APROP IS A TYPE 2 ROP WHICH NEEDS ANTIVEGF INJ AND LASER

1. Aggressive POSTERIOR Retinopathy
of Prematurity
APROP
AJAY I DUDANI
MUMBAI RETINA CENTRE
ZEN EYE CENTRE

2. • Retinopathy of prematurity is a multifactorial vasoproliferative retinal
disorder that increases in incidences with decreasing gestational age.
• Its a developmental vascular proliferative disorder that occurs in the
incompletely vascularized retina of primarily premature infants.
• First described by TERRY in 1941
• Originally known as Retrolental fibroplasia
• Term RETINOPATY OF PREMATURITY was coined by Health in 1951.
• Campbell suggested the relationship of intensive oxygen therapy &
subsequent development of ROP.
• Kinsey: ROP was inversely proportional to birth weight.
Introduction
AVRY BOOK OF NEONATOLOGY
PERSONS BOOK OPTHALMOLOGY

3. CASE SCENARIO
• 27 WEEKER PRETERM ,1200 GRAMS
• VENTILATOR,SEPSIS,SURFACTANT,OXYGEN
• ROP SCREEN AT 30 WKS: CORNEAL HAZE, PUPIL
SEMIDILATING,ZONE 1 DISEASE,PLUS DISEASE,
ACUTE U TURN OF VESSELS AT MACULA ,
AVASCULAR PERIPHERY
• NOW WHAT????
• LASER
• ANTI VEGF INJECTION

4. • Vulnerable patient population
• Rare patient population
• Involvement of multiple clinical disciplines:
– Immediate – pediatric ophthalmology, neonatology
– Long-term –developmental pediatrics,
neuropsychology
• Clinical investigation challenges
– Parental consent
– Blood sampling
– Intravitreal administration of low volumes
Challenges of the Neonatal Population
4

5. Between 16 and 40 weeks gestation
Normal Intrauterine Fetal Retinal Vascularization
5 AVRY BOOK OF NEONATOLOGY
PERSONS BOOK OPTHALMOLOGY

6. Retinopathy of Prematurity (ROP)
6
• Retinopathy of prematurity (ROP) affects around
20 per cent of babies who are born prematurely.
– Leading cause of pre-school blindness in the US
– Around 50,000 children are blind from ROP worldwide
• Multiple risk factors
– Degree of prematurity
– Low birth weight
– Post-natal oxygen delivery
– Hyperglycemia
Low / Middle income countries
High income countries

7. Role of IGF-1 and VEGF in the pathogenesis of ROP
Effect of IGF-I inhibition on vascular growth. Flat-mounted
whole retina shows that, in IGF-I -/- mice (A), there is less
progression of vascular development (bright area)
compared with IGF-I+/+ littermate controls (B).
Mean serum IGF-I at matched gestational ages in infants
with and without ROP. The mean IGF-I level for infants
with ROP (○) and without ROP (●) is shown vs.
gestational age. (Bars = SEM.)
(Hellstrom et al. PNAS 2001; 98:5804)

8. Prematurity Can Disrupt Retinal Vascularization
The VEGF theory
8
↑O2 and ↓VEGF
Exposed to more
oxygen than in
womb
(environmental and
therapeutic)
Retinal tissue
produces less VEGF
Retinal vessel growth
slows
Continue retinal tissue maturation and growth
Oxygen demand
increases
Hypoxic avascular
retinal tissue
produces VEGF
↑VEGF
Retinal vessel growth
accelerates – over-
proliferation and
abnormalities can
develop
Abnormal tissue
development
Can lead to scarring,
retinal detachment
and blindness
Mintz-Hittner et al. N Engl J Med 2011

9. Color Fundus Images of ROP
9 http://focusrop.com/
Presence of ridge
Extraretinal
fibrovascular
proliferation
Partial retinal detachment
Total retinal detachment
Stage
2
Stage
3
Stage
5
Stage
4

10. • Unifying principle
– The more posterior the disease and the greater amount
of involved retinal tissue, the more serious the disease
• Key observations essential in describing the disease:
1. Location of retinal involvement by zone
2. Extent of retinal involvement by clock hour
3. Stage or severity of retinopathy at the junction of the
vascularized and avascular retina
4. Presence or absence of dilated and tortuous posterior
pole vessels (plus or pre-plus disease)
International Committee for the Classification of Retinopathy of Prematurity 2005 Arch Ophthalmology
International Classification of ROP
Consensus statement updated 2005

