2. DEFINITION
• Retinopathy of prematurity(ROP) is a disorder
of premature low birth weight infants
featuring abnormal proliferation of the
developing blood vessels at the junction of
vascular and the avascular retina.
3. EMBRYOLOGY
• The retina comprises tissues derived from the
optic vesicle, an outgrowth from the
diencephalon at approximately 25 days in foetal
development.
• The optic vesicle invaginates during the fourth
foetal week to form a cup, the inner wall of which
differentiates into the multilayered neuro-
sensory retina.
• The outer wall of the cup becomes the pigment
epithelium.
4.
5. RETINAL VASCULATURE –
• Until the fourth month of gestation, the retina remains avascular as
the hyaloid vasculature provides the nutrients to the developing
retina.
• In the fourth month of gestation, the first retinal vessels appear
when solid endothelial cords sprout from the optic nerve head to
form a primitive central retinal arterial system.
• By the sixth month, these vessels start developing a faint lumen that
occasionally contains a red blood cell. At this time, the vessels extend
1–2 mm fromthe optic disk and continue to migrate outward
extending to the ora serrata nasally and to the equator temporally by
the seventh to eighth month.
• The tissue penetrates nerve fibre layer and grows centrifugally
reaching nasal ora serrata by 36 weeks of gestation and more
temporally by 40 weeks of gestation.
• The retinal vasculature achieves the adult pattern by the fifth month
after birth.
• it is generally accepted that VEGF secreted in a temporal and spatial
pattern by microglia and astrocytes plays a critical role in the
development of the superficial and deep layers of the retinal
vasculature.
6. HISTORICAL PERSPECTIVE
• Retinopathy of prematurity, first identified as retrolental
fibro plasia by Terry in 1942
• The term ROP was coined by Heath in 1951
• Campbell established role of oxygen in ROP
• Two epidemics of ROP have been described in industrialized
countries, the ‘first epidemic’ (of blindness) occurred in the
1940s and early 1950s and affected principally premature
babies in USA, lesser extent in western Europe. At that time,
unmonitored supplemental oxygen was the principal risk
factor.
• The ‘second epidemic’ started in 1970s, as a consequence of
improved understanding of risk factors of ROP and better
neonatal care which led to higher survival rates of
premature babies.
7. • A universally accepted classification system
called as the International Classification of
Retinopathy of Prematurity was devised under
the leadership of John Flynn in 1983.
• Causes of‘third epidemic’ in middle income
countries and India are-
• 1)High Birth Rates
• 2) High rates of preterm birth(<1500g)
• 3) Improving survival rates
• 4) varying levels of neonatal care
• 5)Screening programs coverage is not 100%.
8. Pathogenesis of ROP
• The first blood supply to the inner retina
appears in the form of “spindle cells “from the
adventitia of the hyaloids artery at about 16
weeks of gestation. Spindle cells canalize and
metamorphose into mature vessels. and reach
the nasal ora serrata by around 36 weeks and
temporal by around 39-41weeks.
9. Two theories are described-
1) The classical theory- proposed by arthon and
patz-
• according to this theory supplemental oxygen
was considered main causative factor.
• Elevated po2 if sustained leads to permanent
vasoconstriction.
• neonate is subjected to room temperature,
endothelial proliferation from nearby capillaries
takes place leading to neovascularisation which
may reach to vitreous producing fibrosis causing
vitreous traction and finally retinal detachment
10. 2) Spindle cell theory-This theory which was proposed by
Kretzer et al
• postulates the induction of retinal and vitreal
neovascularization by spindle cell insult
• After birth the spindle cells are exposed to hyperoxic
environment because of increased oxygen diffusion
through this retina from choroidal vasculature which
leads to formation of gap junctions.
• Oxygen free radical, a cytotoxic agent attacks
compromised spindle cells, which has efficient anti-
oxidative defence mechanism.
• This abnormal spindle cells stop migration and
canalization. The damaged spindle cells secrete
angiogenic factors that trigger neovascular response
11. 3) The current theory/recent theory-
• This is extension of the above two theories
after greater understanding of events at
cellular level.
• In phase 1 there's hyperoxic environment
(supplemental oxygen), leading to cessation of
VEGF driven vessel growth and vaso-
obliteration of parts of retinal vasculature by
vascular endothelial cells apoptosis and
excessive capillary regression with retinal
ischemia
12. • In phase 2 ROP, which is hypoxic driven
• due to retinal ischemia and high metabolic
demand of developing vessel, overproduction
of VEGF is stimulated resulting in
neovascularisation. Retinal neovascularisation
is hallmark of phase 2 ROP.
