Retinopathy of Prematurity Current Trends and Advances. Susmito Biswas Consultant Paediatric Ophthalmologist Manchester Royal Eye Hospital

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1 Retinopathy of Prematurity Current Trends and Advances Susmito Biswas Consultant Paediatric Ophthalmologist Manchester Royal Eye Hospital

2 Preventative strategies Neonatal care Oxygen management Optimising screening regimes Identifying infants at risk Effective coverage Treatment Timing Options Visually disability Preventing blindness Improving visual outcomes in successfully treated ROP Challenges of ROP

3 Challenges of ROP

4 Incidence In UK it affects approximately 60-70% of infants born at less than 32 weeks Gestational Age at birth or 1500 g birthweight Accounts for around 3% of childhood visual impairment in UK In babies were born in Greater Manchester Approx 740 pre-term babies each year In Central Manchester Approximately 150 neonates are screened each year

5 Trends in Number of ROP Treatments in Greater Manchester

6 Trends in Gestational Age in Greater Manchester

7 Trends in Birth weight Birth Weight Birth Weight

7 mm Hg; SaO 2 > 93% aligned with mean PaO 2 of 107.3 ± 59.

8 Oxygen Management Oxygen management Phase 1 hyperoxia Phase 2 hypoxia Vaso-obliteration occurs in humans when exposed to high oxygen Oxygen Saturation levels SaO 2 of 85%-93% aligned with mean PaO 2 of 56± 14.7 mm Hg; SaO 2 > 93% aligned with mean PaO 2 of ± 59.3 mm Hg and >80 mm Hg 60% of time SUPPORT and BOOST II trials Increased mortality in neonates in lower saturation groups Shah P K et al. Arch Dis Child Fetal Neonatal Ed 2012;97:F371-F375

9 Oxygen Management Extremely Low Gestation Age Newborn (ELGAN) study Increased risk of zone 1 and severe ROP in infants in highest quartile PaO 2 and PaCO 2 STOP-ROP trial (94-99% SaO 2 targets for pre-threshold ROP) No difference in progression to threshold ROP in low vs high O 2 groups Sub-group analysis indicated significant reduction in progression to threshold in infants without plus disease What Oxygen levels are the right levels? Tight control of Oxygen targets Chow et al reduction in incidence of ROP stage 3 or 4 from 12.5% to 2.5% and laser from 2.5% to 0% over a 3 year period Prevent SaO 2 < 90%; prevent Sa0 2 > 95% Time to revisit STOP-ROP? 70%-96% SaO 2 in first several postnatal weeks associated with a reduced risk of severe ROP (R.R versus High SaO 2 (94-99%) >32 weeks associated with decreased risk of severe ROP R.R Meta-analysis Chen et al. Pediatrics 2010;125:e

10 Inability of Neonatal Choroid and retina to limit oxygen mediated through the effects of PGD 2 and PGE 2 Generation of reactive oxygen species with low levels of antioxidants in neonates Peroxidation of NO peroxynitrite and other nitro-oxidative products Peroxidation of PUFA s in cell membranes increased production of TXA 2 Increased production of prostanoids and isoprostaines cis-aa converted to Trans-AA thorugh nitrative stress increasing Thormbospondin-1 Conversion of membrane phospholipids to LPA Pathogenesis

11 Growth Factors VEGF-A via VEGFR-2 mediates pathological neovascularisation IGF-1 Placental supply increasing in last trimester of pregnancy permissive factor for VEGF promoting endothelial cell survival Infusions of recombinant IGF-1 increases serum IGF- 1, promotes growth and reduces OIR in rat model Other growth factors; FGF PDGF Hepatocyte growth factors

Other mediators of neovascularisation Semaphorins Control growth and migration of both neuronal and vascular components Increased expression of Semaphorin

12 Other mediators of neovascularisation Semaphorins Control growth and migration of both neuronal and vascular components Increased expression of Semaphorin 3A from avascular retina due to inflammatory stress mediated via IL-1β Prevents angiogenesis within the avascular retina diverting new vessels into vitreous

