Lynch -Leukocoria MOA Outline

J E F F R E Y T . L Y N C H , M D , M P H

P E D I A T R I C O P H T H A L M O L O G Y & A D U L T S T R A B I S M U S

A S S O C I A T E D E Y E C A R E , L T D

M I N N E S O T A O P T O M E T R I C A S S O C I A T I O N M E E T I N G

F E B R U A R Y 2 , 2 0 1 3

Leukocoria: An Ominous Find

Disclosure

No financial interest to disclose

Overview

Introduction

Pre-test

Top 4 Causes

Less common causes

Post-test

Summary

Leukocoria

“White Pupil”

Lesion at or behind iris plane

Potentially vision and/or life threatening

Requires urgent assessment

Many possible causes

Pre-test

Overview

Introduction

Pre-test

Top 4 Causes

Less common causes

Post-test

Summary

Diagnosis?

Retinoblastoma

Retinoblastoma

Malignant tumor of primitive retinal cells

Epidemiology #1 primary malignant intraocular tumor of childhood.

#8 most common childhood cancer

2nd most common intraocular tumor (#1 melanoma)

Incidence: 1:20,000 births

250-300 new cases/year in USA

No gender or racial variation

+Family history in ~10%

Retinoblastoma

Age of diagnosis Typically diagnosed during 1st year of life if:

Positive family history

Bilateral disease

Typically diagnosed age 1-3

Sporadic unilateral cases

Diagnosis later than age 5 is rare

Retinoblastoma

Presentation #1 sign: Leukocoria (63% of cases)

Typically noticed by family. “Glow”, “glint”, “cat’s eye” appearance

#2 sign: Strabismus (25% of cases)

Less common presenting signs

Vitreous hemorrhage

Hyphema

Ocular/periocular inflammation

Glaucoma

Proptosis

Hypopyon

Retinoblastoma

Growth pattern Endophytic

White/cream colored mass that breaks through ILM

Sometimes associated with vitreous seeding

Seeding can resemble endophthalmitis or cause pseudohypopyon

Exophytic

Yellow-white, occur in subretinal space

Overlying retinal vessels commonly increased in caliber/tortuosity

Associated with sub-retinal fluid, which can obscure tumor

Retinoblastoma

Pathogenesis Mutational inactivation of both alleles of RB1 gene at 13q14

(Tumor suppressor gene)

Knudson’s Two Hit Model

Hereditary form – Mutation at RB1 locus already exists in all cells. Second somatic mutation occurs later leading to multifocal and bilateral tumors

Nonhereditary form - Both allelic mutations of RB1 locus arise spontaneously leading to unifocal tumor

Retinoblastoma

Spontaneous regression of retinoblastoma is possible This results in development of benign retinocytoma

This is rare

Retinoblastoma

Evaluation MRI

+ No radiation, high resolution

- Expensive, availability, no visible calcification

Ultrasound

+ No radiation, visible calcification, inexpensive

- not always available, low resolution

CT

+ Typically available, good resolution, visible calcification

- Expense, radiation exposure

Avoid aspiration of intraocular fluids disseminate malignant cells

Retinoblastoma

Retinoblastoma

Retinoblastoma

Retinoblastoma

Histopathology “Islands of blue tumor in a sea of pink necrosis”

Flexner-Winterstein Rosettes

Homer-Wright Rosettes

Flexner-Winterstein Rosettes

Retinoblastoma

Retinoblastoma

Flexner-Wintersteiner Rosettes

Homer-Wright Rosettes

Retinoblastoma

Genetics RB1 gene maps to locus within q14 band of chromosome 13

This gene codes for protein (pRB), that functions as suppressor of tumor formation

pRB binds to DNA and controls cell cycle from the G1 to S phase, thereby inhibiting cellular proliferation

Retinoblastoma

Genetics ~60% of retinoblastoma cases arise from somatic non-

hereditary mutations of both alleles of RB1 in a retinal cell

These mutations generally result in unifocal and unilateral tumors

The other 40% of cases, a mutation in 1 of the 2 alleles of RB1 either is inherited from affected parent (10%) or occurs spontaneously in one of the gametes

A second somatic mutation occurs in one or more retinal cells, resulting in multicentric and usually bilateral tumor formation.