• A hyperproliferative response may follow in
which the vessel leave the retinal plane and
enter vitreous gel, the vessels accompanying
glial cells develop contractile properties and
can result in detachment of retina from RPE.
13. RECENT ADVANCES IN PATHOGENESIS-
a)Role of oxygen free radicals in ROP-
• The balance between the production and
catabolism of oxygen metabolites is essential
in maintaining normal physiological conditions
• an increased level of superoxide found in the
retina under hyperoxic conditions suggests
either overproduction of superoxide or a
reduced level of SOD, such as is found in
prematurity.
14. b) Insulin like Growth Factor – lack of insulin-like
growth factor I (IGF-I) in knockout mice
prevents normal retinal vascular growth
c) Granulocyte Colony–Stimulating Factor
d) Jun Kinases (Jnk) Inhibitors
15. Classification of ROP
• The International Classification of Retinopathy of
Prematurity (ICROP) was published in 1984 under the
leadership of John Flynn later expanded in 1987.
• Classification of ROP requires assessment of the
following four parameters-
1. Severity or stage of retinopathy
2. Anteroposterior location of disease
3. Extent of retinopathy at border between vascular and
avascular retina
4. Determination of presence of peripapillary vessel
abnormalities characterised as plus disease
16. Extent of ROP:
• Zone I – it is the most posterior zone, consists
of a circle whose radius is twice the distance
from the optic disc to the macula.
• Zone II- shaped like a doughnut, extends
centrifugally from the edge of zone 1
peripherally to the nasal ora serrata.
• Zone III-most peripheral zone, residual
crescent of the retina temporally, extends from
edge of zone II to the ora serrata.
17.
18. Staging of the diseases:
Stage 1 - Demarcation line: a flat white line within the plane
of the retina at the junction between the vascularized and
the avascularized retina. the vessels end abruptly at the
demarcation line with no vessels extending beyond it.
19. • Stage 2- characterised by development of ridge at the
junction between the vascularized and the avascularized
retina. This develops in the region of demarcation line
and is generally white or gray in colour, may have tiny bud
like vascular abnormalities called popcorn just posterior
to it.
• Popcorn Isolated tufts of neovascular tissue ,posterior to
ridge at the level of retina
20. Stage 3 – External fibrovascular proliferation or neovascularization
that extends from the ridge into the vitreous. The severity of
the lesion can be subdivided into-
a) Mild- presence of only limited amount of vascular tissue.
b) Moderate: Significance amount tissue infiltrating into the
vitreous.
c) Severe: massive infiltration of tissue surrounding the ridge is
seen.
21. Stage 4- characterised by subtotal retinal detachment
• 4a – extra foveal partial retinal detachment (RD)
• 4b – partial RD involving the fovea
22. Stage -5 – characterised by total retinal detachment. The funnel
shaped appearance of anterior and posterior portions of
retinal detachment is described as open or closed.
• Extent of disease- circumferential extent of ROP is indicated by
sector involvement with twelve 30 degree sectors describing
the complete extent of disease.
23. • ICROP was updated in 2005 by adding:
1) The concept of a more virulent form of
retinopathy – APROP (Aggressive posterior
Retinopathy of Prematurity).
2) Description of an intermediate level of
vascular dilatation and tortuousity of posterior
pole vessels that are insufficient for the
diagnosis of plus disease (Pre-plus disease)
24. • Plus disease- used to indicate abnormal vascular
dilatation of posterior pole vessels in the
presence of peripheral retinopathy. A “Plus” (+) is
added, if at least 2 quadrants (usually 6 or
more clock hours) of dilation and tortuosity of
the posterior retinal blood vessels is seen.
• Pre plus disease- recent classification uses thus
term to describe eyes in which peripapillary
vessels are not normal, but not sufficiently
abnormal to be called plus disease. Used to
indicate clinicians that frequent examinations
may be needed.
26. • Prethreshhold ROP was defined as:
1) Zone I, any stage ROP without plus disease.
2) Zone II, stage 2 ROP with plus disease
3) Zone II, stage 3 ROP without plus disease.
4) Zone II, stage 3 ROP with plus disease but
fewer than 5 contiguous or 8 cumulative clock
hours.
• Threshold disease is defined as five
contiguous or eight non-contiguous clock
hours of involvement of stage III with plus
disease in zone I or zone II.
