RETINOPATHY OF PREMATURITY, LANDMARK STUDIES IN ROP, ICROP CLASSIFICATION,

1. RETINOPATHY OF PREMATURITY (ROP)
DR. VADAPALLI SATISH
CLINICAL FELLOW IN NEONATOLOGY
2/21/2017
Dept Of Neonatology,
Royal Gwent Hospital, Newport

2. RETINOPATHY OF PREMATURITY (ROP)
• IA. INTRODUCTION
• IB. EMBRYOLOGY
• II. PATHOGENESIS
• III. CLASSIFICATION
• IV. DIAGNOSIS
• V. TIMING OF TREATMENT
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• VI. PROGNOSIS
• VII. PREVENTION
• VIII. TREATMENT
• IX. LANDMARK STUDIES
• X. ADVANCES

3. INTRODUCTION
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Dept Of Neonatology,
Royal Gwent Hospital

4. I. INTRODUCTION
• multifactorial vasoproliferative
retinal disorder that increases in
incidence with decreasing
gestational age.
• 65% of infants with a B wt <1,250 g
and
• 80% of those with a B wt <1,000 g
will develop some degree of ROP.
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‘THE THIRD EPIDEMIC’

5. RETINAL VASCULAR DEVELOPMENT (ONTOGENY)
• The choroidal vessels can supply the thin retina via diffusion
• The retinal nerve cells (photoreceptors) develop from the optic nerve to the
periphery
• Additional blood supply develops as the retinal nerve cell layer becomes thick
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Inner vascular plexus
-Within the nerve fiber layer
-Capillaries appear around the 16th week of
gestation and reach the ora serrata at about
32 – 36 weeks gestation nasally and
temporally at term (40 weeks)
-Vasculo-genesis
Outer vascular plexuses
-Develops later in gestation and continues
to develop post-natally
-Capillaries arise as cellular buds from the
innermost vessels
-Angiogenesis

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8. PATHOGENESIS
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Dept Of Neonatology,
Royal Gwent Hospital

9. PATHOGENESIS
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10. PATHOGENESIS
1. The first stage (Ischemic phase)
• initial insult- such as hyperoxia, hypoxia, or hypotension = vasoconstriction
and decreased blood flow - subsequent arrest in vascular development.
2. second stage (Vaso-proliferative stage)
• neovascularization occurs. This aberrant retinal vessel growth is thought to
• be driven by excess angiogenic factors (such as vascular endothelial growth
factor) released by the ischemic relatively hypoxic avascular retina.
• New vessels grow through the retina into the vitreous. These vessels are
permeable and hemorrhage and edema can occur. Extensive and severe
extra-retinal fibrovascular proliferation can lead to retinal detachment and
abnormal retinal function.
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11. WHERE DO WE STAND ??
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Dept Of Neonatology,
Royal Gwent Hospital

12. RGH STATISTICS
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13. RGH STATISTICS
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14. SCREENING
2/21/2017
Dept Of Neonatology,
Royal Gwent Hospital

15. 1. SCREENING CRITERIA:
• "All babies less than 32 weeks gestational age (up to 31 weeks
and 6 days) or less than 1501g birthweight should be screened for ROP.
One criterion to be met for inclusion.
• All babies less than 31 weeks gestational age (up to 30 weeks and
6 days) or less than 1251g birthweight must be screened for ROP. One
criterion to be met for inclusion."
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16. 2. SCREENING PROTOTCOL:
• "Babies born before 27 weeks gestational age (i.e. up to 26 weeks and 6
days) - the first ROP screening examination should be undertaken at 30
to 31 weeks postmenstrual age.
• Babies born between 27 and 32 weeks gestational age (i.e. up to 31 weeks
and 6 days) - the first ROP screening examination should be undertaken
between 4 to 5 weeks (i.e. 28-35 days) postnatal age.
• Babies >32 weeks gestational age but with birthweight <1501 grams -
the first ROP screening examination should be undertaken between 4 to
5 weeks (i.e. 28-35 days) postnatal age."
• Babies <32 weeks gestational age or birthweight <1501g should have their
first ROP screening examination prior to discharge”.
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17. TIMING OF SCREENING SIMPLIFIED
Gest age
(weeks)
Postnatal
weeks
Post Con.
Age
22 8 30
23 7 30
24 6 30
25 5 30
26 4 30
27 4 31
28 4 32
29 4 33
30 4 34
31 4 35
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18. 3. Subsequent screening examinations
Minimum frequencies of screening should be:
Weekly when:
• The vessels end in zone I or posterior zone II; or
• There is any plus or pre-plus disease; or
• There is any stage 3 disease in any zone
Every 2 weeks:
• In all other circumstances until termination criteria reached 2/21/2017
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19. WHY 32 weeks ???
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20. TERMINATION OF SCREENING
• no risk of sight-threatening ROP
• Once fully vascularised
• Evidence of ROP regression
- “In babies without ROP”-
• when vascularisation has
extended into zone III and
• usually after 36 completed
weeks postmenstrual age”.
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- “In the presence of ROP” -
• Lack of increase in severity
• Partial resolution progressing
towards complete resolution
• replacement of active ROP
lesions by scar tissue
• Change in colour in the ridge
from salmon pink to white
• Transgression of vessels
through the demarcation line

