Nystagmus ™ Does the Baby ™ Cataracts Respond to Light? ™ CNS Disorders ™ Does the Baby Reach for Objects

10/16/2009

Ophthalmic Anomalies in the Pediatric Patient Does my child see? Mark kT T. Dun bar, ODO.D., FAAOF.A.A.O. Director of Optometric Services Optometric Residency Supervisor Bascom Palmer Eye Institute University of Miami, Miller School of Medicine Miami, Florida

Does my child see? Visual Acuity

How well does a Relatively poor in the 1st months to yrs neonate/infant of life see? Adult acuity not attained until 1-11/2 How do we yrs determine vision Well below the standard for legal in an infant or blindness neonate?

Development Birth History

Turn over by 2-3 months Birth Weight Sit-up by 5-6 months Full-term vs Premature Reach for an object by 4 months What kind of delivery Complications Play with objects in hand by 6 months ¾ During pregnancy How well does the baby respond to ¾ During delivery other stimuli (touch, sound)? Hypoxia Is the baby floppy or hypotonic? Bleeding

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Family History Visual Acuity

Night blindness Does the baby Color vision fixate while eating? High myopia Do the eyes follow the parent’s face? Nystagmus Does the baby Cataracts respond to light? CNS disorders Does the baby reach for objects

Good Vision Bad Vision

Parents will tell Parents unsure if you the baby sees baby sees well Stares at bright light Will smile at a face Nystagmus Will follow the fact of a parent Hand waving Eye poking Will fixate while eating Disinterested in the environment Failure to smile

Visual Acuity Fix and Follow

Fixate within days Fixate and Follow of birth Central Steady and Follow by 6 weeks Maintained (CSM) Babies loose target OKN (Optokinetic after 5-10° nystagmus) ¾ Pursuit movement not well established Familiar figures ¾ Watch for micro- ¾ Allen Figures saccadic eye movements

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Teller Acuity Cards Electrodiagnostic Testing Preferential Looking ERG

Rotation of the Infant OKN “Response to spin”

Answers the Assesses the vestibulo-ocular response question “Does Tests the ability to generate a saccadic my child see? ” eye movements Motor response used to assess a Slow drift of the eyes in the direction sensory function of the spin Check Fast phase, jerk nystagmus in the monocularly and opposite direction vertical

Rotation of the Infant

Two observations made: ¾ Does the child develop a nystagmus in response to vestibulo-oculi stimuli ¾ What is the time interval that the baby dampens the nystagmus when swinging stopped

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Rotation of the Infant Alignment of EOM’s

Sighted child will visually inhibit the Cover test induced nystagmus in 3-5 seconds Hirshberg ¾ Nl05Normal 0.5 mm Blind child cannot visually inhibit the nasal nystagmus and it may continue for 15- Krinsky 20 seconds ¾ Neutralizing the corneal light reflex with prism

Pupils Nystagmus

Extremely important – Never lie! Rhythmic oscillation of the eyes Dim illumination Sign of poor vision Check size, direct and consensual ¾ Un til proven oth erwi se Check for “APD” Will mimic focal neurologic disease Paradoxical pupil ¾ Constriction in dim illumination, dilation in bright illumination

Nystagmus Nystagmus

Afferent visual Cataracts pathway disease Corneal opacities Congenital (1:10) High Rx errors Focal neurologic Foveal hypoplasia disease (CNS Albinism disorders) Aniridia

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Congenital Motor Nystagmus Nystagmus

Bilateral macular scar Benign condition (Toxoplasmosis) Present at birth (or shortly after) Leber’s Pendular or jerk CSNB Symmetric ROP ON Hypoplasia Horizontal Achromatopsia Horizontal on up-gaze Dampens on convergence

Congenital Motor Paradoxical Pupil Nystagmus

Latent component Pupil constricts in darkness Null point Dilates in with bright light Head turn Seen with: Near visual acuity usually better ¾ Leber’s ¾ CSNB ¾ ON Hypoplasia

Neuro-Imaging Not Neuro-Imaging Necessary Mandatory

Poor vision Poor vision Acquired nystagmus Acquired nystagmus Sluggish pupil Brisk pupil response Normal appearing fundus Normal appearing fundus Paradoxical pupil No paradoxical pupil

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Nystagmus Nystagmus

Good case history Afferent Visual Pathway Disease Characteristics ¾ 20/200 Vision Variability ¾ If you can superimpose an OKN overtop of their nystagmus, visual prognosis is Symmetry excellent

