rop.pptx

CONTENTS
• INTRODUCTION
• EPIDEMIOLOGY
• RELEVANT ANATOMY
• RISK FACTORS
• PATHOGENESIS
• CLASSIFICATION
• DISEASE ENTITY
• DIFFERENTIAL DIAGNOSIS
• COMPLICATIONS
• PREVENTION
• SCREENING PROTOCOL
• MANAGEMENT AND LANDMARK TRIALS

INTRODUCTION
• HISTORY: Terry coined the term- “Retro-lental fibroplasia” in 1942 which is now exclusively used for Stage-5
ROP.
• Heath coined the term “Retinopathy of Prematurity” in the year 1951.
• Retinopathy of Prematurity (ROP) is a disorder of the developing retina of Low Birth Weight premature
infants that potentially leads to blindness in a small but significant percentage of those infants.
• It can be:
• 1) Mild with no visual defects or
• 2)May be Aggressive with new vessel formation (Neovascularisation) and
• 3)Progress to retinal detachment and blindness.
• In pre-term infants, the development of the retina which proceeds from the optic nerve head anteriorly is
incomplete with the extent of the immaturity of the retina depending mainly on the degree of prematurity
at birth.
• Timely screening and treatment of ROP can prevent blindness and minimize visual handicaps.
W M Fierson; Screening Examination of Premature Infants for Retinopathy of Prematurity; AMERICAN ACADEMY OF PEDIATRICS Section on
Ophthalmology, AMERICAN ACADEMY OF OPHTHALMOLOGY, AMERICAN ASSOCIATION FOR PEDIATRIC OPHTHALMOLOGY AND STRABISMUS and AMERICAN
ASSOCIATION OF CERTIFIED ORTHOPTISTS
Pediatrics December 2018, 142 (6) e20183061; DOI: https://doi.org/10.1542/peds.2018-3061

EPIDEMICS OF ROP
Gilbert et al, Retinopathy of Prematurity: Epidemiology; Community Eye Health Journal; 1997

THIRD EPIDEMIC OF ROP
Blencowe et al; Preterm-associated visual impairment and estimates of retinopathy of prematurity at regional and global
levels for 2010; Pediatric Research; 2013
In 2010, an estimated 184,700 preterm babies developed any stage of ROP,
20,000 of whom became blind or severely visually impaired from ROP
a further 12,300 (8,300–18,400) developed mild/moderate visual impairment.
65% of those visually impaired from ROP were born in middle-income regions

EPIDEMIOLOGY OF RETINOPATHY OF
PREMATURITY
Reported incidence of ROP in the West ranges from 21 to 65.8%.
In infants weighing <900 gms at birth and gestational age of <25 weeks, the incidence is as high as
80-100%.
Recent Indian studies have shown that the incidence of ROP varies from 38-51.9% among low birth-
weight babies.
An Ambispective study (2013-2017): Infants with birth weights<1750 g and gestational ages<34
weeks were screened for ROP.
Number of infants screened and treated for ROP increased from 190 and 29, respectively (2013) to
818 and 132, respectively (2017).
The overall incidence of “any ROP” was 32.3% and severe ROP was 17.7%.
ROP Stage 1 seen in 12%, Stage 2 in 34%, Stage 3 in 13%, Stage 4 in 6%, Stage 5 in 14% and A-ROP in
20%.
Subhadra Jalali, R V Azad et al; Programme Planning and Screening Strategy in Retinopathy of Prematurity; Indian J Ophthalmology 2003
Tekchandani, Uday et al; Five-year Demographic profile of ROP at a tertiary care institute in North India, Indian J Ophthalmology; August 2021

DEVELOPMENT OF RETINAL VESSELS
• Immature retina has 2 blood supplies:
• 1) Outer- Choroidal vessels
• 2) Inner- Retinal vessels
• At the age of 6 weeks (5 mm stage), HYALOID ARTERY- a major branch of the primitive
dorsal ophthalmic artery enters the globe and grows forwards towards the posterior
pole of the lens.
• The fetal fissure along the optic stalk closes around the hyaloid artery and the
portions of the vessels within the stalk become ‘CENTRAL RETINAL ARTERY’.
• At around 16 weeks, mesenchymal spindle cells arise from the adventitia of the
hyaloid artery and migrate from optic disc to the ora serrata.
• Nasal retina fully vascularized by 36 weeks or after 8 months of gestation.
• Temporal retina fully vascularized at birth or 1 month after delivery.
R V AZAD et al; A Practical Approach to Retinopathy of Prematurity, Screening and Management; 2001

RISK FACTORS FOR ROP
• Prematurity/Gestational age <30 weeks
• Low birth weight < 1500 kg
• High exposure to Oxygen for prolonged period-
• Endogenous anti-oxidant deficiency ( of Vit-E)
• Apnoea, Chronic uterine hypoxia
• Sepsis
• Anaemia,
• Intraventricular haemorrhage, shock
• Hypercarbia/ Hypocarbia
• Prolonged Parenteral nutrition (PPN)
• Necrotising Enterocolitis
• Cerebral palsy
• Candidemia- independent risk factor for severe ROP in babies weighing <1000g
• Cardiac defects
• Multiple blood transfusion
• Respiratory distress syndrome, Bronchopulmonary dysplasia
Myron Yanoff and Duker et al; Ophthalmology; Elsevier; 2019