21. TIMING OF TREATMENT
• Treatment for ROP should be undertaken if
• Zone I, any ROP with plus disease.
• Zone I, stage 3 without plus disease.
• Zone II; stage 3 with plus disease.
• Treatment for ROP should be seriously considered if –
• Zone II, stage 2 with plus disease.
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22. TREATMENT - SIMPLIFIED
• Treatment staging without PLUS disease
• Treatment Range with PLUS disease
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Zone Stage 1 Stage 2 Stage 3 Stage 4 Stage 5
Zone 1
Zone 2
Zone 3
Zone Stage 1 Stage 2 Stage 3 Stage 4 Stage 5
Zone 1
Zone 2
Zone 3

23. ICROP 2007
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Dept Of Neonatology,
Royal Gwent Hospital

24. 1. LOCATION
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25. 2. STAGE OF DISEASE= SEVERITY.
• Stage 1. A demarcation line between the normal retina and the
undeveloped avascular retina.
• Stage 2. A ridge of fibrovascular tissue with height and width
• Stage 3. The ridge has extraretinal fibrovascular proliferation. Abnormal
blood vessels and fibrous tissue develop on the edge of the ridge and
extend into the vitreous.
• Stage 4. Partial retinal detachment -when scar tissue pulls on the retina.
• Stage 4A is partial detachment outside the macula, a chance for good
vision.
• Stage 4B is partial detachment that involves the macula,
• Stage 5. Complete retinal detachment occurs. The retina assumes a
funnelshaped.
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26. Immature Retina
Retinal vessels taper

27. Stage 1: Demarcation Line
Separates vascular from avascular retina

28. Stage 2: Ridge
Ridge occupies volume

29. Stage 3: Ridge + Epiretinal Fibrovascular Proliferation
Arborization of vessels into EFP lesion

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32. regressed stage 3
Treated ROP with severe macular dragging

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Stage 4a 4b –Retinal detachment extra
foveal and involving macula

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Stage 5 – Total Retinal detachment

35. avascular retina
shunt vessel
zone 1 zone 2
Aggressive Posterior ROP (AP-ROP)

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PLUS Disease PLUS Disease with ROP

37. 3. PLUS DISEASE
• 3. Plus disease is an additional designation that refers to the presence of
vascular dilatation and tortuosity of the posterior retinal vessels in at least
two quadrants. This indicates a more severe degree of ROP, and may also
be associated with iris vascular engorgement, pupillary rigidity, and
vitreous haze.
• Preplus disease describes vascular abnormalities of the posterior pole (mild
venous dilatation or arterial tortuosity) that are present but are
insufficient for the diagnosis of plus disease.
• 4. Extent refers to the circumferential location of disease and is reported
as clock hours in the appropriate zone.
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38. DEFINITIONS OF OTHER TERMS
• 1. Aggressive posterior ROP (previously -Rush disease) is an uncommon,
rapidly progressing, severe form of ROP –
• Zone 1, and plus disease out of proportion to the peripheral retinopathy.
• Stage 3 ROP may appear as a flat, intraretinal network of
neovascularization. When untreated, this type of ROP usually progresses to
stage 5.
• 2. Threshold ROP is present if 5 or more contiguous or 8 cumulative clock
hours (30-degree sectors) of stage 3 with plus disease in either zone 1 or 2
are present.
• risk of blindness is predicted to be at least 50%,
• CRYO-ROP -the risk of blindness could be reduced to approximately 25%
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39. 3. Prethreshold ROP is any of the following:
• zone 1 ROP of any stage less than threshold;
• zone 2 ROP with stage 2 and plus disease;
• zone 2 ROP with stage 3 without plus disease; or
• zone 2 ROP with stage 3 with plus disease with fewer than the threshold
number of sectors of stage 3.
• The ETROP study showed that for eyes with high risk prethreshold ROP,
early treatment may reduce the risk of blindness to approximately 15%
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40. DIAGNOSIS
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41. RETCAM
• 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
• “REFFERAL WARRANTED ROP”
• PHOTO ROP, KID ROP
Fluorescein Angiography can be done

