ROP

1. RETINOPATHY OF PREMATURITY
DR ANISHA RATHOD
MS,FPOS(Pediatric Ophthalmology And Strabismus)

2. FINANCIAL DISCLOSURE
THE AUTHOR HAS NO FINANCIAL INTEREST IN THE SUBJECT MATTER BEING PRESENTED

6. • Preterm: born before 37 weeks
gestation
• Extremely preterm: born before 28
weeks gestation
• About 6-8% of deliveries are preterm
• 1.5% of babies are born before 32
weeks
• Blindness from ROP
• 50,000 children blind world wide from
ROP
• ROP accounted for 3% UK childhood
blindness in 2000
• ROP causes 60% of childhood
blindness in Argentina, > 50% in
Poland, Russia
• Every 2hrs 3 babies in India reach
threshold

7. • Normal retinal vascularisation
• Choroid vascularises at 6 weeks
• Retinal vascularisation starts at optic nerve
head at 16 weeks gestation
• Proceeds outward to the periphery
• Vascularisation is almost complete by term
• Vasculogenesis: primitive plexus formed
from precursor cells, not VEGF dependant
• Angiogenesis: new vessels from pre existing
vasculature, VEGF dependant
• Central 1/3 formed by vasculogenesis

9. Pathogenesis of ROP
• Premature delivery interrupts normal vascular growth
• Phase 1 : delayed retinal vascularisation (birth-31/32 weeks)
• Developing retina exposed to hyperoxic environment (ambient and
supplemental)
• Reduces angiogenic factors delaying retinal vascularisation
• Phase 2: neovascularisation
• Neuroretina continues to develop causing hypoxia with overproduction of
angiogenic factors especially VEGF
• Causes uncontrolled retinal blood vessel growth

10. • Vasculogenesis = de novo tube formation
• Angiogenesis = sprouting of new tubes off of pre-existing tubes
• Endothelial Cell = cell type that makes up and lines blood vessels
• Mural Cells = specialized cells that surround blood vessels
• Pericytes
• Smooth muscle cells
• Angiogenic Factors
• Vascular Endothelial Growth Factor (VEGF-A, VEGF-B, PlGF, VEGF-C, VEGF-D
• Angiopoietins (Ang 1, Ang2,etc)
• Notch ligands
Vascular Development

11. Vasculogenesis
Lymphangiogenesis
Angiogenesis
Mesoderm formation
Hemangioblasts
Blood island formation
Endothelial cells
Hematopoietic
cells
Primary vascular
plexus
Lymphatics
Lymphangioblasts
Veins
Capillaries
Arteries
VE-Cadherin
bFGF
VEGF A
VEGFR-1/2/3
TGFb
EphrinB2/EphB4
Endoglin Notch
Tal1/scl
Gata 1
Ang1/2
Tie2
PDGF B
Id1/3
VEGF C/D
VEGFR-3
VEGF A
VEGFR-2
TGFb
Tal1/scl
Gata 1
Vascular Development
Karkkarnin et al., 2002 Nature Cell Biology
GM-CSF
Notch on Notch off

12. Angiogenesis - Basement Membrane Breakdown
Smooth Muscle
Cells
Endothelium
Basement
Membrane
Proteases
Angiogenic
Stimulus
(VEGF)

13. Angiogenesis - Endothelial Cell Migration
Endothelium
Nascent
Vascular Sprouts
VEGF
Smooth Muscle
Cells
Basement
Membrane

14. Angiogenesis - Endothelial Cell Proliferation
Endothelium
VEGF
Sprout
ElongationSmooth Muscle
Cells
Basement
Membrane

15. Angiogenesis - Capillary Morphogenesis
Endothelium
VEGF
New
Lumen
FormationSmooth Muscle
Cells
Basement
Membrane

16. Angiogenesis - Vascular Maturation
Endothelium
VEGF
Vascular Pruning
(apoptosis?)
SMC, pericyte
recruitment
Smooth Muscle
Cells
Basement
Membrane

17. Angiogenesis - Vascular Maturation
Endothelium
VEGF
Endothelial
cell-cell junctions
Smooth Muscle
Cells
Basement
Membrane
Negative
Feedback

18. Retinopathy of Prematurity

19. Screening
• Start screening between 20 to 30 days of life.
• One screening session must definitely be completed before day 30 of life (day-
30 strategy).
• Screening must be done for babies born before 34 – 35 weeks of gestational age
at birth and/ or birth weight of 1500 g or less
• Earlier (20 days) screening is strongly recommended for babies under 30 weeks,
and/or those with weight of less than 1500 g at birth.

22. • Zone I (posterior pole or inner zone consists of a circle), the radius of which extends
from the centre of the optic disc to twice the distance from the centre of the optic disc
to the centre of the macula.
• The radius of this zone subtends an angle of 30 degrees.
• The limits of the zone are consequently defined as twice the disc-foveal distance in all
directions from the optic disc; an arc of 60 degrees.