Null point Children can be mainstreamed into Head turn regular schools Latent component

5 Month Old Work Up?

Suspected blindness or poor vision Only observation? Nystagmus noted at 6 wks of age Neuro-imaging? Sluggish pupil Electrodiagnostic testing? Cycloplegic retinoscopy + 5.00 No family Hx of nystagmus Normal appearing fundus Your Move

Leber’s Congenital 5 Month Old Amaurosis Additional Information Rod cone dystrophy Present at birth or shortly after Photophobia 10-15% of kids in schools for the blind ERG performed Poor vision ¾ Depressed in both photopic and scotopic states Nystagmus or roving eye movements Poor pupil response: Paradoxical pupil Moderate Hyperopia Autosomal recessive

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Leber’s Congenital Diagnostic Criteria Amaurosis Fundus Leber’s Congenital Amaurosis May appear normal Diagnosis of exclusion Attenuated vessels Visual dysfunction since birth 10% bilateral macular dystrophy Abnormal ERG 10% peripheral RPE changes Nystagmus or roving eye movement Optic atrophy Moderate – high hyperopia Extinguished ERG

Electrodiagnostics 6 Month Old Female

When to do in children: No fix or follow Nystagmus or poor vision from birth No nystagmus ¾ Not due to obvious afferent visual pathway Brisk pupils – No afferent pupil defect conditions No paradoxical pupil Overt, but nondiagnostic macular lesion Absent OKN Generalized retinal degeneration Normal fundus exam present or suspected What are we missing? Decreased VA of unknown cause

6 Month Old Female Cortical Blindness

Case History Loss of vision stemming from injury to the geniculostriate pathway Full term pregnancy Hypoxic insult to the posterior Cardiac surgery at 4 months pathway, occlusion of the post Cardiac arrest cerebral arteries Cannot see upon awakening

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Cortical Blindness Cortical Blindness

Generalized hypotension Positive history Cardiac surgery No visual response Birth aphyxia No Nystagmus Hypotensive crisis Absent OKN Hydrocephalus Intact pupil response Metabolic derangements No paradoxical pupil Normal fundus exam

Cortical Blindness Cortical Blindness

CNS Defects Radiologic findings Mental retardation Diffuse atrophy of the occipital cortex Cerebral palsy Bi-occipital lobe infarction Seizure disorder Periventricular leukomalacia Hydrocephaly or microcephaly Parieto-occipital “watershed” infarction

Cortical Blindness Cortical Blindness

Prognosis Work-up Transient or permanent MRI Complete restoration of VA rare CT 50% may show significant improvement ERG Recovery is slow – months to years NLP -> LP -> Color -> Form perception-> Pediatric neurological work-up All will recover some vision No tests accurate in prediction recovery

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The Wet Watery Eye The Wet Watery Eye

Nasal lacrimal duct Discharge obstruction Injection or redness (NLDO) Swe lling Viral conjunctivitis Corneal involvement Herpetic keratitis Does the eye feel hot Congenital Systemic involvement developmental anomalies

Nasal Lacrimal Duct Obstruction (NLDO) Blockage at the lower end of the nasal lacrimal duct 6% of babies Failure of canalization of the epithelial cells ¾ At the valve of Hasner Chronic epiphora, mucopurulent discharge

NLDO

80% spontaneously open by 6 months Probing after 6 months Advise parents to massage lacrimal sac ¾ Massage up to express mucous, then down to increase hydrostatic pressure May need antibiotic for 2° infection ¾ Zymar, Polytrim

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Blepharoconjunctivitis in Children

Lorena 8 ½ yo Female Rosacea: “Acne Rosacea”

3 yr history of chronic “blepharitis” Last Dr rxed Bacitracin, Polytrim X 3 wks A chronic acneiform skin disorder affecting cheeks, chin, nose, forhead, Had been on Cefaclor, Max ung, Ocuflox and eye Medical Hx unremarkable, twin Etiology: Poorly understood ¾ Sister did not have the same eye sx VA: 20/15 OU Ant Seg: L > R ¾ Mild PEE RE and SEI RE – Photos LE

Dermatologic Findings Ocular Rosacea Findings

Meibomian gland Dz Axial facial erythema/hypere ¾ Foamy tears mia Recurrent chalazia Chronic blepharitis Telangiectasis ¾ Staph blepharoconjunctivitis Papules ¾ Lid margin telangiectasia Pustules Papillae, follicules Sebaceous gland Hyperemia hypertrophy Rhinophyma