PATHOGENESIS OF ROP- SPINDLE CELL MODEL
BY KRETZER ET AL
TERM-NEWBORN PRETERM-NEWBORN
• Relatively less hyperoxic environment
• Spindle cells with normal anti-oxidative property is
capable of scavenging oxygen free-radicals
Normal migration and Canalization
Mature vessels formation
• Relatively higher hyperoxic environment
• Spindle cells with defective anti-oxidative
property and excessive junctional gaps
incapable of scavenging oxygen free radicals
• Comparatively thin and large avascular retina
Spindle cells damage d/t plasma membrane lipid
peroxidation causes:
• Gap junction formation
• Increased Synthesis of Angiogenic factor
• Increased Endoplasmic reticulum
• Migration and canalization halt
• Neovascularization at shunt site
R V AZAD et al; A Practical Approach to Retinopathy of Prematurity, Screening and
Management; 2001

SPINDLE CELL MODEL BY KRETZER ET AL-
Contd.
After 8-10 weeks
• Myofibroblasts from stem cells
• Proliferation of myofibroblasts
• Contractile sheet fomation
Regression
• Fibrosis
• Vitreous traction
• Retinal detachment

PATHOGENESIS ( MOST ACCEPTED RECENT
THEORY)
Multifactorial : developmental, genetic, and environmental factors
Premature birth
Ex- utero Hyperoxic
environment
Disruption of retinal
vasculogenesis and neural
development( XANTHINE
OXIDASE produces superoxide
anions and H2O2
Placental and maternal
cytokines and growth
factors
VEGF, IGF-1 AND Wnt-
signalling pathway
Abnormal vasoproliferation and
retinal neo-vascularisation
Myron Yanoff and Duker et al;
Ophthalmology; Elsevier; 2019

“WINROP” ALGORITHM:
• The ‘Weight’, ‘IGF-1’, ‘Neonatal ROP’ is being assessed for more
targeted screening efforts.
• ADVANTAGE: It has been found to be 100% sensitive in detecting at-
risk infants while identifying as many as 90% of the infants that do
not need screening.
Retina and vitreous; American Academy of Ophthalmology; BCSC-2019-20

NEWER GENETIC BIOMARKERS TO
ESTIMATE RISK OF ROP
WHAT WE KNOW NEWLY REORTED GENETIC
ASSOCIATION IN CASE REPORTS
NDP gene (Norrie disease pseudoglioma) TUBA1A in de Morsier syndrome
BDNF( Brain derived Neurotrophic factor)
LRP-5
FZD4

LOCATION-ZONES
• ZONE-I: From optic disc to twice disc-macular distance within a 60 degree
circle.
• ZONE-II: A ring-shaped region extending nasally from the outer limit of
Zone- I to the nasal ora serrata and a similar distance temporally, superiorly
and inferiorly.
• ZONE-III: Residual crescent of peripheral retina that extends beyond ZONE-
II.
Chiang et al; International Classification of Retinopathy of Prematurity; Third Edition; Elsevier on behalf of AAO; 2021

ICROP 3RD EDITION CLASSIFICATION
• CHANGES:
• POSTERIOR ZONE-II: region that begins at the margin between zone I and zone II and extends
into zone II for 2 disc diameters.
• “ NOTCH “: describe an incursion by the ROP lesion of 1-2 clock hours into a more posterior zone.
• the most posterior zone of retinal vascularization with the qualifier “notch” (e.g., “zone I
secondary to notch”).
• STAGE OF ACUTE DISEASE (STAGES-1-3): If more than 1 ROP stage is
• present, the eye is classified by the most severe stage.
• AGGRESSIVE-ROP: Due to increasing recognition that this may occur beyond the posterior retina
and in larger preterm infants, particularly in regions of the world with limited resources
• PRE-PLUS AND PLUS DISEASE: Focus on vessels within ZONE-1
• STAGE-5 SUBCATEGORIES: 5A: Optic disc is visible by Ophthalmoscopy
• 5B: Optic disc is not visible because of retrolental fibrovascular tissue
• 5C: 5B is accompanied by anterior segment changes

IMMATURE RETINA ROP AT ZONE 2
TEMPORAL AVASCULAR RETINA AT ZONE 2

STAGE 1
• DEMARCATION LINE: A thin but definite line separating the avascular
retina anteriorly from the vascularized retina posteriorly

STAGE 2
• RIDGE:
• A ridge arising from the demarcation line which has 3 dimensions (height and
width) and extends above the retina

STAGE 3
• EXTRA-RETINAL FIBROVASCULAR PROLIFERATION:
• Extends into the vitreous from the ridge
• The posterior aspect of the ridge appears irregular as the
proliferation becomes more extensive

STAGES-1 TO 3 ROP- OCT IMAGES

STAGE 4
• PARTIAL RETINAL DETACHMENT:
• Retinal detachments are generally concave and most are circumferential.
• Divided into 2 stages:
• Stage 4A: Extra-foveal
• Stage-4B: Foveal

STAGE 5
• TOTAL RETINAL DETACHMENT:
• Retinal detachments are generally tractional but may occasionally be exudative.
• They are usually funnel-shaped:
• 1)Open or
• 2)Closed

STAGES OF ROP
Chiang et al; International Classification of Retinopathy of Prematurity; Third Edition; Elsevier on behalf of AAO;
2021
Myron Yanoff and Duker et al; Ophthalmology; Elsevier; 2019