23. • Zone II is the area extending from the edge of zone I peripherally to a point
tangential to the nasal ora serrata at the 3 o clock position in the right eye and
the 9 o clock position in the left eye.
• The temporal edge of zone II cannot be more accurately defined as the anatomic
landmarks needed to identify the equator in premature infants are obscured.

24. • Zone III is the residual crescent of retina anterior to zone II. By convention zones
I and II are considered mutually exclusive.
• Retinopathy of prematurity should be considered in zone II until it can be
confirmed that the nasal most 2 clock hours are vascularised to the ora serrata.

25. ZONES

26. Atypical ROP
• Rop in older and heavier infants above 1500 gms
• Quinn pointed out that screening in higher birth weight infants is difficult due to
• 1)Lack of clear definition of population at risk
• 2)No clear description of Rop with birth weight more than 1250 gms
• 3)No effective strategy for examining infants with high likelihood of being
discharged from hospital prior to development of disease
• STOP-ROP trial for larger infants
• Greater than 1249 g and 2 greater than 1999g were included 34.14 to 38 wks
eyes showed macular heterotopia

27. • Wright et al screened 7-infants based in AAP guidelines of 1988-1996 in which
birth weight less than 1800 g and less than 35 weeks were screened exposed to
supplemental oxygen.
• Stage 2 and prethreshold stage 3 ROP seen in infants with birth weight less than
1201-1500 g
• No ROP seen beyond stage 1
• Based on their cohort study,the incidence of threshold was no higher than 0.9%
• Andruscavage and Weissgold-Infants less than or =2500g
• 310 infants birth weight 1500 and 2499g .
• 10 of them developed Stage1/stage 2 ROP,2 developed Stage 3 ROP which later
progressed to threshold

28. • Hutchinson et al reported 1118 infants with birth weight >1250 g
• 697 had birth weight>1500 g
• Fewer than 20% developed ROP with stage 2 in 3%,stage 3 in 3%,stage 4 in l<1%
and stage 5 in 0%
• Stage 3 Rop seen in GA upto 38 wks with birth weight 1874g
• 7 infants with birth weight greater than 1500g developed stage 3 ROP
• Chiang et al used New York database to examine newborn with initial hospital
stay termed”extended stay new born infants”
• 15691 infants-Extended stay
• 132(6.4%) extended stay patients with birth weight>1500g or 17(2.5%)patients
with birth weight >2000g.

29. Screening method :
• Indirect ophthalmoscope with a
20, 28 or 30 D lens (28D or 30D lens
are usually preferred as they allow
easier viewing of the peripheral
retina).
• Eye speculum
• Scleral indentor
• Nesting (wrapping) of infants can
significantly reduce the stress
during screening procedure

30. • The RetCam examination is not sufficiently
sensitive to be a substitute for indirect
ophthalmoscopic examination.

31. Counselling
• Counselling of the parents is essential depending on the severity of the disease .
• Parents of all babies at risk - written general information should be provided.
• Parents of infants with severe ROP - the ophthalmologist should personally
discuss about the disease and availability of management with the parents.

33. Stage 1
• Demarcation line
• This is a thin but destructive
structure separating the
avascular anteriorly and
vascular retina posteriorly.

34. Stage 2
• Ridge - Hallmark of stage 2 ROP.
• Demarcation line that has now
grown, has height and width,
and extends above the plane of
the retina.
• These small isolated tufts are
commonly referred to as
‘popcorn’.

35. Stage 3
• Extraretinal fibrovascular extends
into the vitreous.
• 3 characteristics
• first -Continuous with the posterior
aspect of the ridge, causing a
ragged appearance.
• Second- immediately posterior to
the ridge but not always appearing
to be connected with it.
• Projects the into the vitreous
perpendicular to the retinal plane.

36. Stage 4: Partial Retinal
Detachment
• Stage 4 is divided into extrafoveal
(stage 4A) and foveal (stage 4B) partial
retinal detachments.
• Caused by exudative effusion of fluid,
traction or both.
• Generally concave,circumferentially
orientated.

37. • Typically, retinal detachments begin at
the point of fibrovacular attachment
to the vascularised retina.
• Progressive cases- tractional retinal
detachment extending both anteriorly
and posteriorly.
•

38. Stage 5
• Typically retinal detachments are
tractional, but may occasionally be
exudative.
• They are usually funnel shaped.
• When open, both anteriorly and
posteriorly the detachment often has
a concave configuration to the optic
disc.
• A second frequent configuration-the
funnel is narrow -anterior and
posterior aspects- the detached
retina behind the lens.

