Case 4

Case 4• 2 y/o, Female

1 month PTC

• Whitish reflection from left eye• Occasional right eye crossing

Case 4

Family History

• (-) Strabismus

Fundus Exam

• OD normal• OS white

retinal mass in posterior pole

Case 4

B scan shows an echo dense intra-retinal mass with posterior shadowing attached to the retina in left eye.

Clinical Impression

RETINOBLASTOMA

What is the differential diagnosis?

• Retrolental fibroplasia• Persistence of the primary vitreous• Retinal dysplasia• Coats’ disease• Nematode endophthalmitis

Retrolental Fibroplasia• Retinopathy of

Prematurity• Disturbance in the

retinal vascularization in premature infants

• May be acute or chronic• Usually bilateral, often

asymmetric• Causative role of

supplemental oxygen

Retrolental Fibroplasia• Major risk factors– Decreasing gestational age– Decreasing birth weight

• Other associated risk factors– Acidosis– Apnea– PDA– Septicemia– Blood transfusions– Intraventricular hemorrhage

Retrolental FibroplasiaClinical Manifestations

White pupil(Leukocoria

)Catarac

tGlauco

maSigns of

inflammation

Painful blind eye

Degenerated phthisical

eyeMyopia Anisom

etropia

Strabismus

Amblyopia

Nystagmus

Reference: Nelson Textbook of Pediatrics. 18th Edition. 2007.

Retrolental FibroplasiaClinical Findings

Demarcation lines

Undervascularization of the peripheral

retina

Abnormal branching,

tortuosity or straightening of retinal vessels

Retinal pigmentary

changes

Dragged disc – dragging of the

retinaEctopia of the

macula

Retinal folds Retinal breaks Total retinal detachment

Reference: Nelson Textbook of Pediatrics. 18th Edition. 2007.

Retrolental Fibroplasia

Stage Clinical Findings1 Demarcation line

2 Intraretinal ridge

3 Ridge with extraretinal fibrovascular proliferation

4 Subtotal retinal detachment

5 Total retinal detachment

Stage 1 ROP Stage 2 ROP

Stage 3 ROP

Stage 4 ROP

Stage 5 ROP

Stage 5 ROP

Retrolental FibroplasiaDiagnosis

• Recommendations– Systematic serial

ophthalmologic examinations of infants at risk

– Infants weighing <1500g at birth

– Infants born before 31 weeks AOG

– Infants weighing >1500g at birth who have an unstable clinical course

Reference: Nelson Textbook of Pediatrics. 18th Edition. 2007.

Retrolental FibroplasiaDiagnosis

• Recommendations– Initial examination should be performed

at 4th to 6th week of chronological age– ROP is diagnosed most often at 32nd to

44th week after conception.– Screening should continue until the

retina is fully vascularized, until the changes of ROP have undergone spontaneous resolution, or until appropriate treatment has been given.

Reference: Nelson Textbook of Pediatrics. 18th Edition. 2007.

Retrolental FibroplasiaTreatment

• Early Treatment of Retinopathy of Prematurity Study– Recommends treatment for infants with

Stage 2 disease with vascular tortuosity and engorgement

• Laser – treatment modality of choice• Vitrectomy and lensectomy in

cicatricial disease

References: Nelson Textbook of Pediatrics. 18th Edition. 2007. Vaughan & Asbury’s General Ophthalmology 17th Edition. 2008.

Persistent hyperplastic primary vitreous (PHPV)

• a congenital developmental anomaly of the eye resulting from failure of the embryological, primary vitreous and hyaloid vasculature to regress, whereby the eye is shorter, develops a cataract, and may present with whitening of the pupil

• children are born with a hazy, scarred vitreous, which blocks light passing to the back of the eye, leading to blurred vision

• The scarred vitreous is often stuck to the back of the lens and areas of the retina. This can damage these parts of the eye as well and lead to other eye conditions:– the lens may become hazy (cataract)– the retina may peel off the back of the

eye (retinal detachment)– the pressure in the eye can rise

(glaucoma)– the eye can be smaller than usual

(microphthalmia)

Why are some children born with PHPV?

