Review
Leukocoria and the red reflex test
Leucocoria e teste do reflexo vermelho
Mirna Yae Yassuda Tamura1, Luiz Fernando Teixeira2
ABSTRACT
Until recently, the ophthalmologic examination of newborns in maternity
hospitals was not a priority; even today, few hospitals perform this
examination adequately. Consequences may be disastrous, because
by the time eye alterations are found, the child may have developed
permanent loss of visual acuity. The ophthalmologic examination in
nurseries, carried out by neonatologists, permits an early diagnosis and
referral for effective therapy and adequate development of vision. This
study underlines the importance of the red reflex test in newborns and
presents the main causes of leukocoria (cataract, retinoblastoma, and
retinal and vitreous diseases) to alert pediatricians and neonatologists
about this condition. Special emphasis is given to retinoblastoma, a
condition affecting 1/14,000 to 1/20,000 live newborns; genetic, clinical,
diagnostic, and therapeutic aspects are presented. Early diagnosis of
retinoblastoma is essential for reducing morbidity and mortality.
Keywords: Reflex, pupillary/etiology; Eye diseases/complications;
Eye manifestations; Diagnostic techniques, ophthalmological
RESUMO
Até há bem pouco tempo, o exame oftalmológico feito em recém-
nascidos, ainda na maternidade, não era uma prioridade; e mesmo
hoje em dia, em um grande número de serviços de Neonatologia, os
olhos dos recém-nascidos não são adequadamente examinados. As
consequências são desastrosas, pois quando a alteração é descoberta
tardiamente, a criança poderá ter perdido irremediavelmente a visão.
O exame oftalmológico, feito ainda no berçário pelo neonatologista,
permite um diagnóstico e encaminhamento precoce da criança,
propiciando um tratamento efetivo que possibilite o desenvolvimento
adequado da visão. O presente artigo salienta a importância da pesquisa
do reflexo vermelho em recém-nascidos e discute as principais causas
da leucocoria, como a catarata, o retinoblastoma e as doenças da
retina e do vítreo, a fim de alertar pediatras e neonatologistas para
o problema. Ênfase especial é dada ao retinoblastoma, problema
que afeta de 1/14.000 a 1/20.000 dos recém-nascidos vivos, sendo
apresentados aspectos genéticos, clínicos, diagnósticos e terapêuticos
dessa afecção. O seu diagnóstico precoce é a base para a redução da
morbimortalidade da doença.
Descritores: Reflexo pupilar/etiologia; Oftalmopatias/complicações;
Manifestações oculares; Técnicas de diagnóstico oftalmológico
MD; Specialist in Retina and Vitreum at Hospital do Servidor Público Estadual “Francisco Morato de Oliveira” – São Paulo (SP), Brazil.
1
MD; Ocular Oncology Sector of the Department of Ophthalmology at Universidade Federal de São Paulo – UNIFESP, São Paulo (SP), Brazil.
2
Corresponding author: Mirna Yae Yassuda Tamura – Rua Pedro de Toledo 1800 – Vila Clementino – CEP 04039-901 – São Paulo (SP), Brasil – Tel.: (11) 5078-9681 – e-mail: mirnayassuda@hotmail.com
Received on Jan 30, 2009 – Accepted on July 30, 2009
einstein. 2009; 7(3 Pt 1):376-82
INTRODUCTION
Leukocoria may be a common sign in various ocular
conditions – such as cataract, retinoblastoma, and
retinal and vitreous diseases – and may be characterized
by a whitish pupillary reflex (leukos: white, kore: pupil)
that differs from the normal red ocular reflex.
The red ocular reflex appears when a light beam
is focused on the eye through the pupil; the light is
partly absorbed and partly reflected by the retina back
through the pupil, appearing as a reddish-orange reflex
characterizing the normal color of the retina and the
choroid.
An early diagnosis is possible with the red reflex test,
which reduces the morbidity and possibly the mortality
of various ocular conditions.
The red reflex test
The red reflex test is used for screening purposes to
detect changes in the fundus of the eye and opacities on
the visual axis, such as cataract and corneal opacities.
This test should be done preferably in a dark room,
as papillary miosis due to light makes the test harder
to interpret. The child may be seated on his or her
parent’s lap or lying on a bed with eyes open, voluntarily
if possible. The examiner should be at about 50 cm
from the child and should examine the pupils with a
direct ophthalmoscope, separately and simultaneously,
comparing their reflexes.