39. Stage 5
• A third less common type is where
the funnel is open anteriorly but
narrowed posteriorly.
• Least common is a funnel that is
narrow anteriorly and open
posteriorly.

41. • Plus disease
• Abnormal vascular dilatation of
the posterior pole vessels in
presence of peripheral
retinopathy
• Denoted by + sign

42. Iris vascular engorgement

43. Poor pupillary dilatation Vitreous haze

44. Pre Plus
• Peripapillary vessels are not normal but sufficiently abnormal to be called plus
disease
• Necessity for increased frequency of ROP examinations
• Aggressive Posterior ROP
• Seen in smallest,most premature babies
• Occurs in zone1 or posterior zone 2
• Recognised by prominent posterior vessels abnormality is out of proportion to
the extent and severity of peripheral retinopathy.
• Always circumferential
• Haemorrhage seen b/w vascular and avascular junctions

48. Laser treatment -not performed and can be followed for spontaneous regression

49. Follow up
• Post screening
• Periodic monitoring of visual acuity is also carried out since severe ROP may be
associated with impaired visual development.
ROP Post treatment follow- up till pre-school years-
1. Development of vision,
2. Refractive status and
3. Strabismus.

50. Children with threshold ROP
• Follow - up examinations should be tailored individually.
• If adequate laser/cryotherapy treatment has been given, and the disease has fully
regressed, a follow-up examination should be carried out at 3 months.
• Cycloplegic refraction - 6 months.
• Follow-up should be annually.
• Sometimes more frequent follow up is necessary if indicated.

54. BEAT-ROP study
• Bevacizumab Eliminates the Angiogenic
Threat of Retinopathy Of Prematurity
• Prospective, randomized, US multicentre,
controlled clinical trial
• Compared intravitreal Avastin 0.625mg
(0.025ml) as primary therapy with
conventional laser therapy for stage 3+ ROP
• 150 infants (300 eyes);
• 7 died and not included in data (5 in Avastin
group, 2 in laser)
• 67 had zone 1 ROP
• 83 had zone 2 posterior ROP
• 75 in each treatment group
• Higher rate of recurrence for zone 1 disease
with laser
• 2 cases (eyes) of recurrence with Avastin, 23
with laser
• Significant effect for zone 1 disease, not for
zone 2 disease

55. BEAT-ROP study
• Avastin significant effect for zone 1 disease, not for zone 2 disease
• Efficacy shown, safety not proved
• Later recurrence after Avastin: 16+/-4.6 weeks, laser 6.2+/-5.7 weeks
• Avastin treated babies need longer follow-up

56. Fundus photo of a left eye with ROP
that was injected with Avastin (top);
fluorescein angiogram after three
injections of Avastin (bottom).

57. ADVANTAGES OF
AVASTIN
• In infants with small pupils or dense
vitreous hemorrhages, visualization for
appropriate laser treatment is difficult.
•
• Shorter procedure that does not
require expensive equipment.
• Injection administered with only
topical anesthesia, precluding the
intense monitoring required for some
laser therapy.
•
ADVERSE EFFECTS
• Acute membrane contraction
leading to retinal detachment
• Delayed-onset retinal
detachment,
• Choroidal rupture.

58. PROPER ADMINISTRATION OF AVASTIN
• Raizada et al.(Kuwait) -Anatomy in a preterm infant variable and that injections
given more than 1.5 to 2.0 mm posterior to the limbus can pass through full
thickness retina.
• High risk of lens touching,
• Inadvertent traction on the vitreous base,
• Infection

59. Ocular complications with anti-VEGF
• Infection: endophthalmitis
• Raised intraocular pressure
• Cataract
• Retinal detachment
• Central retinal artery occlusion
• Vitreoretinal fibrosis
• Uveitis
• Subretinal haemorrhage
• Retinal pigment epithelial tears

60. Safety concerns
• Intravitreal Avastin enters the general circulation, suppresses plasma VEGF levels
and remains in the blood for more than 8 weeks in primates.
• Possible adverse effects on VEGF-dependent development must be considered.
• Normal angiogenesis,
• Regulation of vascular permeability,
• Endothelial differentiation during fetal brain development,
• Signalling between major neural cells,
• Maintenance and development of the blood–brain barrier

61. LASER
• Aim of treatment:
• To ablate the entire avascular retina as rapidly and as completely as possible with
minimum side effects.
• The effect is usually apparent within one week of adequate therapy.
• At present, the standard-of-care in ROP is the diode red (810 nanometer
wavelength) laser indirect ophthalmoscope

62. • The lids must be wiped with cotton to remove spilled droplets.
• Autoclaved or chemically sterilized instrument sets must be used.
• The child must be fed and burped 30 – 60 minutes before treatment
• The initial settings on the laser console depend on the fundus pigmentation and
area to be treated.
• Start with 250 milliwatts for 150 milliseconds with the repeat mode set at 300
milliseconds.