11. • Defining the anteroposterior location of the
retinopathy
Location of Disease

12. • Describe the abnormal vascular response at the junction of the vascularized and
avascular retina (i.e., at the leading edge)
– For the eye as a whole, staging is determined by the most severe manifestation present
– However, if recording the complete examination, each stage that is present is defined and
the extent of each stage by clock hours is documented
• Classification:
– Demarcation line (Stage 1)
– Ridge (Stage 2)
– Extraretinal fibrovascular proliferation (Stage 3)
– Partial retinal detachment (Stage 4)
– Total retinal detachment (Stage 5)
• Aggressive Posterior ROP
– Ill-defined retinopathy with prominence of plus disease
and predominant posterior location
– Does not progress through the classic stages 1 to 3
Staging the Disease

13. • Plus disease
– If sufficient vascular dilatation and
tortuosity are present in at least two
quadrants of the eye
• Based on standard photographs
• Pre-plus disease
– Abnormal dilatation and tortuosity that are
insufficient for diagnosis of plus disease
Plus and Pre-plus Disease
STOP-ROP Pediatrics 2000;105:295-310

14. SCREENING GUIDELINES
Recommendations based on review of data from the CRYO-ROP and
LIGHT-ROP studies
• Initial screening should be
performed by 31 weeks PMA or 4
weeks CA
• Screening can be discontinued if any
of the following three signs are
identified:
– Lack of development of pre-
threshold or worse ROP by 45 weeks
PMA
– Progression of retinal vascularization
into zone 3 without previous ROP in
zone 2
– Full vascularization
(Reynolds et al. Arch Ophthalmol 2002; 120:1470)

15. Rationale for Treatment of ROP
Reduce VEGF production by avascular retinal tissue
15
↑O2 and ↓VEGF
Exposed to more
oxygen than in womb
(environmental and
therapeutic)
Retinal tissue produces
less VEGF
Retinal vessel growth
slows
Continue retinal tissue growth
Oxygen demand
increases
Hypoxic avascular
retinal tissue
produces VEGF
↑VEGF
Retinal vessel growth
accelerates –can lead
to over-proliferation
of vessels and
development of
abnormalities
Abnormal tissue
development
Lead to scarring, retinal
detachment and
blindness
Mintz-Hittner et al.
N Engl J Med 2011

16. Laser Ablation Therapy
Destroy VEGF-producing retinal tissue
16
Laser burn scars
http://focusrop.com/

17. • Technical
– Equipment
– Anesthetic support
– Visualization of target area
• Clinical
– Treated patients at 9 months corrected age:
• 14% unfavorable visual acuity outcomes (“poor” or
“blind/low vision”)
• 9% unfavorable structural outcomes (abnormalities affecting
the macula)
– Treated patients at 3 years corrected age:
• 38% highly myopic (≥ 5 diopters)
Challenges of ROP Ablation Therapy
17

18. • Potential advantages
– Targets underlying pathophysiology
– Rapid onset of action
– No retinal tissue destruction
– May allow normal retinal vascularization to resume
– Can be less technically demanding to perform
Anti-VEGF Therapy in ROP
A game-changer in ROP treatment?
18

19. Studies in the past
Michael A. Klufas, MD; R. V. Paul Chan, MD, FACS
Journal of Pediatric Ophthalmology & Strabismus • Vol. 52, No. 2, 2015
19
The number of clinical studies in neonates investigating the use of intravitreal
anti-vascular endothelial growth factor therapy for the treatment of retinopathy of
prematurity has been rapidly increasing in recent years

20. BEAT-ROP Study
20
Mintz-Hittner et al NEJM 2011
0
10
20
30
40
50
Bevacizumab
0.625 mg
Laser
Proportion
of
patients
Posterior Zone II

21. 1. Is anti-VEGF really better than ablation therapy?
– Support coming from predominantly case reports
– BEAT-ROP study (published in 2011 in NEJM)
• A prospective randomized controlled study that appeared to show the benefits of
bevacizumab over laser therapy
– But an unusually high failure rate in the laser therapy arm
2. Is anti-VEGF safer than ablation therapy?
– No consistent safety signals reported to date - ? late retinal detachment
– But minimal data on long-term impact of anti-VEGF in developing neonates
– ↓systemic VEGF levels have been reported after anti-VEGF in ROP
3. What is the right dose and type of anti-VEGF?
– Most experience is with ½ adult dose bevacizumab – likely for availability /
practical / handling reasons
– Can lower doses be as effective and safer than current doses?
Anti-VEGF Therapy in ROP
Three key questions remain
21

22. 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.