PLUS DISEASE
• Present as a major complicating factor at any stage.
• Significant level of venous dilation and arteriolar tortuosity of the posterior
retinal vessels- reflects increase of blood flow to the retina
• 2 quadrants of the eye retina must be involved for the changes to be
characterized as plus disease- Acc to STOP-ROP, ET-ROP
• 4 vascular arcade quadrants- in CRYO-ROP study
• Associated changes:
• Iris vascular engorgemet
• Poor pupillary dilatation (rigid pupil)
• Vitreous haze and anterior chamber haze
Multicenter Trial of Cryotherapy for Retinopathy of Prematurity: ophthalmological outcomes at 10 years
Cryotherapy for Retinopathy of Prematurity Cooperative Group; Arch Ophthalmology ; 2001

PRE-PLUS DISEASE
• Indicates Posterior pole tortuosity and dilatation that are not
sufficiently abnormal to reach the criteria of plus disease, but greater
than that regarded as normal.
• Pre-plus disease may or may not progress to plus disease

Aggressive Posterior ROP (APROP) in ICROP 2005
(NOW, A-ROP IN ICROP-3rd REVISION-2021)
Uncommon
Rapidly progressive, severe form of ROP
“Rush disease”.
Usually occurs in the smallest, most immature infants.
Untreated, it usually progresses to Stage 5 ROP
Most commonly observed in ZONE I or posterior Zone II
Characteristic features are
posterior location
prominence of plus disease
ill-defined, mild-appearing, and easily over-looked retinopathy
(flat network of neo-vascularisation) at the junction between the
avascular and vascular retina
It may not have classical ridge or extra-retinal fibrovascular
proliferation.

DISEASE EXTENT
• Disease extent is recorded as clock hours 1-12 hours or as 12 30°
sectors or 360°
• The clock hours recorded is the total clock hours involved, not just
the contiguous sectors.

DIFFERENTIAL DIAGNOSIS
ROP
STAGE 1,2,3,4)
FEVR
(STAGE2)
SIMILARITIES
Peripheral avascular retina with ridge or line with or
without dilated tortous vessels
Elevated fibrovascular scar in the temporal periphery
with dilated tortous vessels in the posterior side of
retina
Disc dragging and ectopic macula (in stage 3,4a and
b resolving stage)
Disc dragging and macular ectopia
Temporal retinal detachment may be seen Temporal retinal detachment may be seen.

DIFFERENCES
Subretinal exudates .A yellowish deposit may be
seen in stage 4 ROP of long standing
Subretinal exudates seen temporally under the
retinal detachment
History of prematurity,low birth weight oxygen
supplementation
May or may not be present
No family history Family history of autosomal dominant transmission
positive
Avascular retina area in early stages Avascular retinal area may not seen
Rapid progression or regression within weeks/days Very slow progression or regression over months
Detectable from 32 weeks onwards Detected and present late.i.e, around 2 years of age

…
• .
ROP RETINOBLASTOMA
HISTORY
Prematurity,low birth weight,oxygen
usage may be positive
Usually negative,Could rarely be
positive(incidently)
FAMILY HISTORY
Negative Positive in 25-30% of cases and many
bilateral cases.
TIME OF PRESENTATION
If neglected,leukocoria due to disease
may be detected after 6-8 weeks as well
,though many cases come by 3-5 months
age in developing countries with poor
medical care.
Usual time of presentation 6-8 months
CLINICAL FINDINGS
Invariably bilateral Usually unilateral(67%)
ROP leukocoria has fibrotic look in the
fundus and a ridge with cicatricial vessels
in periphery
Invariably heterogenous mass filling eye
with hemorrhages and many vessels on
surface.
Usually none May be hyphema,Vitreous
hemorrhage,Pseudohypopyon

ROP VERSUS RETINOBLASTOMA
X RAY
No significant lesion detected Calcification may be present in large percentage of
cases.
ULTRASOUND
Complex pattern of detachment showing the open
and closed funnels
Bscan ultrasound may clearly demonstrate the origin
of this mass from underlying retina. The A scan
ultrasound is diagnostic, since the calcification within
the tumor gives spikes which make V-W pattern due
to high reflectivity from the tumor interface.
CT SCAN
No specific pattern is usually detectable. The
attachment and origin from the retina further
strengthens suspicion
Calcification within the mass
More than one mass also suggests tumor

COMPLICATIONS
• Myopia with Astigmatism in about 80% of infants with ROP.
• Strabismus and amblyopia: The prevalence of strabismus ranges from 23%
to 47% in infants with ROP and found to be 20% in a regional study.
• Cataract
• Retinal detachment in 22% patients. Retinal detachment can occur as
early as 6 months up to 31 years from the time of diagnosis, with a mean
age of 13 years in regressed ROP patients.
• Retinal detachment may even occur in sub-threshold ROP.
• Acute angle closure glaucoma can be seen in cicatricial ROP.
• Macular pigment Epitheliopathy
• Vitreo-retinal scarring/adhesions
• Anomalous foveal anatomy

PREVENTION OF ROP
COMMON RISK FACTORS SUGGESTED INTERVENTIONS
PREMATURITY Improving quality of ante-natal care
In-situ transfer to NICU/SNCU
ANTENATAL STEROIDS Prompt injection to mother in imminent or planned pre-term
delivery
OXYGEN Monitoring using pulse oximetry with a target saturation of
91-95%
O2 blenders are very important in a NICU/SNCU
POSTNATAL NUTRITION ( GROWTH FACTORS LIKE IGF-1) IGF is correlated strongly with post-natal weight gain
BLOOD PRODUCTS Thrombocytopenia is a risk factor for A-ROP
Delays healing post-laser therapy as well
Vinekar A et al; Textbook of Clinical Neonatology; IAP AND NNF; 2021