Retinoblastoma

Genetic counseling Complex and challenging

Patient’s parents and siblings should all be examined.

In ~1% of cases, a parent may be found to have an unsuspected fundus lesion that represents spontaneously regressed retinoblastoma or retinocytoma. Genetic

counseling chart p. 395 bcbs

Retinoblastoma

Genetic Testing Available, but has limitations

Karyotype studies can identify only large deletions (only 3-5% of retinoblastoma cases

Indirect methods require 2 or more affected family members

Accuracy of indirect methods increases with exam of proband tumor-derived DNA (not always available).

Retinoblastoma

Did you know?

Retinoblastoma

Management Primary enucleation

Avoid globe manipulation, long segment of optic nerve desired

External beam radiation

Seldom used as primary treatment

Systemic chemotherapy (chemoreduction) followed by local therapy (consolidation)

Currently this is the preferred vision-sparing technique.

Choice of agents and cycles of treatment varies by institution

Retinoblastoma

Extraocular retinoblastoma Uncommon in USA

Developing countries delay in diagnosis

4 major types Optic nerve involvement Orbital invasion CNS involvement Distant metastasis

Treatment Multimodal chemotherapy External beam radiation therapy Autologous stem cell rescue.

Retinoblastoma

Trilateral retinoblastoma Primitive neuro-ectodermal tumor of the pineal gland or

parasellar region, in addition to retinoblastoma

Risk of trilateral retinoblastoma

<0.5% in unilateral retinoblastoma

5-15% in bilateral retinoblastoma

Serial MRI scans every 6 months used to screen high risk patients until age 5

Retinoblastoma

Monitoring Patients with unilateral unifocal tumors have 20% chance of

developing Rb in fellow eye

Risk diminishes with age, and is low after age 24 months

Hereditary form

Patient and siblings should be examined every 3-4 months until age 3-4, then every 6 months until age 6

General anesthesia is indicated to obtain a thorough peripheral examination.

Children > age 8 should be examined yearly in office.

Retinoblastoma

Monitoring (cont’d) Non-ocular tumors common in patients with germinal

mutations.

Incidence rate estimated 1% per year of life

Example, 30% prevalence of non-ocular tumor by age 30.

Incidence is higher in patients treated with EBR before age 1

Most common secondary tumors:

Osteogenic sarcoma of the skull & long bones

Soft tissue sarcomas

Cutaneous melanoma

Breast cancer, lung cancer, brain tumors

Hodgkins lymphoma

Diagnosis?

Coats’ Disease

Idiopathic retinal vascular abnormality Small multifocal outpouchings of the retinal vessels.

Leukocoria due to: A) Extensive yellow intraretinal and subretinal exudate

B) Exudative retinal detachment

Coats’ Disease

Usually develops in boys age 0-20

Almost always unilateral

No familial predisposition

Coats’ Disease

Did you know?

Coats’ Disease

Diagnosis Clinical

Fluorescein Angiography may be helpful

Treatment

Obliterate abnormal vessels

Cryotherapy

Laser Photocoagulation

PPV/Scleral buckle if retinal detachment occurs.

FA photo p. 618 kanski

Coats’ Disease

Prognosis Study: 22 untreated patients followed x 5 years

Disease progressed in 50%, remained stable in 50%

Study: 43 eyes, 29 treated.

Of the treated group:

8 (27.5%) deteriorated

15 (52%) stabilized

6 (20.5%) improved.

Aggressive treatment of the abnormal vessels and prolonged follow-up are recommended

Ridley et al, 1982

Diagnosis?