• in children with PHPV, the first (primary) vitreous that grows in the eye fails to become clear

• it grows too much (hyperplastic) and becomes hazy and scarred

• Usually it would disappear and become clear but instead it stays (persists)

• the etiology is unknown• most cases of PHPV occur by chance, although some

cases are known to run in families• usually the condition only affects one eye

It can be present in three forms: – purely anterior (persistent tunica

vasculosa lentis and persistent posterior fetal fibrovascular sheath of the lens)

– purely posterior (falciform retinal septum and ablatio falcicormis congentia)

– combination of both

How is PHPV first suspected?

• PHPV can present in different ways. These include:– White pupil (leucocoria) – MOST COMMON

PRESENTATION– Squint (when both eyes don't appear to point in

the same direction)– Painful red eye– Blurred vision– Nystagmus

• Most children with PHPV in only one eye usually have good vision in the other. These children do not normally complain of reduced vision.

• If both a child's eyes suffer from PHPV then they are much more likely to have serious visual impairment. They may only see bright lights and large shapes. This usually allows the child to get around but may not notice kerbs and smaller objects on the floor. They are likely to recognize faces from close up and be able to play with large toys.

Treatment depends on:• Whether both eyes are affected or not and• What other eye conditions develop

• If only one eye is affected operations are avoided. The main aim is to try to preserve the eye. If the other eye has good vision it is often best not to try operations that are unlikely to offer an affected child any overall visual benefit.

• If both eyes are affected operations can be done to try to improve vision. If an eye becomes red and painful due to high pressure operations may also be needed. An operation normally tries to take away the hazy vitreous and usually the lens as well. This would let light travel through to the back of the eye without being blocked. It also helps to reduce pressure in the eye.

Retinal dysplasia

• usually a nonprogressive disease and can be caused by viral infections, drugs, vitamin A deficiency, or genetic defects

• is characterized by folds or rosettes (round clumps) of the retinal tissue

• very rare congenital, nonhereditary eye disorder, causing full or partial blindness, characterized by abnormal development of blood vessels behind the retina

• result from breakdown of the blood-retinal barrier in the endothelial cell, resulting in leakage of blood products containing cholesterol crystals and lipid-laden macrophages into the retina and subretinal space. Over time, the accumulation of this proteinaceous exudate thickens the retina, leading to massive, exudative retinal detachment.

exudative retinitis retinal telangiectasis

Patient with Coats' disease, showing conjunctival

hyperemia, mild corneal edema, posterior synechiae and cataract.

Coats’ Disease

Presentation

• Unilateral• Predominantly in young males• Peak age of onset: 6-8 years of age• Results in a gradual loss of vision• Progresses slowly• At advanced stages, retinal detachment is likely to occur• Glaucoma,atrophy, and cataracts can develop secondary to Coats’ disease• Most common sign at presentation: leukocoria• Symptoms typically begin as blurred vision, usually pronounced when one

eye is closed due to the unilateral nature of the disease• Flashes of light (photopsia and floaters) are common symptoms• One early warning sign of Coats’ disease is yellow-eye in flash photography• Coats’ disease itself is painless. Pain may occur if fluid is unable to drain

from the eye properly, causing the internal pressure to swell, resulting in painful glaucoma.

Five Stages Based on the severity of the

abnormalities that resulted from the vascular changes (1965, Gomez Morales):

Stage 1: only focal exudatesStage 2: massive intraretinal

exudationStage 3: partial exudative

retinal detachmentStage 4: total retinal

detachmentStage 5: complications

secondary to chronic retinal detachment (neovascular glaucoma)

Based selecting treatment and predicting the ocular and visual outcomes of the disease (Shields et al.):

Stage 1: retinal telangiectasiaStage 2: telangiectasia and exudation A: extrafoveal exudation B: foveal exudationStage 3: exudative retinal detachment A: subtotal detachment

1: extrafoveal2: foveal

B: total retinal detachmentStage 4: total retinal detachment and glaucomaStage 5: advanced end-stage disease

Diagnosis• Slit lamp biomicroscopy

– normal findings of anterior segment– differentiation of Coats disease from congenital cataract and

persistent hyperplastic primary vitreous • Funduscopic eye examination

– retinal vessels in early Coats' disease appear tortuous and dilated, mainly confined to the peripheral and temporal portions of retina

– moderate to severe Coat's disease, massive retinal detachment and hemorrhage from the abnormal

• Fundus examination with indirect ophthalmoscopy and detailed, large fundus drawing, fundus photography and fluorescein angiography– differentiating Coats disease from retinoblastoma.

