Retinopathy Of PrematurityRetinopathy Of PrematurityDr. samarth mishraDr. samarth mishra

Introduction Introduction

Retinopathy of prematurity (ROP) was formerly known Retinopathy of prematurity (ROP) was formerly known as retrolental fibroplasia (RLF).as retrolental fibroplasia (RLF).

It is a developmental proliferative retinopathy that It is a developmental proliferative retinopathy that occurs in the premature infants due to incomplete occurs in the premature infants due to incomplete vasculogenesis of the retina at the time of birth.vasculogenesis of the retina at the time of birth.

““Vision 2020 program”- important cause of blindness in Vision 2020 program”- important cause of blindness in children.children.

Incidence Incidence

Overall incidence: 16-17% for all premature infants.Overall incidence: 16-17% for all premature infants.

68% ROP in BW < 1250 g68% ROP in BW < 1250 g

98% among those having BW < 750 g98% among those having BW < 750 g

Risk Factors Risk Factors

Pathogenesis Pathogenesis Normal Retinal Vascular DevelopmentNormal Retinal Vascular Development

Nasal side Temporal side

8 months

Stage 1 VasculogenesisFormation of primitive Vascular tube

Stage 2 Angiogenesis

Newly develop hypoxicNeural retina

Secreted VEGF

From birth to postmenstrual age30-32 wks

Relatively hyperoxic condition (supplemental O2) suppresses VEGF mRNA & normal VEGF driven growth

Apoptosis of vascular endothelial cells &Vaso-obliteration

Begins around 32-34 weeks Post-menstrual age

Nonvascularized retina becomesMetabolically active due to continuedDevelopment of retinal neural cells

Hypoxia which stimulate overProduction of VEGF

Increased level of VEGF with IGF

uncontrolled neovascularization

Vascular growth into vitreous & finally RD

Classification of ROPClassification of ROP

International Classification of ROP International Classification of ROP –– 1984 1984

1.1.ZZoneone2.2.ExtentExtent3.3.SStagetage4.4.PPlus diseaselus disease

Zone:Zone:

Zone 1: Zone 1: circle centered on disc with radius = 2 x “disc to circle centered on disc with radius = 2 x “disc to fovea” distancefovea” distanceZone 2: Zone 2: circle centered on disc with radius = “disc to nasal circle centered on disc with radius = “disc to nasal ora” distance (nasal ora to temporal equator) but outside ora” distance (nasal ora to temporal equator) but outside Zone 1Zone 1Zone 3Zone 3: remaining temporal crescent beyond Zone 2 : remaining temporal crescent beyond Zone 2

Extent: Extent: Divide the retinal surface into 12 segments (clock hours).Divide the retinal surface into 12 segments (clock hours).Stage of retinopathy can vary among segments.Stage of retinopathy can vary among segments.

Stages ( 1-5) Stages ( 1-5)

Stage 1:Stage 1:

Demarcation lineDemarcation line -a flat, thin, whitish, clear-cut -a flat, thin, whitish, clear-cut demarcation between vascularised and avascular retina. demarcation between vascularised and avascular retina.

Stage 2:Stage 2:

Elevated ridge Elevated ridge -- demarcation line has ”3D” appearnce & demarcation line has ”3D” appearnce & extends anteriorly from the retinal plane as a ridge into the extends anteriorly from the retinal plane as a ridge into the vitreous.vitreous.

Stage 3:Stage 3:

NeovascularisationNeovascularisation - Extraretinal fibrovascular tissue begins - Extraretinal fibrovascular tissue begins to grow on the top of the ridge or posterior to the ridge and to grow on the top of the ridge or posterior to the ridge and extends into the vitreous.extends into the vitreous.

““Pop-corn lesion”Pop-corn lesion”

Stage 4: Stage 4: Partial RDPartial RD

1.1. 4A: Extra-Foveal4A: Extra-Foveal

2.2. 4B: Foveal4B: Foveal

Stage 5: Stage 5: Total RDTotal RD

1.1. Open-Open funnelOpen-Open funnel

2.2. Open-Narrow funnelOpen-Narrow funnel

3.3. Narrow-open funnelNarrow-open funnel

4.4. Narrow-Narrow funnelNarrow-Narrow funnel

Plus DiseasePlus Disease Venous dilatation or arteriolar tortuosity in at least two quadrantsVenous dilatation or arteriolar tortuosity in at least two quadrants

poor pupil dilatationpoor pupil dilatation

vitreous hazevitreous haze

vascular engorgement of the iris with extension onto anterior lens surface vascular engorgement of the iris with extension onto anterior lens surface k/a tunica vasculosa lentis.k/a tunica vasculosa lentis.

