Ophthalmic Anomalies in the Pediatric Patient Mark T. Dunbar, O.D., F.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? Does my child see? How well does a neonate/infant see? How do we determine vision in an infant or neonate? Visual Acuity Relatively poor in the 1st months to yrs of life Adult acuity not attained until 1-11/2 yrs Well below the standard for legal blindness Development Turn over by 2-3 months Sit-up by 5-6 months Reach for an object by 4 months Play with objects in hand by 6 months How well does the baby respond to other stimuli (touch, sound)? Is the baby floppy or hypotonic? Birth History Birth Weight Full-term vs Premature What kind of delivery Complications ¾ During pregnancy ¾ During delivery Hypoxia Bleeding Family History Night blindness Color vision High myopia Nystagmus Cataracts CNS disorders Visual Acuity Does the baby fixate while eating? Do the eyes follow the parent’s face? Does the baby respond to light? Does the baby reach for objects Good Vision Parents will tell you the baby sees well Will smile at a face Will follow the fact of a parent Will fixate while eating Bad Vision Parents unsure if baby sees Stares at bright light Nystagmus Hand waving Eye poking Disinterested in the environment Failure to smile Visual Acuity Fixate and Follow Central Steady and Maintained (CSM) OKN (Optokinetic nystagmus) Familiar figures ¾ Allen Figures Fix and Follow Fixate within days of birth Follow by 6 weeks Babies loose target after 5-10° Pursuit movement not well established ¾ Watch for microsaccadic eye movements ¾ Teller Acuity Cards Preferential Looking Electrodiagnostic Testing ERG OKN Answers the question “Does my child see?” Motor response used to assess a sensory function Check monocularly and vertical Rotation of the Infant “Response to spin” Assesses the vestibulo-ocular response Tests the ability to generate a saccadic eye movements Slow drift of the eyes in the direction of the spin Fast phase, jerk nystagmus in the opposite direction 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 Rotation of the Infant Sighted child will visually inhibit the induced nystagmus in 3-5 seconds Blind child cannot visually inhibit the nystagmus and it may continue for 1520 seconds Alignment of EOM’s Cover test Hirshberg ¾ Normal 0.5 mm nasal Krinsky ¾ Neutralizing the corneal light reflex with prism Pupils Extremely important – Never lie! Dim illumination Check size, direct and consensual Check for “APD” Paradoxical pupil ¾ Constriction in dim illumination, dilation in bright illumination Nystagmus Rhythmic oscillation of the eyes Sign of poor vision ¾ Until Will proven otherwise mimic focal neurologic disease Nystagmus Afferent visual pathway disease Congenital (1:10) Focal neurologic disease (CNS disorders) Nystagmus Cataracts Corneal opacities High Rx errors Foveal hypoplasia Albinism Aniridia Nystagmus Bilateral macular scar (Toxoplasmosis) Leber’s CSNB ROP ON Hypoplasia Achromatopsia Congenital Motor Nystagmus Benign condition Present at birth (or shortly after) Pendular or jerk Symmetric Horizontal Horizontal on up-gaze Dampens on convergence Congenital Motor Nystagmus Latent component Null point Head turn Near visual acuity usually better Paradoxical Pupil Pupil constricts in darkness Dilates in with bright light Seen with: ¾ Leber’s ¾ CSNB ¾ ON Hypoplasia Neuro-Imaging Not Necessary Poor vision Acquired nystagmus Sluggish pupil Normal appearing fundus Paradoxical pupil Neuro-Imaging Mandatory Poor vision Acquired nystagmus Brisk pupil response Normal appearing fundus No paradoxical pupil Nystagmus Good case history Characteristics Variability Symmetry Null point Head turn Latent component Nystagmus Afferent ¾ 20/200 Visual Pathway Disease Vision ¾ If you can superimpose an OKN overtop of their nystagmus, visual prognosis is excellent Children can be mainstreamed into regular schools 5 Month Old Suspected blindness or poor vision Nystagmus noted at 6 wks of age Sluggish pupil Cycloplegic retinoscopy + 5.00 No family Hx of nystagmus Normal appearing fundus Your Move Work Up? Only observation? Neuro-imaging? Electrodiagnostic testing? 