13 Other mediators Succinate Intermediate within the Krebs Cycle Produced by ganglion cells in response to hypoxia Mediates neovascularisation via g-protein coupled receptor which increases VEGF and other angiogenic factors

Role of Inflammation Systemic infection or inflammation independent risk factor for severe ROP Elevated levels of IL-6, IL-8 and TNF-α Evidence of a pre-phase of ROP Chorioamnionitis Pre-eclampsia

14 Role of Inflammation Systemic infection or inflammation independent risk factor for severe ROP Elevated levels of IL-6, IL-8 and TNF-α Evidence of a pre-phase of ROP Chorioamnionitis Pre-eclampsia Prenatal inflammation prephase of ROP sensitising the retina to further proinflammatory effects of hyperoxia and hypoxia Peritoneal injection of LPS into rat pups at days 1, 3 and 5 induces proliferative retinopathy more akin to ROP than OIR Hong et al J Neuroinflammation. 2014; 11: 87.

15 Preventative Strategies

16 Screening for Retinopathy of Revised guidelines for screening and treatment of ROP produced in 2008 in UK Population at risk defined as infants < 32 weeks or less than 1501 grams in birthweight should all be screened for ROP Prematurity

17 Severe ROP Incidence by Country (Gilbert et al.)

18 Problems with screening Not really screening but case detection Labour intensive Low yield Time consuming Skilled procedure carried out by relatively few High cost

19 Telemedicine Screening Training of technician to obtain 6 standardised images of the retina. Review of 50 consecutive infants screened by ROP nurse and graded Both graders masked to other grader outcome Agreement to zone, stage, presence of plus or not, follow up recommendation

20 Telemedicine Agreement Agreement on Zone 93.75% Agreement of Stage 84% Agreement of Plus / preplus / no plus 92% (*no cases of plus disease in series) Agreement of follow up 96% Nurse would have brought 2 infants back sooner based on Retcam assessment Image quality All gradable images 52% good 42% moderate 6% poor (hazy media requiring significant image processing)

21 Telemedicine Screening With adequate training and supervision images of adequate quality for grading can be obtained in the majority of infants by a technician using wide angle retinal imaging Telemedicine screening reduces ophthalmologist time for screening Secure system required With further training image grading of low risk infants can be undertaken by technician with good agreement with ophthalmologist

22 NEATT Image courtesy of Tariq Aslam

24 WINROP Country Sensitivity USA 100% Sweden 100% Scotland SE incomplete dataset 73% Scotland complete dataset 87% Korea 90% Mexico( <32 weeks) 84.7% Mexico (>34 weeks) 5.3% Brazil 90.5% Taiwan 64.7% China 87.5%

25 E-Selectin Adhesion molecule expressed on the surface of activated endothelial cells A soluble form is shed from activated endothelial cells and is measurable in plasma Possible role as a surrogate marker for the development of ROP, by measuring in the plasma of infants. Study showed that Soluble E-Selectin levels greater than 86 ng/ml measured as early as day 1 had a high sensitivity / specificity and high postive predictive and negative predictive value for ROP Quite what role e-selectin plays in angiogenesis remains to be fully elucidated but works along a similar kinase pathway to VEGF

85% - functional (favourable VA outcomes) Laser rescues vision

26 Laser treatment now standard of care Treat near confluent burns over the avascular retina Success rates 90% - structural 85% - functional (favourable VA outcomes) Laser rescues vision from blind to moderate sighted (6/24 or 0.6 logmar) ROP Treatment

27 Problems Small pupil Media opacity Vitreous haemorrhage Engorged tunica vasculosa lentis Complications Cataract Hyphaema Further vitreous haemorrhage Glaucoma inflammation Laser Treatment

(Lucentis) Fab fragment derived from bevacizumab.