WHEN TO SCREEN?
First screening at 4-6 weeks of post-natal age or alternatively
between 31 and 33 weeks’ post-conceptional age or post-menstrual
age whichever is LATER ( In INDIA, whichever is EARLIER)
All infants with a birth weight of <1500g or a gestational age of <= 30
weeks should be screened.
Screening Examination of Premature Infants for Retinopathy of Prematurity
AMERICAN ACADEMY OF PEDIATRICS Section on Ophthalmology, AMERICAN ACADEMY OF OPHTHALMOLOGY, AMERICAN ASSOCIATION FOR PEDIATRIC
OPHTHALMOLOGY AND STRABISMUS and AMERICAN ASSOCIATION OF CERTIFIED ORTHOPTISTS
Pediatrics January 2013, 131 (1) 189-195; DOI: https://doi.org/10.1542/peds.2012-2996

SCREENING FOR ROP- NATIONAL ROP
GUIDELINES
Whom to screen? If gestational age is known: <=34 weeks
If GA is not known/unsure: All infants with <=2000g birth weight
Pre-term infants with GA>34 weeks if risk factors are present (mentioned earlier)
When to perform 1st
screening?
Before discharge from the NICU or 30 days of life, whichever is earlier
Methods Indirect Ophthalmoscopy by a trained Ophthalmologist
Retinal imaging using a wide-field retinal camera( eg: 3 NetraNeo or RETCAM)
Where to screen? Preterm infants not discharged from NICU/SNCU examined in unit
Discharged infants followed up in NICU/SNCU or ophthalmologist’s clinic
Vinekar A etal; Textbook of Clinical Neonatology; IAP AND NNF; 2021

FOLLOW-UP INTERVALS FOR INFANTS AT RISK
• If there is pre-plus disease, baby should be screened at 3-4 day interval.
ZONE1 STAGE FOLLOW-UP INTERVAL
1 Immature
Stage-1,2 or regressing ROP
Stage-3 or A-ROP
1-2 weeks
1 week or earlier
TREAT
2 Immature
Stage-1
Stage-2 / Regressing ROP
Stage-3
2-3 weeks
2 weeks
• TREAT if PLUS disease +nt
• FOLLOW-UP 1-2 weeks: PLUS disease –nt
• TREAT : PLUS disease +nt
• FOLLOW-UP <=1 week: PLUS disease -nt
3 Stage-1 and 2/regressing ROP 2-3 weeks
Post-Anti-VEGF Long-term follow-up needed May need laser treatment if recurrence or
persistence of avascularity
After ROP screening is completed Preterm infants: at high risk for vision
impairment and refractive errors
Regular follow-up for atleast 7 years of age

SCREENING INTERVALS
• One-Week-or-Less Follow-up
• Zone I: immature vascularization, no ROP;
• Zone I: stage 1 or stage 2 ROP;
• Immature retina extending into posterior zone II, near the boundary of zone I–zone II;
• Suspected presence of AP-ROP; and
• Stage 3 ROP, zone I requires treatment, not observation.
• One- to 2-Week Follow-up
• Posterior zone II: immature vascularization;
• Zone II: stage 2 ROP; and
• Zone I: unequivocally regressing ROP.
• Two-Week Follow-up
• Zone II: stage 1 ROP;
• Zone II: no ROP, immature vascularization; and
• Zone II: unequivocally regressing ROP.

SCREENING INTERVALS
• Two- to 3-Week Follow-up
• Zone III: stage 1 or 2 ROP; and
• Zone III: regressing ROP.
• 5. The termination of acute retinal screening examinations should be based on age and
retinal ophthalmoscopic findings. Findings in which is it suggested that examinations can
be terminated include the following:
• Full retinal vascularization in close proximity to the ora serrata for 360°, that is, the
normal distance found in mature retina between the end of vascularization and the
ora serrata.
• Zone III retinal vascularization attained without previous zone I or II ROP
• Postmenstrual age of 45 weeks and no type 1 ROP (previously called “prethreshold”)
disease (defined as stage 3 ROP in zone II, any ROP in zone I) or worse ROP is
present.
• Regression of ROP

DURATION AND FREQUENCY OF SCREENING
• Screening examinations will continue at least every two weeks until:
• Vascularization of the retina reaches normal completion or
• ROP regresses or
• ROP requiring treatment develops.

PREPARATION AND SCREENING PROCEDURE
• Personnel required- a visiting trained ophthalmologist, 1 doctor, 1 nurse from SNCU and
optometrist from DEIC
• Place of examination
• Equipment checklist:
• Indirect Ophthalmoscope 20, 28 D lens
• Paediatric speculum
• Infant scleral depressor
• Dilator eye drops (a) Tropicamide 0.5% b) Phenylephrine 2.5% (c) Cyclopentolate 0.5%
• Topical anaesthetic eye drop (proparacaine 0.5%)
• Topical antibiotic eye drop
• Sterile cotton and gloves
• ROP documentation sheet
• Pamphlets regarding ROP
• Optional: Wide field Digital camera