Toxocariasis

Nematode larvae of common intestinal ascarid Toxocara canis (dogs)

80% of puppies 2-6mos old

10-30% soil samples from public parks & playgrounds

Toxocara catis (cats)

Can also result from eating improperly cleaned foods

Kanski text 899 adult worms

Toxocariasis

Transmission Children ingest ova from dirt contaminated by dog/cat feces

Human intestine, ova larvae

Larvae migrate wall of small intestine, hematogenous spread

Toxocariasis

Did you know?

Toxocariasis

Systemic infection “Visceral larval migrans” (VLM)

Most common in children 6mos-3yrs

Asymptomatic or associated with fever, cough, malaise, hepatosplenomegaly, pneumonitis, rarely death.

Toxocariasis

Ocular involvement “Ocular toxocariasis”

Almost always unilateral

Presentation: Vision loss, strabismus, or leukocoria

Usually diagnosed between 6mos and 10 yrs age

Simultaneously with VLM or may appear years later

473 a kanski

Toxocariasis

Damage to eye Migration of motile larvae

Toxicity due to secretory products of worm

Host inflammatory response

Histopathology Intraocular larvae incite intense inflammatory reaction

Surrounded by eosinophils, mononuclear cells, histiocytes, epithelioid cells, and giant cells

This conglomeration granuloma/abscess.

p. 899 kanski b larvae tissue surrounded

Toxocariasis

Ocular findings include: Posterior pole granuloma (localized, white, elevated)

Peripheral granuloma with macular traction/dragging

Endophthalmitis

Exterior eye is almost always white and quiet

Intraocular inflammation severity varies

Mild hazy vitreous

Severe granulomatous ant uveitis, hypopyon, dense membranes.

Cataract

p. 474 kanski a, b, c, d, and b inferiorly.

Toxocariasis

Diagnosis Clinical

Ultrasound to rule out RD, short axial length, calcifications

Blood/aqueous testing for eosinophilia

ELISA testing of serum or intraocular fluid

Antibodies to the toxocara organism

p. 473 D kanski eosinophilia

Toxocariasis

Treatment Observation (if peripheral)

Periocular or systemic steroids

For posterior lesions or endophthalmitis

Surgery

For retinal traction, cataract, glaucoma

Laser photocoagulation/systemic antihelminthics with caution

Diagnosis?

Persistent Fetal Vasculature (PFV)

Developmental anomaly During 1st trimester of pregnancy, internal ocular structures

supplied by the tunic vasculosa lentis

PFV = Failure of the fetal hyaloid vascular complex to regress.

Persistent Fetal Vasulature

Usually associated with small eye If eye is not small, be suspicious of another diagnosis

Or consider elevated IOP & secondary enlargement of eye.

Rarely bilateral

No familial predilection

Persistent Fetal Vasculature

Did you know?


Mild cases Mittendorf dot

Bergmeister papillae

Severe cases (Progressive) Cataract present at birth or early in life

Progressive shallowing of anterior chamberACG

Fibrous stalk tractional retinal detachment

Iris/angle neovascularization Hemorrhages

Retina atlas photo vit stalk p. 321, retrolental mass p. 90 kanski


Diagnosis Clinical

Microphthalmia/microcornea

Ocular ultrasonography

Presence of stalk/retinal traction

Axial length

Treatment Early cataract surgery combined with membrane excision

Most surgeons prefer anterior approach

Challenging cases!

Postoperatively, typically contact lens + patching

Post-mortem p. 90 kanski, advanced case “c” tough

Diagnosis?

Congenital/Childhood Cataract

Multiple types/etiologies Isolated or part of systemic infection

Congenital or acquired

Inherited or sporadic

Unilateral or bilateral

Partial or complete

Stable or progressive


Epidemiology Responsible for 10% all visual loss in children worldwide

Estimated: 1/250 newborns have some form of cataract


Unilateral usually sporadic Workup is not typically warranted

Bilateral can be associated with systemic disease Appropriate workup guided by clinical exam

Morphology can offer clues to etiology


Management Surgery if visually significant

Timing critical

Surgery ideally performed between 4-10 weeks of age

Amblyopia therapy after surgical excision

Diagnosis?