HHallmark of rapidly progressive ROP & noted by adding a “+” sign after the allmark of rapidly progressive ROP & noted by adding a “+” sign after the number of ROP stage.number of ROP stage.

ICROP Revisited 2005ICROP Revisited 2005

1.1. Aggressive posterior ROP (APROP)Aggressive posterior ROP (APROP)

2.2. Pre-plus DiseasePre-plus Disease

3.3. Clinical pearl for clarification of the extent of Zone 1Clinical pearl for clarification of the extent of Zone 1

Aggressive posterior ROP (APROP)Aggressive posterior ROP (APROP) Ill defined ROP with plus Ds in Zone 1 or sometimes posterior Ill defined ROP with plus Ds in Zone 1 or sometimes posterior

Zone 2Zone 2 Posterior pole vessels show increased dilatation & tortuosity Posterior pole vessels show increased dilatation & tortuosity

in all 4 quadrants out of proportion to periphery in all 4 quadrants out of proportion to periphery Direct AV shunting Direct AV shunting Doesn’t progress through classic stages 1 to 3Doesn’t progress through classic stages 1 to 3 Neovascularization may be flat, featureless Neovascularization may be flat, featureless Typically extends circumferentially & is often accompanied by Typically extends circumferentially & is often accompanied by

a circumferential vessel.a circumferential vessel. Observed in smallest premature infants & requires prompt Observed in smallest premature infants & requires prompt

laser T/tlaser T/t Previously called “Rush Ds”.Previously called “Rush Ds”.

APROPAPROPzone 1

zone 2

shunt vessel

avascular retina

Pre-Plus DsPre-Plus Ds

More arterial tortuosity & more venous dilation of More arterial tortuosity & more venous dilation of posterior pole that are insufficient for Dx of Plus Ds.posterior pole that are insufficient for Dx of Plus Ds.

Dx of Pre-plus Ds has prognostic value.Dx of Pre-plus Ds has prognostic value.

Clarification of the extent of Zone 1Clarification of the extent of Zone 1

Spontaneously regressed ROPSpontaneously regressed ROP

Peripheral changes:Peripheral changes:1.1. Telangiectatic retinal vesselsTelangiectatic retinal vessels

2.2. Pigmentary changesPigmentary changes

3.3. Lattice like degenerationLattice like degeneration

4.4. Vitreous membraneVitreous membrane

5.5. Localized tractional detachmentLocalized tractional detachment Posterior pole changes:Posterior pole changes:1.1. Tortuous vesselsTortuous vessels

2.2. Narrow temporal arcadeNarrow temporal arcade

3.3. Disk dragDisk drag

4.4. Macular heterotopiaMacular heterotopia

5.5. Falciform foldFalciform fold

regressed stage

Differential DiagnosisDifferential Diagnosis

SCREENING GUIDELINESSCREENING GUIDELINESRecommendations based on review of data from the CRYO-Recommendations based on review of data from the CRYO-

ROP and LIGHT-ROP studiesROP and LIGHT-ROP studies

Screening method Screening method 1.1. IDO with a 20 or 28 D lens. IDO with a 20 or 28 D lens. 2.2. Eye speculum Eye speculum 3.3. Scleral indenterScleral indenter

Whom to screen Whom to screen 1.1. BW < 1500 g or BW < 1500 g or 2.2. Gestational age < 30 weeks or Gestational age < 30 weeks or 3.3. Infants with an unstable clinical course who are at high Infants with an unstable clinical course who are at high risk (as determined by paediatrician)risk (as determined by paediatrician)

In Indian ScenarioIn Indian Scenario

BW < 2000 gBW < 2000 g

GA < 34-35 weeksGA < 34-35 weeks

Initial screening recommended between 20-30 days of Initial screening recommended between 20-30 days of life.life.

Early screening (i.e. < 20 days of life) is strongly Early screening (i.e. < 20 days of life) is strongly recommended for babies < 30 weeks of GA.recommended for babies < 30 weeks of GA.

