This document summarizes the management of retinopathy of prematurity (ROP) with ranibizumab (Lucentis) and laser photocoagulation. It discusses the pathogenesis, classification, and risk factors of ROP. Current treatment modalities include laser photocoagulation, anti-VEGF therapies like ranibizumab and bevacizumab, and cryotherapy. The document also describes a case study where 20 eyes with zone-1 stage 3+ ROP were successfully treated with intravitreal injections of ranibizumab followed by laser photocoagulation, with no complications. Ranibizumab was chosen due to its smaller size, shorter half-life, and reduced risk of systemic effects compared

1. Management of APROP With
Ranibizumab (LUCENTIS®) and
Laser
Dr. Ajay Dudani
Professor k j somaiya medical
college
Mumbai retina centre

2. Retinopathy of
prematurity
 Retinopathy of prematurity (ROP) is a vaso
proliferative disorder of the retina and it is a
major factor of morbidity especially in neonates
with extremely low birth weight (LBW)
 Several risk factors (abrupt fluctuations in
oxygen levels, gender, low birth weight, etc)
Vasileios Giapros, Aikaterini Drougia, Ioannis Asproudis. Early Human Development 87 (2011) 653–657

3. Incidence
 Related to gestational age (GA) and birth weight
(bw).
 ROP rare in bw > 2000 grams.
 70% ROP in bw < 1250g and 7% develop
threshold ROP.
 Threshold ROP very rare in bw > 1250g.
 95% ROP begins at 32-34 weeks GA.
 Threshold disease at 36 weeks.
 Regression with spontaneous healing at 45-48
weeks GA.

4. Incidence
 Survival increased from 5% to 65% in last 40
years in case of ELBW
 In case of VLBW infants survival increased from
35% to 90%.1
 CRYO-ROP: 65.8% prevalence in pre-matures
of <1251g2
 ETROP study (X/2000-IX/2002) concluded with
a prevelance of 68% amongst low birth weight
of <1251g
1. Gergely K, Gerinec A. Bratisl Lek Listy 2011; 119(9)
2. Cryotherapy for retinopathy of prematurity Co-operative group,1990; Palmer,1991; National Eye Institute, 2003

5. Epidemiology
 The incidence of ROP in various Western studies
has been reported to vary from 21 to 65.8%.
 In developing countries prevalence rate of 16-48
%, is reported in low weight infants (1000g-
1500g)
 In India incidence of ROP varies from 11.9% to
52% (table 1)
 More recent studies have reported lower incidence
rates of 20% to 30%.
 But with more number of extreme low-birth-weight
infants surviving in developed and developing
countries, we may be on the verge of an ROP
epidemic
1. Dr. Santosh Mahapatra, Incidence of ROP at Neonatal Intensive Care Units, AIOC 2008 PROCEEDINGS
2. William Tasman, Arch Ophthalmol. 2011;129(8):1083-1086
3. Chawla D, Agarwal R, Deorari AK, Paul VK. Indian J Pediatr 2008;75:73-76.

6. Incidence and risk factors of ROP in
India

7. Pathogenesis: Phase 1
 Premature infants have incomplete
vascularized retinas ( peripheral avascular
zone depends on gestational age)
 Prematurity restricts normal in-utero retinal
vasculogenesis and with maturity of infant
avascular retina becomes hypoxic
A.M Roth. Am J Ophthalmol, 1977;84, 636–640

8. Pathogenesis: Phase 2
 Ph 2 is driven by hypoxia leading
overproduction of growth factors,
orchestrated by vascular endothelial
growth factor (VEGF) and other factors
that induce neo vascularisation.
J Stone, A Itin and T Alon, et al. J Neurosci, 1995;15, 4738–4747

9. ROP - Pathogenesis
 16 weeks of gestation -
primitive spindle cells
gradually grow out over
the surface of the retina.
 29 weeks reached ora
serrata. At this time these
spindle cells start to form
blood vessels.
 The vessels reach the
anterior edge of the
retina and stop their
progression at about the
time of birth.

10. Understanding VEGF
 VEGF is a relatively endothelial cell specific
mitogen, promoting endothelial cell growth and
survival1
 ROP phase1: decrease in VEGF due to relative
hyperoxia ( VEGF agonists)
 ROP phase 2: compensatory increase in VEGF
leading to neovascularization ( VEGF antagonist)

11. Role of VEGF in Pathogenesis
of ROP
Schematic representation
Seminars in Neonatology Volume 8, Issue 6, December 2003, Pages 469-473 Conundrums and Controversies in Neonatal Intensive Care

12.  VEGF encompasses a number of proteins
belonging to a family of heparin binding
growth factors.
 Secreted in response to hypoxic and
inflammatory stimuli
 Main role is to orchestrate the development
and growth of blood vessels, by promoting EC
proliferation (mitogenesis), migration and tube
formation, under physiological and pathological
conditions.
Qazi Y, Maddula S, Ambati BK. Mediators of ocular angiogenesis. J Genet 2009;88 (4):495–515
Role of VEGF in Pathogenesis of ROP

13. ROP - Classification
International Classification of ROP:
•3 Zones (location)
•Clock hours (extent)
•Stages 1 through 5
•Plus Disease

14. ROP: Anatomical Location
 The area of the retina affected by ROP is divided
into three zones
Zone 1: It is the most centrally located, and ROP
develops in this zone if the retina in this area is most
underdeveloped Zone 1 is more severe compared with
disease limited to zones 2 or 3
Zone 2: It is the intermediate zone where blood vessels
often stop in ROP
Zone 3: It is the peripheral zone of the retina, where
vessels are absent in ROP, but present in normal eyes.

