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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
Thessaloniki 2014
Outline
• ROP
• Classification: revised ICROP (2005)
• Etiology
• Pathofysiology: 2 phase theory
• Treatment: laser, anti-VEGF
• Screening
Thessaloniki 2014
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
Thessaloniki 2014
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
Thessaloniki 2014
Thessaloniki 2014
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
Thessaloniki 2014
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
Thessaloniki 2014
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
Thessaloniki 2014
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
Thessaloniki 2014
Pathofysiology: 2 phase theory
Thessaloniki 2014
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
Thessaloniki 2014
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
Thessaloniki 2014
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
Thessaloniki 2014
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
Thessaloniki 2014
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 -
Thessaloniki 2014
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
Thessaloniki 2014
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
Thessaloniki 2014
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
Thessaloniki 2014
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
Thessaloniki 2014
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
Thessaloniki 2014
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)
Thessaloniki 2014
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)
Thessaloniki 2014
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
Thessaloniki 2014
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
Thessaloniki 2014
Hypoxia en pro-angiogenic factors: mechanism
Thessaloniki 2014
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
Thessaloniki 2014
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)
Thessaloniki 2014
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)
Thessaloniki 2014
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
Thessaloniki 2014
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
Thessaloniki 2014
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
Thessaloniki 2014
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
Thessaloniki 2014