seminar on ROP - retinopathy of prematurity

1. Welcome to Seminar
Dr. Anindita Bose, FCPS student
Dr. Farah Naz Dola, Resident, year 2
Department of Neonatology
BSMMU

2. Case scenario
• Fatema, diagnosed as a case of Preterm (30 weeks) VLBW
(1420 gm), AGA, PNA, HIE (stage 2), Late onset neonatal
sepsis(Acinetobacter growth positive in blood culture),
BPD, Laryngomalacia.
• During NICU course baby was treated with O2 inhalation,
CPAP care, Mechanical ventilation, several antibiotics,
Blood transfusion for several times

3. • At 21 days of post natal age, ROP screening
was done which revealed APROP.
Ophthalmologist had advised to do Laser
photocoagulation.

4. RETINOPATHY OF PREMATURITY
(ROP)

5. Overview of presentation
• Introduction
• Incidence and historical background
• Embryology of retinal vessels
• Pathogenesis of ROP
• Risk factors
• International classification of ROP
• Diagnosis and Screening of ROP
• Treatment and Complication of treatment
• Prevention
• Prognosis

6. Introduction
• Retinopathy of prematurity is defined as a disorder
of the developing retinal vasculature resulting from
interruption of normal progression of newly forming
retinal vessels.
• Premature birth may result in abnormal retinal blood
vessels development, ROP, which may progress to
blindness or severe visual impairment.

7. • The ‘window’ for treatment is narrow , 1-2 weeks in
some cases. Failure to diagnose and treat ROP at the
right time can lead to permanent, bilateral, complete
blindness.
• ROP is the leading cause of childhood blindness
worldwide.

8. • A baby developing blindness in early days of life, can
never regain vision and will have no perception of
light of this colourful world. Therefore he or she has
to bear this lifetime visual disability as a long lasting
scar of premature birth.

9. History of ROP
• ROP was first described in 1942 by Terry.
• Association with oxygen use in newborn was
described by Patz in 1984.
• There were two epidemic of blindness in last century.
• First was in 4th and 5th decades and was caused by
the use of unrestricted oxygen.
• 2nd ‘epidemic’ of ROP emerged during the late 1970s
because of improved survival of very-low-birth
weight infants.

10. Incidence
• Related to gestational age and birth weight
• ROP rare in birth weight > 2000 grams.
• 70% ROP in birth weight<1250g & 7% develop threshold
ROP.
• Threshold ROP very rare in bw > 1250gm
• 95% ROP begins at 32-34 weeks GA.
• Threshold disease at 36 weeks.
• Incidence of ROP in West ranges from 21 to 65.8%
Ref: Mayet & Cockinos et al.Eye(London).2006(23)322-327.
Fielder AR et al.Natural history of retinopathy of prematurity: A prospective study.
Eye 1992;6:233-42.

11. Incidence of ROP in Bangladesh
• In Bangladesh preterm infants of gestational age <33 weeks
between December 1998–July 2003 had an incidence of 5.5%
(five babies) in 114 babies, all presenting at various stages.
• Another study assessed the presence of ROP and potential
risk factors other than supplementary oxygen in premature
infants ≤34 wks and or ≤1500g, and detected ROP in 40% of
cases (23 out of 58).
Ahmed ASMA, Muslima H, Anwar KS, Khan NZ, Chowdhury MAKA,Saha SK, Darmstadt GL.
Retinopathy of Prematurity in Bangladeshi Neonates. Journal of Tropical Pediatrics, Volume
54, Issue 5, 1 October 2008, Pages 333–339
Akter S,Hossain MM, Shirin M, Anwar KS. Retinopathy of Prematurity -
Neonatologists’Experience. J Bangladesh Coll Phys Surg 2013; 31: 181-
188,nov.2014.ISSN1015-0870.