Baby should be well clothed and wrapped. Baby should receive a feed and burped an hour before
screening.
Baby should not be fed just before examination to avoid vomiting and aspiration
Pupil should be fully dilated
Informed consent should be obtained from parents.
The baby is swaddled and arms restrained to minimise general movements and an assistant positions
the baby for the examination.
Topical anesthetic drop proparacaine 0.5% should be applied at conjunctival sac.
After instillation of topical anesthesia, a sterile wire lid speculum and scleral indentor for eye rotation
may be used. Pediatric speculum should be applied 30 seconds after anesthetic drop.
The use of oral sucrose may be considered to help with analgesia.
Screening should be done by an ophthalmologist trained in ROP screening.

anterior segment examination to check for dilated iris vessels and extent of pupillary dilatation
Examine Posterior pole as well as 360 degree peripheral retina
Scleral depression with wire Vectis
Brief findings recorded according to ICROP guidelines and provided to parent with clear instruction to adhere strictly to
follow up schedule.
Antibiotic drop instilled in each eye at the completion of examination.
Baby observed for 15 minutes before handing over to parents
Infant with ROP not amenable to laser photo-ablation (stage 4 and stage 5) - referred to tertiary center for surgical
intervention

NEWER IMAGING MODALITIES
IMAGING MODALITY FIELD OF VIEW
SROP (SmartROP) camera, condensing lens 20D 46 degrees
28D 53 degrees
40D (attached with MII Retcam device) 90 degrees
Video Indirect Ophthalmoscopy 46 degrees (20D)
53 degrees (28D)
RETCAM SHUTTLE WIDE FIELD DIGITAL IMAGING
SYSTEM
120 degrees
3 Netra neo Wide field camera 120 degrees
Optos 200Tx Ultra-Wide Field imaging -FFA 200 degrees
Goyal et al; Smartphone guided wide-field imaging for retinopathy of prematurity
in neonatal intensive care unit – a Smart ROP (SROP) initiative, Indian Journal of Ophthalmology; 2019
Mao et al; Ultra wide-field imaging and Intravenous FFA in infants with Retinopathy of Prematurity; Retina; 2020

DOCUMENTATION OF FINDINGS
• Zone of vascularisation
• Stage of ROP
• Extent of ROP (in clock hours)
• Presence of plus, or pre-plus, disease
• Presence of A-ROP (earlier AP-ROP)
• Whether treatment is indicated and
• When follow-up is planned.

KIDROP TRIAL- ROLE OF TELE-ROP SCREENING
• AIM: To report the Karnataka Internet Assisted Diagnosis of Retinopathy of Prematurity (KIDROP)
program for retinopathy of prematurity (ROP) screening in underserved rural areas using an
indigenously developed tele-ROP model.
• METHODS:
• Technicians were trained to use a portable Retcam Shuttle (Clarity, USA) and validated against ROP
experts performing indirect ophthalmoscopy.
• An indigenously developed 20-point score (STAT score) graded their ability (Level I to III) to image
and decide follow-up based on a three-way algorithm.
• Images were also uploaded on a secure tele-ROP platform and accessed and reported by remote experts
on their smart phones (iPhone, Apple).
• RESULTS: A level III technician agreed with 94.3% of all expert decisions.
• CONCLUSION: The KIDROP tele-ROP model demonstrates that ROP services can be delivered to the
outreach despite lack of specialists and may be useful in other middle-income countries with similar
demographics.
Vinekar et al; The KIDROP model of combining strategies for providing retinopathy of prematurity screening in underserved
areas in India using wide-field imaging, tele-medicine, non-physician graders and smart phone reporting; iIndian J
Ophthalmology; 2014

MANAGEMENT OF ROP
• PRINCIPLE:The treatment involves ablation of peripheral avascular
retina and thereby abolishing hypoxic drive of retina (mediated by
over-expression of vascular endothelial growth factor; VEGF).
• TIMING AND PLACE OF TREATMENT: When indicated, treatment
should be carried out as soon as possible, ideally within 2-3 days of
the diagnosis. However treatment is warranted within 48 hours of
diagnosis of classical form of disease and as soon as possible in A-
ROP.

LASER PHOTOCOAGULATION
• PROCEDURE OF CHOICE (ADVANTAGES):
• less invasive
• less traumatic to the eye and causes less discomfort to the infant
• simpler to apply in treating posteriorly located disease.
• ‘laser spots’ on retina are visible during the procedure minimizing the skip areas requiring re-treatment.
• The procedure can be carried out under topical anesthesia with or without sedation.
• MODALITIES:Both double frequency Nd-YAG laser and Diode red wavelengths laser can be delivered through an indirect
ophthalmoscope.
• TECHNIQUE: Laser burns should be applied on the entire peripheral avascular retina anterior to the ridge, excluding the ridge.
• Ideally, laser applications should be spaced one half burn-widths apart. Better results were documented with near confluent burn.
• COMPLICATIONS:
• Laser treatment may cause burns in cornea and iris.
• cataract
• retinal and vitreous haemorrhage
• Ocular ischemic syndrome
• angle closure glaucoma
• inadvertent damage to the vascularized retina including macula
Good et al; Final Results for the Early Treatment of Retinopathy of Prematurity(ET-ROP) Randomised Trial; Transactions of the American
Ophthalmological Society; 2004

