VISUAL ACUITY:

You will not be able to measure the visual acuity of newborns or infants. You can use visual reflexes to indirectly assess vision:
direct and consensual pupillary constriction in response to light, blinking in response to bright light (optic blink reflex), and
blinking in response to quick movement of an object toward the eyes. During the first year of life, visual acuity sharpens as the
ability to focus improves. Infants achieve the following visual milestones:

IMPRESSION: BILATERAL RETINOBLASTOMA

Kanski 8th ed
NEURAL RETINAL TUMORS
Retinoblastoma
 is rare, occurring in up to 1:18000 live births, but is the most common primary intraocular malignancy of childhood and
accounts for about 3% of all childhood cancers. After uveal melanoma, it is the second most common malignant intraocular
tumour. Survival rates are over 95% in specialized centres, with preservation of vision in a majority of eyes, but are much
lower in the developing world.
 Tumours are composed of small basophilic cells (retinoblasts) with large hyperchromatic nuclei and scanty cytoplasm.
Many retinoblastomas are undifferentiated but varying degrees of differentiation are characterized by the formation of
structures known as rosettes (Flexner–Wintersteiner, Homer–Wright and fleurettes – Fig. 12.37A).
 Growth (Fig. 12.37B) may be endophytic (into the vitreous) with seeding of tumour cells throughout the eye, or exophytic
(into the subretinal space) leading to retinal detachment, or mixed, or the retina may be diffusely infiltrated.
 Optic nerve invasion (Fig. 12.37C) may occur, with spread of tumour along the subarachnoid space to the brain. Metastatic
spread is to regional nodes, lung, brain and bone.
 Genetics: bilateral is heritable, unilateral is non-heritable
 Clinical features
 Presentation is within the first year of life in bilateral cases and around 2 years of age if the tumour is unilateral.
 Careful enquiry about a family history of ocular tumours is critical.
 Leukocoria (white pupillary reflex) is the commonest presentation (60%) and may first be noticed in family
photographs (Fig. 12.38A).
 Strabismus is the second most common (20%); fundus examination is therefore mandatory in all cases of
childhood squint.
 Painful red eye with secondary glaucoma, which may occasionally be associated with buphthalmos (Fig. 12.38B).
 Poor vision
 Inflammation or pseudoinflammation (Figs 12.38C and D)
 Routine examination of a patient known to be at risk.
 Orbital inflammation mimicking orbital or preseptal cellulitis may occur with necrotic tumours (Fig. 12.38E).
 Orbital invasion or visible extraocular growth may occur in neglected cases (Fig. 12.38F).
 Metastatic disease involving regional lymph nodes and brain before the detection of ocular involvement is rare.
 Signs
 An intraretinal tumour is a homogeneous, dome-shaped white lesion (Fig. 12.39A) that becomes irregular, often
with white flecks of calcification.
 An endophytic tumour projects into the vitreous as a white mass that may ‘seed’ into the gel (Figs 12.39B).
 An exophytic tumour forms multilobular subretinal white masses and causes overlying retinal detachment (Figs
12.39C and D).

INVESTIGATION
 Red reflex testing with a direct ophthalmoscope is a simple screening test for leukocoria that is easily employed in the
community.
 Examination under anaesthesia includes the following:
 General examination for congenital abnormalities of the face and hands.
 Tonometry.
 Measurement of the corneal diameter.
 Anterior chamber examination with a hand-held slit lamp.
 Ophthalmoscopy, documenting all findings with colour drawings or photography.
 Cycloplegic refraction.
 US is used mainly to assess tumour size. It also detects calcification (Fig. 12.39E) within the tumour and is helpful in the
exclusion of simulating lesions such as Coats disease.
 Wide-field photography (portable if necessary) is useful for both surveying and documentation, and offers particular
advantages in the management of retinoblastoma.
 CT also detects calcification (Fig. 12.39F) but entails a significant dose of radiation so is avoided by many practitioners. Plain
X-rays may be used to detect calcification in resource-poor regions.
 MRI does not detect calcification but is useful for optic nerve evaluation, detection of extraocular extension and
pinealoblastoma, and to aid differentiation from simulating conditions.
 Systemic assessment includes physical examination and MRI scans of the orbit and skull as a minimum in high-risk cases. If
these indicate the presence of metastatic disease then bone scans, bone marrow aspiration and lumbar puncture are also
performed.
 Genetic studies on tumour tissue and blood samples from the patient and relatives.

