Leukocoria

Leukocoria is a white or grey pupillary reflex, seen in place of the normal red reflex. It is an emergency in infants and children because it may signal retinoblastoma, which can be fatal, as well as cataract, retinopathy of prematurity and other sight threatening disease.

Anatomy and mechanism. The red reflex arises from light reflecting from the choroid. Any opacity in the cornea, lens or vitreous, or a mass or detachment behind the lens, reflects white light instead.

Classification. Retinal tumour (retinoblastoma), lens opacity (congenital and developmental cataract), vascular and developmental (persistent fetal vasculature, retinopathy of prematurity, Coats disease, familial exudative vitreoretinopathy), infective and inflammatory (toxocariasis, congenital infection, endophthalmitis, uveitis), structural (retinal detachment, coloboma, retinal dysplasia, Norrie disease), and haemorrhage.

Key distinctions. A red reflex that is absent or white in one eye with the other normal suggests retinoblastoma, cataract or persistent fetal vasculature. A family history of eye cancer or a child with strabismus (the second commonest presentation) raises the probability of retinoblastoma. A premature infant with leukocoria suggests retinopathy of prematurity. A child with a dog or soil contact and a white pupil suggests toxocariasis.

History.

• Who noticed the white reflex and when (photographs: white or yellow eye in flash images)
• laterality, squint, poor tracking or vision, red eye, eye pain, eye size
• prematurity (gestational age, birth weight, oxygen exposure)
• maternal infection (rubella, cytomegalovirus, toxoplasmosis, syphilis, herpes)
• family history of retinoblastoma, childhood eye cancer, cataract or retinal disease
• consanguinity, developmental delay, prior trauma
• contact with puppies or soil
• previous eye examination results

Examination.

Red reflex test in a dim room with a direct ophthalmoscope held at arm's length (both eyes together and each eye separately; a white or absent reflex or a difference between eyes is abnormal).

• corneal light reflex (strabismus)
• eye size (corneal diameter, buphthalmos)
• pupils
• visual behaviour (fixation and following)
• conjunctiva, cornea, anterior chamber
• iris (neovascularisation, heterochromia, pseudohypopyon)
• lens
• dilated fundus examination by ophthalmology (under anaesthesia when necessary)

General examination for syndromes, dysmorphic features, hearing and growth.

Red flags

• Any white or absent red reflex in a child (same day or next working day ophthalmology)
• Leukocoria with strabismus, red painful eye, hyphaema or enlarged eye
• Family history of retinoblastoma or childhood eye cancer
• Premature infant with leukocoria
• Rapidly increasing pupil whiteness or proptosis
• Failure to fix and follow, or visual inattention
• Congenital infection signs (hearing loss, microcephaly, hepatosplenomegaly)

Special groups. Infants: congenital cataract and persistent fetal vasculature. Premature infants: retinopathy of prematurity screening by gestational age and birth weight (screen those born before 32 weeks or under 1,500 g, or larger infants with unstable course). Region specific: late presentation of retinoblastoma with proptosis and delayed diagnosis in low resource settings, congenital rubella, toxocariasis, and onchocerciasis.

Neoplastic

• Retinoblastoma (unilateral, bilateral, hereditary and sporadic), retinal astrocytic hamartoma (tuberous sclerosis), medulloepithelioma, leukaemic and lymphomatous infiltration, choroidal tumour and haemangioma, and metastatic neuroblastoma

Lens

• Congenital cataract (idiopathic, hereditary, metabolic: galactosaemia, hypoglycaemia, hypocalcaemia; infectious: rubella, cytomegalovirus, toxoplasmosis; syndromic: Down syndrome, Lowe syndrome), developmental cataract, traumatic cataract, lens subluxation

Vascular and developmental

• Persistent fetal vasculature (persistent hyperplastic primary vitreous), retinopathy of prematurity (stage 4 and 5 and retrolental fibroplasia), Coats disease, familial exudative vitreoretinopathy, Norrie disease, incontinentia pigmenti, retinal dysplasia, coloboma of the choroid and optic disc, morning glory disc, myelinated nerve fibres, retinal detachment, vitreous haemorrhage

Infective and inflammatory

• Ocular toxocariasis (granuloma), toxoplasmic chorioretinitis, congenital cytomegalovirus, rubella, herpes simplex, endophthalmitis, uveitis (juvenile idiopathic arthritis), pars planitis, onchocerciasis, ocular tuberculosis, Behcet disease

Corneal and other

• Corneal opacity (congenital glaucoma, birth trauma, infection, Peters anomaly), cloudy cornea from metabolic disease, and optical illusions (photographic artefact, red eye reflex failure due to eye position)

Reasoning. Treat every leukocoria as retinoblastoma until proven otherwise. Examine both eyes fully under anaesthesia when required and image the orbit and brain before any intraocular procedure. Do not biopsy a suspected retinoblastoma.

First line. Red reflex test, pupil examination, ophthalmoscopy by a paediatric ophthalmologist, and examination of the family (red reflex in siblings and parents).

Targeted tests.