LASER PROCEDURE
• 1. Informed consent to be taken from parents before the procedure.
• 2. Oral feeds should be discontinued 1 hour prior to the procedure.
• 3. Baby should be put on cardio-respiratory monitor and if large area of retina needs to ablated like in Zone I and Zone 2 posterior
disease I.V. fluid should be started.
• Dilatation of pupil is ensured by using tropicamide 0.5% and phenylephrine 2.5% or cyclopentolate 0.5% and phenylephrine 2.5%
eye drops can be used to have pupillary sustained dilatation for laser photoablation.
• 4. Can be done under topical anesthesia to avoid systemic side effects of general anesthesia or sedation.
• 5. 24% dextrose solution can be given orally to minimize the pain during the procedure.
• 6. If required general anesthesia or sedation can be used.
• 7. Precaution to be taken to prevent hypothermia, hypoglycemia during and after the procedure
• 8. Both the eyes can be treated at the same sitting unless contraindicated by instability of the baby.
• 9. Vitals to be monitored during and for 2 hours after the procedure.
• 10. Oral feed to be given 30 minutes after procedure.
• 11. If baby is not tolerating the procedure, consider abandoning the procedure for the time being. Vital signs and oxygen
saturation should be monitored very closely.
• 12. Premature babies, especially those with chronic lung disease may have increased or re-appearance of apneic episodes or an
increase in oxygen requirement. Therefore they should be carefully monitored for 48-72 hours after the procedure.

INDICATIONS FOR BOTH ACTIVE PERIPHERAL
RETINAL ABLATION AND PASSIVE WAITING FOR
PROGRESSION/REGRESSION
• Treatment of ROP is based on differentiation of following two types of ROP:
• Type 1 ROP: Administer peripheral ablation treatment
• Zone I, any stage ROP with plus disease
• Zone I, stage 3 ROP without plus disease
• Zone II, stage 2 or 3 ROP with plus disease
• Type 2 ROP: Wait and watch for progression/regression
• Zone I, stage 1 or 2 ROP without plus disease
• Zone II, stage 3 ROP without plus disease

CRYOTHERAPY
• Cryotherapy significantly improves the outcome of severe ROP.
• This has been largely superseded by laser photocoagulation due to its higher incidence of
treatment related complications.
• PRINCIPLE: Triple free-thaw principle cause crystallization of the proteins in the vessels leading to
ablation of neovascularisation
• TECHNIQUE: Start row of contiguous and single applications at ora serrata followed by more
posterior applications.
• COMPLICATIONS OF CRYOTHERAPY:
• eyelid oedema
• laceration of the conjunctiva
• pre-retinal and vitreous haemorrhage
• systemic complications like bradycardia, cyanosis and respiratory depression.
Multicenter Trial of Cryotherapy for Retinopathy of Prematurity: ophthalmological outcomes at 10 years
Cryotherapy for Retinopathy of Prematurity Cooperative Group; Arch Ophthalmology ; 2001

LANDMARK TRIALS IN ROP
• STOP-ROP: efficacy and safety of supplemental therapeutic oxygen
for infants with prethreshold retinopathy of prematurity (ROP) to
reduce the probability of progression.
• CRYO-ROP: Evaluating cryotherapy for ROP.
• ET-ROP: Early treatment of ROP.
• BEAT-ROP: Efficacy of Intravitreal Bevacizumab for Stage-3+ ROP.
• RAINBOW: Safety and efficacy of Ranibizumab.

STOP-ROP TRIAL
• PURPOSE: To determine efficacy and safety of supplemental therapeutic oxygen for infants
with prethreshold retinopathy of prematurity (ROP) to reduce the probability of
progression to threshold disease.
• METHODS: Premature infants with confirmed prethreshold ROP in at least 1 eye and
median pulse oximetry <94% saturation were randomized to 2 arm trial:
• 1) conventional oxygen arm with pulse oximetry targeted at 89% to 94% saturation
• 2) supplemental arm with pulse oximetry targeted at 96% to 99% saturation, for at least 2
weeks
• RESULTS: supplemental oxygen at pulse oximetry saturations of 96% to 99% did not cause
additional progression of prethreshold ROP but also did not significantly reduce the
number of infants requiring peripheral ablative surgery.
Supplemental oxygen at pulse oximetry saturations of 96% to 99% did not cause additional progression of prethreshold ROP but also
did not significantly reduce the number of infants requiring peripheral ablative surgery; Pediatrics; 2000

FEATURES CRYO-ROP ET-ROP
PURPOSE To resolve the uncertainty of
peripheral retinal ablation in ROP
by evaluating outcomes at 10 year
intervals
Identify treatment selection criteria
that would result in earlier
treatment only In those eyes at
higher risk for developing threshold
ROP
TIME PERIOD Between 1986-2003 2000-2002
STUDY DESIGN Large Multicentre RCT- 291
preterm children with birth weights
< 1251 g
Larger multicentre RCT
PARTICIPANTS Randomized- treatment in 1 eye
and fellow eye served as control.
492 eyes- comparing bilateral
symmetrical threshold ROP and
unilateral threshold ROP.
Treatment with peripheral retinal
ablation within 48hr of
identification of high-risk pre
threshold disease
The fellow eye was control
(conventional management-
observed until reached threshold
and then treated
Multicenter Trial of Cryotherapy for Retinopathy of Prematurity: ophthalmological outcomes at 10
years

FEATURES CRYO-ROP ET-ROP
RESULTS At 3 months post cryotherapy,
49.3% reduction in the
unfavourable outcomes in treated
eyes versus controls.
1)Grating acuity results showed a
reduction in unfavorable visual
acuity outcomes with earlier
treatment, from 19.8% to 14.3% (P
< .005).
2)Unfavorable structural outcomes
were reduced from 15.6% to 9.0%
(P < .001) at 9 months.
CONCLUSION 1) Defined Threshold disease and
application of cryotherapy within
72 hours of its detection.
2) Cryotherapy- gives better
structural and functional outcomes
at 1-15 years v/s controls.
3)Suggested treated amd
untreated eyes with severe ROP- at
high risk for development of high
myopia.
4)Those with ROP in Zone-1
developed worse disease- hence,
served as PRECURSOR TO ET-ROP
Early treatment of high-risk
prethreshold ROP significantly
reduced unfavorable outcomes in
both primary and secondary
(structural) measures.