23. Plus disease

24. Examples of AP-ROP

25. 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

26. Summarization of treatment modalities

27. • 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

29. Bevacizumab vs Ranibizumab
SAN-NI CHEN, MDRETINA 35:667–674, 2015THE JOURNAL OF RETINAL AND VITREOUS DISEASES 2015 VOLUME 35 NUMBER 4
29
• Retrospective case series
• 72 eyes of 37 patients with Type 1 ROP
Baseline
Results

30. PLOS ONE | DOI:10.1371/journal.pone.0148019 January 27, 2016
30

31. Pharmacological characteristics of anti-VEGF therapies
Fc-containing aflibercept and bevacizumab have more prolonged
systemic half-lives than ranibizumab
Ranibizumab Bevacizumab
MOA /class
Anti-VEGF-A antibody fragment
[targets all VEGF-A isoforms]1
Anti-VEGF-A
full-length antibody
[targets all VEGF-A isoforms]7
Molecular weight 48 kDa2 149 kDa7
Half-life in the
rabbit eye
2.88 days3 4.32 days3
Half-life in the
human eye
9 days1 6.7 days8
Systemic elimination
half-life
~2 hours2 20 days7
Licensed
indications
Wet AMD, visual impairment
due to DME, visual impairment due to ME
secondary to RVO (BRVO and CRVO)1
Metastatic colorectal cancer, non-
small cell lung cancer, glioblastoma,
metastatic kidney cancer7
Formulation/
administration
Intravitreal injection
For licensed indications: intravenous
infusion from a single-use vial7

32. Serum Concentrations of Bevacizumab and VEGF in Infants With ROP
0002-9394/$36.00 © 2012 BY ELSEVIER INC. 327 doi:10.1016/j.ajo.2011.07.005
32
• 11 infants with ROP with mean gestation of 25 weeks
• All had undergone laser and 0.25 mg or 0.5 mg of bevacizumab by intravitreal injection
• Serum samples of bevacizumab and VEGF collected before treatment and 1 day, 1 week, and 2 weeks after
treatment
• There was a significant negative correlation between the serum concentration of bevacizumab and VEGF
• “These results indicate that bevacizumab can escape from the eye into the systemic circulation and reduce
the serum level of VEGF in infants with ROP. Continued extensive evaluations of infants are warranted for
possible effects after intravitreal bevacizumab in ROP patients.”

33. Invest Ophthalmol Vis Sci. 2015;56:956–961. DOI:10.1167/ iovs.14-15842
33
• Serum bevacizumab was detected 2 days after the injection, peaked at 14 days, and persisted
for up to 60 days with half-life of 21 days.
• Serum free VEGF levels decreased in all three subgroups 2 days post treatment, with more
significant reductions found in both IVB-treated groups

34. 34
• Six eyes of 4 premature infants with threshold ROP 3 plus disease in zone II, were
treated with one intravitreal injection of 0.03 ml ranibizumab
• Treatment of ROP 3 plus disease with intravitreal ranibizumab was effective in all
cases and should be considered for treatment.

35. | Presentation Title | Presenter Name | Date | Subjey
35
Group 1
IVR only
Group 2
2A Initial IVR 2B Initial Laser
16 eyes 13 eyes 28 eyes

36. | Presentation Title | Presenter Name | Date | Subject | Business Use Only
36
6 days after IVR monotherapy 6 months after IVR monotherapy
Image before IVR monotherapy

37. Case Study
• 20 consecutive eyes of 10 preterm babies
• 27- 32 weeks age
• 5 boys 5 girls
• Gestational weight: 940- 1200 gms
• Presentation:
- Zone-1, stage-3 ROP
- Corneal haze
- Media hazy
- Iris neovascularisation