27. • AP-ROP: aggressive posterior ROP
-Earlier known as ‘RUSH Disease’
-posterior location
-rapidly evolving preplus and plus disease
neovascularization that may be subtle or even
intraretinal in nature.
-Progress to stage IV & V in 2-3 weeks without passing
through characteristic stages II and III
- requires laser treatment more than once
30. 1) Prematurity and low birth weight-
• Numerous studies have found out that
prematurity and low birth weight are two
most important factors associated with ROP.
• (CRYO-ROP)
• Early Treatment of Retinopathy of Prematurity
Cooperative Group (ET-ROP) reported this
incidence at 68% and the Light Reduction in
Retinopathy of Prematurity Cooperative
Group (LIGHT-ROP) at 58%.
31. 2) Oxygen
• Hyperoxia, fluctuation of oxygen levels and
hypoxia have been associated with development
of ROP.
3) Light
• The exposure to the bright ambient light following
premature birth has been suggested as a factor in
the pathogenesis of ROP, since the premature
infant normally would be in dark.
• LIGHT-ROP study demonstrated that there is no
protective effect on our ROP by limiting light
exposure to newborn premature infants.
32. 4) Sepsis
• Studies found that in premature infants with late
onset sepsis greater than 14 days the incidence of
ROP was 61.25 times greater in the newborns
with an late onset sepsis (LOS) of less than 14
days suggesting that sepsis may play an important
role in development of ROP.
5) Intraventicular haemorrhage
• Some studies have confirmed the association
between intraventricular hemorrhage and ROP.
6) Blood transfusions
• The relationship between ROP and blood
transfusion has been reported in several studies
33. Screening of ROP
The need for a ROP screening program arises
from the fact that
(a) ROP is a blinding disease
(b) Identification of all babies is essential who
are at risk or likely to get severe ROP
(c) Its timely and early detection prevents
undesirable sequelae and progression to
advanced stages
34. Current guidelines for screening- by American
Academy of Ophthalmology
• 1. Infants with birth weight of less than 1500 g
or gestational age of 32 weeks or less
• 2. Infants with birth weight between 1500g to
2000g or gestational age of more than 32
weeks with unstable clinical course, including
those requiring cardio-respiratory support.
35. SCREENING PROCEDURE
• The procedure is performed at NICU by pediatric
opthalmologist , under the supervision of neonatologist so
that complication can be handled.
• The pupil are dilated with a mixture of phenyl phrine 2.5%
and tropicamide 0.4 % or cyclopentolate 0.5% instilled 3
times at 10min intervals before the scheduled examination.
• Topical anesthetic and lid speculum should be used to
reduce discomfort.
• Indirect opthalmoscopy is performed with 20D / 30D lens
using fresh sterile instruments.
• Scleral depression is done to stabalize the eye , rotate it ,
indent it.
• RETCAM can be used to provide real time video display of
images
36.
37.
38. RETCAM
Wide angle digital paediatric retinal imaging
system
Mobile, self contained system for use in nursery,
ICU, O.T
Easily used by technicians or nurses
Provide retinal images at 130 degree
Avoids stress & expertise of I/O examination &
indentation, but as specific and sensitive as I/O
Useful for diagnosis, telemedicine &
documentation
40. • WIDE FIELD CONTACT RETINAL PHOTOGRAPHY – 130 deg
• Easy use by nurses and technicians
• Eliminates inter observer variability
• Teaching tool
• Overcomes logistics of screening
• More cost effective than examination
• Tele ophthalmological screening
Fluorescein Angiography can be done
41. FOLLOW UP
• Follow-up examinations should be recommended by
the examining ophthalmologist on the basis of retinal
findings classified according to the international
classification. The following schedule is suggested.
42. a) 1-Week or Less Follow-up
• Immature vascularisation: zone I—no ROP, immature
retina extends into posterior zone II, near the boundary
of zone I, stage 1 or 2 ROP in zone I, stage 3 ROP in zone
II, the presence or suspected presence of aggressive
posterior ROP
b) 1- to 2-Week Follow-up
• Immature vascularisation; posterior zone II, stage 2 ROP
in zone II, unequivocally regressing ROP in zone I
c) 2-Week Follow-up
• Stage 1 ROP in zone II, immature vascularisation: zone
II—no ROP, unequivocally regressing ROP in zone II
d) 2- to 3-Week Follow-up
• Stage 1 or 2 ROP in zone III, regressing ROP in zone III
43. TERMINATION OF SCREENING
• COMPLETE VASCULARIZATION
• VASCULARIZATION in ZONE III (till 1 DD of
temporal ora) – if no previous ROP in zone I &
II
• REGRESSED ROP ( b/w 40 -44 weeks PCA)– no
active disease left
• 45 weeks PCA with less than pre threshold
disease
45. CRYOTHERAPY
• Mostly outdated
• Firstly used by hindle and leyton
• Rationale- elimination of production of vasoproliferative factor
produced by avascular retina
• Indications-
46. TECHNIQUE-
• rx done when infant age between 7-20 weeks
post delivery
• Under GA
• Distance from ridge to limbus noted
• Applied to the anterior avascular area wherever
ridge is present
• Ridge avoided
• End point of cryotherapy is the appearance of
mild whitening.