The ocular reflex should be visible and symmetrical
in color and intensity in both eyes (Figure 1). The reflex
color in children with little ocular pigmentation (white
race) is reddish-orange; in children with more intense
ocular pigmentation (black race), the reflex is darker
(reddish-brown).
Examination with midriasis (papillary dilatation)
increases the test sensitivity. Dilatation may be attained
using eye drops with sympaticomimetic agents (2.5%

Figure 1. Normal red reflex test
phenylephrin) and/or anticolinergics (1% tropicamide);
one drop is administered in each eye 15 to 30 minutes
before testing. Although sporadic complications of
these medications has been reported – such as increased
arterial pressure and heart rate, rashes and contact
dermatitis – papillary dilatation has been used routinely
in most pediatric patients in ophthalmological offices
and neonatal units without complications in most
cases, showing that this procedure appears to be safe in
children and premature neonates(1).
The red reflex test should be repeated in routine
visits up to age 3 years.
Alterations in the red reflex, such as asymmetrical
intensity and color, whitish spots, or absent reflexes,
may suggest crystalline, retinal or vitreous disease. Any
changes in the red reflex should prompt a referral of the
child to a more detailed ophthalmological assessment,
which should include examination of the fundus of the
eye by indirect ophthalmoscopy.
Causes of leukocoria
Leukocoria may be unilateral or bilateral (Figures 2 and
3). The differential diagnosis of leukocoria includes the
following diseases: cataract; uveitis; ocular toxocariasis;
persistent hyperplasic primary vitreous (PHPV);
coloboma; retinopathy of prematurity; Coats’ disease;
retinoblastoma.
Cataract
Infantile cataract is one of the main causes of avoidable
blindness and sub-normal vision in children(2). This
condition arises when the crystalline is partially or fully
opaque, on one eye only or bilaterally, decreasing visual
acuity.
There may be many causes of crystalline opacity,
such as congenital ocular malformation, intra-uterine
Leukocoria and the red reflex test 377
Figure 2. Bilateral leukocoria
Figure 3. Unilateral leukocoria
infection (rubella, cytomegalovirus, chickenpox,
toxoplasmosis), genetic syndromes (the Down, Patau
and Lowe syndromes), metabolic diseases (galactosemia,
hypoparathyroidism, hypoglycemia), heredity (dominant
autosomal inheritance is more common, but there have
been reports of recessive autosomal and X-linked
inheritance), medications (corticosteroids), and
radiation; it can also be an acquired condition (trauma,
secondary to uveitis) or have idiopathic causes(3).
The cause of vision loss in most cases is irreversible
amblyopia. Congenital cataract should be detected and
treated early for eyesight to develop normally. Thus, all
children should undergo the red reflex test at birth.
Children with cataract may present leukocoria,
low visual interest (especially when the condition is
bilateral), strabismus, poor visual fixation on objects,
and nystagmus, the latter resulting from early visual
deprivation, and carrying a poor visual prognosis.
Treatment of partial cataract may be conservative,
depending on the scope and on the child’s visual acuity.
Surgery is done in cases of marked loss of vision or if there
is total cataract. The visual prognosis depends on how early
the diagnosis was made and the treatment was started.
Uveitis
Uveitis is an inflammation of any uveal tract segment,
comprising the iris, ciliary body and choroid. Uveitis
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378 Tamura MYY, Teixeira LF
may be anterior, intermediate or posterior, according
to the site.
Uveitis may be associated with leukocoria, as in
cases of chronic anterior uveitis, which is commonly due
to juvenile rheumatoid arthritis in pediatric patients. It
may progress to cataract and leukocoria. In cases of
posterior uveitis, leukocoria may be associated with
vitreitis (progressing to vitreous opacity), choroiditis
or retinitis. Infections such as toxocariasis, syphilis,
candidiasis, toxoplasmosis, rubella, CMV, and herpex
simplex (TORCH) should be excluded in these cases(4).
Ocular toxocariasis
Toxocariasis is caused by a parasite (Toxocara canis)
endemic in dogs; it is also the cause o visceral Larva
migrans infection.
Human infection takes place after a person
consumes earth contaminated with parasite eggs or food
contaminated with dog feces. In the human intestine, the
egg gives rise to the nematode larva, which penetrates
the wall of the intestine. There is systemic infestation of
various organs – liver, lungs, brain and eyes – through
the bloodstream and lymphatic system.
In the eye, nematodes induce focal choroidal
inflammation and granuloma formation; if they reach
the vitreous cavity, nematodes may cause intense vitreitis
associated with choroiditis that results in endophtalmitis
(Figure 4).