Indications of treatment Indications of treatment

CRYO-ROP StudyCRYO-ROP Study: : Treat “Threshold disease” of Treat “Threshold disease” of ROP ROP

1.1. Stage 3 ROP in zone 1, or zone 2 Stage 3 ROP in zone 1, or zone 2 2.2. Involving 5 or more contiguous or 8 cumulative Involving 5 or more contiguous or 8 cumulative

clock hours clock hours 3.3. presence of plus diseasepresence of plus disease

With threshold disease there is a 50% predicted risk With threshold disease there is a 50% predicted risk of blindness. of blindness.

8 Noncontiguous or 5 Contiguous Clockhours of NV (Stage 3) 8 Noncontiguous or 5 Contiguous Clockhours of NV (Stage 3)

ETROP studyETROP study

Type 1/ High risk Pre-threshold ROP:Type 1/ High risk Pre-threshold ROP:

1.1. Zone 1 ROP, any stage with plus disease Zone 1 ROP, any stage with plus disease 2.2. Zone 1 ROP, stage 3 without plus disease or Zone 1 ROP, stage 3 without plus disease or 3.3. Zone 2 ROP, stage 2 or 3 with plus disease Zone 2 ROP, stage 2 or 3 with plus disease

Type 2/ Low risk Pre-threshold ROP:Type 2/ Low risk Pre-threshold ROP:1.1. Zone 1, stage 1 or 2 without plus DsZone 1, stage 1 or 2 without plus Ds2.2. Zone 2, stage 3 without plus DsZone 2, stage 3 without plus Ds

Type 1 ROP should be treated promptly within 72 hrs of DxType 1 ROP should be treated promptly within 72 hrs of Dx

Treatment ModalityTreatment Modality

Principle: Principle: To remove the stimulus (VEGF) for To remove the stimulus (VEGF) for growth of new blood vessels by ablating the growth of new blood vessels by ablating the peripheral avascular retina.peripheral avascular retina.

1.1. CryotherapyCryotherapy2.2. Laser photocoagulation – standard treatmentLaser photocoagulation – standard treatment3.3. Surgical interventionsSurgical interventions

A.A. Scleral bucklingScleral bucklingB.B. VitrectomyVitrectomy

CryotherapyCryotherapy

Trans-scleral or TransconjunctivalTrans-scleral or TransconjunctivalComplication:Complication:

1.1.IOHIOH

2.2.Eyelid edemaEyelid edema

3.3.Conjunctival hematomaConjunctival hematoma

4.4.Conjuntival lacerationConjuntival laceration

5.5.BradycardiaBradycardia

6.6.Respiratory distressRespiratory distress

Laser PhotocoagulationLaser Photocoagulation

less invasiveless invasive

less traumatic to the eyeless traumatic to the eye

causes less discomfort to the infantcauses less discomfort to the infant

Easy to apply in posteriorly located disease. Easy to apply in posteriorly located disease.

Both Argon green and Diode red wavelengths laser can be delivered Both Argon green and Diode red wavelengths laser can be delivered through an indirect ophthalmoscope. through an indirect ophthalmoscope.

Aim: Aim: near-confluent ablation of peripheral avascular retina near-confluent ablation of peripheral avascular retina with burns with burns spaced one half burn-width apart, from ora serrata upto the ridge for 360 spaced one half burn-width apart, from ora serrata upto the ridge for 360 degree.degree.

Complication: corneal burn, hazy, Iris burn, cataract, burns of tunica Complication: corneal burn, hazy, Iris burn, cataract, burns of tunica vasculosa lentis causing IOH.vasculosa lentis causing IOH.