15. ROP: Location of Zones

16. Severity of the disease
Stage 1
Demarcation Line
 A line that is seen at the
edge of vessels, dividing
the vascular from the
avascular retina.
 Retinal blood vessels fail
to reach the retinal
periphery and multiply
abnormally where they
end .

17. Severity of the disease
Stage 2
Ridge
The line structure of
stage 1 acquires a
volume to form a ridge
with height and width.

18. Stage 2 ROP at the junction between
vascularized and avascular retina

19. Stage 3
Ridge with extra-retinal
fibrovascular proliferation
 The ridge of stage 2 develops
more volume and there is
fibrovascular proliferation into
the vitreous.
 This stage is further
subdivided into mild,
moderate and severe,
depending on the amount of
fibrovascular proliferation
Severity of the disease

20. Stage 3 ROP

21. Stage 4
 Partially detached retina.
 Traction from the scar produced by
bleeding, abnormal vessels pulls the retina
away from the wall of the eye.
Severity of the disease

22. Stage 5
• Completely detached retina and the
end stage of the disease.
• If the eye is left alone at this stage,
the baby can have severe visual
impairment and even blindness.
Severity of the disease

23. Stage 5 retinopathy of prematurity

24. Aggressive posterior ROP-Stage 3
(AP-ROP)
 Also referred to as Rush disease
 Is a rapidly progressive form of ROP
 Observed most commonly in zone-I.
 Features of AP-ROP are, its posterior location
and prominence of Plus disease.
 Progression occurring in days, rather than
weeks.

25. Plus disease

26. Examples of AP-ROP

27. Treatment
 Retinal Cryotherapy
 Laser photocoagulation
 Anti-VEGF therapies
 Erythropoetin
 Angiopoetin
 Gene therapy
 Physiologic reduced oxygen protocol
(PROP)

28. ROP - Management
 PREVENTION -
– Prevent preterm labor.
– (Optimal) minimum use of oxygen.
– Prevention of complications.
– Screen all infants <34 wks gestational age
AND <1800 g birth weight between 4-6 weeks
of age.

29. Cryotherapy

30.  LASER PHOTOCOAGULATION
– Laser treatment for ROP is similar to cryotherapy.
The laser spot size is smaller than a spot of
cryotherapy. Usually 600-1000 spots of laser as
compared to 30-50 spots of cryotherapy needed.
– Laser is a direct treatment of the retina and its
underlying tissue instead of the entire thickness of
the eye wall like in cryotherapy.
– Most ophthalmologists treating ROP are now using
laser.
ROP - Management

31. Laser Photocoagulation
 Laser photocoagulation is the most
common treatment modality.
 A laser is directed to a designated spot
to destroy abnormal vessels and seal
leaks.
 Laser photocoagulation is the
preferred method of treatment by
surgeons, because there is little
postoperative pain and swelling

32. Laser Photocoagulation

33. Anti-VEGF therapies
 Is the use of anti-VEGF justified for
retinopathy of prematurity?
– Higher concentration of VEGF in the vitreous of
ROP patients has been demonstrated and
compared with those who do not develop the
disease
– The rationale for this treatment approach is that
VEGF promotes retinal vascularization.
– However it is not a replacement for existing
therapies as it should demonstrate demonstrate
similar efficiency rates and lower iatrogeny than
existing therapies

34. Summarization of treatment modalities

35. Efficacy of Intravitreal
Bevacizumab for Stage 3+
Retinopathy of Prematurity:
BEAT-ROP
 Prospective, controlled, randomized, stratified,
multicenter trial to assess intravitreal bevacizumab
monotherapy for zone I or zone II posterior stage 3+
(i.e., stage 3 with plus disease) retinopathy of
prematurity
 Showed increased efficacy of intravitreal bevacizumab
as compared with conventional laser therapy for stage
3+ retinopathy of prematurity when both zones I and II
were considered
 Sample was sufficiently large to show significant efficacy
of intravitreal bevacizumab for zone I disease.
 Insignificant risk of loss of vision due to ablative therapy
Efficacy of Intravitreal Bevacizumab for Stage 3+ Retinopathy of Prematurity Helen A. Mintz-Hittner, M.D., Kathleen A. Kennedy, M.D. N Engl J Med 2011;364:603-15.