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Ocular Rosacea Findings Rosacea Keratitis

Represents more significant clinical Corneal problem vascularization Cutaneous rosacea: Sterile corneal ¾ 5-30% cornea l i nvol vement infiltrates Ocular rosacea: Corneal ulceration ¾ 75-85% corneal involvement Corneal perforation Inferior cornea usual site Episcleritis Characteristic “spade-shaped” infiltrates Scleritis Iritis

Ocular Rosacea in Ocular Rosacea in Children Children Erzurum SA, Feder RS, Greenwald MJ Rybojad BE, Deplus S, Morel P. Ann Arch of Ophthal 1993 Dermatol Venereol 1996 ¾ 3 Cases of Rosacea keratitis between 10- 10 yo girl with red painful eye X 6mo 12 yo ¾ Dxed with episcleritis ¾ Characteristic dermatologic findings Erythematous papular and pustular ¾ All had ocular Sx > 6 mo duration eruption mid face X 1 mo ¾ 2 bilateral, 1 unilateral Txed with oral antibiotics and ¾ Tx oral TCN and/or Doxycycline erythromycin

Patient Characteristics N = 20

Bilaterality 74% (usually asymmetric) Evaluation and treatment of Mean age of onset 6.3 yrs (range: 6 mos-17 yr) children with ocular rosacea Mean aggge of diagnosis 9.2 years Mean time to diagnosis 2.6 years Cornea. 2007 Jan;26(1):42-6. Gender 70% female/ 30% male Donaldson KE, Karp CL, Dunbar, MT Skin changes 40% Decreased vision 30% Family History 10% (not elicited) Mean length of follow-up 19.6 months (0-4 years)

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Symptoms Clinical Features

Redness - 65% FEATURE INCIDENCE Chronic chalazia – 40% MGD/Blepharitis 95% Pain/irritation/burning – 39% Secretions – 28% ClPthlCorneal Pathology 90% Photophobia – 22% PEE 70% Tearing – 17% Neovasc/Pannus/Scarring 80% Itching – 11% Conjunctival Hyperemia 85% Blurry vision – 5% Chalazia 40% Constant eye rubbing – 5% No complaints - 5%

Rosacea in Children Blepharokeratoconjunctivitis in Children

Submitted to AJO – Rejected Underdiagnosed chronic ¾ They didn’t believe Rosacea in inflammatory disorder observed in children really exists children Archives of Ophthal. December 2005; 123:1667-1670 Represents a spectrum of clinical Wills Eye Hospital manifestations, ranging from: Blepharokeratoconjunctivitis in Children ¾ Chronic eyelid inflammation 29 Cases (16 girls, 13 boys) ¾ Recurrent chalazia Mean age was 6 ½ y/o (range 2-12) ¾ Conjunctival and corneal phylctenules ¾ Neovascularization and scarring

Literature Ambiguous Clinical Findings

Hammersmith, K. M. et al. Arch Ophthalmol 2005;123:1667-1670 No definitive etiology in the literature Bilateral in 28/29 (97%) ¾ Significantly asymmetric in 6/29 (21%) Many terms have been given Ambylopia attributed to BKC in 2/29 (7%) including: 100% h ad eyelid i nfl ammati on ¾ Nontuberculous or staphylococcal 16/29 (55%) had superficial punctate phlyctenular disease keratitis 15/29 (52%) corneal vascularization ¾ Childhood acne rosacea Corneal infiltration 8/29 (28%) ¾ Blepharokeratitis 4 patients (14%) had classic phlyctenules ¾ Chronic blepharokeratoconjunctivitis, Corneal scarring was seen in 11/29 (38%)

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Treatment Treatment

At the Time of Diagnosis: Warm compresses were prescribed to all 11/29 (38%) topical 1% prednisone or patients 0.1% dexamethasone at the time of Dx Topppical antibiotic ointment was prescribed to 27 (97%) of 29 patients 4/29 (14%) were taking oral Oral therapy, in the form of erythromycin erythromycin (n = 21) and doxycycline (n = 1), was prescribed to 22 (76%) of 29 patients. Length of oral therapy ranged from 1 to Hammersmith, K. M. et al. Arch Ophthalmol 2005;123:1667-1670 14 months Hammersmith, K. M. et al. Arch Ophthalmol 2005;123:1667-1670

