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
8.
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
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 â 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.
20.
21.
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.
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 termedâextended stay new born infantsâ
⢠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.
32.
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
âpopcornâ.
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.
â˘
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.
40.
41. ⢠Plus disease
⢠Abnormal vascular dilatation of
the posterior pole vessels in
presence of peripheral
retinopathy
⢠Denoted by + sign
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
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.
51.
52.
53.
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.
â˘
⢠Shorter procedure that does not
require expensive equipment.
⢠Injection administered with only
topical anesthesia, precluding the
intense monitoring required for some
laser therapy.
â˘
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
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 bloodâbrain 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 â 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. ⢠âSkipâ 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 â 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 â 2000, is needed to manage
prethreshold/ threshold zone II with non-APROP eyes
65. Technique of stabilizing the babyâs 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.
â˘
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 .
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 âskipâ area
(between the black and white arrows)
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.