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43. OPTICAL COHERENCE TOMOGRAPHY
• Optical coherence tomography
(OCT) is a non-invasive
diagnostic imaging tool that
uses light waves to take cross-
sectional images of the retina.
• It was first described in 1991
by Huang and colleagues.
• Utilizing this imaging modality
one can visualize the retina,
choroid and optic nerve at
microscopic level.
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45. PREVENTION
2/21/2017
Dept Of Neonatology,
Royal Gwent Hospital

46. PREVENTION OF SEVERE DISEASE
• Primary
• Decrease the number of infants born at the gestations with highest risk
• Secondary
• An agent that will prevent the retinal blood vessel drop out after birth
in very premature infants
• Limit the vaso-proliferative phase
• Safe oxygen administration
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47. SECONDARY PREVENTION
• Intravitreal bevacizumab (Avastin) injection
• Cryotherapy and laser therapy limit the vasoproliferative phase by
destroying the avascular retina once THRESHOLD has been reached
• Inappropriate oxygen use is a neonatal health hazard associated with
aging, DNA damage and cancer, retinopathy of prematurity, injury to the
developing brain, infection and others. Neonatal exposure to pure O2,
even if brief, or to pulse oximetry >95% when breathing supplemental O2
must be avoided as much as possible
• Sola, A, et al. Acta Paediatrica. 96(6):801-812, June 2007.
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48. BEVACIZUMAB (AVASTIN)
• VEGF is a key cytokine in the development of normal blood vessel and in
tumors
• VEGF is imp. Role in both Ischemic and vasoproliferative stage
• Advantages-
• Ease of use, rapid response, better visual fields,
• BEAT-ROP study. Better long term visual acuity.
• Disadvantages-
• 20% recurrence, unknown long term effects, dose?
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49. TREATMENT
A. Laser therapy.
• Laser photocoagulation therapy for ROP is the preferred initial treatment
in most centers.
• Indirect ophthalmoscope and is applied to the avascular retina anterior to
the ridge of extra-retinal fibrovascular proliferation for 360 degrees.
• An average of 1,000 spots are placed in each eye, but the number may
range from a few hundred to approximately 2,000.
• Both argon and diode laser photocoagulation have been successfully used
in infants with severe ROP.
• Complx- cataracts, glaucoma, or anterior segment ischemia 2/21/2017
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50. B. Cryotherapy.
• A cryoprobe -external surface of the sclera and areas peripheral to the
ridge of the ROP
• are frozen until the entire anterior avascular retina has been treated.
• Approximately 35-75 applications
• general anesthesia. more inflammation
• when there is poor pupillary dilation or vitreous hemorrhage,
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51. • C. Retinal reattachment.
• If macula detaches in stage 4B or 5 ROP, retinal surgery -to reattach the
retina. This may include vitrectomy with or with out lensectomy, and
membrane peeling
• A scleral buckling - for more peripheral detachments, with drainage of
subretinal fluid, for effusional detachments.
• the visual outcome is in the range of legal blindness.
• untreated stage 5 ROP eventually leads to no light perception vision.
• The achievement of even minimal vision can result in
a large difference in a child's overall quality of life. 2/21/2017
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52. PROGNOSIS
2/21/2017
Dept Of Neonatology,
Royal Gwent Hospital