5 Month Old Additional Information Photophobia ERG performed ¾ Depressed states in both photopic and scotopic Leber’s Congenital Amaurosis Rod cone dystrophy Present at birth or shortly after 10-15% of kids in schools for the blind Poor vision Nystagmus or roving eye movements Poor pupil response: Paradoxical pupil Moderate Hyperopia Autosomal recessive Leber’s Congenital Amaurosis Fundus May appear normal Attenuated vessels 10% bilateral macular dystrophy 10% peripheral RPE changes Optic atrophy Extinguished ERG Diagnostic Criteria Leber’s Congenital Amaurosis Diagnosis of exclusion Visual dysfunction since birth Abnormal ERG Nystagmus or roving eye movement Moderate – high hyperopia Electrodiagnostics When to do in children: Nystagmus or poor vision from birth ¾ Not due to obvious afferent visual pathway conditions Overt, but nondiagnostic macular lesion Generalized retinal degeneration present or suspected Decreased VA of unknown cause 6 Month Old Female No fix or follow No nystagmus Brisk pupils – No afferent pupil defect No paradoxical pupil Absent OKN Normal fundus exam What are we missing? 6 Month Old Female Case History Full term pregnancy Cardiac surgery at 4 months Cardiac arrest Cannot see upon awakening Cortical Blindness Loss of vision stemming from injury to the geniculostriate pathway Hypoxic insult to the posterior pathway, occlusion of the post cerebral arteries Cortical Blindness Generalized hypotension Cardiac surgery Birth aphyxia Hypotensive crisis Hydrocephalus Metabolic derangements Cortical Blindness Positive history No visual response No Nystagmus Absent OKN Intact pupil response No paradoxical pupil Normal fundus exam Cortical Blindness CNS Defects Mental retardation Cerebral palsy Seizure disorder Hydrocephaly or microcephaly Cortical Blindness Radiologic findings Diffuse atrophy of the occipital cortex Bi-occipital lobe infarction Periventricular leukomalacia Parieto-occipital “watershed” infarction Cortical Blindness Prognosis Transient or permanent Complete restoration of VA rare 50% may show significant improvement Recovery is slow – months to years NLP -> LP -> Color -> Form perception-> All will recover some vision No tests accurate in prediction recovery Cortical Blindness Work-up MRI CT ERG Pediatric neurological work-up The Wet Watery Eye Nasal lacrimal duct obstruction (NLDO) Viral conjunctivitis Herpetic keratitis Congenital developmental anomalies The Wet Watery Eye Discharge Injection or redness Swelling Corneal involvement Does the eye feel hot Systemic involvement 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 Blepharoconjunctivitis in Children Lorena 8 ½ yo Female 3 yr history of chronic “blepharitis” Last Dr rxed Bacitracin, Polytrim X 3 wks Had been on Cefaclor, Max ung, Ocuflox Medical Hx unremarkable, twin 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 Rosacea: “Acne Rosacea” A chronic acneiform skin disorder affecting cheeks, chin, nose, forhead, and eye Etiology: Poorly understood Dermatologic Findings Axial facial erythema/hypere mia Telangiectasis Papules Pustules Sebaceous gland hypertrophy Rhinophyma Ocular Rosacea Findings Meibomian gland Dz ¾ Recurrent chalazia Chronic blepharitis ¾ ¾ Foamy tears Staph blepharoconjunctivitis Lid margin telangiectasia Papillae, follicules