioma: Enucleation is the standard treatment for advanced ciliary body tumors. Exenteration of the orbit is required when the orbit is involved. Local excision can be done for small tumors involving 3 to 4 clock hours.
Incontinentia pigmenti: Laser ablation of retinal non-perfusion areas and cryotherapy may be helpful.
Leukocoria is an altered pupillary reflex presenting as a white/greying reflex when compared to the bright red/orange reflex of the fellow eye. The following conditions mimic leukocoria, but they haven't actually altered pupillary reflexes instead a differently looking eye which the parents bring it to the doctor's attention:
Causes of Intraocular calcification:
Tartarella et al have classified leukocoria as below:
International Classification of Retinoblastoma (ICRB)
International Classification of Retinopathy of Prematurity
‘Plus’ disease: Dilated tortuous retinal vessels surrounding the optic disc, vitreous haze, and iris vascular congestion.
Aggressive posterior ROP(AP-ROP): ‘Plus’ disease in zone 1 or posterior zone 2 with vascular loops. Such aggressive disease may worsen rapidly and may not follow the typical stages of ROP.
Classification of retinochoroidal coloboma
Retinoblastoma (RB) has a survival rate of 90% to 95% with a good prognosis, although the affected eye might lose vision. Poor prognostic signs of retinoblastoma are optic nerve/extra-scleral/uveal invasion, multifocal tumors, delayed diagnosis, and degree of differentiation. Bilateral involvement doesn’t worsen the prognosis, while the degree of necrosis and calcification does not influence the prognosis. The prognosis of RB depends on the status of the tumor is the worst eye. High-risk features for recurrence are optic nerve invasion, massive choroidal involvement, orbital spread, and involvement of anterior segment and uveal tissue.
Congenital cataract has a good prognosis if diagnosed early and if operated before six weeks. Developmental cataract has a better prognosis than congenital cataract. Bilateral cataracts have a better prognosis than unilateral cataracts. Even a mild opacity can cause significant amblyopia. Unilateral cataracts also pose a higher risk of anisometropia.
Endogenous endophthalmitis doesn’t have a favorable prognosis. Most cases result in retinal detachment and uncontrolled infection, eventually requiring enucleation or evisceration.
FEVR is a lifelong disease and can reactivate at any time. Following treatment, patients with FEVR should be followed up every six months with fundus examination and fluorescein angiography. Prognosis of retinal detachment surgery is very poor because children often present with poor visual acuity with a higher percentage of macular involvement. Besides these, the child possesses a lifelong risk of cataracts, glaucoma, and recurrence in retinal detachment.
Medulloepithelioma that is confined to the globe has an excellent prognosis with a 5-year survival rate of 90-95% after enucleation.
The prognosis for retinochoroidal coloboma is reasonably good if amblyopia is managed in time and if the prophylactic laser is done to prevent retinal detachment. Foveal involvement in coloboma causes severe loss of vision.
Cataract and cataract surgery:
Leukocoria is a pediatric manifestation. So parents of the child should be properly educated about investigating the child fully to know the cause for the leukocoria. It could be as benign as an altered Bruckner reflex to most sinister retinoblastoma, which could be sight or life-threatening. The family doctor or the pediatrician or the primary care physician are the first to diagnose leukocoria, and thus they play an essential role in the outcome of the eye condition. Any complaint of altered pupil reflex should be taken seriously and thoroughly investigated.
Parents should be reassured and counseled appropriately about the cumbersome process of the full investigation, including neuroimaging and also screening siblings for a hereditary disorder. Genetic counseling of retinoblastoma is complex and very much essential. Only 5 percent of retinoblastoma patients have a family history of RB. Bilateral retinoblastoma survivor parent has a 45 percent chance of having an affected child. A unilateral retinoblastoma survivor parent has a 7 percent chance of having an affected child. Normal parents of a child with bilateral RB has less than 5 percent risk of having another child with RB. If two or more siblings are affected, then the chance of another child having RB is 45 percent.
Primary care physicians, pediatricians, and optometrists are the first to assess leukocoria. Early diagnosis and referral to an ophthalmologist are mandatory for a successful outcome. Inter sub-specialty liaison between a general ophthalmologist, pediatric ophthalmologist, ocular oncologist, and a retinal surgeon is essential in a faster diagnosis and management of the child as conditions like retinoblastoma are life-threatening in addition to being a vision-threatening disease. Siblings and parents should all be involved in care management as some of the conditions causing leukocoria are hereditary. Involving a geneticist early in the care management helps int the genetic counseling of the parents. American Academy of Pediatrics has laid down the following recommendations in children with leukocoria:
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