Retinopathy

of Prematurity

ROP

Prof Nicoline Schalij-Delfos

Department of Ophthalmology

Leiden University Medical Center

The Netherlands

Thessaloniki 2014

• Nothing to disclose

Disclosure Statement of Financial Interest

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Outline

• ROP

• Classification: revised ICROP (2005)

• Etiology

• Pathofysiology: 2 phase theory

• Treatment: laser, anti-VEGF

• Screening

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Retinopathy of prematurity / ROP

• Abnormal development of retinal vessels in prematures

• Born < 32 weeks of gestation

• Retinal vessels start to grow from the optic nerve head towards

the periphery of the retina in week 16

• Full vascularization: nasally week 36, temporaly week 40

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Avascular retina

• Incomplete vascularization

• Tapering of vessels near the avascular zone

• The younger the infant, the larger the avascular zone

Arch Ophthalmol 2005;123:991-9

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Zone (area of retinal vascularization)

• Zone I

• Circle with radius 2x distance center optic disc - center macula

• Field seen in indirect ophthalmoscopy with 25 – 28D lens

• Zone II

• Posterior Zone II : 3x distance center optic disc - center macula

• Circle with radius center optic disc – nasal ora serrata

• Zone III

• Residual temporal crescent

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Revised-ICROP stages

ROP 2ROP 1

ROP 5ROP 4

ROP 3

Arch Ophthalmol 2005;123:991-9AP ROP

Agressive Posterior ROP: AP-ROP

• Gestational age ≤ 25 weeks

• Zone I or posterior zone II:

• Increased dilatation and tortuosity

• 4 quadrants (360°)

• Not in concordance with peripheral changes

• Shunting of circular vessels Arch Ophthalmol 2005;123:991-9

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Plus disease (+)

• Increased arterial tortuosity and venous dilatation

• At least 2 quadrants zone I

• Severe plus:

• Dilatation of iris vessels

• Rigidity of pupil

• Vitreous haze

• Major criterion for treatment

MMC Veldhoven

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Richter GM et al. Surv Ophthalmol. 2009 Nov-Dec;54(6):671-85

Pre-plus disease

• Pre-plus disease warning sign:

• Increased arterial tortuosity and venous dilatation of posterior pole

• Not severe enough for plus disease

Pre-plus PlusNo plus

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2760626/figure/F1/http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2760626/figure/F1/http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2760626/figure/F1/

Etiology

• Multifactorial

• Gestational age most important risk

factor

• Oxygen and vascular growth factors play

a keyrole

• WINROP: algorithm using weekly weight

gain as predictor for ROP

Gestational age

Birth weight

Hypoxia

Hyperoxia

Fluctuations O2Hypocapnia

Duration AV

Duration suppl O2

Acidosis

Transfusions

Transferrine deficiency

Steroid use

Apnea

RDS

BPD

PDA

Sepsis

Vitamin E deficiency

Hypobilirubinaemia

Gender

Race

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Pathofysiology: 2 phase theory

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Mintz Hittner

Factors influencing

retinal vessel growth:

Oxygen regulated

VEGF

EPO

Produced by placenta

IGF

ω-3 PUFA (fatty acids)

Vascular Endothelial Growth Factor

• VEGF• Produced in avascular areas

• Oxygen regulated

− hyperoxia: decrease VEGF

− hypoxia: increase VEGF

• Necessary for normal outgrowth of retinal vessels

• Overproduction induces neovascularisations

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Focus of ROP treatment

• Increase oxygen saturation: higher target saturation

• Destruction of avascular area: Diode laser (cryo)

• Decrease release of growth factors: anti-VEGF injections

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NeOProM (NEJM 2014)

• Neonatal Oxygenation Prospective Meta-analysis

• Target oxygen saturations until 36 weeks PMA

• SUPPORT, BOOST studies, COT

• N=4911

• GA < 28 wkn

• Target saturation 85-89%: increased risk of mortality,

cerebral palsy, PDA, apnea and NEC

• Target saturation 90-95%: increased risk for ROP and

chronic lung disease

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Target saturations dilemma

• Neonatologists:

• GA < 28 weeks target saturation 90-95% until 36 weeks PMA

• Ophthalmologists:

• Lower target saturations in 1st phase: 85-89% (

ROP and higher target saturation

• Pre-plus: increased tortuosity en dilatation

• Increase O2-saturation: 85-90% to 95-98%: VEGF ↓

• Awaiting / prevention lasertreatment

• Short period: negative effect on pulmonal development

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ROP and laser

• Diodelaser

• Destruction peripheral retina: VEGF ↓

• Good results using ETROP-criteria (>95%)

• Reduced visual field

25 wkn 570 g

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Criteria for treatment

Type 1 Zone Plus

ROP 1 of 2 of 3 I +

ROP 3 I -

ROP 1 of 2 II +

• Treatment with laser

• Discussion about treatment of ROP 2+ in Zone II

• Careful observation

Type 2

ROP 1 of 2 I -

ROP 3 II -

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ROP and Bevacizumab

• Mintz Hittner (NEJM 2011): treatment of ROP 3+ in zone I beneficial

• Many questions

• Indications

• All ROP with plus, Zone I ? Zone II ?