• Examination under anaesthesia with indirect ophthalmoscopy and scleral depression, fundus photography and wide field retinal imaging (RetCam) and optical coherence tomography.
• B scan ultrasound (intraocular mass with calcification), MRI orbits and brain with gadolinium for staging, optic nerve invasion and trilateral disease (pineal tumour); CT is avoided because of radiation risk and the genetic predisposition to second cancers.
• Genetic testing of RB1 (blood and tumour) with counselling; screening of siblings and offspring (examination under anaesthesia on a schedule).
• Staging for suspected extraocular spread: lumbar puncture and bone marrow aspirate and biopsy.
• Toxocara antibody in serum and aqueous, toxoplasma, cytomegalovirus, rubella and syphilis serology and polymerase chain reaction, TORCH screen in infants.
• Metabolic screen for cataract: urine reducing substances and red cell galactose 1 phosphate uridyl transferase, glucose, calcium, phosphate, and TORCH serology; genetic testing for hereditary cataract.
• Retinopathy of prematurity screening by indirect ophthalmoscopy.
• Haemoglobin electrophoresis and lipid profile when indicated.

Limitations. Small tumours in the periphery can be missed without a complete examination under anaesthesia. Ultrasound may not differentiate retinoblastoma from other masses without calcification.

Immediate steps. Same day or next working day referral to a paediatric ophthalmologist or retinoblastoma service for any abnormal or asymmetric red reflex. Do not dilate pupils or perform procedures in primary care unless advised. Document and reassure the family while avoiding delay.

Retinoblastoma (specialist centre).

• Multidisciplinary treatment by paediatric oncology, ophthalmology and radiation oncology. Aims: life, then eye, then vision.
• Systemic chemotherapy (carboplatin, etoposide and vincristine, given in cycles every 3 to 4 weeks, with doses by body surface area or weight by oncology), intra-arterial melphalan, intravitreal melphalan for vitreous seeds, focal laser (transpupillary thermotherapy), cryotherapy, and brachytherapy (plaque).
• Enucleation for advanced unilateral disease, with histology for high risk features (optic nerve, choroid, anterior segment invasion) and adjuvant chemotherapy.
• External beam radiotherapy is avoided because of second cancer risk in hereditary disease.
• Extraocular disease: high dose chemotherapy with stem cell rescue and radiotherapy.
• Genetic counselling, family screening, and long term surveillance for second cancers (osteosarcoma, sarcoma, melanoma) in hereditary disease.

Congenital cataract.

• Dense unilateral cataract: surgery before 6 weeks of age. Dense bilateral cataract: surgery before 10 weeks. Partial cataract: observation with refraction and patching.
• Aphakic correction with contact lens or intraocular lens (age dependent), amblyopia therapy (patching of the better eye, 2 to 6 hours daily by age and response), and glaucoma surveillance after surgery.
• Treat causes: galactosaemia (galactose free diet), hypocalcaemia (calcium and vitamin D replacement), hypoglycaemia; infection screening and treatment with paediatric infectious disease; genetic counselling.

Persistent fetal vasculature. Ophthalmology: lensectomy and vitrectomy in selected eyes; amblyopia treatment; glaucoma monitoring.

Retinopathy of prematurity.

• Screening by gestational age and birth weight.
• Type 1 disease is zone I any stage with plus disease, zone I stage 3 without plus disease, or zone II stage 2 or 3 with plus disease.
• Treat it with laser photocoagulation or intravitreal anti-vascular endothelial growth factor injection (bevacizumab 0.625 mg or ranibizumab 0.2 mg) within 72 hours.
• Vitrectomy for stage 4 and 5 disease.
• Oxygen saturation targets of 90 to 95 percent in premature infants.

Coats disease. Laser photocoagulation, cryotherapy, intravitreal anti-vascular endothelial growth factor, and surgery by retinal specialists.

Ocular toxocariasis. Ophthalmology and infectious disease care:

• oral prednisolone 0.5 to 1 mg/kg daily for 2 to 4 weeks tapered
• periocular or intravitreal steroid for inflammation
• vitrectomy for traction
• albendazole 400 mg orally twice daily for 5 days (children 15 mg/kg daily in 2 doses, maximum 800 mg daily; evidence of benefit is limited) with corticosteroid cover
• hygiene and deworming of pets

Toxoplasmosis and congenital infections. Specialist treatment:

• congenital toxoplasmosis with pyrimethamine, sulfadiazine and folinic acid for 12 months
• congenital cytomegalovirus with valganciclovir 16 mg/kg orally twice daily for 6 months
• syphilis with benzylpenicillin 50,000 units/kg IV every 12 hours for the first 7 days then every 8 hours to complete 10 days
• rubella with supportive care and prevention by vaccination

Endophthalmitis and uveitis. Emergency ophthalmology for intravitreal antibiotics and vitrectomy; uveitis with prednisolone acetate 1 percent drops and systemic immunosuppression by specialists.

Retinal detachment. Surgical repair.

Visual rehabilitation. Early intervention services, vision therapy, low vision aids, educational support, and psychological support for families.

Monitoring. Frequent examination under anaesthesia during retinoblastoma treatment (every 3 to 4 weeks), then at widening intervals until about age 6 years. MRI surveillance for trilateral disease in hereditary cases. Amblyopia and refraction every 3 months after cataract surgery.

Referral and escalation. Same day or next working day paediatric ophthalmology for any leukocoria. Paediatric oncology, genetics, and neuroradiology for retinoblastoma. Paediatric ophthalmology and anaesthesia for congenital cataract surgery. Neonatology and ophthalmology for retinopathy of prematurity screening.

Admission criteria. Suspected retinoblastoma requiring urgent examination under anaesthesia and staging, endophthalmitis, extraocular disease, severe retinopathy of prematurity, or systemic congenital infection.

Discharge and safety netting. Return for a white reflex, squint, red painful eye, eye enlargement, proptosis, or poor vision in a child. Parents of children with a family history of retinoblastoma should arrange screening from birth.