12. • Between January 2013 and March 2017 over 2000 preterm
infants were screened.
• About a third of these babies had different stages of ROP.
• 40% of the babies had birth weight between 1500- 2000g and
38% had BW < 1500g.
• The mean gestational age of babies with ROP was 31.09 ±
2.28 weeks (range: 26-36 weeks) and mean birth weight was
1354.13 ± 266.38g (range: 700 -1900g).
Nahar, Nazmun & Adolore Badmus, Sarat & Kumer Das, Sanjoy & Malek, Mohammad &
Rahman, Mostafizur & Abdul Mahid Khan, Mohammad. (2018). Retinopathy of prematurity
in Bangladesh: an overview. Community eye health. 31. S25-S26.

14. Some Data of ROP in NICU, BSMMU
• From January 2017 to December 2017, total 142
newborns were screened; among them 31 infants
had ROP
• From august 2018 to march 2019, 92 newborns were
screened and 22 infants had ROP

15. Embryology of retinal blood vessels
• Retinal vascularization begins at
15 to 18 weeks’ gestation.
• Retinal blood vessels extend out
from the optic disc and grow
peripherally.
• Vascularization in the nasal
retina is complete at
approximately 32 – 34 weeks
and temporal retina by 40
weeks.
• Insulin-like growth factor-1 (IGF-
1) supports normal retinal
vascular growth and interacts
with VEGF under influence of
hypoxic state in utero.

16. Pathogenesis
First stage
Second
stage

17. Risk factors for ROP
• Preterm , low birth
weight.
• Small for gestational age.
• Unrestricted oxygen.
• Low level of the serum
IGF-I
• Blood transfusion
• Exchange transfusion.
• Anaemia
• IVH
• Acidosis
• Sepsis.
• Apnea.
• Reduced postnatal growth
velocity.
• Raised level of
erythropoietin.
• Necrotising enterocolitis.
• Bronchopulmonary
dysplasia.
• Sepsis.
• Hypoxia.

18. International Classification for
Retinopathy of Prematurity (ICROP)
The classification system consists of 4 components:
 Zone (1-3): zone refers to how far the developing
retinal vessels have progressed.
 Stage (1-5): refers to the severity of the disease
 Extent: refers to the circumferential location of
disease; reported as clock hours in the appropriate
zone (30° clock hours in a total of 12 clock hours of
30° each)
 Plus disease (Plus disease is a primary factor in
treatment decision)and Pre-plus disease

19. International classification of ROP
1. According to zone:
The retina is divided into three concentric circles or zones.
a. Zone 1: consists of an imaginary circle with the optic
nerve at the centre and a radius of twice the distance from
the optic nerve to the macula.
b. Zone 2: extends from the edge of zone 1 to the ora
serrata on the nasal side of the eye and approximately half
the distance to the ora serrata on the temporal side.
c. Zone 3: consists of the outer crescent shaped area
extending from zone 2 out to the ora serrata temporally.

20. Retinal zones

21. 2. According to severity:
A. Stage I:
Thin white demarcation
line between vascularized
area of the retina and
avascular zone.
Classification of ROP (cont..)

22. B. Stage II:
The line develops into a
ridge and protruding into
vitreous.
Classification of ROP (cont..)

23. C. Stage III:
Extraretinal fibrovascular
proliferation occurs with
the ridge. Neovascular
tufts may be found just
posterior to the ridge.
Classification of ROP (cont..)

24. D. Stage IV:
Fibrosis and scarring
occur as the neo-
vascularization extends
into the vitreous.
 Traction occurs on the
retina causing partial
retinal detachment.
Classification of ROP (cont..)

25. Stage 4

27. E. Stage V:
 Complete retinal
detachment occurs.
 Retina assumes a funnel
shaped appearance and
is described as either
open or closed in the
anterior and posterior
regions
Classification of ROP (cont..)

28. STAGE 5 : TOTAL RETINAL DETACHMENT

29. F. Plus disease:
It is an additional designation that refers to the
presence of vascular dilatation and tortuosity of the
posterior retinal vessels in at least two quadrant. This
indicates a more severe degree of ROP and may also
be associated with iris vascular engorgement, pupillary
rigidity and vitreous haze.
G. Pre plus disease:
Vascular abnormalities of the posterior pole that are
present but are insufficient for the diagnosis of plus
disease.
Classification of ROP (cont..)