Figure 4. Endophtalmitis caused by ocular toxocariasis
The most frequent clinical manifestations of ocular
toxocariasis are: chronic endophtalmitis, granulomas
in the posterior pole or peripheral granulomas.
Granulomas are whitish rounded lesion consisting of
fibrin, epithelioid cells, lymphocytes, giant cells and
numerous eosinophils. Complications may ensue, such
einstein. 2009; 7(3 Pt 1):376-82
as retinal detachment and vitreous-retinal traction
areas.
These conditions generally involve one eye only;
bilateral involvement is rare. The mean age for
presenting the disease is 7 to 8 years, ranging from 2 to
9 years; visceral Larva migrans infection, on the other
hand, occurs at ages 2 to 3 years(5). The diagnosis is
based on clinical findings and specific laboratory tests
(ELISA).
Medical therapy consists of topical or systemic
corticosteroids, depending on the degree of intraocular
inflammation. Single use of antihelminthic therapy,
such as thiabendazol, is questionable, since larval death
increases inflammation that may result in ocular damage.
It should therefore be used together with corticosteroids.
Surgery is reserved for retinal detachment cases(6).
PHPV
PHPV is a generally unilateral congenital, non-hereditary
ocular malformation that is usually not associated with
other congenital defects, except for cataract formation.
It results from persistent fetal vascularization – the
fetal hyaloids system – that usually disappears by the 8th
month of pregnancy.
In most cases, the fibrovascular membrane fed by
the persistent hyaloid artery adheres to the posterior
capsule of the crystalline. In more severe cases,
fibrovascular invasion of the crystalline may ensue,
leading to cataract, a shallow anterior chamber,
and closed angle glaucoma. Central or peripheral
retinal detachment may also be present. The most
feared complications are closed angle glaucoma
and intraocular hemorrhage, which may originate
from bleeding in the fibrovascular membrane in the
retrocrystalline space(7).
PHPV may be associated with microphthalmia. The
affected eye is generally smaller than the contralateral
eye; in some cases, this difference is only visible on
ocular ultrasound. Documenting and diagnosing
microphthalmia is important to exclude retinoblastoma,
which may occasionally be associated with PHPV.
Early therapy includes cataract surgery and removal
of the fibrovascular membrane. The prognosis for
vision depends on how much the posterior segment is
involved(8).
Optic nerve coloboma
This is a congenital disease due to an altered
embryological development of the optic nerve in about
1 of 12,000 patients. It is probably due to incomplete
closure of the embryonic cleft that develops from the
optic vesicle when the ocular globe is formed.

The clinical features are: fully or partially increased
papillary cupping, a widened papillary area, a whitish
surface, and retinal vessels entering and exiting the
borders of this defect. These findings may be associated
with coloboma of the iris and the retina(9).
Colobomas may be unilateral or bilateral; visual
acuity may range from normal to absence of light
perception. In some cases, generally adults, the
condition may be accompanied by regmatogenic retinal
detachment requiring surgery (vitrectomy through a
pars plana approach).
Various systemic conditions have been associated
with ocular colobomas, such as cardiovascular,
neurological, dermatological, gastrointestinal,
genitourinary, and musculoskeletal diseases. A classical
example is the CHARGE syndrome, which manifests
as: coloboma, cardiopathy, choanal atresia, mental
and development retardation, genital hypoplasia,
and ear malformations with hearing loss(10). Children
with colobomas should be examined systemically to
investigate these conditions.
Retinopathy of prematurity
Retinopathy of prematurity is a retinal vascular disease
of preterm newborn, especially those below 1,500 grams
and 32 weeks gestational age at birth.
Retinal vascularization is complete by 42 weeks
gestational age; thus, the peripheral retina is not fully
vascularized at birth. After birth, vascularization of the
peripheral retina proceeds normally. However, if this
process does not occur, anomalous vessels may grow
and result in retinopathy of prematurity.
In most cases, retinopathy of prematurity regresses
spontaneously, with full resolution in milder cases.
Leukocoria may be associated with more advanced
cases, when there is retinal detachment. The prognosis
of vision is poor in this phase; the most important risk
factor is extremely low birth weight.
Cryotherapy or laser photocoagulation of avascular
retina, when performed at the appropriate time, are
treatments that induce disease regression, avoiding
retinal detachment in most cases.
Coats’ disease
This is an idiopathic disease described by George Coats
in 1908. It is characterized by retinal vessel telangiectasia
and engorgement with intra- and sub-retinal exudation
(Figure 5). It is thought that exudation is due to leaking
of anomalous vessels.