TREATMENT
The approach to management is collaborative between the ophthalmologist, paediatric oncologist, ocular pathologist, geneticist,
allied health professionals and parents. Treatment is highly individualized.
 Chemotherapy is a mainstay of treatment in most cases, and may be used in conjunction with local treatments (focal
consolidation – see below). Intravenous carboplatin, etoposide and vincristine (CEV) are given in three to six cycles
according to the grade of retinoblastoma. Single- (carboplatin alone) or dual-agent therapy has also given favourable
results in some circumstances, such as bridging therapy to allow deferral of more aggressive measures. Selective
ophthalmic artery infusion has shown promising outcomes and study is ongoing. Intravitreal melphalan seems to be
effective for vitreous seeding, though carries a very small risk of extraocular dissemination. Sub-Tenon carboplatin injection
is now less commonly used given the availability of effective alternatives. Chemoreduction may be followed by focal
treatment with cryotherapy or TTT to consolidate tumour control.
 TTT (transpupillary thermotherapy) achieves focal consolidation following chemotherapy, or is sometimes used as an
isolated treatment. Focal techniques such as TTT and cryotherapy exert both a direct effect and probably increase
susceptibility to the effects of chemotherapy.
 Cryotherapy using a triple freeze–thaw technique is useful for pre-equatorial tumours without either deep invasion or
vitreous seeding.
 Brachytherapy using a radioactive plaque can be utilized for an anterior tumour if there is no vitreous seeding, and in other
circumstances such as resistance to chemotherapy (Fig.12.40).
 External beam radiotherapy is avoided if possible, particularly in patients with heritable retinoblastoma because of the risk
of inducing a second malignancy; retinoblastoma is highly radiation-sensitive, however. Adverse effects include cataract,
radiation neuropathy, radiation retinopathy and hypoplasia of the bony orbit.
 Enucleation is generally indicated if there is neovascular glaucoma, anterior chamber infiltration, optic nerve invasion or if
a tumour occupies more than half the vitreous volume. It is also considered if chemoreduction fails and is useful for diffuse
retinoblastoma because of a poor visual prognosis and a high risk of recurrence with other modalities. Enucleation should
be performed with minimal manipulation and it is imperative to excise a section of optic nerve to at least 10 mm.
 Extraocular extension
 Adjuvant chemotherapy consisting of a 6-month course of CEV is given subsequent to enucleation at some centres if
there is retrolaminar or massive choroidal spread.
 External beam radiotherapy is indicated when there is tumour extension to the cut end of the optic nerve at
enucleation, or extension through the sclera.
 Review. Careful review at frequent intervals is generally required following treatment, in order to detect recurrence
or the development of a new tumour, particularly in heritable disease.

