Retinopathy of prematurity rop satish 1

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RETINOPATHY OF PREMATURITY (ROP)DR. VADAPALLI SATISH

CLINICAL FELLOW IN NEONATOLOGY

Dept Of Neonatology,Royal Gwent Hospital, Newport

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2RETINOPATHY OF PREMATURITY (ROP)

• IA. INTRODUCTION• IB. EMBRYOLOGY• II. PATHOGENESIS• III. CLASSIFICATION • IV. DIAGNOSIS• V. TIMING OF

TREATMENT

• VI. PROGNOSIS• VII. PREVENTION• VIII. TREATMENT• IX. LANDMARK STUDIES• X. ADVANCES

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INTRODUCTION

Dept Of Neonatology,Royal Gwent Hospital

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4I. 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.

‘THE THIRD EPIDEMIC’

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5RETINAL 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 thickInner 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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PATHOGENESIS


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9PATHOGENESIS

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10PATHOGENESIS

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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WHERE DO WE STAND ??


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12RGH STATISTICS

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13RGH STATISTICS

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SCREENING


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151. 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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162. 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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17TIMING OF SCREENING SIMPLIFIEDGest age(weeks)

Postnatal weeks

Post Con. Age

22 8 3023 7 3024 6 3025 5 3026 4 3027 4 3128 4 3229 4 3330 4 3431 4 35

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183. 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

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19WHY 32 weeks ???

Click icon to add picture

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20TERMINATION 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”.

- “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

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21TIMING 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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22TREATMENT - SIMPLIFIED

• Treatment staging without PLUS disease

• Treatment Range with PLUS disease

Zone Stage 1 Stage 2 Stage 3 Stage 4 Stage 5Zone 1Zone 2Zone 3

Zone Stage 1 Stage 2 Stage 3 Stage 4 Stage 5Zone 1Zone 2Zone 3

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ICROP 2007


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241. LOCATION

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252. 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.

Immature RetinaRetinal vessels taper

Stage 1: Demarcation LineSeparates vascular from avascular retina

Stage 2: RidgeRidge occupies volume

Stage 3: Ridge + Epiretinal Fibrovascular ProliferationArborization of vessels into EFP lesion

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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

avascular retina

shunt vessel

zone 1 zone 2

Aggressive Posterior ROP (AP-ROP)

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PLUS Disease

PLUS Disease with ROP

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373. 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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38DEFINITIONS 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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393. 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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40DIAGNOSIS

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 ROPFluorescein Angiography can be done

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43OPTICAL 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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PREVENTION


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48PREVENTION 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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49SECONDARY 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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50BEVACIZUMAB (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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51TREATMENT

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

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52B. 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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53• 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.

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PROGNOSIS


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55PROGNOSIS

• 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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WHATS HAPPENING AROUND THE WORLD

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57LANDMARK STUDIES

• Corroborative study – Role of O2 – 1950• ICROP- 1984, 1987, 2005• CRYO ROP • ETROP• STOP ROP• COT• SUPPORT• BOOST

• NEOPROM• LIGHT ROP• BEAT ROP • RAINBOW• SUND ROP• ELEGAN• HOPE ROP• POST ROP• PHOTO ROP

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58CRYOTHERAPY 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

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59CRYO 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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60EARLY 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.

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61• 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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62NEOPROM: NEONATAL OXYGENATION PROSPECTIVEMETA-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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65• 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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68SUPPLEMENTAL 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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• 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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70STANFORD 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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71• 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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72BEAT 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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73• 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.

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74EXTREMELY 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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75RAINBOW

• Ranibizumab compared with laser for treatment of Infants Born preterm with ROP• FEB 2017• For unfavourable structural outcome

Retinopathy of prematurity rop satish 1

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