Lynch -Leukocoria MOA Outline
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Transcript of 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?
Persistent Fetal Vasculature
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
Persistent Fetal Vasculature
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
Congenital/Childhood Cataract
Epidemiology Responsible for 10% all visual loss in children worldwide
Estimated: 1/250 newborns have some form of cataract
Congenital/Childhood 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
Congenital/Childhood Cataract
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
Retinopathy of Prematurity
Stage 1 Demarcation line
Goyal et al, 2012
Retinopathy of Prematurity
Stage 2 Ridge +/- small tufts of fibrovascular proliferations (popcorn)
Goyal et al, 2012
Retinopathy of Prematurity
Stage 3 Ridge with extraretinal fibrovascular proliferation
Goyal et al, 2012
Retinopathy of Prematurity
Stage 4 Subtotal retinal detachment
4a = extrafoveal 4b = foveal involvement
Goyal et al, 2012
Retinopathy of Prematurity
Stage 5 Total Retinal Detachment
Retinopathy of Prematurity
“Plus” disease Marked shunting with enlargement & tortuosity of vasculature.
Retinopathy of Prematurity
Did you know?
Retinopathy of Prematurity
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
Chorioretinal Coloboma
Congenital lesion Absence of normal retina, RPE, and choroid.
Symptoms depend on location of coloboma
Chorioretinal 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
Chorioretinal Coloboma
Did you know?
Chorioretinal Coloboma
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
Incontinentia Pigmenti
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
Incontinentia Pigmenti
CNS problems Seen in 1/3 of individuals with IP
Microcephaly, hydrocephalus, seizures, variable MR
Dental abnormalities seen in 2/3 patients.
Incontinentia Pigmenti
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)
Incontinentia Pigmenti
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
Retinopathy of Prematurity
Incontinentia Pigmenti
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.
Questions?