• 360 degrees circumference, under direct
visualization avoid the ridge.
47. EFFECT-
• Within 24 hours plus disease usually disappears, next 2
weeks- neovascular retina involutes and about 3 weeks
retina looks normal except cryoscars
COMPLICATIONS-
a)retinal/ vitreous haemmorhage
b)Occlusion of central retinal artery- bradycardia, cyanosis
c)Macular pigmentation
d)
48. LASER THERAPY
• According to ETROP study, current indications for laser
treatment are high risk ROP-
1) Zone I, stages 1-3 ROP with plus disease
2) Zone I, stage 3 ROP without plus disease
3) Zone II, stage 2 or 3 ROP with plus disease
• In the past decade, laser photoablation has almost
supplanted cryotherapy as the standard treatment for
ROP.
• Procedure of choice, being less invasive, less traumatic
and causes less discomfort to the infant.
• Compared to cryotherapy, laser photoablation seems to
be associated with better structural and visual
outcomes, fewer post-operative complications and less
myopia.
49. • Laser treatment is delivered through an indirect
opthalmoscope .
• It can be performed in NICU and under local
anesthesia
• Easy to treat posterior located lesion.
• Argon green and Diode red LASER has been used
• An average of 1000 to 2000 spots of 100 mm size
1½ burn width apart can be placed in each eye.
• Entire avascular retina till ora, avoid the ridge.
• End point – grade II gray burn
50. After LASER treatment
• zone 2 ROP
– generally regresses after a single treatment
session.
• APROP
– may regresses but can reactivate with return of
plus disease
– progressive posterior hyaloidal contraction, and
progression to tractional posterior retinal
detachment
– Post-treatment vigilance is necessary
51. AP ROP : Treatment in 2 Steps
Ist – upto Flat Neovascular Fronds
IInd – after regression of Fronds
(area beneath fronds continue to remain
source of VEGF and hence reappearance of
disease)
52.
53. ANTI VEGF
Monotherapy
Single injections
Multiple injections for recurrence
Less desirable if periphery not perfused
Adjunctive therapy
Injections to allow regression beyond Zone 1
Laser for recurrent ROP
Anti-VEGF as a Bridge to laser peripherally
Treatment after laser / cryotherapy failure
Perioperative therapy before surgery
Reduce bleeding
Promote regression of neovascularization
Vitrectomy and scleral buckles
54. SURGERY
• GOAL- increase likelihood and vision of each
patient
• Pathophysiologically – proliferation of
epiretinal glial cells in stage 4/5 ROP, the
membranes exert traction and lead to retinal
detachment
• Once the macula detaches in stage 4b or 5
ROP retinal reattachment is done.
55.
56. SCLERAL BUCKLE
• done for progressive stage 4a and 4b
• It is done under GA
• Peritomy
• 2.5 mm encircling band passed beneath 4 recti
• One anchoring mattress 4-0 ethibond suture
applied in all quadrants, final knot in temporal
quadrant( easy removal)
• Removal after 3-6 months
57. VITRECTOMY
• INDICATIONS- detachment in stage 4b/5 too
severe to be relieved by scleral buckling alone,
history of recent rapid progression to
detachment, extensive total RD
• Treat pupillary block glaucoma and corneal
edema before sx
• GOAL- complete release of preretinal tissue
with release of traction
• Approach- closed and open sky
58. TECHNIQUE-
• Peritomy, infusion canula 1-1.5 mm from limbus
• Standrad pars ciliaris entry to avoid subretinal entry of
instruments
• Lensectomy done only when required
• Multiple radial incisions made in retrolental plane
towards equitorial area, creating stellate appearance
• Delamination and peeling of membranes- cut as closely
as possible to retina
• SRF drainge- usually not necessary ( non
rhegmatogenous)
COMPLICATIONS-
• Iatrogenic retinal breaks, haemmorhage, corneal clouding