Hyperemia Ocular Rosacea Findings Corneal vascularization Sterile corneal infiltrates Corneal ulceration Corneal perforation Episcleritis Scleritis Iritis Rosacea Keratitis Represents more significant clinical problem Cutaneous rosacea: ¾ 5-30% corneal involvement Ocular rosacea: ¾ 75-85% corneal involvement Inferior cornea usual site Characteristic “spade-shaped” infiltrates Ocular Rosacea in Children Erzurum SA, Feder RS, Greenwald MJ Arch of Ophthal 1993 ¾ 3 Cases of Rosacea keratitis between 1012 yo ¾ Characteristic dermatologic findings ¾ All had ocular Sx > 6 mo duration ¾ 2 bilateral, 1 unilateral ¾ Tx oral TCN and/or Doxycycline Ocular Rosacea in Children Rybojad BE, Deplus S, Morel P. Ann Dermatol Venereol 1996 10 yo girl with red painful eye X 6mo ¾ Dxed with episcleritis Erythematous papular and pustular eruption mid face X 1 mo Txed with oral antibiotics and erythromycin Evaluation and treatment of children with ocular rosacea Cornea. 2007 Jan;26(1):42-6. Donaldson KE, Karp CL, Dunbar, MT Patient Characteristics N = 20 Bilaterality Mean age of onset Mean age of diagnosis Mean time to diagnosis Gender Skin changes Decreased vision Family History Mean length of follow-up 74% (usually asymmetric) 6.3 yrs (range: 6 mos-17 yr) 9.2 years 2.6 years 70% female/ 30% male 40% 30% 10% (not elicited) 19.6 months (0-4 years) Symptoms Redness - 65% Chronic chalazia – 40% Pain/irritation/burning – 39% Secretions – 28% Photophobia – 22% Tearing – 17% Itching – 11% Blurry vision – 5% Constant eye rubbing – 5% No complaints - 5% Clinical Features FEATURE MGD/Blepharitis Corneal Pathology PEE Neovasc/Pannus/Scarring Conjunctival Hyperemia Chalazia INCIDENCE 95% 90% 70% 80% 85% 40% Rosacea in Children Submitted to AJO – Rejected ¾ They didn’t believe Rosacea in children really exists Archives of Ophthal. December 2005; 123:1667-1670 Wills Eye Hospital Blepharokeratoconjunctivitis in Children 29 Cases (16 girls, 13 boys) Mean age was 6 ½ y/o (range 2-12) Blepharokeratoconjunctivitis in Children Underdiagnosed chronic inflammatory disorder observed in children Represents a spectrum of clinical manifestations, ranging from: ¾ Chronic eyelid inflammation ¾ Recurrent chalazia ¾ Conjunctival and corneal phylctenules ¾ Neovascularization and scarring Literature Ambiguous No definitive etiology in the literature Many terms have been given including: or staphylococcal phlyctenular disease ¾ Childhood acne rosacea ¾ Blepharokeratitis ¾ Chronic blepharokeratoconjunctivitis, ¾ Nontuberculous Clinical Findings Hammersmith, K. M. et al. Arch Ophthalmol 2005;123:1667-1670 Bilateral in 28/29 (97%) ¾ Significantly asymmetric in 6/29 (21%) Ambylopia attributed to BKC in 2/29 (7%) 100% had eyelid inflammation 16/29 (55%) had superficial punctate keratitis 15/29 (52%) corneal vascularization Corneal infiltration 8/29 (28%) 4 patients (14%) had classic phlyctenules Corneal scarring was seen in 11/29 (38%) Treatment At the Time of Diagnosis: 11/29 (38%) topical 1% prednisone or 0.1% dexamethasone at the time of Dx 4/29 (14%) were taking oral erythromycin Hammersmith, K. M. et al. Arch Ophthalmol 2005;123:1667-1670 Treatment Warm compresses were prescribed to all patients Topical antibiotic ointment was prescribed to 27 (97%) of 29 patients Oral therapy, in the form of erythromycin (n = 21) and doxycycline (n = 1), was prescribed to 22 (76%) of 29 patients. Length of oral therapy ranged from 1 to 14 months Hammersmith, K. M. et al. Arch Ophthalmol 2005;123:1667-1670 Treatment A Stepwise Approach Step 1 – Lid Hygiene Step 2 – Topical Medications ¾ Low-dose steroids (FML, Blephamide, PF, MP) ¾ Antibiotic ointment (Erythromycin) Step 3 – Systemic antibiotics ¾ Erythromycin ¾ Doxycycline