28 Anti-VEGF Treatment Role yet to be fully defined Bevacizumab (Avastin) large molecule still enters systemic circulation Ranibizumab (Lucentis) Fab fragment derived from bevacizumab. Higher affinity and shorter half life Pegaptanib (macugen) pegylated aptamer binds to VEGF 165 isoform

29 Avastin 24 week gestational age 583 g Severe SDLD / BPD Renal failure Thrombocytopaenia Aggressive posterior disease 35 GA

30 Intravitreal Avastin

31 Anti-VEGF outcomes Author Indication Outcomes Results VA Mean age at Author Agent Dose Mean BW Mean GA treatment Martinez-Castellanos (2013) Type 1 ROP or threshold with Plus regression and absence of Numbers treated Follow up recurrence 100% 6/12 or better 100% Martinez- Castellanos (2013) Ranibizumab 0.25mg ± ±3.5 36±5.2 6 eyes 3 years reattachment and Martinez-Castellanos regression and 5 yrs ocular Martinez- (2013) Castellanos Stage 4a or 4b and systemic outcomes 50% 6/60 or worse in 75% (2013) Bevacizumab 1.25 mg ± ± ±4.6 4 eyes 5 years Martinez-Castellanos Type 1 prethreshold - no fundal view regression and 5 yrs ocular and systemic outcomes 100% 6/12 or better in 60% (2013) Martinez- Castellanos (2013) Bevacizumab 1.25 mg ± ± ±4.6 5 eyes 5 years Martinez-Castellanos (2013) Type 1 prethreshold. New diagnosis regression and 5 yrs ocular and systemic outcomes 100% 6/12 or beterr 100% Martinez- Castellanos (2013) Bevacizumab 1.25 mg ± ± ±4.6 9 eyes 5 years Wu et al 2013 Pre-threshold (90% zone 2); primary treatment in 91%; salvage in 9% regression 88% none Wu et al 2013 Bevacizumab mg 930.1± ± ± eyes 17.8±7.6 months pre-threshold type 1 (AP- None (refractive error Harder BC Bevacizumab ROP in % ; or conventional ±153 regression & final 25.2± ± eyes significantly 11.4±2.3 less myopic Harder BC threshold in 75%) Refractive error 100% than laser control grp)

32 Anti-VEGF dosimetry Lucentis Gestational Amount dose of Age VEGF (ng) in Lowest Mean -2 conc VEGF SD (ml) of Median Mean Vitreous conc VEGF VEGF Vol Highest Mean +2 VEGF SD (ml) conc Vitreous (Weeks) whole vitreous VEGF levels (pg) VEGF concentration Median (pg/ml) (ml) concentration Range concentration Vascularly active (stage 4) Vasularly inactive (stage 4) Lowest Vol Control (cataract) Lowest Vol Mean Vol Mean Vol Highest 40 Vol Highest Vol Leakage of drug on injection may require 100X calculated dose = 1000 micrograms. (0.2% of adult dose)

33 Visual Disability Laser outcomes at MREH (48 cases with follow up data over 10 year period) 6/9 or better vision 25% Moderate visual loss 64% Low or no vision 12% Mainly related to poor neurological outcomes 1 case of anterior segment ischaemia

34 Visual Consequences of ROP Extreme Prematurity - Arrest in development of the anterior segment of the eye Myopia (increased curvature of the cornea) Structural Damage Retinal detachment Retinal Dragging Neuronal damage At the level of the retina Brain injury e.g. PVL

35 Future Directions Increased capability of retinal imaging Deep range OCT / SS-OCT imaging choroid Retinal oximetry OCT angiography deeper retinal vascular development Further modulation of oxygen levels requires more trials Molecular interventions beyond anti - VEGF treatment Neuroprotective measures Anti-inflammatory strategies

36 Thank you

Childhood blindness due to ROP

Childhood blindness due to ROP Number of blind children/10 million pop, by cause and level of development Proportion of blindness due to ROP, by World Bank region Estimates of numbers blind from ROP, by