53. PROGNOSIS
• 90% stage 1-2
• 50% stage 3+ regress spontaneously.
• Other 50% ( 25% benfits with treatment)
• Sequelae of regressed disease eg. Myopia, strabismus, amblyopia,
glaucoma, detachment= follow up.
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54. WHATS HAPPENING
AROUND THE WORLD
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55. LANDMARK STUDIES
• Corroborative study –
Role of O2 – 1950
• ICROP- 1984, 1987, 2005
• CRYO ROP
• ETROP
• STOP ROP
• COT
• SUPPORT
• BOOST 2/21/2017
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• NEOPROM
• LIGHT ROP
• BEAT ROP
• RAINBOW
• SUND ROP
• ELEGAN
• HOPE ROP
• POST ROP
• PHOTO ROP

56. CRYOTHERAPY FOR RETINOPATHY OF
PREMATURITY STUDY (CRYO-ROP)
• the largest investigations ever organized for a pediatric ophthalmic
disease.
• more than 20 years, hundreds of ophthalmologists, neonatologists,
photographers, visual acuity testers, and other investigators
• 23 clinical centers across the United States,(mid 1980)
• The primary goal of the CRYO-ROP study, “to resolve uncertainty about the
value of peripheral retinal ablation treatment.”
• A secondary goal of CRYO-ROP has been to determine the long-term
outcome of eyes with severe ROP both with and without ablative
treatment.
• It is possible that treatment at an earlier stage may also have been
effective in some cases = ETROP 2/21/2017
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57. CRYO ROP RESULTS
• 246 infants (492eyes) tested, only 385 eyes (78%) had photographs
• 49.3% reduction in the unfavorable outcome rate at 3months in the treated eyes
vs the untreated eyes (21.8% compared with 43.0%)
• At the 10-year outcome measurement, 44.4% of eyes had unfavorable visual
function outcomes (distance acuity <20/200), but only 27.2% showed unfavorable
anatomical outcomes.
• both groups with severe ROP have a high risk for high myopia.
• The differences in treatment outcome among the eyes with different stages of
ROP, especially zone 1 vs zone 2, have also been an important finding in this
study.
• The study identified the zone 1 eyes to have the worst prognosis both with and
without treatment. This important finding led to the development of the ETROP
and revised treatment recommendations for earlier treatment of patients with
involvement of zone 1
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58. EARLY TREATMENT FOR RETINOPATHY OF
PREMATURITY (ETROP)
• The purpose of the (ETROP) study was to test whether earlier treatment,
• applied to prethreshold eyes determined to be at high risk for a poor
outcome,was more effective than treatment at CRYO-ROP threshold in
improving functional outcome (visual acuity) and ocular structural outcome
(anatomical status of the posterior pole)
• Method: : Infants with bilateral high-risk prethreshold retinopathy of
prematurity (ROP) (n = 317) had one eye randomized to early retinal
ablative treatment and the fellow eye managed conventionally (control
eye). The primary outcome was visual acuity assessed by masked testers
using the Teller acuity card procedure.
• Structural examinations were performed at 6 and 9 months. 2/21/2017
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59. • Results: Grating acuity results showed --
• reduction in unfavorable visual acuity outcomes with earlier treatment,
from 19.8% to 14.3% (P < .005).
• reduction in unfavorable structural outcomes from 15.6% to 9.0% (P < .001)
at 9 months.
• Further analysis supported retinal ablative therapy for eyes with type I
ROP, and a “wait and watch” approach to type II ROP.
• Conclusion: Early treatment of high-risk prethreshold ROP significantly
reduced unfavorable outcomes in both primary and secondary (structural)
measures.
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60. NEOPROM: NEONATAL OXYGENATION PROSPECTIVE
META-ANALYSIS COLLABORATION STUDY PROTOCOL
• The appropriate level of oxygenation for extremely preterm neonates (<28
weeks’ gestation) to maximise the greatest chance of survival, without
incurring significant morbidity
• To detect a small but important 4% increase in death or severe disability in
survivors, over 5000 neonates would need to be recruited. As extreme
prematurity affects 1% of births.
• Hence, the Neonatal Oxygenation Prospective Meta-analysis (NeOProM)
Collaboration has been formed
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63. • Infants in the low saturation target group had an increased rate of death at
36 weeks postconceptual age compared with the high saturation target
group (21.8 vs. 13.3%) .
• At that time, recruitment to the New Zealand study was finished and
recruitment to the UK and Australia studies was closed.
• These two BOOST II studies were therefore aborted prematurely, the