Treatment Lid Hygiene (AT, LS, HC) Erythromycin or bacitracin ung lids hs Topical Corticosteroids Tetracycline, 250 mg. QID PO Doxycycline, 50-100 mg. BID PO Erythromycin, 250 mg. QID PO Topical metroniadazole Pablo 24 yo Hispanic Male Wants contact lenses -> has always been nearsighted Has never had good vision VA: 20/80 RE; 20/30 LE RE: -17.00 -3.00 X 175 LE: - 15.00 -1.00 X 180 Retinopathy of Prematurity (ROP) Vasoproliferative retinopathy that occurs principally, but not exclusively, in premature infants Largest cause of blindness < 1 yr age Retinopathy of Prematurity Identified by Terry in 1942 and coined the name “Retrolental Fibroplasia (RLF) ¾ Believed the pathologic process was proliferation of embryonic hyaloid system ¾ 10 years became the largest cause of childhood blindness 1950’s the relationship b/w supplemental O2 became understood and resulted in rigid curtailment O2 -> respiratory distress (RDS) ROP Late 60’s early 70’s arterial blood gas analysis became standard resulted in drastic decline in RDS With the development of neonatology, highest risk premature infants were now surviving Survival infants with BW < 1000 g ¾ 1950: 8% Survival ¾ Today: >72% Survival % of Survival < 1500 g 1960 -> 32% 1971 -> 39% 1982 -> 63% 1992 -> 75% 2003 -> 85% Risk Factors for ROP Prematurity Low birth weight Complex hospital course Prolonged supplemental O2 ¾ Not a significant factor since the 1970’s ¾ Due in part to arterial blood gas monitoring Time for ROP Development Critical Window for Development of ROP ¾ 10 wk interval b/w -> 32-42 weeks postconception 95% ROP develops by 2 wks postterm, or 42 weeks postmenstrual age Screenings mandated for infants weighing < 1500g or < 28 weeks gestational age ¾ Exam should be done 4-6 weeks from birth or 31-33 wks postconceptional age ROP and Birth Weight BW > 1250 gms (2.75 lbs): odds are slim BW < 1250 gms: 10% BW < 1000 gms (2.2 lbs): 75% ROP Approximately 500 new cases each year in US of blindness from ROP Classification of ROP Not done since 1950’s Increased ROP -> increased survival of low BW neonates Treatment had reared its ugly head Unifying Principle The more posterior the disease process, and the greater the circumference, the worse the prognosis International Classification Location Extent ¾ Clock hours Stage ROP Classification Stage I: Stage II: Stage III: Demarcation line Ridge ¾ Retinal fibrovascular proliferation ¾ Plus disease Stage IV: ¾ Macula-On Stage V: Retinal Detachment vs Macula-Off Total funnel RD Stage I: Demarcation Line Stage II: Ridge Stage III Fibrovascular proliferation Stage III Plus Disease Stage IV Macula-on vs Macula-off Stage V Total RD ROP Natural History 90% spontaneously regress 10% progress to Stage III or worse Regressed ROP High myopia (often unilateral) Dragging of retinal vessels Lattice degeneration Peripheral retinal folds Vitreoretinal interface changes Retinal thinning Retinal breaks Retinal detachment Treatment of ROP Controversy surrounding value of Cryotherapy prompted the CRYOROP study 1985 Study stopped early as it proved the value of Cryo in threshold disease ¾ 45.4% vs. 26.9 % reduction in RD, Retinal folds, abnormal retinal tissue ¾ Blindness reduced from 61.7% to 47.1% Treatment of ROP < Stage III threshold: monitor carefully Stage III threshold: Cryo vs laser Stage IV: ¾ Macula on: observation weekly/biweekly ¾ Macula off: SBP ¾ SBP Stage 46-70% success reattaching retina V: SBP/PPV/PPL for open funnel or bilateral RD’s Treatment of ROP Stage IV (Macular on and Macular off) Chang/Yang Retrospective study of 23 eyes (18 infants) w/ Stage 4 A or B Tx with SBP ¾ Segmental ¾ 11 ¾ buckle used in 15 eyes (79%) Achieved macular reattachment Encircling buckle used in 9 eyes ¾4 (44%) Achieved macular reattachment Ophthalmic Surg Lasers Sep-Oct 2000 Treatment of Stage V ROP Anatomical and visual results of vitreoretinal surgery for stage 5 retinopathy of prematurity Retina. 