• Ultrasound – hyperechoic mass in the posterior vitreous without posterior acoustic

shadowing; vitreous and subretinal hemorrhage• CT

– globe appears hyperdense compared to normal vitreous due to the proteinaceous exudate, which may obliterate the vitreous space in advanced disease

– anterior margin of the subretinal exudate enhances with contrast.– retina is fixed posteriorly at the optic disc, this enhancement has a V-shaped

configuration

• MRI– subretinal exudate shows high signal intensity on both T1- and T2-weighted

images– exudate may appear heterogeneous if hemorrhage or fibrosis is present– subretinal space does not enhance with gadolinium contrast.– Mild to moderate linear enhancement may be seen between the exudate and the

remaining vitreous.– exudate shows a large peak at 1-1.6 ppm onproton MR spectroscopy.

Diagnosis

Diagnosis

Computed Tomography image of a patient with Coats' disease, showing total exsudative retinal detachment in the right eye.

• Grossly– retinal detachment and yellowish subretinal

exudate containing cholesterol crystals• Microscopically– wall of retinal vessels may be thickened in some

cases, while in other cases the wall may be thinned with irregular dilatation of the lumen

– subretinal exudate consists of cholesterol crystals, macrophages laden with cholesterol and pigment, erythrocytes, and hemosiderin

– granulomatous reaction, induced by the exudate, may be seen with the retina

Diagnosis

Diagnosis

A case of Coats' disease, showing total retinal detachment with subretinal exudate containing

cholesterol crystals and a fibrous nodule in the posterior pole.

A case of Coats' disease, showing total exsudative retinal detachment, and subretinal exudate containing

cholesterol crystals (H&E).

Treatment• Stage 1 disease (telangiectasia only)

– either periodic observations or laser photocoagulation– high probability that the eye can be saved– visual prognosis is usually favorable– uncommon in a clinical practice, usually advanced at the time of diagnosis.

• Stage 2 disease (telangiectasia and exudation)– laser photocoagulation or cryotherapy, depending on the extent of the

disease and the preference of the ophthalmologist– exudation is limited to one quadrant or located nasally, a reasonably good

visual outcome– stage 2A

• visual prognosis is generally good, because the fovea is not involved by exudation.

– stage 2B• visual prognosis is relatively good if the foveal exudation is not advanced• associated with a dense yellow gray nodule centered within the foveal

exudation, the visual prognosis worsens

Treatment• Stage 3A disease (subretinal retinal detachment)

– photocoagulation or cryotherapy– Even if the retinal detachment involves fovea, it will resolve when

the telangiectasia is eradicated– subretinal fluid in the retinal detachment makes laser

photocoagulation less effective than cryotherapy.• Stage 3B disease (total retinal detachment)

– cryotherapy if the retinal detachment is shallow, but may require an attempt at surgical reattachment if the detachment is advanced and immediately posterior to the lens.

• Stage 4 disease (total retinal detachment with glaucoma)– enucleation for the severe ocular pain

• Stage 5 disease– patients have generally blind, but comfortable eye– require no aggressive treatment

TreatmentSurgical treatment– Coats disease complicated by exudative retinal

detachment– pars plana vitrectomy to drain the subretinal fluid,

thus allowing the treatment of pathologic vessels– removal of tractional vitreous membranes, mostly

invisible, can be required to reattach the retina– removal of the epiretinal membrane and

endocryocoagulation of the affected retina result in a complete resorption of subretinal fluid exudates

Nematode Endophthalmitis• Inflammatory condition of the intraocular cavities

(aqueous or vitreous humor) usually caused by infection.• Noninfectious (sterile) endophthalmitis may result from

various causes such as retained native lens material after an operation or from toxic agents

• Two types of endophthalmitis are endogenous (metastatic) and exogenous

• Endogenous endophthalmitis results from the hematogenous spread of organisms from a distant source of infection (endocarditis)

• Exogenous endophthalmitis results from direct inoculation as a complication of ocular surgery, foreign bodies, and/or blunt or penetrating ocular trauma.

PresentationSYMPTOMS• visual loss• eye pain and irritation• Headache• Photophobia• ocular changes• intense ocular and

periocular inflammation

.