DIFFERENTIAL DIAGNOSIS
 Persistent anterior fetal vasculature (persistent hyperplastic primary vitreous – see also Ch. 17) is confined to the anterior
segment and often involves the lens.
 Presentation is with leukocoria (Fig. 12.41A) involving a retrolental mass into which elongated ciliary processes are
inserted (Fig. 12.41B).
 The size and density of the retrolental fibrovascular tissue is variable (Fig. 12.41C).
 Complications include cataract (Fig. 12.41D) and angle-closure glaucoma.
 Early lens and vitreoretinal surgery may preserve useful vision in some cases.
 Persistent posterior fetal vasculature is confined to the posterior segment and the lens is usually clear.
 Presentation is with leukocoria, strabismus or nystagmus.
 A dense fold of condensed vitreous and retina extends from the optic disc to the ora serrata (Fig. 12.42).
 Treatment is not effective.
 Coats disease is almost always unilateral, more common in boys and tends to present later than retinoblastoma (R/O- avg
onset 8 y.o) (see Ch. 13)
 Retinopathy of prematurity, if advanced, may cause retinal detachment and leukocoria. Diagnosis is usually
straightforward because of the history of prematurity and low birth weight (R/O-not premature) (see Ch. 13).
 Toxocariasis. Chronic Toxocara endophthalmitis (see Ch. 11) may cause a cyclitic membrane and a white pupil. A
granuloma at the posterior pole may resemble an endophytic retinoblastoma.
 Uveitis may mimic the diffuse infiltrating type of retinoblastoma seen in older children. Conversely, retinoblastoma may be
mistaken for uveitis, endophthalmitis or orbital cellulitis.
 Vitreoretinal dysplasia is caused by faulty differentiation of the retina and vitreous that results in a detached dysplastic
retina forming a retrolental mass with leukocoria (Fig. 12.43). Other features include microphthalmos, shallowanterior
chamber and elongated ciliary processes. Dysplasia may occur in isolation or in association with systemic abnormalities:
 Norrie disease is an X-linked recessive disorder in which affected males are blind at birth or early infancy. It is caused
by mutations in the NDP gene. Systemic features include cochlear deafness and mental retardation.
 Incontinentia pigmenti is an X-linked dominant condition that is lethal in utero for boys. Mutations have been found
in the NEMO gene. It is characterized by a vesiculobullous rash on the trunk and extremities that with time is replaced
by linear pigmentation. Other features include malformation of teeth, hair, nails, bones and CNS.
 Walker–Warburg syndrome is an autosomal recessive condition characterized by absence of cortical gyri and
cerebellar malformations that may be associated with hydrocephalus and encephalocele. Neonatal death is common
and survivors suffer severe developmental delay. Apart from vitreoretinal dysplasia other ocular features include
Peters anomaly, cataract, uveal coloboma, microphthalmos and optic nerve hypoplasia.
 Other tumours
 Retinoma (retinocytoma) is a variant of retinoblastoma that generally exhibits benign behaviour but has a
genetic profile indicating premalignancy – rarely, a retinoma can undergo late transformation into a rapidly
growing retinoblastoma. It manifests as a smooth whitish dome-shaped lesion, which typically involutes
spontaneously to a calcified mass associated with RPE alteration and chorioretinal atrophy (Fig. 12.44).
 Retinal astrocytoma, which may be multifocal and bilateral (see below).

Vaughan 19th ed
MALIGNANT INTRAOCULAR TUMORS
Retinoblastoma
 is a primary malignant intraocular neoplasm that arises from immature neuroepithelial cells of the developing retina
(retinoblasts).
 Most develop within the first few years of life. Some are present at birth, and occasionally, they have been identified by
prenatal imaging
 Pathologically, retinoblastoma is composed of small round neoplastic cells that invade and replace the normal retina.
 Individual tumor cells tend to have a large nucleus and disproportionately small amount of cytoplasm.
 Intralesional necrosis and foci of calcification are usually evident.
 Clinically retinoblastoma can affect one eye (usually unifocal) or both eyes (usually multifocally). Most individuals with
bilateral and/or multifocal retinoblastoma have a functionally significant mutation or deletion involving one allele of the
retinoblastoma gene (a tumor suppressor gene localized to the long arm of chromosome 13 that is normally responsible for
production of a nuclear phosphoprotein with DNA binding activity) in most, if not all, of their cells, in which case
retinoblastoma is transmitted as an autosomal dominant condition with approximately 90–95% penetrance.
 Children of such individuals have a nearly 50% chance of having the disease, and regular screening until the child has been
shown by genetic testing not to be at risk is important in the early detection of tumors.
 Most individuals with unilateral, unifocal retinoblastoma do not have a germline mutation in the retinoblastoma gene and
will not transmit the disease to their offspring.
 Recognized risk factors for occurrence of retinoblastoma include a positive family history and chromosome 13q deletion
syndrome.
 Unaffected parents who have produced one child with retinoblastoma have a 4–7% risk of having a subsequent child with
the disease. Sequencing of the gene allows identification of carriers and hence more specific genetic counseling.
 The typical small retinoblastoma appears as a translucent to dull white retinal nodule (Figure 10–42). As the tumor gets
larger, it attracts dilated tortuous afferent and efferent retinal blood vessels and develops a fine network of capillaries on
its surface (Figure 10–43).
 Larger discrete retinal tumors tend to develop intralesional foci of degenerative calcification, which usually can be detected
by B-scan ultrasonography and computed tomography scanning.
 Exudative retinal detachment develops around the tumor and can become extensive. Eventually tumor cells are shed from
the surface of the tumor into the surrounding subretinal fluid and/or overlying vitreous (Figure 10–44), and these tumor
“seeds” can implant on the retina, ciliary body, zonule, or posterior surface of the iris, and even extend into the anterior
chamber to implant on the anterior surface of the iris and trabecular meshwork.
 In eyes with extensive retinoblastoma, secondary iris neovascularization and neovascular glaucoma develop frequently.
 Retinoblastoma has a tendency to invade the optic disk and extend into the orbital optic nerve, invade the choroid with
possible hematogenous dissemination, and extend transsclerally to the orbit via scleral vascular and neural foramina into
the orbit. Once retinoblastoma extends outside the eye, it tends to grow aggressively in the periocular tissues, extend via
the optic nerve to the brain, and rapidly metastasize widely.
 Untreated, children with metastatic retinoblastoma rarely survive for more than 1 year.
 Retinoblastoma in children with a positive family history is frequently identified by screening examinations when the extent
of intraocular disease is limited (ie, few tumors, small tumors, and no vitreous seeds). In contrast, retinoblastoma in
 children with unilateral and/or nonfamilial retinoblastoma is usually not detected until the parents or pediatrician note a
white pupil (“leukocoria”; Figure 10–45) due to external light reflecting off the white intraocular tumor, strabismus due to
impaired vision in one or both eyes, or discoloration of the iris due to iris neovascularization.
 In most developed countries, the median age at initial diagnosis of retinoblastoma is about 12 months for bilateral cases
and about 24 months for unilateral cases. In countries with limited health care services, the median age at detection of
both groups tends to be substantially higher.