2006 Sep;26(7):729-35 601 infants with stage 5 ROP in at least one eye 1977 and 2001 had surgery 28% success, 5% partial success, 55% failure, and 11% lost eye Visual function of > LP was achieved in 74% of the 183 eyes with data on visual acuity ¾ (8 of 183) achieved visual acuity better than 5/200 Surgical Results Stage IV, Mild Stage V 50-70% of patients have attached retina’s with some useful vision Stage V 40-50% have some attached retina 50% of attached retina have some useful vision Natural Course of ROP 90% spontaneous regression 10% progress to Stage III or beyond Excellent prognosis for Stage III threshold Good prognosis for Stage IV macula on Very poor prognosis for Stage V Approximately 500 new cases each year in US of blindness from ROP Pediatric Cataracts When do you do a work-up? In clinically healthy children, an extensive peroperative evaluation is not necessary to establish the cause… Congenital Cataract Nonsurgical management VA may improve after dilation Cycloplegia Amblyopia patching therapy ¾ Patch good eye Congenital Cataract Surgical Management Only when visual function is jeopardized Bilateral Cataracts: Critical time for achieving binocular vision: 6-8 wks Unilateral Cataracts: “Window of opportunity:” birth to 6 wks Bilateral Cataracts Operated ¾ 60% > 20/60; 27% < 20/200 Operated ¾1 by 8 weeks after 8 weeks in 7 achieve better than 20/200 ¾ No patient with nystagmus had > 20/200 Surgical Management Historical Perspective Needling Intracapsular extraction Discision/aspiration anterior approach Lensectomy/vitrectomy Capsulotomy/Anterior vitrectomy IOL’s Focal Points AAO 1999 Pediatric Cataracts When to use IOL’s? As late as 1991 IOL in children were controversial for children < 2 yo ¾ Small globe size ¾ Increased tissue reactivity ¾ Marked axial length changes 1994 study of 234 pedi ophthalmol, 46% indicated implanting IOL’s in children Wilson et al (1994 J Cat Refract Surg) IOL’s in Pediatric Cataracts Why the trend towards younger ages? Better, smaller more flexible PMMA IOL’s Proven biocompatibility > 40 yrs Longer follow up in adults give more confidence in “capsular fixation” of IOL’s Advances in surgical technology -> smaller wounds etc… Better management of anterior/posterior capsules at the time of surgery IOL’s in Pediatric Cataracts: Outcomes Hutchinson et al (1998 J Cat Refract Surg) Reported on IOL children < 2 yrs of age ¾ 22 eyes of 17 pts operated 12 d– 22 mo ¾ Axial length, complications, need for further surgery ¾ Equal axial lengths ¾ Amblyopia developed in most eyes ¾ Kids still too young to accurately access VA IOL’s in Pediatric Cataracts: Outcomes Hutchinson et al (1998 J Cat Refract Surg) Post op Rx error mean 1.5 D (-1.8 to 4.1) ¾ Shot for hyperopia No difference rates in complications Recommended under-correcting IOL power to account for myopic shift ¾ Leave Safe kids hyperopic and anisometropic alternative to Specs and CL’s IOL’s in Pediatric Cataracts: Outcomes Peterseim/Wilson July 2000 Ophthalmology ¾ Bilateral CE/PCIOL 30 eyes (12 d to 13 yrs) ¾ 91% VA better than 20/40 IOL’s in Pediatric Cataracts: Outcomes Peterseim/Wilson July 2000 Ophthalmology Bilateral CE/PCIOL 30 eyes (12 d to 13 yrs) 91% VA better than 20/40 Age # Pts 1st Pop F-up Last <2 2-4 5-6 8 3 6 Refract mo Refraction Change/ Yr +6.8 D 29 +3.2 D 26 +0.8 D 27 +0.8 D +1.8 D -0.8 -2.5 D/yr -0.8 D/yr -0.7 D/yr Refractive Changes Following CE/IOL Crouch et al. J AAPOS, Oct 2002 52 eyes of 42 pts developmental cats Ages 12 