Before laser therapy After laser therapy

SurgicalSurgical

Scleral buckling or lens sparing vitrectomy are indicated for Scleral buckling or lens sparing vitrectomy are indicated for stage 4 ROPstage 4 ROP

Lens sacrificing vitrectomy for stage 5 ROPLens sacrificing vitrectomy for stage 5 ROP

Current Trends in ROP Treatment Current Trends in ROP Treatment

BEAT-ROP (Bevacizumab Eliminates the Angiogenic Threat in BEAT-ROP (Bevacizumab Eliminates the Angiogenic Threat in ROP) 2011ROP) 2011

RCT (150 infants, 300 eyes) RCT (150 infants, 300 eyes) SStudy: tudy: Stage 3, plus, Stage 3, plus, Zone 1 and posterior Zone 2 Zone 1 and posterior Zone 2 CCompare: ompare: Intravitreal Bevacizumab (Intravitreal Bevacizumab (0.625 mg / 0.025ml, 2.5 0.625 mg / 0.025ml, 2.5

mm post limbus) mm post limbus) vs. vs. Peripheral Laser (ETROP) Peripheral Laser (ETROP)

Results:Results:

1. Bevacizumab reduced recurrence of ROP 1. Bevacizumab reduced recurrence of ROP Bevacizumab recurrence: 6 of 140 eyes (Bevacizumab recurrence: 6 of 140 eyes (4%4%) ) Laser recurrrence: 32 of 146 eyes (Laser recurrrence: 32 of 146 eyes (22%22%) ) 2. Bevacizumab benefit over laser in Zone 1 2. Bevacizumab benefit over laser in Zone 1 3. Bevacizumab allowed continued peripheral vascularization into 3. Bevacizumab allowed continued peripheral vascularization into

avascular retina avascular retina

Cons & Pros of Anti VEGFCons & Pros of Anti VEGFAnti-VEGF agents are being used in ROP treatment as Anti-VEGF agents are being used in ROP treatment as 1. Monotherapy 1. Monotherapy Becoming less desirable if periphery not perfused Becoming less desirable if periphery not perfused Concern for late retinal detachments Concern for late retinal detachments 2. Adjunctive therapy with laser (or cryotherapy) 2. Adjunctive therapy with laser (or cryotherapy) 3. Perioperative therapy to induce NV regression3. Perioperative therapy to induce NV regression Dosing, schedule, and ROP recurrence patterns are still Dosing, schedule, and ROP recurrence patterns are still uncertain uncertain Retinal detachments after anti-VEGF have occurred Retinal detachments after anti-VEGF have occurred Long term safety data still uncertain Long term safety data still uncertain Extended follow up is required for anti-VEGF treated ROP eyes Extended follow up is required for anti-VEGF treated ROP eyes with incomplete vascularization with incomplete vascularization Screening ~ every 1-2 weeks Screening ~ every 1-2 weeks

Recombinant human erythropoietin (rhEPO) has been Recombinant human erythropoietin (rhEPO) has been tried.tried.

Long Term Complications of ROPLong Term Complications of ROP 70% became myopic due to macular heterotopia (temporal 70% became myopic due to macular heterotopia (temporal

macular drag) & straightened blood vessels.macular drag) & straightened blood vessels. Curvature myopiaCurvature myopia Astigmatism >2D, if uncorrected leads to amblyopia.Astigmatism >2D, if uncorrected leads to amblyopia. Strabismus 20.3%Strabismus 20.3% Late onset RD 25.6%Late onset RD 25.6% Cataract 83.7%Cataract 83.7% GlaucomaGlaucoma Exudative retinopathyExudative retinopathy

Retinal Dragging and Folds

Strabismus

AdvancesAdvances

Computer-assisted Quantification of Plus DsComputer-assisted Quantification of Plus Ds

TelescreeningTelescreeningImportant in areas with limited access to ophthalmic careImportant in areas with limited access to ophthalmic care

Take the picture of immature fundus using RetCam by trained Take the picture of immature fundus using RetCam by trained nurse or technician.nurse or technician.

Multiple image telemedicine perform to determine the stages Multiple image telemedicine perform to determine the stages n early initiation of treatment n follow up.n early initiation of treatment n follow up.

Conclusion Conclusion

Ultimate prevention = prevent premature births.Ultimate prevention = prevent premature births.

The role of VEGF and IGF-1 may lead to pharmacologic The role of VEGF and IGF-1 may lead to pharmacologic interventions in preventing progression.interventions in preventing progression.

Evidence based data reshape our understanding of who to Evidence based data reshape our understanding of who to screen and determines the critical timing of treatment.screen and determines the critical timing of treatment.

Surgical intervention preserves vision in ROP-related retinal Surgical intervention preserves vision in ROP-related retinal detachment esp. before macular detachment.detachment esp. before macular detachment.

THANK YOU….!THANK YOU….!