Retinopathy of prematurity

Occurs in premature children

Screening guidelines: Birthweight <1500g

Gestational age A <28wks

Selected infants with difficult hospital course.

Retinopathy of Prematurity


Stage 1 Demarcation line

Goyal et al, 2012


Stage 2 Ridge +/- small tufts of fibrovascular proliferations (popcorn)

Goyal et al, 2012


Stage 3 Ridge with extraretinal fibrovascular proliferation

Goyal et al, 2012


Stage 4 Subtotal retinal detachment

4a = extrafoveal 4b = foveal involvement

Goyal et al, 2012


Stage 5 Total Retinal Detachment


“Plus” disease Marked shunting with enlargement & tortuosity of vasculature.


Did you know?


Treatment Cryotherapy

Laser photocoagulation

Anti-VEGF (controversial)

Pars Plana Vitrectomy/Scleral Buckle if RD occurs

Diagnosis?

Retinal Astrocytoma

A sessile/slightly elevated yellow-white retinal mass Most commonly seen in Tuberous Sclerosis

Not pathognomonic for TS

Seen occasionally in Neurofibromatosis

Retinal Astrocytoma

Tuberous Sclerosis

Classic findings (Vogt Triad)

Mental Retardation

Seizures

Facial angiofibromas (“Adenoma Sebaceum)

Other findings

Ungual fibromas

Cortical tuber

Ash leaf spots (skin)

Multiple retinal astrocytomas

Retinal Astrocytoma

Astrocytoma arises from innermost layer of retina Composed of nerve fibers and undifferentiated cells (glial)

Can be seen anywhere on retinal, posterior pole most common

Vision rarely affected significantly

Retinal Astrocytoma

Two types commonly seen Young children

Flat, gray-white in color, smooth surface with indistinct margins

Translucent & difficult to detect

Older children/adults

Sharply demarcated, elevated, irregular surface (‘Mulberry’)

Opaque, glistening, yellow-white as result of calcification

Retinal Astrocytoma

Management Observation

No evidence that # of lesions increases with age

Individual tumors have been documented to grow over time.

Diagnosis?

Chorioretinal Coloboma


Congenital lesion Absence of normal retina, RPE, and choroid.

Symptoms depend on location of coloboma


Typically located inferotemporal retina Can be unilateral or bilateral

May extend to involve the macula

May be associated with coloboma of other ocular structures along the embryonic fissure

Optic nerve

Iris

Eyelid


Did you know?


Management Observe for amblyopia, anisometropia

Observe for choroidal neovascularization at margins

Higher incidence of retinal detachment

Treatment Observation

Correct refractive error

Anti-VEGF for CNV

PPV/Buckle for RD

Cosmetic contact lens for iris coloboma

Diagnosis?

Incontinentia Pigmenti

AKA Bloch-Sulzberger syndrome Involves skin, brain and eyes

X-linked dominant (unusual inheritance pattern)

Lethal effect on hemizygous male fetus

Nearly all affected persons are female


Cutaneous lesions – distinctive 1st Phase

Erythema & bullae develop during first few days of life

Persists weeks – months

2nd Phase

Verrucous chagnes begin at ~2 months of age

Subsides after several weeks/months

3rd Phase

Clusters of small hypopigmented macules – ‘splashed paint’

Seen most commonly on trunk


CNS problems Seen in 1/3 of individuals with IP

Microcephaly, hydrocephalus, seizures, variable MR

Dental abnormalities seen in 2/3 patients.


Eye Findings in 25-33 % of cases Typically proliferative retinal vasculopathy

Resembles retinopathy of prematurity

Abnormal A-V connections

Microvascular abnormalities

Neovascular membranes

Rapid progression can lead to:

Total retinal detachment

Retrolental membrane (pseudoglioma)


Diagnosis Clinical

Corroborative skin biopsy

Management

Photocagulation

Cryotherapy

Variable success, similar outcomes to ROP treatment

Diagnosis?