months – 18 years 85% 20/40 or better ¾ 95% 10 VA > 20/30 eyes had surgery @ 12 mo to 2 yrs ¾ -5.96 D myopic shift Refractive Changes Following CE/IOL Crouch et al. J AAPOS, Oct 2002 Age # Eyes 1-2 10 F-Up (yrs) 6.35 Change Δ/Yr -5.96 -0.93 D 3-4 7 4.42 -3.66 -0.82 D 5-6 11 6.12 -3.40 -0.55 7-8 8 4.38 -2.03 -0.46 (dioptors) IOL’s in Pediatric Cataracts: Outcomes Study of 68 infants IOL’s implanted 118 months of life Follow up 7 yrs VA average 20/40 (20/20 to 20/1200) ¾ Despite 3.5 mm axial growth Focal Points 1999 AAO Becoming IOL’s in Pediatric Cataracts “Standard” for > 2 yrs old ¾ Warranted unilateral cataract > 1 year old Still controversial for < 2 and much more controversial for < 1 yo ¾ Change in globe size ¾ Greater post op inflammation ¾ Refractive changes ¾ Unpredictability of post op refractive error makes IOL calculations difficult/unreliable IOL’s in Pediatric Cataracts General Considerations What IOL power to shot for? ¾ Emmetropia? Get more myopia later ¾ Less problems with Amblyopia now and easier to manage ¾ Myopia later is easier to deal with ¾ Hyperopia ¾ Problems – expect shift toward myopia of amblyopia, anisometropia ¾ Most surgeons aim 1-3 D hyperopia What To Do With the Post Capsule? Leave it or take? Leave it in? ¾ High incidence of post operative capsular opacification -> amblyopia Take it out? ¾ Primary posterior capsulotomy (posterior capsulorhexis) or a central capsulotomy Dictates where to put the IOL IOL’s in Infants: When to Use? 12 d Old, 1 day Post op Focal Points AAO 1999 Silsoft Contact Lens +20 to + 32 D in 3 D steps +12 to +20 in 1D steps Birth to 6 mo: overplus by 3-4 D 6 mo to 2 yrs: overplus by 1-2 D > 2 yo: Plano to 1D 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 Retinoblastoma Leukocoria (61%) Normal globe size White, gray tumor Chalky calcification Necrosis Retinal detachment Retinoblastoma Multiple or solitary tumor(s) ¾ Exophytic vs endophytic Total exudative retinal detachment Invade choroid, optic nerve -> subarachnoid space -> brain 1% spontaneous regression ¾ Phthisis bulbi Amber 7 mo old with leukocoria in both eyes and strabismus for 6 weeks Referred for evaluation of leukocoria FHX: unremarkable Amber Bilateral, ¾ RE non-familial retinoblastoma Stage IV, LE Stage Vb Treatment ¾ External options beam radiotheraphy ¾ Systemic chemotherapy with focal ablation ¾ Enucleation Amber External beam radiotherapy ¾ 180 cGy single daily fractions ¾ Anterior –lateral opposed wedge pair planning ¾ Total treatment dose: 4500 cGy Focal laser hyperthermia/ablation ¾ Argon Green Laser Indirect Genetics and Molecular Pathophysiology Normal cell division (regulation of cell growth and proliferation): ¾ depends on a balance of activating and inhibiting growth regulators Genetics and Molecular Pathophysiology Cancer results from an irreversible imbalance of these factors tilted towards uncontrolled cell growth and proliferation Genetics and Molecular Pathophysiology Rb gene (RB1) located on the long arm of chromosome 13 (at region 13q14) ¾ It codes for Rb nucleoprotein (tumor suppressor protein) which normally suppresses cell division Protein also functions to inhibit cancer Not only in the eye, but throughout the body Genetics and Molecular Pathophysiology Rb occurs when both copies of the Rb gene are mutationally inactivated ¾ Both maternal and paternal alleles of the RB gene are lost ¾ So that RB protein is deficient Knudson’s “Two-hit” Hypothesis 1 functional copy of Rb1 gene is required for normal embryogenesis 2 normal genes provides double protection 1 abnormal gene renders the cell susceptible to development of Rb Knudson’s “Two-hit” Hypothesis Hereditary ¾ One (Germline) Rb Rb mutation is already present