MANAGEMENT
 For a child with purely intraocular retinoblastoma, the recommended initial treatment depends on the number, size,
locations, and types (primary intraretinal tumors, tumor seeds, implantation tumors) of intraocular tumors; the visual
status and potential of the affected eye(s); whether the disease is unilateral or bilateral; the types and severity of
secondary abnormalities of the eye (eg, retinal detachment, iris neovascularization); the general health of the child; and
available technologies and resources.
 Because some children with familial and/or bilateral-multifocal retinoblastoma develop an independent retinoblastoma-
like malignant neoplasm in the brain (pineoblastoma or ectopic intracranial retinoblastoma) and because of the propensity
for retinoblastoma to extend extraocularly via the optic nerve and sclera, if available, magnetic resonance imaging of the
orbits and brain is performed routinely prior to treatment.
 Children with one or a few small discrete extramacular tumors, without associated tumor seeding or subretinal fluid, are
typically managed by focal laser therapy (postequatorial tumors) and/or focal cryotherapy (peripheral tumors).
 Children with a solitary medium-sized intraretinal tumor in one or both eyes may be managed initially by plaque radiation
therapy.
 Most children with one or more larger tumors, macular or juxtapapillary tumor, extensive nonrhegmatogenous retinal
detachment, and/or subretinal and/or intravitreal tumor seeds at baseline are currently treated initially by intravenous
chemotherapy or selective ophthalmic artery infusion chemotherapy, supplemented by focal obliterative therapies to the
residual tumors once the original tumors have shrunken and the retinal detachment has diminished or resolved.
 Fractionated external beam radiation therapy (EBRT), once the mainstay of treatment for bilateral retinoblastoma, is now
generally reserved for eyes with residual or recurrent retinoblastoma following intravenous chemotherapy or selective
ophthalmic artery infusion chemotherapy supplemented by local obliterative therapies and possibly intravitreal injections
of chemotherapeutic drugs.
 Some eyes with extensive intraocular retinoblastoma, particularly ones that are blind and painful, have neovascular
glaucoma or have extensive intraocular bleeding and/or ocular congestion, and eyes that have failed to respond to eye-
preserving therapies are managed by enucleation.
 Any eye enucleated for retinoblastoma must undergo histopathologic examination for optic nerve invasion, transscleral
tumor extension to the orbit, massive choroidal invasion, and other adverse prognostic factors for subsequent orbital
tumor relapse or metastasis that may prompt postenucleation adjuvant chemotherapy or orbital radiotherapy.
 Initial treatment for a child with regional extraocular extension of retinoblastoma but no intracranial invasion or evident
metastasis is being determined by a number of cooperative oncology group studies. Currently the most common treatment
is enucleation of the affected eye followed by intensive chemotherapy and orbital irradiation.
 Initial treatment for children with metastatic retinoblastoma or retinoblastoma-associated pineoblastoma is intensive
intravenous chemotherapy, surgical debulking of the residual intracranial and/or extracranial tumor(s), focal adjuvant
radiation therapy to residual disease, and bone marrow transplantation. Although there have been some lasting cures of
children with extracranial metastasis, there have been few, if any, cures of children with intracranial extension or
metastasis of retinoblastoma or pineoblastoma.