TREATMENT CRITERIA BASED ON ET-ROP
GUIDELINES
ZONE I NO PLUS Stage I
Stage II
Stage III
Close follow-up
Close follow-up
TREAT
PLUS Stage I
Stage II
Stage III
TREAT
TREAT
TREAT
ZONE II NO PLUS Stage I
Stage II
Stage III
FOLLOW-UP
FOLLOW-UP
FOLLOW-UP
PLUS Stage I
Stage II
Stage III
FOLLOW-UP
TREAT
TREAT

TREATMENT INDICATIONS AND FOLLOW-
UP-NATIONAL GUIDELINES
WHEN TO TREAT? TYPE-I ROP, HYBRID ROP
A-ROP
WITHIN 48 HOURS
AS SOON AS POSSIBLE
WHOM SHOULD YOU
TREAT?
An Ophthalmologist”trained and
competent” in treating sight threatening
ROP
METHOD OF TREATMENT Laser treatment delivered by indirect
ophthalmoscopy to the avascular retina in
periphery
Course and outcome after Laser treatment is
more predictable
Anti-VEGF injections given intravitreally
can be given in selected cases
Anti VEGF treatment may be used
in”rescue” cases to buy time,or when laser
expertise not available.In certain cases of
Zone 1 APROP ,it may offer certain
advantages.Dose drug and long term safety
are currently not established.special consent
for the “Off-Label use of these drugs must
be obtained
Advanced cases of retinal detachment
require vitreoretinal surgery in centers
with such facility
Surgery for ROP ,Especially Stage 5 has very
poor prognosis and must include special
consent and counseling

Pain and Protection Orally administrated sweet agents(24%
sucrose or 25% dextrose) with topical
anesthesia and multisensory stimulation
may be used
Delay in treatment due to lack of
general anesthesia must be
avoided.ROP treatment is an
emergency.Topical anesthesia is
safe and has longsafety record
especially in India
Some special conditions GA may be required
Staff trained in neonatal resuscitation and
basic neonatal care must be present.
Those in the room during Laser must wear
protective goggles
Where to treat? In the SNCU/NICU if inpatient or the infant is
unstable/sick
If discharged,then can be done in an eye
department ,if the infrastructure and
personnel are available
Follow-up after
treatment
Ophthalmologist should follow up after 1
week ,further laser may be required
Follow up following anti VEGF is currently
unclear as recurrence /recrudescene are
reported to occur months/years later

BEAT-ROP STUDY
• RATIONALE BEHIND THE STUDY:
• Background
• VEGF is a key factor in the progression of ROP
• Phases of ROP
• Phase 1: 22-30 weeks ,involves a relative hypoxia and decreased
VEGF
• Phase 2: 31-44 weeks, Relative hypoxia and increased VEGF level
Mintz-Hittner et al; Efficacy of intravitreal bevacizumab for stage 3+ retinopathy of prematurity
;The New England Journal Of Medicine; 2011

COMPARING THE VARIOUS ANTI-VEGF
TREATMENT TRIALS
FEATURES BEAT-ROP BLOCK-ROP RAINBOW TRIAL
PURPOSE Explore vascular endothelial
growth factor inhibitors in
ROP as they avoid
destructive complications of
peripheral laser retinal
ablation
To determine whether a single
intravitreal (into the gel of the
eye) injection of BEVACIZUMAB
0.625mg or 0.75mg is equivalent
(non-inferior) to treatment with
standard of care laser in infants
with Type I pre-threshold
retinopathy of prematurity
(ROP) diagnosed at 30-36 weeks
gestational age.
To determine if intravitreal
ranibizumab is superior to
laser ablation therapy in the
treatment of ROP
TIME PERIOD 2008-2010 2012-2018 Dec 2015-June 2017
STUDY DESIGN Prospective RCT assessed
intravitreal bevacizumab
monotherapy (0.625 mg in
0.025ml) vs conventional
laser therapy for Zone 1 or
Zone 2 posterior stage 3+
ROP
Prospective RCT assessed
intravitreal Bevacizumab
monotherapy(0.75mg/0.03cc
or 0.625mg/0.025cc) in one
eye vs conventional laser
ablation in the fellow eye- 3
arm trial
Randomized open label multi
centric 3 arm trial
Randomized R 0.2mg or R 0.1
mg or Laser
Mintz-Hittner et al; Efficacy of intravitreal bevacizumab for stage 3+ retinopathy of prematurity
;The New England Journal Of Medicine; 2011

COMPARISON OF RETURN TO RESPIRATORY
BASELINE
Barry et al; Comparison of Respiratory Outcomes after treating ROP with Laser Photocoagulation or Intravitreal
Bevacizumab; Ophthalmology Retina; 2020