PHYSICAL EXAMINATION • Eyelid swelling and erythema• Hypopyon, Vitreitis, and

Chemosis• Reduced or absent red reflex• Proptosis• Papillitis• Cotton-wool spots• Corneal edema and infection• White lesions in the choroid and

retina• Chronic uveitis and vitreal mass

and debris• Purulent discharge• Fever• Cells and flare in the anterior

chamber on slit lamp examination

Diagnosis• check of visual acuity• examine both eyes by slit lamp biomicroscopy• intraocular pressure• dilated funduscopy• ultrasonography if fundus not well visualized

help determine if a retained intraocular foreign body is present, the density of the vitreitis, and if the retina is attached or not

• routine cultures should include aerobic, anaerobic, and fungal cultures

Treatment• Once the diagnosis has been made,

or strongly considered, prompt consultation to an ophthalmologist is needed.

• Treatment depends on the underlying cause of endophthalmitis.

Onchocerciasis• nematode infection in humans that affect the eye• caused by O. volvulus.• Ocular changes

– oncintraocular microfilariae– punctate keratitis– sclerosing keratitis– anterior uveitis chorioretinitis– optic neuritis– optic atrophy– Glaucoma– river blindness.

• Diagnostic tests– skin snip– Nodulectomy– slit-lamp examination,– Mazzotti test

Onchocerciasis• Goals of pharmacotherapy: eradicate the

infestation, to reduce morbidity, and to prevent complications

• Anthelmintic agents can be used• Parasite biochemical pathways are different

from the human host; thus, toxicity is directed to the parasite, egg, or larvae.

• Ivermectin (Mectizan) 150 mcg/kg PO as single dose; may repeat q6-12mo until asymptomatic can be used for Cutaneous larva migrans (onchocerciasis)

What are the test to diagnose?

• CBC, electrolyte determination, urinalysis, liver function test to exclude other conditions cofused with retinoblastoma

• Aqueous humor enzyme level – aqueous humor lactate dehydrogenase (LDH) to serum LDH ratio

• < 1.0 in patients with ocular disease other than retinoblastoma• > 1.0 – aqueous humor for eyes with

retinoblastoma exhibits increased LDH activity

• Cranial and orbital computerized tomography – Sensitive for diagnosis and detecting

intraocular calcification – shows intraocular extent of the tumor even

in the absence of calcification. – also invaluable in assessing the CNS

anatomy, including the optic nerve, for possible extension of retinoblastoma.

• Ultrasonography – distinguishing retinoblastomas

from non-neoplastic conditions. – also useful in detecting

calcifications.• MRI

– estimating the degree of differentiation of retinoblastomas but is not as specific as computerized tomography because of its lack of sensitivity in detecting calcium.

– identifying any associated hemorrhagic or exudative retinal detachment. • seen as a localized subretinal

area of higher signal intensity compared to vitreous on both T1- and T2-weighted sequences.

MRI T1 weight contrast enhanced image of retinoblastoma (Image from Abeloff, M.D., Clinical oncology. 3rd ed. 2004, Philadelphia, Pa.: Elsevier Churchill Livingstone. xxiv, 3205.)

seen as an irregular mass lesion in the vitreous cavity with calcification. Presence of calcification is helpful in the diagnosis of retinoblastoma, but absence does not rule out retinoblastoma. On A-Scan there is irregular high reflectivity with distal shadowing.

• X-ray studies: – In areas of the world where

ultrasonography and computerized tomography are not available, x-ray studies may be the only means of identifying intraocular calcium in patients with opaque media.

• GENETIC COUNSELING– Blood specimens should be taken not only

from the patient but also from the parents and any siblings for DNA analysis

– direct method aims to find the initial mutation that precipitated the development of the tumor; then, it is determined whether that mutation is in the germline of the affected patient.

– Indirect methods can be used in cases where the initial mutation cannot be located or it is uncertain whether it exists.

• Immunohistopathologic staining– to decide whether retinoblastomas come

from a common progenitor cell capable of differentiation into either glial or neuronal cells or from neuron-committed cells.

