Retinopathy of Prematurity

1. Retinopathy of prematurity
Narciso F. Atienza, Jr. MD. DPBO
Legaspi Eye Center
Chief of Section - Vitreo-Retinal Surgery -
Cardinal Santos Medical Center
St. Lukes Medical Center

2. PATS - American Society of
Retina Specialists - 2005

3. PATS - American Society of
Retina Specialists - 2005

4. Historical prespective
 First described by Terry (1942)
 Designated as “retrolental fibroplasia”
 Thought to be caused by a primary
change in the proliferation of the
embryonic hyaloid system.

5. Historical prespective
 Oxygen as the culprit (1950’s)
Reported decrease in incidence of RLF, but
increased neonatal mortality and cerebral
palsy rates.
Kinsey, VE: Retrolental fibroplasia.
Cooperative study of retrolental
fibroplasia and the use of oxygen,
Arch Ophthalmol 56:481-543, 1956

6.  Incompletely vascularized retina was
susceptible to oxygen.
 The more immature the vascularization,
the greater the response to oxygen.
Ashton, N, Ward, B, and Serpell, G: Effect of
oxygen on developing retinal vessels with
particular reference to the problem of retrolental
fibroplasia, Br J Ophthalmol 38:397-432, 1954

7. Mechanism of oxygen effects on
immature retina
 Primary stage -
Retinal
vasoconstriction and
vascular occlusion.

8.  Secondary stage –
Retinal
neovascularization.
 Marked endothelial
proliferation from
residual vascular
complexes driven by
hypoxia.

9.  The occurrence of Retinopathy of
prematurity was:
Not related to arterial oxygen levels.
Duration of oxygen exposure was a risk
factor.
Kinsey, VE, Arnold, HJ, Kalina, RE, Stern,
L, Stahlman, M, Odell, G, Driscoll, JM Jr,
Elliott, JH, and Patz, A: PaO2 levels and
retrolental fibroplasia: a report of the
cooperative study, Pediatrics 60:655-668,
1977

10. Postulates on the following sequence
of events in the development of ROP
 Injury to the endothelium occurs after
differentiation from mesenchyme to form
the primitive capillary meshwork.
 After injury to the vascular endothelium,
the mesenchyme and mature arteries and
veins "survive" the toxic injury and "unite"
via the few remaining vascular channels,
replacing the destroyed or damaged
capillary bed.

11.  The mesenchymal arteriovenous shunt is
located at the demarcation between the
avascular anterior retina and the
vascularized posterior retina.

12.  Cells inside the shunt differentiate into
normal capillary endothelium, forming
capillaries towards the avascular retina.
 This represents regression, which he
observed to occur in more than 90% of
cases of early stage of ROP.

13.  Primitive cells inside the shunt proliferate
and erupt through the internal limiting
membrane, into the surface of the retina
and into the vitreous body.
 This is the chief event in the process of
membrane proliferation leading to traction
detachment.

14. Involvement of GF in growth phases
 VEGF is required for normal blood vessel growth – Phase I
Normal retinal development anteriorly causes increased
oxygen demand and localized hypoxia
Induced physiologic hypoxia the precedes
vessel growth
As hypoxia is relieved by oxygen, VEGF mRNA
is suppressed, moving the wave forward.

15. What does supplemental oxygen do
in the cycle?
Oxygen interferes with the normal development,
causing cessation of normal vessel growth through
suppresion of VEGF mRNA.
Causes loss of the physiologic wave of VEGF anterior
to the growing vascular front.

16.  VEGF and oxygen plays are role the
development of retinal blood vessels
 Other chemical mediators are involved
 ROP is multifactorial, as other factors
pertaining to prematurity itself are at work

17.  GH and IGF-1 – potential candidates in
mediators involved in Phase II.
IGF is usually provided by the placenta and
amniotic fluid.
Lack of IGF is associated with poor vascular
growth and with subsequent proliferative
ROP.
 VEGF alone may not be sufficient for
promoting vigorous retinal angiogenesis.

18.  Blood vessel growth is dependent on both
IGF-1 and VEGF.
In premature infants, absence of IGF stops
blood vessel growth.
Causes oxygen starvation, mediating
increased production of VEGF
As infants mature, IGF levels rise again,
suddenly allowing VEGF to produce new
blood vessels.

20. Clinical implications
 Early inhibition of either VEGF or IGF
early after birth can prevent normal blood
vessel growth development and
precipitate disease.
Replacement of IGF may promote normal
retinal development
 Inhibition at phase II might prevent
destructive neovascularization.
Late supplementation may exacerbate the
disease.

21. Who are at risk of developing ROP?
 Prematurity
 Low birth weight
 Complex hospital course
 Prolonged supplemental oxygen

22. Criteria for examination
 Screening currently is suggested for children
less than 1500 grams birth weight.
 Instituted prior to a postmenstrual age of 31
weeks and continue until 50 weeks PMA.
 It is important to examine the child
 Two-week intervals if no retinopathy of prematurity is
present
 One week intervals if retinopathy of prematurity is
present.