• Dosage: 0.125 – 0.375 mg?

• Timing (extraretinal fibrovascular reaction / RD !)

• Monotherapy or combined with laser

• Systemic effects

• Increased plasm concentrations > 8 weeks

• Decreases plasm concentration VEGF (lungs, brain)

• Late recurrences / long term effects

• Follow up

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BEAT-ROP late effects

• Recurrence: 4 – at least 70 weeks

• Former and current border to avascular zone

Mintz Hittner, Early Human Development 2012;88:937-41

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Bevacizumab - Complications

• Cataract

• Choroidea ruptures

• Retinal detachment (rapid progression: Crunch syndrome)

• Macular hole

• Optic atrophy

• Exsudations / exsudative RD

• Vitreous bleeding

• Intracameral: severe liver function disturbances

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Bevacizumab – late recurrences

• > 1 year after treatment

• Larger vessels progress but:

• No capillairy meshwork

• Peripheral ischaemia

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Follow up study

• 20 eyes

• Follow up 5 years

• Zone I, posterior Zone II

• Bevacizumab 1x

• 11/20 abnormal

retinalvessels / capillaries

• 9/20 peripheral leakage at

FLU

• Images at 46 weeks

Tahija SG BJO 2014;98:507-512

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Follow up 86 weeks – 4 years

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Bevacizumab - evaluation

• Case series with favorable and unfavorable outcome

• Lasertreatment following ETROP criteria: >90% succes

• Long term effects:

• Recurrences after years: regular long term follow up necessary

• Effects of ischaemia at the long term

• Other organs ?

• Company in USA has given negative advice

• More phase 1 and 2 trials necessary (BLOCK-ROP)

Keep in mind: VEGF is necessary for normal vessel development

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Screening: Why?

• Potentially sight threatening disease

• Visual disability largely preventable when detected and

treated in time

• 20-50% develop any form of ROP

• Most resolve spontaneously

• Small proportion progresses to severe ROP

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Screening criteria

• Different screening criteria are used dependent on national

data mainly influenced by

• Socioeconomic factors

• Local neonatal care

• All screen GA < 30 weeks and BW < 1250 gram

• Variable criteria for infants > 30 weeks and > 1250 g based on

• Good Clinical Practice (GCP)

• Experience of physician

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1st screening PMA - PNA

• 1st screening: 4-5 weeks PNA but not before 31 weeks PMA

• Follow up screening

• Depends on stage, plus and zone

• Adjustment of screening schedule

• More frequent: rapid progression ROP

• Less frequent:

• Several examinations showing regression of ROP

• PMA 40 weeks without ROP

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Pitfalls in screening

• No screening / unintended loss

• Transfer / discharge: up to 30% loss

• Ophthalmologist not notified

More drop outs

• Transferral before 1st screening examination

• More transferrals

• Inadequate information in transfer letter

• Instructions for follow up not clear (define week or date !)

• No appointment for follow up

• No show or change of appointment

• Parents not informed about purpose or necessity of screening

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Screening technique

• Indirect ophthalmoscopy

• Reports

• Drawings

• Written (EPD)

• Comparison of FU examinations subjective

• Interpretation is personally

• Issue in case of transfer to another hospital

• Transportation for expert opinion (babylance)

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Screening with camera

• Digital images

• Can be done by nurse (practitioner) or physician assistant

• Objective comparison of data

• Easy to ask expert opinion without transpotation of the infant

• Timing of treatment more exact

• Most used: Retcam

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MMC Veldhoven

Obstacles for digital imaging

• Pricing: € 130.000

• Number of infants per hospital with severe ROP is small

• Rate paid by insurance companies is marginal

• Cost effectiveness studies are not widely available and may

differ per country

• More cameras on the market

• Expensive

• Not all easy to handle

• Quality issues (i-phone pictures)

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Retcam in the Netherlands

• Prospective, national inventory on ROP (NEDROP)