Coats’ disease may present in an adult and a juvenile
form. Males are more often affected in the juvenile
form; the disease is unilateral in 80% of cases. There
Leukocoria and the red reflex test 379
Figure 5. Coats disease, presence of serous retinal detachment and intense exudation
is no race predominance or genetic transmission. The
most frequent age of diagnosis is 8 to 10 years(11).
Clinical manifestations may include poor vision,
strabismus, and leukocoria. The typical finding on the
fundus of the eye is a yellow exudate rich in lipids, and
engorged, tortuous vessels with telangiectasia, and
occasionally revascularization of retinal vessels.
This disease may progress at a variable rate. Acute
exacerbation may alternate with non-progression
periods. Spontaneous remission has been reported,
albeit rare. Generally, as the disease progresses, intense
exudation results in serous retinal detachment. In more
severe cases, the eye may undergo bulbar atrophy
(phithisis bulbi) secondary to complications such as
retinal hemorrhage and neovascular glaucoma.
The purpose of therapy is to preserve or improve
visual acuity; in advanced cases, where loss of vision
is irreparable, the aims are to preserve the remaining
retina and the eye. Interventions focus on the vascular
leakage area to obliterate vessels so that the exudate is
reabsorbed; this may be done with cryotherapy or laser
photocoagulation.
Results for vision vary, depending on the extent
of the disease and the site of retinal alterations. The
prognosis for vision is poor if the macula (central retina)
is involved.
Retinoblastoma
Retinoblastoma is a tumor that originates from
immature retinoblasts in the neural retina; it is the most
frequent intraocular tumor in children. The incidence
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380 Tamura MYY, Teixeira LF

ranges from 1/14,000 to 1/20,000 live births, depending

on the country(12). Over 90% of cases are diagnosed
before age 5 years.

Genetics
Retinoblastoma was one of the first malignancies to be
associated with genetic alterations. The retinoblastoma
gene (gene RB1) is located on the long arm of
chromosome 13 on region 14 (13q14). This is a tumor
suppressant gene that codes a protein (p RB) responsible
for controlling the cell cycle between phases G1 and S
to inhibit cell proliferation.
Tumor growth requires two mutated retinal cell Figure 6. Leukocoria due to retinoblastoma
RB alleles. These mutations are two isolated events(13).
The first mutation (or first event) may be somatic (non-
inherited) or germinal (inherited), which affects the
presentation of the disease. The second mutation is
always somatic.
Mutation of both alleles in non-inherited tumors
occurs in a single retinal cell, forming a single tumor
in one eye (unifocal and unilateral disease). This
form comprises about 60% of all cases, and generally
arises in the second year of life. The first mutation
in the inherited form of the disease occurs in a germ
cell; the mutate allele, thus, is present in all body cells,
including retinal cells. Mutation of the second allele
(second event) may take place in some of these retinal
cells and give rise to multiple tumors located in one or Figure 7. Campaign for early diagnosis of retinoblastoma, carried ou by the
both eyes of children (multifocal unilateral or bilateral Associação para Crianças e Adolescentes com Tumor Cerebral (TUCCA)
disease). This form is generally diagnosed in the first
year of life, and comprises about 40% of retinoblastoma
cases. The latter patients, having a mutated allele in all
Diagnosis
body cells, have a higher chance of developing other Early diagnosis of retinoblastoma is essential to reduce
malignancies during life, particularly if they are exposed disease morbidity and mortality. Initial lesions are
to radiation(14). more easily treated and result in a higher cure rate and
conservation of the eye and vision. Continued education
Clinical presentation of pediatricians and general ophthalmologists – and red
The most frequent clinical presentation of retinoblastoma reflex testing with dilated pupils – at maternity hospitals
is leukocoria (from 60 to 80% of cases), also known as and in routine pediatric examinations during the first
“cat’s eye reflex”(15). Leukocoria may be unilateral or three months of life are important measures for early
bilateral, according to each type of retinoblastoma in detection of retinoblastoma and other ocular diseases
children (Figures 6 and 7). in children.