Norrie’s Disease

X-linked recessive disorder (Primarily Males affected) Mutation of NDP gene

Bilateral congenital blindness associated with: Progressive hearing impairment

Mental retardation

Yellowish retinal detachment 1st days-weeks of life

Over time lens/cornea opacification, phthisis.

Diagnosis?

Myelinated Nerve Fiber Layer

Congenital, non-progressive White superficial retinal area

Frayed and feathered edges

Follows orientation of nerve fibers

Usually continuous with optic disc

Retinal vessels obscured

Usually asymptomatic Vision loss can occur from:

Macular involvement

Unilateral high myopia and amblyopia.

Diagnosis?

Aicardi Syndrome

X-linked dominant (Females only, lethal in males)

Chorioretinal lesions Round or oval, widespread, depigmented “Lacunae”

Colobomas and microphthalmos can also occur

Associated with: Agenesis of the corpus callosum on neuroimaging

Infantile spasms

Severe Mental Retardation

Post-test

Summary

Differential for Leukocoria is broad

Leukocoria – Differential

Retinoblastoma

Persistent fetal vasculature (PFV, formerly PHPV)

Coats disease

Toxocariasis

Congenital Cataract



Toxoplasmosis

Retinopathy of prematurity

Retinochoroidal coloboma

Retinal dysplasia

Juvenile retinoschisis

Norrie’s disease

Combined hamartoma of retina and RPE

Retinal detachment

Myelinated nerve fibers

Incontinentia pigmenti

Norrie disease

Retrolental Membrane

Retinal astrocytoma

Summary

History is important: Age at presentation

Birth (PFV)

1-3 years (RB)

Preschool (Coats, toxocara)

Sex

Male (Coats, Norrie’s)

Female (Incognentia Pigmenti)

Pregnancy History

Gestational age (ROP)

Maternal Health (TORCH infections)

Summary

History is important (cont’d) Birth History

Weight (ROP)

Trauma (Congenital cataract, retinal detachment, Vit hemorrhage)

Oxygen exposure (ROP)

Family History

None (PFV, Coats’, Toxocara)

Autosomal Dominant (RB)

X-linked recessive (Norrie’s disease)

X-linked dominant – Incontinentia pigmenti

Summary

Examination Unilateral

RB, PFV, Coats, Toxocara, Cataract

Bilateral

RB, ROP, cataract, Norrie’s disease, Incontinentia Pigmenti

Normal sized eye and no cataract (RB)

Microphthalmia or concomitant cataract (PFV)

Other ocular abnormalities (Norries)

Summary

Investigation Ultrasound

Acoustically solid tumor with high internal reflectivity (RB)

Calcification (RB, astrocytoma)

Stalk (PFV)

CT

Calcification (RB)

Optic nerve, orbital, CNS involvement (RB)

MRI

Detect pinealoblastoma (RB)

Optic nerve involvement (RB)

References

Kanski JJ. Clinical Ophthalmology, A systematic approach, 6th edition. Butterworth Heinemann publishers, 2006

Pediatric ophthalmology& Strabismus, BCSC section 6. American Academy of ophthalmology, 2008-2009.

Ridley ME, Shields JA, Brown GC et al. Coats’ disease. Evaluation and management. Ophthalmology. 1982;89:1381-1387

Goyal, R et al. Retinopathy of Prematurity Present Scenario. Rajasthan Journal of Ophthalmology. ROP images. Available at: [http://www.rostimes.com/2011RJO/RJO20110113.htm]

Taylor D, Hoyt CS. Pediatric ophthalmology & Strabismus, 4th Ed. El Sevier Saunders, 2012.

Wong TY. The Ophthalmology Examinations Review, 2nd Ed. World Scientific Publishing Co, 2011.

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Lynch -Leukocoria MOA Outline