36. BEAT ROP
 Conclusion:
- Compared to conventional therapy showed
significant benefit in zone I, but not in zone
II
- Development of peripheral retina continued
after therapy unlike complete destruction in
conventional laser therapy
- Safety yet to be established by similar trials
with larger subjects
Efficacy of Intravitreal Bevacizumab for Stage 3+ Retinopathy of Prematurity Helen A. Mintz-Hittner, M.D., Kathleen A. Kennedy, M.D. N Engl J Med 2011;364:603-15.

37.  What is the current indication for anti-VEGF
in ROP?
(a) Cases in which laser cannot be applied due to
opacification, poor midriasis, etc.
(b) To be used as adjuvant treatment, in cases where
vascular activity persists after laser application;
provided there is no-marked fibrous component to
avoid retina detachment due to membrane
contraction.
(c) in cases with advanced zone 1 retinopathy, where
anti-VEGF can be considered as a first choice or as a
co-adjuvant treatment for laser.
Anti-VEGF for ROP

39. OUR Study

40. Case Study
 We report results from a case series of preterm,
extremely low-birth-weight infant, with zone-1,
stage 3+ AP-ROP, treated successfully with
intravitreous ranibizumab injection (LUCENTIS®;
Novartis inc.),
 Ranibizumab is an anti-angiogenic, monoclonal
antibody fragment, with strong binding to VEGF-
A
 A detailed search of content in medical databases
like Medline, EMBASE, etc., failed to reveal
mention of any case study, illustrating treatment

41. Case Study
 20 consecutive eyes of 10 preterm babies
 5 boys 5 girls
 Gestational weight: 940- 1200 gms
 Presentation:
- Zone-1, stage-3 ROP, PLUS DISEASE ,shunts
- Corneal haze
- Media hazy
- Iris neovascularisation
 The International Classification of ROP Revisited
was referred to define Zone I and to subdivide the
severity of stage 3

42. Procedure
 All eyes treated with intravitreal Ranibizumab (IVR)
and laser photocoagulation
 Intravitreal Ranibizumab at a dose of 0.3mg
mg/0.02 ml (60% of the normal adult dose) was
administered
 Ranibizumab was administered through the pars
plicate of each eye, under topical anesthesia, in
sterile conditions
 Injections were administered using continuous
cardiorespiratory monitor

43. Procedure
 All infants received peripheral indirect diode laser
ablation using the ultra fast technique
 At setting: 0.05second exposure; 0.1 second
INTERVAL repeat mode; as a result 5000 shots
could be given in 7 to 9 minutes
 7 infants received laser, followed by IVR injections
for persistent new vessels in zone-1
 3 infants with persistent tunica vasculosa lentis
with poor pupillary dilation, were administered
IVR injections prior to laser IN NICU
 Laser was done to avascular zone at 1 week

44. Procedure
 Indirect ophthalmoscopy was utilized to look for:
– Any injury to the lens
– To determine the presence of adequate blood
flow through the central retinal artery
– To identify any retinal tears or vitreous
hemorrhage immediately after the injection.
 The procedure resulted in regression of plus
disease and pupillary dilation.

45. Results
 Improvement seen with in 48hrs.
 Over the next 7 days AP-ROP significantly ceased
 Within next 4 week following the injections, the AP-
ROP disappeared
 Extra retinal fibrovascular proliferation superior and
inferior to the typical indentation toward the macula
disappeared
 Retinal vessels continued their anterior growth into
the previously avascular retina.
 The laser reach in the avascular zone was good

46. Results
 Laser improved dilation of eyes and potentially
blinding eyes were salvaged
 Ophthalmic examinations revealed
– Central and steady fixation
– No strabismus,
– Clear corneas and lenses
– Minimal or no myopia or anisometropia.
 No ocular or systemic complications were reported.
 Infants were closely followed in the life time to look
for potential neuro developments and defects

47. Intravitreal ranibizumab plus peripheral
laser photocoagulation for APROP

48. Rationale for Ranibizumab Use
 The choice of ranibizumab in our case study was
deliberate
 Ranibizumab is derived from the same parent murine
antibody as bevacizumab , but
– has low molecular weight (48 kDa) compared to bevacizumab
(149 kDa) , which provides greater retinal penetration
– with Intravitreal half-life of ~9 days and Binding affinity of
0.14 nM
– Shorter half life ~15 hours versus 20 days for bevacizumab,
which reduces the risk of systemic complications
– Also as compared to bevacizumab, ranibizumab does not
comprise Fc fragment , reducing risk of complement-mediated
toxicity and eye inflammation
 This encouraged us for experimenting IVR in combination
with laser, for treatment of AP-ROP

49. Conclusion
 In our case series, AP-ROP was successfully treated
by ranibizumab and revealed the effectiveness of
IVR injectionsfor treatment of severe stage 3 ROP
in zone I.
 Appropriate studies with long-term follow-up are
warranted to determine the potential safety and
benefit of such therapy.

50.  THANK YOU