Treatment Treatment A Stepwise Approach

Step 1 – Lid Hygiene Lid Hygiene (AT, LS, HC) Step 2 – Topical Medications Erythromycin or bacitracin ung ¾ Low-dose steroids (FML, Blephamide, PF, lids hs MP) Topical Corticosteroids ¾ Antibiotic ointment (Erythromycin) Tetracycline, 250 mg. QID PO Step 3 – Systemic antibiotics Doxycycline, 50-100 mg. BID PO ¾ Erythromycin Erythromycin, 250 mg. QID PO ¾ Doxycycline Topical metroniadazole

Retinopathy of Pablo Prematurity (ROP)

24 yo Hispanic Male Vasoproliferative retinopathy that Wants contact lenses -> has always occurs principally, been nearsighted but not exclusively, Has never had good vision in premature infants VA: 20/80 RE; 20/30 LE Largest cause of RE: -17.00 -3.00 X 175 blindness < 1 yr age LE: - 15.00 -1.00 X 180

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Retinopathy of ROP Prematurity

Identified by Terry in 1942 and coined the Late 60’s early 70’s arterial blood gas name “Retrolental Fibroplasia (RLF) analysis became standard resulted in drastic decline in RDS ¾ Believed the pathologic process was proliferation of embryonic hyaloid system With the development of neonatology, ¾ 10 years became the largest cause of highest risk premature infants were childhood blindness now surviving Survival infants with BW < 1000 g 1950’s the relationship b/w supplemental O2 became understood and resulted in rigid ¾ 1950: 8% Survival

curtailment O2 -> respiratory distress (RDS) ¾ Today: >72% Survival

% of Survival < 1500 g Risk Factors for ROP

Prematurity 1960 -> 32% Low birth weight 1971 -> 39% Complex hospital course 1982 -> 63% Prolonged supplemental O2 1992 -> 75% ¾ Not a significant factor since the 1970’s 2003 -> 85% ¾ Due in part to arterial blood gas monitoring

Time for ROP ROP and Birth Weight Development Critical Window for Development of ROP BW > 1250 gms (2.75 lbs): odds are slim ¾ 10 wk interval b/w -> 32-42 weeks postconception BW < 1250 gms: 10% 95% ROP develops by 2 wks postterm, or 42 BW < 1000 gms (2.2 lbs): 75% ROP weeks postmenstrual age Screenings mandated for infants weighing < 1500g or < 28 weeks gestational age Approximately 500 new cases each year ¾ Exam should be done 4-6 weeks from birth or in US of blindness from ROP 31-33 wks postconceptional age

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Classification of ROP Unifying Principle

Not done since 1950’s The more posterior the disease process, Increased ROP -> increased survival and the greater the circumference, the of low BW neonates worse the prognos is Treatment had reared its ugly head

International ROP Classification Classification

Location Stage I: Demarcation line Extent Stage II: Ridge ¾ Clock hours Stage III: Stage ¾ Retinal fibrovascular proliferation ¾ Plus disease Stage IV: Retinal Detachment ¾ Macula-On vs Macula-Off Stage V: Total funnel RD

Stage II: Ridge

Stage I: Demarcation Line

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Stage III Stage III Plus Disease

Fibrovascular proliferation

Stage IV Macula-on vs Macula-off

Stage V Total RD

ROP Natural History Regressed ROP

High myopia (often unilateral) 90% spontaneously regress Dragging of retinal vessels 10% progress to Stage III or worse Lattice degeneration Peripheral retinal folds Vitreoretinal interface changes Retinal thinning Retinal breaks Retinal detachment

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Treatment of ROP Treatment of ROP

< Stage III threshold: monitor Controversy surrounding value of carefully Cryotherapy prompted the CRYO- ROP study 1985 Stage III threshold: Cryo vs laser Stage IV: Study stopped early as it proved the ¾ Macula on: observation weekly/biweekly value of Cryo in threshold disease ¾ Macula off: SBP ¾ 45.4% vs. 26.9 % reduction in RD, ¾ SBP 46-70% success reattaching retina Retinal folds, abnormal retinal tissue Stage V: SBP/PPV/PPL for open funnel or ¾ Blindness reduced from 61.7% to 47.1% bilateral RD’s