– show an S-antigen detected in well-differentiated retinoblastomas using immunoperoxidase staining of paraffin sections

• Transmission electron microscopy– provided evidence of the presence of

photoreceptor cell elements in retinoblastoma, and a strong evidence of retinoblastoma to human fetal retina

• Patients noted to have presenting signs of retinoblastoma should undergo prompt office examination– Complete eye examination should be

performed including an estimation of the patient's visual acuity for both eyes

– A dilated fundus examination with indirect ophthalmoscopy should be completed since ancillary diagnostic studies play only a secondary role when the fundus can be visualized clearly

– A bone marrow aspiration and biopsy could be performed as well as lumbar puncture with cytocentrifuge examination for tumor cells. These may prove useful in the early diagnosis of distant spread since the primary mode of spread of retinoblastoma is hematogenous to the bone marrow and back through the optic nerve into the cerebrospinal fluid (CSF)

HISTOLOGIC FINDINGS• The classic histologic findings of

retinoblastoma are Flexner-Wintersteiner rosettes and less commonly fleurettes.

• A Homer-Wright rosette can be encountered, but they are also seen in other neuroblastic tumors

Flexner-Wintersteiner rosette is a spoke and wheel shaped cell formation seen in retinoblastoma and certain other ophthalmic tumors. A rosette is a structure or formation resembling a rose, such as the clusters of polymorphonuclear leukocytes around a globule of lipid nuclear material, as observed in the test for disseminated lupus erythematosus.The tumor cells that form the Flexner-Wintersteiner rosette surround a central lumen containing small cytoplasmic extensions of the encircling cells.It represents a specific form of tumor differentiation.

Reese-Ellsworth classification system

What is the treatment?

Treatment of Retinoblastoma

• Choosing the most appropriate cancer treatment is a decision that ideally involves the patient, family, and health care team.

• It is important to the patient’s family about the possible late effects caused by some treatments.

• Late effects of cancer treatment:– Physical problems; changes in mood, feelings,

thinking, learning or memory; second cancers– May be treated or controlled

http://www.enotalone.com/article/7563.html

ChemotherapyRadiation therapy External beam radiation therapy (EBRT)Radioactive isotope plaques

Six Types of Standard Treatment

Chemotherapy Radiation therapy

External beam radiation therapy (EBRT)Indications:

For eyes with significant vitreous seedingFor children who have progression of disease while

undergoing chemoreductionFor tumors extending up to or beyond the cut margin of

the optic nerve of an enucleated eye Advantages: incidence of local control is high and retinal

late effects are minimalDisadvantages: cessation of bone growth, 6-fold increase in

development of cancer in the patient’s lifetimeRadioactive isotope plaques

Six Types of Standard Treatment

Chemotherapy Radiation therapy External beam radiation therapy (EBRT)Radioactive isotope plaques

Advantage: locally directed treatment to the tumor, minimizing radiation to the normal tissue

Disadvantage: incomplete treatment, high dose to local sclera, significantly less irradiation for anterior lesions, and difficulty placing posterior plaques

Six Types of Standard Treatment

Enucleation Surgery to remove the eye and part of the optic nerve. This is done if the tumor is large and there is little or no chance that vision can be saved. The patient will be fitted for an artificial eye after this surgery.

Cryotherapy Uses an instrument to freeze and destroy abnormal tissue, such as carcinoma in situ; Can be used primarily for small anteriorly located tumors

Photocoagulation A procedure that uses laser light to destroy blood vessels to the tumor, causing the tumor cells to die; Can be used as primary therapy for small posteriorly located tumors

ThermotherapyUse of heat to destroy cancer cells. Thermotherapy may be given using a laser beam aimed through the dilated pupil or onto the outside of the eyeball, or using ultrasound, microwaves, or infrared radiation

Six Types of Standard Treatment

FOR THE PATIENT• Chemotherapy- initial• Enucleation- if unsuccessful

MEDICAL• Chemotherapy – Preservation of normal vision– Primary neoadjuvant chemotherapy or

chemoreduction has been the most significant recent advance in the treatment of retinoblastoma.

– Prophylactic chemotherapy is recommended if a tumor is in the optic nerve past the lamina cribrosa because these cases have a poor survival prognosis.

– Use of neoadjuvant chemotherapy has the advantage of limiting the necessity for EBRT and reducing the possibility of EBRT-related complications.

SURGICAL• Enucleation – Enucleation is performed when there is no

chance of preserving useful vision in an eye. – Treatment of choice for large

retinoblastomas– Indicated for: patients who present with

total retinal detachments and/or the posterior segment is full of the tumor, in which case it is clear the patient cannot retain any form of useful vision.