and therefore needs only one subsequent mutation Knudson’s “Two-hit” Hypothesis The “2nd hit” inactivates the other copy Unlike the 1st mutation, the 2nd hit occurs at a higher frequency and is more sensitive to environment factors ¾ Such as exposure to ionizing radiation Increases the risk of tumorigenesis It occurs frequently enough during retinal development that multiple tumors occur Also tumors thought out the body Retinoblastoma (Rb) Nonhereditary (Somatic): 60-70% ¾ Rb1 gene occurs in a single retinal cell ¾ Unilateral ¾ No increased risk for cancers elsewhere Hereditary ¾ Due (Germline) 30-40% to sporadic germline mutations ¾ Autosomal dominant Retinoblastoma Hereditary (Germline) 30-40% ¾ This type of mutation results in every cell in the body having only 1 normal chromosome (and 1 abnormal) High risk of multiple bilateral tumors Lifelong predisposition to cancers throughout the body Retinoblastoma 2nd Malignant Neoplasms External beam radiotherapy is associated with ↑ incidence of 2nd malignancy in the irradiated field (dose related) 35% of pts die by 40 yrs of age of 2nd malignancy ¾ Incidence is greater if radiotherapy done before 12 months of age Retinoblastoma nd 2 Malignant Neoplasms If no external beam radiotherapy has been administered…..by age 40 yo ¾ 5% of patients (with Germline mutations) develop second malignant neoplasms Osteosarcomas of skull and long bones Cutaneous melanoma Soft tissue sarcomas Slight ↑ incidence of breast Ca and Hodgkin’s disease Retinoblastoma Treatment Enucleation External beam radiation Plaque brachytherapy (radiotherapy) Chemoreduction Chemothermotherapy Combination Cryo, Laser 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 Plaque Radiation Small tumors Unilateral RB < ½ retina Bilateral RB May use combination of other chemotherapeutic agents Chemothermotherapy Involves IV carboplatin Followed by transpupillary thermotherapy (TTT) Combined effect of chemotherapy and heat treatment causes tumor destruction Chemoreduction Combination of carboplatin, vincristine, and etoposide Given in hopes of either controlling tumor(s) or reducing size so more conservative Tx method can be used Very large tumors with RD have shown a dramatic initial response Genetics One affected child: 6% risk Two or more children: 50% chance RB survivor with hereditary form: 50% Linked to small arm of chromosome 13 Retinoblastoma Prognosis Overall 5 yr survival rate: > 92% Poor prognosis ¾ Optic nerve involvement ¾ Massive choroidal invasion ¾ Orbital invasion Survival for metastatic RB: < 6 mo VA 20/200 85% when macular or ON not involved Trilateral Retinoblastoma Primitive neural ectodermal tumor (PNET) Develops in 3% of germline mutations Located in the pineal gland ¾ May also arise in the parasellar region Histological characteristics similar to retinoblastoma Systemic Work Up CT scan (follow up MRI) r/o PNET LP if ON involvement Bone marrow aspiration if choroidal or orbital involvement Persistent Fetal Vasculature (PFV) “Persistent Hyperplastic Primary Vitreous” (PHPV) Failure of the primary vitreous to regress Plaque of fibrous tissue adherent to the posterior lens Variable degrees of vascularization Anterior, posterior, both PFV: Anterior Unilateral Leukocoria Microphthalmia Shallow anterior chamber Vascularization of the retrolental membrane Drawn in ciliary processes Clear lens PFV: Posterior May have all or none of the anterior features ¾ May Fold be isolate to posterior pole only of condensed vitreous and retina running from the disc to ora serrata Retinal detachment PFV Management Goal: avoid complications of glaucoma and phthisis Enucleation should be avoided Lensectomy/Vitrectomy Management of amblyopia Thank You!