Treatment of ROP Treatment of Stage V ROP

Stage IV (Macular on and Macular off) Anatomical and visual results of vitreoretinal surgery for stage 5 retinopathy of prematurity Chang/Yang Retrospective study of 23 Retina. 2006 Sep;26(7):729-35 eyy(es (18 infants ) w/ Sta ge 4 A or B Tx 601 infants with stage 5 ROP in at least one with SBP eye 1977 and 2001 had surgery ¾ Segmental buckle used in 15 eyes 28% success, 5% partial success, 55% failure, ¾ 11 (79%) Achieved macular reattachment and 11% lost eye Visual function of > LP was achieved in 74% ¾ Encircling buckle used in 9 eyes of the 183 eyes with data on visual acuity ¾ 4 (44%) Achieved macular reattachment ¾ (8 of 183) achieved visual acuity better than 5/200 Ophthalmic Surg Lasers Sep-Oct 2000

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Surgical Results Natural Course of ROP

Stage IV, Mild Stage V 90% spontaneous regression 50-70% of patients have attached 10% progress to Stage III or beyond retina’s with some useful vision Excellent prognosis for Stage III threshold Stage V Good prognosis for Stage IV macula on 40-50% have some attached retina Very poor prognosis for Stage V 50% of attached retina have some Approximately 500 new cases each year useful vision in US of blindness from ROP

Pediatric Cataracts Congenital Cataract

When do you do a work-up? Nonsurgical In clinically healthy children, an management extensive peroperative evaluation is VA may improve after not necessary to establish the cause… dilation Cycloplegia Amblyopia patching therapy ¾ Patch good eye

Congenital Cataract Bilateral Cataracts

Surgical Management Operated by 8 weeks Only when visual function is jeopardized ¾ 60% > 20/60; 27% < 20/200 Bilateral Cataracts: Critical time for Operated after 8 weeks achieving binocular vision: 6-8 wks ¾ 1 in 7 achieve better than 20/200 Unilateral Cataracts: “Window of ¾ No patient with nystagmus had > 20/200 opportunity:” birth to 6 wks

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Surgical Management Historical Perspective Needling Intracapsular extraction Discision/aspiration anterior approach Lensectomy/vitrectomy Capsulotomy/Anterior vitrectomy Focal Points IOL’s AAO 1999

Pediatric Cataracts IOL’s in Pediatric When to use IOL’s? Cataracts As late as 1991 IOL in children were Why the trend towards younger ages? controversial for children < 2 yo Better, smaller more flexible PMMA IOL’s ¾ Small globe size Proven biocompatibility > 40 yrs ¾ Increased tissue reactivity Longer follow up in adults give more ¾ Marked axial length changes confidence in “capsular fixation” of IOL’s 1994 study of 234 pedi ophthalmol, Advances in surgical technology -> smaller 46% indicated implanting IOL’s in wounds etc… children Better management of anterior/posterior capsules at the time of surgery Wilson et al (1994 J Cat Refract Surg)

IOL’s in Pediatric IOL’s in Pediatric Cataracts: Outcomes Cataracts: Outcomes Hutchinson et al (1998 J Cat Refract Surg) Hutchinson et al (1998 J Cat Refract Surg) Reported on IOL children < 2 yrs of age Post op Rx error mean 1.5 D (-1.8 to 4.1) ¾22 eyes of 17 pts operated 12 d– 22 mo ¾ Shot for hypero pia ¾Axial length, complications, need for No difference rates in complications further surgery Recommended under-correcting IOL ¾Equal axial lengths power to account for myopic shift ¾Amblyopia developed in most eyes ¾ Leave kids hyperopic and anisometropic ¾ Kids still too young to accurately access VA Safe alternative to Specs and CL’s

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IOL’s in Pediatric IOL’s in Pediatric Cataracts: Outcomes Cataracts: Outcomes Peterseim/Wilson July 2000 Ophthalmology Peterseim/Wilson July 2000 Ophthalmology Bilateral CE/PCIOL 30 eyes (12 d to 13 yrs) ¾ Bilateral CE/PCIOL 30 eyes (12 d to 13 yrs) 91% VA b etter th an 20/40 ¾ 91% VA better than 20/40 Age # Pts 1st Pop F-up Last Change/ Refract mo Refraction Yr < 2 8 +6.8 D 29 +0.8 D -2.5 D/yr 2-4 3 +3.2 D 26 +1.8 D -0.8 D/yr 5-6 6 +0.8 D 27 -0.8 -0.7 D/yr