30. Composite Categories of ROP
A. Aggressive posterior ROP ( AP-ROP)
B. Pre-threshold ROP
C. Threshold ROP

31. A. Aggressive posterior ROP ( AP-ROP):
This is rapidly progressive severe form of ROP
primarily in zone I, if untreated progresses rapidly to
stage 5 ROP. The characteristics features of this type
of ROP includes it’s posterior location, prominence
of plus disease, and the ill-defined nature of the
retinopathy.
This requires immediate treatment

32. B. Pre-threshold ROP:
 Type 1 Pre threshold ROP includes:
1.In Zone 1: Any stage of ROP and plus disease or
stage 3 with or without plus disease
2.In Zone 2: Stage 2 or 3 ROP with plus disease
treatment at this stage showed significant benefit
 Type 2 Pre threshold ROP includes:
1.In Zone 1: Stage 1 or 2 ROP, without plus disease
2.In Zone 2: Stage 3 ROP, without plus disease
close observation;
Treatment is needed if progresses to type 1 or
threshold ROP

33. C. Threshold ROP
• Stage 3 ROP with 5 or more contiguous clock hours or
8 cumulative clock hours with plus disease in either
zone 1 or 2
• ROP with 50% likelihood of progression to retinal
detachment if left untreated
• Risk of blindness reduced to 25% after treatment
Ref:James D et al,Evidence based screening criteria for ROP:Natural history data from
CRYO-ROP and LIGHT-ROP studies:Arch Ophthalmol.2002;120(11):1470-1476

34. Rush disease
• Occurs at neonates whose birth weight less than
1200 gm and those born at 24-30 weeks gestational
age.
• It develops earlier.
• More aggressive.
• Need to screen these smaller babies at the earliest
(Not later than 3 weeks).
Ref: Jalali S et al,Programme Planning and Screening Strategy in Retinopathy of Prematurity
Indian J Ophthalmol 2003;51:89-99

35. Diagnosis
• Timely and regular retinal examination (ROP
screening) is the key to diagnosis.
• Ophthalmologic examination by an expert examiner
usually confirms the diagnosis.
• Binocular indirect ophthalmoscopy (BIO) is generally
used.

36. •Newer digital camera
technology demonstrated 100%
sensitivity in detecting ROP
requiring treatment. But it does
not permit adequate
assessment of retinal periphery.
RetCam

37. Pre-requisites for
indirect ophthalmoscopy
• Pupillary Dilation : 2.5% phenylephrine + 0.5%
Tropicamide – 3 times , 10 minutes apart 30 minutes
before exam
• Speculum
• Indirect ophthalmoscope
• Expert ophthalmologist

38. Equipments used in Indirect Ophthalmoscopy
Speculum
Hand-held
condenser lens
Binocular indirect
ophthalmoscope

40. ROP screening
In BSMMU:
Candidate
• Birth weight <2000 gm and/or gestation <35 weeks
• Birth weight ≥ 2000 gm or gestation > 35 weeks are
screened if they had an unstable neonatal period.
Timing
• At 4 weeks of postnatal age for infants born>30
weeks of gestation or birth weight ≥1200 gm
• At 3 weeks of postnatal age for infants < 30 weeks of
gestation or birth weight <1200 gm.

41. Frequency of screening
Zone of retinal findings Stage of retinal findings Follow up interval
Zone 1 Immature vascularization 1- 2 weeks
Stage 1 or 2 1 week or less
Regressing ROP 1- 2 weeks
Zone 2 Immature vascularization 2- 3 weeks
Stage 1 2 weeks
Stage 2 1- 2 weeks
Stage 3 1 week or less
Regressing ROP 1- 2 weeks
Zone 3 Stage 1 or 2 2- 3 weeks
Regressing ROP 2- 3 weeks
Mannan, M., Moni, S., & Shahidullah, M. (2015). Retinopathy of Prematurity (ROP):
Current Understanding and Management. Bangladesh Journal of Child Health, 38(3),
142-150.