three studies ending up including 2,445 of the aimed 2,740 infants.
• Compared with a functional oxygen saturation level (SpO2) of 91-95%,
targeting SpO2 85-89% within 24 hours of birth is associated with <4%
absolute risk difference from 42% [4,10] to 46% or from 42% to 38%(10%
relative risk increase or reduction (RRR)) in mortality and major disability
by 2 years corrected age
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66. SUPPLEMENTAL THERAPEUTIC OXYGEN FOR
PRETHRESHOLD ROP (STOP-ROP),
• To determine the efficacy and safety of supplemental therapeutic oxygen
for infants with prethreshold retinopathy of prematurity (ROP) to reduce
the probability of progression to threshold ROP and the need for peripheral
retinal ablation.
• Conventional= 89-94% Supplemental = 96-99%
• 1996-1999, USA.
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67. • prethreshold ROP without plus disease- benefit
• No significant decrease in other ROP cases.
• Pneumonia chronic lung disease (8.5%
conventional vs 13.2% supplemental).
• More supplemental infants remained
• hospitalized (6.8% vs 12.7%),
• on oxygen (37.0% vs 46.8%), and
• on diuretics (24.4% vs 35.8%).
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68. STANFORD UNIVERSITY NETWORK FOR DIAGNOSIS
OF RETINOPATHY OF PREMATURITY SUND ROP
• objective: To report the 6-year results of the (SUNDROP) initiative in the
context of telemedicine screening initiatives for retinopathy of
prematurity (ROP).
• remote retinal photography by an ROP specialist. A total of 608 preterm
infants meeting ROP examination criteria were screened with the RetCam
II/III (Clarity Medical Systems, Pleasanton, Calif.)
• Results: During the 6 years, 1216 total eyes were screened during 2169
examinations, generating 26 970 retinal images, 22 (3.6%) infants screened
met criteria for TW-ROP.
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69. • Compared with bedside binocular ophthalmoscopy, remote interpretation
of RetCam II/III images had a sensitivity of 100%,specificity of 99.8%,
• negative predicative value of 100% positive predicative value of 95.5% for
the detection of TW-ROP.
• Conclusions: Telemedicine appears to be a safe, reliable, and cost-
effective complement to the efforts of ROP specialists, capable of
increasing patient access to screening and focusing the resources of the
current ophthalmic community on infants with potentially vision-
threatening disease
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70. BEAT ROP= BEVACIZUMAB ELIMINATES THE
ANGIOGENIC THREAT OF ROP
• METHODS—We conducted a prospective, controlled, randomized, stratified,
multicenter trial to assess intravitreal bevacizumab monotherapy for zone I
or zone II posterior stage 3+ (i.e., stage 3 with plus disease) retinopathy of
prematurity. Infants were randomly assigned to receive intravitreal
bevacizumab (0.625 mg in 0.025 ml of solution) or conventional laser
therapy,bilaterally. The primary ocular outcome was recurrence of
retinopathy of prematurity in one or both eyes requiring retreatment
before 54 weeks’ postmenstrual age.
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71. • RESULTS—We enrolled 150 infants (total sample of 300 eyes); 143 infants
survived to 54 weeks’ postmenstrual age, A significant treatment effect
was found for zone I retinopathy of prematurity (P = 0.003) but not for
zone II disease (P = 0.27).
• CONCLUSIONS—Intravitreal bevacizumab monotherapy, as compared with
conventional laser therapy, in infants with stage 3+ retinopathy of
prematurity showed a significant benefit for zone I but not zone II disease.
• Development of peripheral retinal vessels continued after treatment with
intravitreal bevacizumab,
• laser -permanent destruction
• This trial was too small to assess safety. 2/21/2017
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72. EXTREMELY LOW GESTATIONAL AGE NEWBORNS
(ELGANS)
• Objective: This study tested the hypothesis that preterm infants who had
a blood gas derangement on at least 2 of the first 3 postnatal days are at
increased risk for more severe retinopathy of prematurity (ROP).
• Method: 1,042 infants born before 28 weeks’ gestational age (GA) were
included. An infant was considered to be exposed if his/her blood gas
measure was in the highest or lowest quartile for GA on at least 2 of the
first 3 postnatal days
• Conclusion: Infants exposed to high PCO2 ,low pH and high PaO 2 appear
to be at increased risk of more severe ROP.
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73. RAINBOW
• Ranibizumab compared with laser for treatment of Infants Born preterm
with ROP
• FEB 2017
• For unfavourable structural outcome
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