• All infants fullfilling the screeningcriteria in 2009

• Complete dataset 83%

• Outcomes

• Screening shifted from 8 NICU’s to 18 HC’s due to early tranferral

• 17/30 infants with severe ROP were treated

• 3/17 developed endstage ROP

• Retcams in NICU but not in HC centra

• Solution

• Involve the Queen, parents and interest the Zip-code lotery

• 10 Retcams for HC centra

• Reading centra

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Closing remarks

• ROP is an exciting and challenging subject

• Ongoing developments

• Ophthalmologists

• Keep up to date

• Monitor our outcomes

• Communicate with neonatologists

• Involve the parents

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EPOS 2014 at www.epos-focus.org

European Paediatric Ophthalmological Society

Annual meeting Barcelona, Spain

November 6-8th

Paediatric cataract and glaucoma

Abstract submission daedline July 7th

Participants ≤ 35 yrs:

Travel grants

Best presentation awards

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Hypoxia en pro-angiogenic factors: mechanism

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2- phase hypothesis

EPO: Erythropoietine

ERK: Extracellualr signal-Regulated Kinase

HIF: Hypoxia Inducable Factor

IGF: Insuline-like Growth Factor-1

MEK: Mitogen-activated protein-ERK

ROS Reactive Oxygen Species

VEGFR: Vascular Endothelial Growth Factor

Receptor

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Prevention ROP 1st phase

• Oxygen levels 91-94%?

• Stable SO2

• Suppletion of IGF-1 and ω 3- PUFA

• No hyperglycaemia

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Prevention progression ROP 2nd phase (↑VEGF)

Preventie van hypoxie

1. Behandeling van anaemie Ht > 0.4

(Gaynon 2006)

2. Blootstelling aan omgevingslicht

buitenste laag retina hoger O2 verbruik

in donker dan in licht (Gaynon 2006)

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Preventie progressie ROP 2e fase (↑VEGF, ↑ EPO)

Geen EPO

• EPO in ROP 2e fase:↑ neovascularisatie

• ↑ ROP bij > 20 doses EPO en > 20 dagen pp

(Suk J AAPOS 2008)

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Dosage

• Dosage 0.375 mg effective

• 57 eyes

• ROP with plus Zone I / ROP 3 zone I-II

• Decrease of plus signs in 2-6 days

• Disappearance of neovascularisations in 2-3 weeks

• FU 4 months

• Note: body surface premature baby ≈ 25% of adult

Harder BC Acta Ophthalmol 2013 Sept 11, Epub

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Screening criteria (1)

Criteria GCP

USA GA ≤ 30 or BW ≤ 1500 Selected infants GA > 30 or BW 1500-2000 with unstable clinical course

Canada GA ≤ 30 or BW ≤ 1250

Australia GA < 30 or BW < 1250 GA > 30 or BW > 1250with unstable clinical course

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Screening criteria (2)

Criteria GCP

UK GA < 31 of BW < 1251 < 32 wk GA of BW < 1501 gr

Germany GA < 32 GA 32 - 36 wks with > 3 days oxygen

uncertain GA : BW < 1500

Sweden GA ≤ 31

Netherlands GA < 30 or BW < 1250

GA 30-32 or BW 1250-1500 + 1 rf

(AV, sepsis, NEC, cardiotonica,

postnatal steroids)

uncertain: GA < 32 or BW < 1500

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1st screening PMA - PNA

• Postmenstrual age (PMA) = GA + postnatal age (PNA)

1st screening: 4-5 weeks PNA but not before 31 weeks PMA

PMA

(GA + PNA)PNA

1st screening31

(27.4-38.1)

6

(4-13.6)

Detection severe ROP36.7

(33.1-41.8)

10.3

(6.9-14.7)

Pre-threshold ROP36.1

(32.4-41.5)

9.6

(6.2-14.8)

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Follow up examinations

Criteria Frequence

ROP with plus disease, no treatment yet More than 1x / week

Avascular Zone I, no ROP

ROP 1 or 2 in Zone I, no plus

ROP 2 or 3 in Zone II, no plus

ROP in regression in Zone I

Adequate staging not possible

Every week

Avascular Zone II, no ROP

ROP 1 in Zone II

ROP in regression in Zone II

2 weeks follow up

ROP 1 or 2 in Zone III

ROP in regression in Zone III2 - 3 weeks follow up

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Adjustment of screening schedule

• More frequent: rapid progression ROP

• Less frequent:

• Several examinations showing regression of ROP

• PMA 40 weeks without ROP

• Stop screening

• Vascularization completed

• No ROP, vessels in Zone III

• Regression at 2 successive examinations, no plus at 40 wks PMA

• Transgression of vessels through demarcation line

• Regressed ROP with color change of ridge from salmon pink to

white

• Commencement of replacement of active lesions by scar tissue

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