42. Termination of Screening:
Criteria to stop further examination:
• Full retinal vascularization; this usually occurs at
about 40th weeks of postmenstrual age and mostly
completed by the 45th weeks.
• Regression of ROP noted
Mannan, M., Moni, S., & Shahidullah, M. (2015). Retinopathy of Prematurity (ROP):
Current Understanding and Management. Bangladesh Journal of Child Health, 38(3),
142-150.

43. Criteria for ROP screening in different
countries
Countries Gestational age Birth weight
United States ≤30 weeks <1500 gm
Or >30 weeks and an
unstable clinical course.
United Kingdom ≤31 weeks ≤1500 gm
Canada ≤30 weeks ≤1250 gm
India < 34-35 weeks. < 1500 gm
•Exposed to oxygen for
more than 30 days
• < 37 weeks and/or <
2000gms with risk factors
•Ref: Elizabeth H M et al ,Mechanisms and management of ROP. N Engl J Med
2012;367:2515-26.
•Ref: Jalali S et al,Programme Planning and Screening Strategy in Retinopathy of
Prematurity.Indian J Ophthalmol 2003;51:89-99

44. AIMS Protocol 2014
Which infants should be screened?
• Babies with birth weight <1500 g
• Babies born at <32 weeks of gestation
• Selected preterm infants with a birth weight
between 1500 and 2000 g or gestation of more than
32 weeks with eventful neonatal period

45. Treatment
• Treatment of ROP consists of destroying the portion of the
retina that is nonvascularized in order to preserve the rest
of it.
• The rationale for why this works is thought to be that the
avascular retina is a source of growth factors (VEGF and
other growth factors) that promote abnormal
neovascularization. When the avascular retina is destroyed,
the release of growth factors ceases, and neovascularization
involutes and regresses.
• Timely recognition of the disease is important because of
the short window of opportunity during which treatment is
effective.

46. Treatment
Indications of treatment:
• ROP in zone 1 retina that has reached stage 3 with
or without plus disease or eyes with any stage of
ROP with plus disease
• ROP in zone 2 that has reached stage 2 or 3 and is
accompanied by plus disease.
When treatment should be started:
Once a treatment decision has been made,
treatment should be performed within 48-72 hours
Ref: WilliamV G et al,Early treatment for ROP:A Randomized trial;Trans Am
Ophthalmol Soc.2004;102:233-250

47. Treatment modalities
• Laser photocoagulation
• Circumferential cryopexy.
• Anti-VEGF therapy
• Gene therapy
• Supplemental oxygen for pre-threshold ROP.
• Dietary supplement of omega-3 polyunsaturated
fatty acid (PUFA).
• Retinal reattachment
o Vitrectomy with or without lensectomy
o membrane peeling, if necessary

48. Laser
• Preferred initial
treatment
• Successful in infants
with severe ROP
• Can be performed with
local anaesthesia and
sedation, thus avoiding
the possible adverse
effects of general
anaesthesia
Cryotherapy
• Necessary in special
cases, e.g. when there
is poor pupillary
dialation or vitreous
hemorrhage
• Usually done under
general anaesthesia
• Causes more
inflammation and
requires more analgesia
than Laser therapy

49. Anti-VEGF Therapy
Indications:
 Zone 1 ROP
 AP-ROP
 Salvage treatment after Laser therapy
 In conjunction with vitroretinal surgery
Agents used:
 Avastin (bevacizumab)
 Macugen (pegaptanib sodium)
 Lucentis (ranibizumab)
 Aflibercept (VEGF Trap)
Route of administration:
Intravitreal injection
•Less stressful
•Procedure time is
short
•Only requires topical
anaesthesia
•Less destruction of
retina compared to
laser or cryotherapy
•Long term adverse
effects are less
Benefits:

50. Comparison between Anti-VEGF agents & Laser
photocoagulation
• Both laser photocoagulation and IVB injection are
effective modalities for the treatment of eyes with
zone II ROP;
• However, re-treatment may be required in some
cases after IVB injection.
• Also, re-injection of IVB is effective for persistent or
recurrent cases with ROP in zone II.
Roohipoor R, Torabi H, Karkhaneh R, Riazi-Eafahani M. Comparison of intravitreal
bevacizumab injection and laser photocoagulation for type 1 zone II retinopathy of
prematurity. J Curr Ophthalmol. 2018;31(1):61-65. Published 2018 Nov 9.
doi:10.1016/j.joco.2018.10.008

52. Outcome of treatment
• Treatment of acute ROP generally results in normal
or near normal anatomy of macula and posterior
retina.
• Treatment fails in small proportion of cases and
retinal detachment ensues.
• Prompt vitreoretinal surgery may be needed to
preserve vision.
• Severe visual impairment continue to occur in some
infants.

53. Complications of LASER photocoagulation
• Intraocular bleeding.
• Iritis.
• Cataract.
• Glucoma
• Anterior segment ischemia
Complications of treatment

54. Complications with anti-VEGF
• Infection: endophthalmitis
• Raised intraocular pressure
• Cataract
• Retinal detachment
• Central retinal artery occlusion
• Vitreoretinal fibrosis
• Corneal abrasion
• Uveitis
• Acute vision loss
• Subretinal haemorrhage
• Retinal pigment epithelial tears

55. Prevention of complications
Laser therapy
Drug:
• Steroid eye drop
• Pupil dilating eye drop
Duration:
Continue for 1 week after
LASER therapy.
Anti VEGF therapy
Drug:
• Antibiotics eye drop
Duration:
For 1 week after giving
intra -vitreal injection

56. Prevention of ROP
 Currently no proven methods are available to prevent ROP.
 Care in NICU:
• Maintain SpO2 88 – 93 %
• Avoid fluctuation of SpO2 while on O2 supplementation.
• Keep Hemoglobin level not less than 10 gm/dl
• Ensure adequate weight gain.
 Prophylactic vitamin- E therapy, administration of D-
penicillamine, and limited exposure to bright light have been
evaluated in multiple large clinical trials to prevent ROP but
none of these have shown clear benefit.

57. Prognosis
Bad Prognostic Factors:
• Posterior location (zone 1 or posterior zone 2)
• Presence of ROP on the first properly timed
examination
• Increasing severity of stage
• Circumferential involvement
• Presence of plus disease
• Rapid progression of disease
• Involvement of macula
• Detachment of retina

58. Short Term Prognosis
Spontaneous regression
• Stage-I and stage-II: 90%.
• Stage III+ disease : 50%.
• Any Zone 3 disease : Excellent prognosis for complete
recovery
• Pre-threshold ROP type 2: 77%
• Pre-threshold ROP type 1 : 32%
Progression to severe ROP
15% type 2 ROP progress to type 1

59. Long Term Prognosis
Retinal Dragging
and Folds
Others:
Acute angle closure glaucoma
Late onset Retinal Detachment( 22%)
Significant myopia (80%)
Anisometropia
Amblyopia
Astigmatism
Strabismus

60. Take Home Message
• Retinopathy of prematurity has become a leading but
preventable cause of childhood blindness worldwide.
• It occurs primarily in infants of low birth weight and low
gestational age at birth.
• Other than blindness, infants with ROP have higher risk for
developing certain eye problems later in life e.g. myopia,
strabismus, amblyopia, glaucoma.
• Some ocular complications can arise after treatment also.
• Timely screening is the key to early diagnosis and treatment.
• Timely intervention can preserve eyesight of many affected
infants
• Safety and efficacy of different treatment modalities are
being studied
• No preventive therapy has been proven effective yet

61. THANK YOU