Other common presentations are strabismus, red Fundus of the eye examinations should be
eyes, enlarged ocular globe due to increased intraocular done since birth in patients with a family history of
pressure, and loss of vision. Less common forms are retinoblastoma.
aseptic orbit cellulitis due to tumor necrosis, altered Most patients are referred to special care when
color of the iris (heterochromia), intraocular bleeding symptomatic. In these cases, a detailed clinical history
(vitreous or hyphema hemorrhage), and pseudo- and fundus of the eye examinations are initial and
uveitis. Retinoblastoma may be diagnosed in a routine fundamental steps for diagnosis.
examination, especially in cases with a family history of Image tests may help the diagnosis; ultrasound
the disease. provides information about the size of the lesions and
Advanced disease, where tumors invade the orbit or may find calcification within the tumor – a typical sign of
the optic nerve, may present with ocular proptosis and retinoblastoma. Magnetic resonance imaging provides
restricted eye motility. information about extraocular involvement and

einstein. 2009; 7(3 Pt 1):376-82


invasion of the optic nerve; it also helps differentiate
retinoblastoma from other ocular conditions, such as
Coats’ disease. Computed tomography is the best exam for
detecting calcium within a tumor; nevertheless, it should
be used parsimoniously, because exposure to radiation
may increase the risk of a second neoplasm, particularly
in patients with germinal retinoblastoma(16).
Invasive procedures, such as fine needle biopsies,
should not be done in suspected retinoblastoma
cases, since such procedures increase the possibility of
extraocular tumor spread, worsening the prognosis.
Classification of the intraocular disease
Use of chemotherapy in place of external beam
radiotherapy as the treatment of choice for intraocular
retinoblastoma has led to a new classification for
this disease. International efforts in 2001 generated
the International Classification for Intraocular
Retinoblastoma, which comprises five groups based
on the natural history of the disease(17). Groups A to
E reflect disease progression and the prognosis after
chemotherapy (Charts 1 and 2).
Chart 1. International Classification for Intraocular Retinoblastoma
Group A Tumors confined to the retina, located in at least 3.0 mm from the
fovea and 1.5 mm from the optic disk. Lesions smaller than 3.0 mm in
height or basal diameter. Absence of vitreous or subretinal seeding.
Group B Tumors larger than those in group A, in any site. Absence of vitreous
or subretinal seeding. Presence of subretinal fluid up to 5.0 mm from
the base of the lesion.
Group C Tumors with focal vitreous or subretinal seeding. Up to one quadrant
of subretinal fluid.
Group D Eyes with diffuse vitreous or subretinal seeding and/or significant
endophytic or exophytic disease. Avascular masses. More than one
quadrant of subretinal fluid.
Group E Eyes that have suffered definitive anatomical and functional changes.
They present one or more than the following alterations: irreversible
neovascular glaucoma; massive intraocular hemorrhage; aseptic
orbital cellulitis; tumor touching the lens; diffuse retinoblastoma;
atrophic eye.
Chart 2. Prognosis of retinoblastoma
Group A Very low risk
Group B Low risk
Group C Moderate risk
Group D High risk
Group E Very high risk eyes
Treatment
The treatment of retinoblastoma is complex and
requires a trained multidisciplinary team for healthcare
at all stages of therapy. The aims of therapy are to save
Leukocoria and the red reflex test 381
the child’s life and, secondarily, to conserve the eye and
vision.
There are different options available for each
individual case. Local and systemic factors should be
taken into account when choosing the treatment, such
as the intraocular tumor size and site, extraocular
involvement, laterality, the prognosis for vision, the
patient’s clinical status, disease spread, and others.
Current therapies of choice for intraocular
disease are chemotherapy through different routes
(endovenous, subconjunctival and intra-arterial), local
cryotherapy and lasertherapy, radiotherapy (teletherapy
and brachytherapy), and enucleation (surgical removal
of the eye)(18).
Chemoreduction has changed the approach to
retinoblastoma; it has become the first choice in most
cases(19-21). Chemoreduction may use an endovenous
approach with various drug protocols in six monthly
cycles. After the tumor is reduced, treatment may be
completed with local therapy, such as cryotherapy, laser
thermotherapy, and brachytherapy.
External beam radiotherapy is less and less used;
it is recommended in cases where tumor cells have
spread to the vitreous cavity and/or the subretinal
space that could not be controlled previously by
chemotherapy(22). Complications include ocular
alterations such as cataract, radiation retinopathy,
facial hypoplasia due to bone atrophy, and an
increased risk of a second neoplasm in patients with
germinal retinoblastomas.
Enucleation is the first treatment in patients with
advanced intraocular tumors with anatomical and
functional alterations(23). Enucleation as secondary
treatment may be used when there is no response to
the initial therapy. The eye should be removed with
the largest possible segment of the optic nerve, which is
considered the most important surgical margin.
High-dose chemotherapy and external beam
radiotherapy are the options in extraocular disease(24).
Exenteration is becoming less used in these cases.
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