FEATURES BEAT-ROP BLOCK-ROP RAINBOW TRIAL
PARTICIPANTS Total 150 infants (300 eyes), 143
surviving to 54 weeks
infants with Type I pre-threshold
retinopathy of prematurity (ROP)
diagnosed at 30-36 weeks
gestational age.
214 babies assessed for Primary
outcome
PRIMARY OUTCOME RECURRENCE of ROP in 1 or both
eyes requiring retreatment
before 54 weeks’ postmenstrual
agent
To demonstrate non-inferiority
of Anti-VEGF treatment to
standard-of-care laser
The primary outcome was
survival with no
active retinopathy, no
unfavourable structural
outcomes, or need for a different
treatment modality at or before
24 weeks
RESULTS ROP recurred in:
6/140 (4%) –Bevacizumab group
32/146 eyes(22%) – Laser
treatment Group
No results have been published
yet
Treatment success :
56 (80%) of
70 infants receiving ranibizumab
0·2 mg
57 (75%) of 76 infants receiving
ranibizumab 0·1 mg
45 (66%) of 68 infants after laser
therapy.
CONCLUSION Intravitreal Bevacizumab
monotherapy showed significant
increased efficacy for treatment
of stage 3+ zone 1 but not Zone II
disease as compared with
conventional laser therapy
Ranibizumab 0.2mg superior to
Ranibizumab 0.1 mg and laser
No safety issues in 24 Month F/U
period
Stahl et al; Ranibizumab versus laser therapy for the treatment of very low birthweight infants with
retinopathy of prematurity (RAINBOW): an open-label randomised controlled trial; Elsevier, 2019

INTRAVITREAL RANIBIZUMAB VERSUS
BEVACIZUMAB IN ROP TREATMENT
• Comparison of intravitreal Ranibizumab and bevacizumab treatment
for retinopathy of prematurity
• First study to compare their efficacy in patients with ROP
• Twenty patients who received anti- VEGF treatment as First line
monotherapy were included in the present study.
• Group 1: Ranibizumab (0.25mg) as the first line therapy and
• Group 2:Bevacizumab (0.625 mg)

RESULTS OF THE COMPARATIVE ANTI-VEGF
TREATMENT STUDY
• Relapse following regression of plus
• 4 eyes of 2 patients from group 1 and
• 2 eyes of 1 patient from group 2
• Relapse was observed on the 8th week in group 1 and 14th week in group 2
• One session of confluent laser photocoagulation was performed in both
groups with relapse
• CONCLUSION:
• Both ranibizumab and bevacizumab are effective in type 1 ROP
• Relapse rates higher and earlier with Ranibizumab.

SURGERY FOR ROP
• INDICATIONS :
• Stage 4A detachments greater than 3 clock hours,
• Stage 4B and
• Stage 5 ROP.

SCLERAL BUCKLING
• Stage 4a and 4b retinal detachment.
• Placement of an encircling exoplant (2.5 mm # 240 solid silicone band) as close to
the ridge as possible.
• +/_ SRFD
• AC paracentesis needed to soften the eye if SRFD not done.
• Success rates 60%–75%
• Current Perspectives in the Management of Retinopathy of Prematurity Delhi J Ophthalmol 2014; 25 (2): 108-
117.Mangat R Dogra et al.
Surgical Management in Advanced Stages of Retinopathy of Prematurity; Our Experience. Ramak Roohipoor et al.
Farabi Eye Hospital, Tehran Medical University, Tehran, Iran.

DISADVANTAGES:
• Doesn”t relieve vitreous traction .
• Myopic refractivechanges due to axial elongation and forward shift of
the crystalline lens( -2.75 D in adults Vs but -9 to -11.0 D in infants )🡪
potentially amblyogenic.
• Need for division or removal of the band 3-6 months after surgery to
allow normal growth of the eyeball.
• Current Perspectives in the Management of Retinopathy of Prematurity Delhi J Ophthalmol 2014; 25 (2): 108-117.Mangat R Dogra et al.
Surgical Management in Advanced Stages of Retinopathy of Prematurity; Our Experience. Ramak Roohipoor et al. Farabi Eye Hospital, Tehran
Medical University, Tehran, Iran.

LENS SPARING VITRECTOMY
• Done with 23, 25,27 G.
• Stage 4A ROP if the detachment extends more than 3 clock hours
and in stage 4B ROP.
• Less than 3 clock hours observe, often the fibrovascular membrane
spontaneously separates into the vitreous cavity causing release of
traction on the retina.
• Current Perspectives in the Management of Retinopathy of Prematurity Delhi J Ophthalmol 2014; 25 (2): 108-117.Mangat R Dogra
et al.
Surgical Management in Advanced Stages of Retinopathy of Prematurity; Our Experience. Ramak Roohipoor et al. Farabi Eye
Hospital, Tehran Medical University, Tehran, Iran.

National Neonatology Forum; Clinical Practice Guidelines, Screening and Management of Retinopathy of Prematurity; 2019

SUMMARY
• We are in the midst of an ever increasing Third Epidemic of ROP blindness.
• Babies are not born with ROP- It is a Preventable cause of childhood blindness.
• Immature retina is a pre-requisite and other risk factors worsen ROP.
• ICROP-3rd Edition- has provided renewed insights and terminologies to modify classification of
ROP.
• Need to focus on the ZONE of involvement and the pattern of retinal vessel branching.
• Screen timely-”Tees Din Roshni Ke”- within 30 days of birth or before discharge, earlier if lesser
birth weight.
• Laser treatment is the Gold standard currently.
• Anti-VEGF injections/ Combined treatment used in severe cases; longer follow-up needed.
• Prompt surgery can save eyes developing dreaded Retinal detachment.
• Counselling and public awareness are key to fight against ROP blindness.

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