Refractive Changes Refractive Changes Following CE/IOL Following CE/IOL Crouch et al. J AAPOS, Oct 2002 Crouch et al. J AAPOS, Oct 2002 52 eyes of 42 pts developmental cats Age # Eyes F-Up Change Δ/Yr Ages 12 months – 18 years (yrs) (dioptors) 85% 20/40 or better 1-2 10 6.35 -5.96 -0.93 D ¾ 95% VA > 20/30 3-4 7 4.42 -3.66 -0.82 D 10 eyes had surgery @ 12 mo to 2 yrs 5-6 11 6.12 -3.40 -0.55 ¾ -5.96 D myopic shift 7-8 8 4.38 -2.03 -0.46

IOL’s in Pediatric IOL’s in Pediatric Cataracts: Outcomes Cataracts Becoming “Standard” for > 2 yrs old Study of 68 infants IOL’s implanted 1- ¾ Warranted unilateral cataract > 1 year old 18 months of life Still controversial for < 2 and much Follow up 7 yrs more controversial for < 1 yo ¾ Change in globe size VA average 20/40 (20/20 to 20/1200) ¾ Greater post op inflammation ¾ Despite 3.5 mm axial growth ¾ Refractive changes ¾ Unpredictability of post op refractive error Focal Points 1999 AAO makes IOL calculations difficult/unreliable

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IOL’s in Pediatric What To Do With the Cataracts Post Capsule? General Considerations Leave it or take? What IOL power to shot for? Leave it in? ¾ Emmetropia? Get more myopia later ¾ Higgpph incidence of post operative ¾ Less problems with Amblyopia now and capsular opacification -> amblyopia easier to manage Take it out? ¾ Myopia later is easier to deal with ¾ Primary posterior capsulotomy ¾ Hyperopia – expect shift toward myopia (posterior capsulorhexis) or a central ¾ Problems of amblyopia, anisometropia capsulotomy ¾ Most surgeons aim 1-3 D hyperopia Dictates where to put the IOL

IOL’s in Infants: When to Use? Silsoft Contact Lens

12 d +20 to + 32 D in 3 D steps Old, +12 to +20 in 1D steps 1day1 day Birth to 6 mo: overplus by 3 -4D4 D Post op 6 mo to 2 yrs: overplus by 1-2 D Focal > 2 yo: Plano to 1D Points AAO 1999

Retinoblastoma

Most common intraocular malignancy in childhood 90% diagnosed before 3 yo 94% sporadic cases, 6% family history 40% of all new pts have inheritable mutation All bilateral RB’s have inheritable form Autosomal dominant (80%) penetrance

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Retinoblastoma

Leukocoria (61%) Normal globe size White, gray tumor Chalky calcification Necrosis Retinal detachment

Retinoblastoma Amber

Multiple or solitary tumor(s) 7 mo old with leukocoria in both eyes ¾ Exophytic vs endophytic and strabismus for 6 weeks Total exudative retinal detachment Referred for evaluation of leukocoria Invade choroid, optic nerve -> sub- FHX: unremarkable arachnoid space -> brain 1% spontaneous regression ¾ Phthisis bulbi

Amber Amber

Bilateral, non-familial retinoblastoma External beam radiotherapy ¾ RE Stage IV, LE Stage Vb ¾ 180 cGy single daily fractions Treatment options ¾ Anterior –lateral opposed wedge pair planning ¾ External beam radiotheraphy ¾ Total treatment dose: 4500 cGy ¾ Systemic chemotherapy with focal ablation Focal laser hyperthermia/ablation ¾ Enucleation ¾ Argon Green Laser Indirect

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Genetics and Molecular Genetics and Molecular Pathophysiology Pathophysiology

Normal cell division (regulation of cell Cancer results from an irreversible growth and proliferation): imbalance of these factors tilted ¾ depends on a balance of activating and towards uncontrolled cell growth and inhibiting growth regulators proliferation

Genetics and Molecular Genetics and Molecular Pathophysiology Pathophysiology

Rb gene (RB1) located on the long arm Rb occurs when both copies of the Rb of chromosome 13 (at region 13q14) gene are mutationally inactivated ¾ It codes for Rb nucleoprotein (tumor ¾ BhBoth materna l and paterna lllll alleles of fh the suppressor protein) which normally RB gene are lost suppresses cell division ¾ So that RB protein is deficient Protein also functions to inhibit cancer