25. Onset of ROP events in
postconceptional age (weeks)
Stage 5th Median 95th
percentile percentile
1 + 34.3 39.1
2 32 35.4 40.7
Threshold 33.6 36.9 42

26. Stages in ROP
Stage No. Characteristics
1 Demarcation line
2 Ridge
3 Ridge with extraretinal fibrovascular proliferation
4 Subtotal RD
A. Extra-foveal
B. Foveal involvement
5 Total retinal detachment
Funnel: Anterior Posterior
open open
narrow narrow
open narrow
narrow open

27. Stages of ROP
 Stage 1 –
demarcation line

28. Stages of ROP
 Stage 2 –
demarcation line with
ridge.

29. Stages of ROP
 Stage 2 – ROP –
“popcorn” appearance
of ridge.

30. Stages of ROP
 Stage 3 – Ridge with
extraretinal
proliferation.

31. Stages of ROP
 Stage 4
 A – retinal detachment
without foveal
involvement
 B – retina detachment
with foveal
involvement

32. Stages of ROP
 Stage 5
 Total retinal
detachment

33. ICROP zoning of involvement

34. Plus disease
 More florrid form of
ROP characterized by
posterior venous and
arterial tortuosity and
dilatation.

35. Other things to look for during
examination
 Anterior chamber depth, presence of
edema
 Iris vascular dilatation, pupillary rigidity
and vitreous haze indicates vascular
insufficiency.

36.  Rubeosis in ROP

37. Treatment for ROP
 Cryotherapy – investigated by the Cryo-
ROP group (1988)
 Studied the outcomes of treated eyes v.s.
controlled eyes.

38. Factors influencing the risk of
developing threshold disease
 Lower birth weight
 Younger gestational age
 White race
 Multiple birth
 Being born outside a Cryo-ROP study
nursery

39. Factors the influence risk of having
unfavorable macular outcomes
 Zone 1 ROP
 Plus disease
 Severity of Stage of ROP
 Amount of circumferential involvement of
ROP
 Rapid rate of progression of prethreshold
disease

40. Results of Cryo-ROP study after 10
years
Treated eyes Untreated eyes
distance visual 44.4% 62.1%
acuity
fundus status 27.2% 47.9%
Retinal status 22.0% 41.4%

41.  Cryotherapy on the
avascular portion of
the retina

42.  Laser ablation
Does not have any large multistage trials
reported
Results from studies show it has same
efficacy as cryotherapy, but with less tissue
destruction.

43.  Laser treatment for
ROP

44. When to treat?
 Optimal timing – with 72 hours of
diagnosis of threshold disease.
 Threshold disease
Five or more contiguous clock hours
Eight or more cumulative clock hours
Stage 3
Zone 1 or 2
Plus disease

45. Regression of ROP
 Cryo-ROP study
94% of ROP patients will have regression
while 6% will progress to threshold disease

46. Regressed ROP-Anterior
Changes
 Vascular
Failure to vascularize peripheral retina
Abnormal, nondichotomous branching of
retinal vessels
Vascular arcades with circumferential
interconnection
Telangiectatic vessels

47. Regressed ROP-Anterior
Changes
 Retinal
 Pigmentary changes
 Vitreoretinal interface changes
 Thin retina
 Peripheral folds
 Vitreous membranes with or without attachment to
retina
 Latticelike degeneration
 Retinal breaks
 Traction or rhegmatogenous retinal detachment

48. Regressed ROP-Posterior
changes
 Vascular
Vascular tortuosity
Straightening of blood vessels in temporal
arcade
Decrease in angle of insertion of major
temporal arcade

49. Regressed ROP-Posterior
changes
 Retinal
Pigmentary changes
Distortion and ectopia of macula
Stretching and folding of retina in macular
region leading to periphery
Vitreoretinal interface changes
Vitreous membrane
Dragging of retina over disc

50.  Myopia (20%)
 Strabismus (14 – 40%)
 Amblyopia (6 – 33%)

51. Late complications of ROP
 Angle closure glaucoma
 Late traction retinal detachment

52. ETROP – Early Treatment of
Retinopathy of Prematurity
 Advocates the treatment of patients with
retinopathy of prematurity before
Threshold stage.

53. Criteria for ETROP
 Zone I, any stage of ROP less than
threshold.
 Zone II, stage 2 with (+), stage 3 without
(+), or stage 3 with (+) disease but less
than threshold

54.  Infants less than 1500 grams at birth
 Infants less than 28 weeks at birth
 Infants between 1500 grams to 2000
grams with a complicated clinical course.

55.  1st
examination should be between 4 to 6
weeks chronological age (post-natal).
 Within 31st to 33rd week of post-
conceptional or post-menopausal age
(gestational age at birth + chronological
age)

56. Differentials
 Dominant familial exudative
vitreoretinopathy (FEVR)
 X-linked retinoschisis
 Incontinentia pigmenti
 Combined hamartoma
 Persistent posterior hyperplastic vitreous
 Norrie's disease
 Retinoblastoma.