63. • The treatment must not be faster as this can result in inadequate burns.
• The intensity must be grayish white rather than white and placement of spots
must be nearly confluent.
• Less energy must be used for the anterior and superior retina compared to
posterior and inferior retina or close to the ridge.
• Ideally laser applications should be spaced one half burn-width apart

64. • ‘Skip’ areas encourage new vessels to grow and prevent active vessels from
regressing in that area, resulting in treatment failure
• In a single session one may place 3000 – 4000 spots in each eye to cover the
avascular retina including the enclosed avascular pockets, to adequately treat
zone I disease/ APROP eyes.
• A smaller number of spots, that is, 1000 – 2000, is needed to manage
prethreshold/ threshold zone II with non-APROP eyes

65. Technique of stabilizing the baby’s chin and evaluating the superior retina; (bottom c to d): stabilizing the forehead to
perform laser on the inferior retina. Appearance of the eyes after two hours of laser therapy under topical anesthesia

66. Laser therapy
• Laser has many advantages over cryotherapy.
• Post-treatment pain is less,
• Adnexal edema,
• Exudative retinal detachment,
• Vitreoretinal traction,
• Vitreous hemorrhage, due to reduced breakdown of the blood-retinal barrier.
• Use of topical anesthesia reduces systemic complications such as bradycardia or
apnea.
•

67. • In case of inadequate treatment or poor response the laser can be repeated
safely at short intervals of one to three days.
• Visual outcomes reported after laser are better than those after cryotherapy.
• Laser is also simpler to apply in treating posteriorly located disease.
• Laser burns should be applied on the peripheral avascular retina.

68. Complications of laser
therapy
• Laser treatment may cause burns in cornea
and iris.
• Other complications include cataract,
• Retinal and vitreous haemorrhage .

70. Conditions where ROP laser treatment required

71. Fundus photos showing (left side) confluent grayish white laser burns going up to the ridge;
Inadequate regression (top right) requiring more laser and adequate regression (top bottom)
needing only close follow-up seven days after laser

72. Completely regressed AP-ROP. Note the triangular lasered area at the horizontal raphe, next to the edge of the macula. (b)
Nonconfluent laser (white arrow) and non-regressed elevated vessels (black arrow) growing adjacent to the unlasered ‘skip’ area
(between the black and white arrows)

73. BEFORE AND AFTER LASER PHOTOCOAGULATION

74. Signs of Regression of retinopathy of prematurity
• Media clear
• Pupil dilates fully and readily
• No new vessels in the iris
• No new vessels in the retina
• All retinal / preretinal and vitreous hemorrhages cleared
• Regression of dilatation and tortuosity of retinal vessels
• No increase in retinal traction manifested by disc / macula / arcade drag
• No elevation of retina / ridge at or posterior to area of laser
• Feeder vessels to area of active new vessels / hemorrhages / elevated ridge and so on, achieve normal caliber
• Demarcation between laser-treated and normal retina is quiet and flat in terms of vasculature, with adequate scar
effect of the laser

75. Cryotherapy
• Cryotherapy significantly improves the
outcome of severe ROP
Superceded by laser photocoagulation due to its
higher incidence of treatment related
complications.
• Complications of cryotherapy
• Eyelid edema,
• Laceration of the conjunctiva,
• Pre-retinal and vitreous haemorrhage as well
as systemic complications like bradycardia,
cyanosis and respiratory suppression.

76. Patients with advanced disease or severe ROP
should be referred for further management.
• Vitreoretinal surgery
• Scleral buckling is advocated for stage
4B and stage 5 ROP
• Lens sparing vitreous surgery can also
be carried out, preferably at 38 to 42
weeks of post gestational age .

77. CRYO ROP
• The incidence of the disease was first reviewed in the Cryotherapy for
Retinopathy of Prematurity Cooperative Group (CRYO-ROP) study, based on a
multicentre trial in the United States.
• 9751 infants from 23 centres were recruited, and 65.8% of those premature
babies with a birthweight less than 1251 grams were noted to have some form of
ROP.
• 18% developed stage 3 disease and 6% were treated

78. Complications of ROP
• Myopia occurs in about 80% of
infants with ROP
• Strabismus and amblyopia are also
common residual findings.
• Strabismus ( 23% to 47% )in infants
with ROP and 20% in a regional
study
• Retinal detachment has been seen
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
• Acute angle closure glaucoma can
be seen in cicatricial ROP.

79. ETROP
• The Early Treatment of ROP study (ET-ROP) study looked at 317 newborns
from 26 different centres with birth weight less than 1251 grams.
• The incidence was very similar at 68%, and was noted to decrease sharply
with increasing birth weight and gestational age.

80. THANK YOU!!!!