Not only in the eye, but throughout the body

Knudson’s “Two-hit” Knudson’s “Two-hit” Hypothesis Hypothesis

1 functional copy of Rb1 gene is required for normal embryogenesis Hereditary (Germline) Rb 2 normal genes provides double ¾ One Rb mutation is already present and protection therefore needs only one subsequent mutation 1 abnormal gene renders the cell susceptible to development of Rb

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Knudson’s “Two-hit” Retinoblastoma (Rb) Hypothesis The “2nd hit” inactivates the other copy Nonhereditary (Somatic): 60-70% Unlike the 1st mutation, the 2nd hit occurs ¾ Rb1 gene occurs in a single retinal cell at a higher frequency and is more sensitive to environment factors ¾ Unilateral ¾ Such as exposure to ionizing radiation ¾ No increased risk for cancers elsewhere Increases the risk of tumorigenesis Hereditary (Germline) 30-40% It occurs frequently enough during retinal ¾ Due to sporadic germline mutations development that multiple tumors occur ¾ Autosomal dominant Also tumors thought out the body

Retinoblastoma Retinoblastoma 2nd Malignant Neoplasms

Hereditary (Germline) 30-40% External beam radiotherapy is ¾ This type of mutation results in every cell associated with ↑ incidence of 2nd in the body having only 1 normal malignancy in the irradiated field chromosome (and 1 abnormal) (dose related) High risk of multiple bilateral tumors 35% of pts die by 40 yrs of age of 2nd Lifelong predisposition to cancers malignancy throughout the body ¾ Incidence is greater if radiotherapy done before 12 months of age

Retinoblastoma 2nd Malignant Neoplasms Retinoblastoma Treatment

If no external beam radiotherapy has Enucleation been administered…..by age 40 yo External beam radiation ¾ 5% of pp(atients (with Germline mutations ) Plaque brachytherapy (radiotherapy) develop second malignant neoplasms Chemoreduction Osteosarcomas of skull and long bones

Cutaneous melanoma Chemothermotherapy

Soft tissue sarcomas Combination Slight ↑ incidence of breast Ca and Cryo, Laser Hodgkin’s disease

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Rb Treatment Enucleation

Unilateral RB > ½ Retina Advanced disease with bilateral RB Advanced disease with no hope of useful vision Eyes unresponsive to all forms of Tx

RB Treatment Chemothermotherapy Plaque Radiation

Small tumors Involves IV carboplatin Unilateral RB < ½ retina Followed by transpupillary Bilateral RB thermotherapy (TTT) May use combination of other chemo- Combined effect of chemotherapy and therapeutic agents heat treatment causes tumor destruction

Chemoreduction Genetics

Combination of carboplatin, One affected child: 6% risk vincristine, and etoposide Two or more children: 50% chance Given in hopes of either controlling RB survivor with hereditary form: 50% tumor(s) or reducing size so more Linked to small arm of chromosome 13 conservative Tx method can be used Very large tumors with RD have shown a dramatic initial response

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Retinoblastoma Prognosis Trilateral Retinoblastoma

Overall 5 yr survival rate: > 92% Primitive neural ectodermal tumor Poor prognosis (PNET) ¾ Optic nerve involvement Develops in 3% of germline mutations ¾ Massive choroidal invasion Located in the pineal gland ¾ Orbital invasion ¾ May also arise in the parasellar region Survival for metastatic RB: < 6 mo Histological characteristics similar to VA 20/200 85% when macular or ON not involved retinoblastoma

Persistent Fetal Systemic Work Up Vasculature (PFV)

CT scan (follow up MRI) r/o PNET “Persistent Hyperplastic Primary Vitreous” (PHPV) LP if ON involvement Failure of the ppyrimary vitreous to Bone marrow aspiration if choroidal regress or orbital involvement Plaque of fibrous tissue adherent to the posterior lens Variable degrees of vascularization Anterior, posterior, both

PFV: Anterior PFV: Posterior

Unilateral May have all or none of the anterior Leukocoria features Microphthalmia ¾ May be isolate to posterior pole only Shallow anterior chamber Fold of condensed vitreous and retina Vascularization of the retrolental running from the disc to ora serrata membrane Retinal detachment Drawn in ciliary processes Clear lens

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PFV Management

Goal: avoid complications of glaucoma and phthisis Thank You! Enucleation should be avoided Lensectomy/Vitrectomy Management of amblyopia