38. Procedure
• All eyes treated with intravitreal Ranibizumab and laser
photocoagulation 4-12 weeks post injections
• 7 infants received peripheral indirect diode laser ablation
using the ultra fast technique INITIALLY
• Followed by intravitreal injections of ranibizumab for
persistent new vessels in zone-1
• 3 infants with persistent tunica vasculosa lentis
with poor pupillary dilation, were administered
intravitreal injections ranibizumab prior to laser,

39. Results
• Improvement seen in with in 48hrs.
• Within next 7 days AP-ROP significantly REGRESSED BUT AREAS
SHOWED RETINAL AND PRERETINAL HAEMORRHAGES
• Extraretinal fibrovascular proliferation superior and inferior to the
typical indentation toward the macula disappeared
• The laser reach in the avascular zone was good
• No strabismus.
• Clear cornea and lenses
• No ocular or systemic complications reported.
• Infants were closely followed UP FOR 7 YRS to look for potential
neuro developmental defects
• Myopia deveopment was reduced

40. Intravitreal ranibizumab plus peripheral laser
photocoagulation for APROP

41. 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
– Shorter half life
– Also as compared to bevacizumab, ranibizumab does not
comprise Fc fragment
• This encouraged us for experimenting Intravitreal
ranibizumab in combination with laser, for treatment of AP-
ROP.

42. Conclusion
• In our case series, AP-ROP was successfully treated by
ranibizumab and revealed the effectiveness of intravitreal
injection of ranibizumab for 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.

43. Management of ROP and case series
Dr. Ajay Dudani
Mumbai retina centre
Zen Eye Centre
Bombay Hospital

44. Selective anti-VEGF in ROP
• Why selectivity?
– VEGF 165 blockade inhibits pathological
angiogenesis at margin of vascular and avascular
retina
– Normal retinal angiogenesis continues at the
periphery
– Systemic safety
• Paramount in premature infants

45. Selective anti-VEGF in ROP
• Pioneering use of Pegaptanib sodium to treat ROP unveils many issues for
future studies- Michael Trese, ARVO 2007
• Five eyes were given half dose (0.15mg) of Macugen intravitreally
• Macugen treatment resulted in reduction of the tunica vasculosa lentis
and improved pupil dilation that allowed laser treatment to be performed
more easily
• All of the Macugen-treated eyes appeared more vascularly quiet than the
controls
http://www.escrs.org/PUBLICATIONS/EUROTIMES/06Sept/pdf/Pioneeringuseof.pdf

46. Our experience IN THE
BEGINNING WITH MACUGEN
2009

47. Case-1- ROP
• 27 weeks infant presented with ROP stage IV A Zone 2
• Areas of TRD with Fibro Vascular Proliferation
• Laser - 5000 shots
• Both eyes pegaptanib sodium (3/4th dose) at one week
interval
• Good regression of NV and TRD

48. Case-1- ROP
Injection Technique
• Topical Anesthesia
• Hold the baby
• Paracentesis Twice
• Injection given 1 mm from Limbus

49. v
Baseline Fundus

50. Case 2
• 27 weeks baby
• Sudden progression to rush disease, zone I
and II
• Laser sittings
• BE Lucentis
• RE developed TRD

51. Case-3
• 27 weeks infant presented with bilateral ROP stage III Zone 1 with new vessels
around macula : persistent
• Bilateral Laser 4000- 5000 shots
• RE pegaptanib sodium (3/4th dose)
• LE pegaptanib sodium delayed by one week
– NV increased with Vitreous Hemorrhage
– Do not delay
• No Side Effects noted

52. v
Baseline Fundus RE

53. USG RE

54. v
Baseline Fundus LE
Post-injection fundus LE

55. USG RE

56. v
Baseline Fundus LE
Post-injection fundus LE

57. USG LE

58. Case-3
• After 6 weeks, BE developed vitreous hemorrhage
• BE underwent lens sparing vitrectomy
– BE bleeding less due to prior anti-VEGF
• Suggestion
– Pre-vitrectomy Inj. Pegaptanib followed by surgery after 2 days
– Prevent intraop bleeding

59. Case 4
• Both eyes ROP stage III zone II with plus
disease
• BE inj Lucentis
• No laser
• FU after 3 weeks
– BE stage I zone III with no plus disease
– BUT peripheral retina remained avascular
• ? Does pan-VEGF blockade prevent normal
vasculogenesis of avascular retina?

60. Thank you