seminar on ROP - retinopathy of prematurity

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 4 th and 5 th decades and was caused by the use of unrestricted oxygen. 2 nd ‘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.

13. 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

14. 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 .

15. Pathogenesis First stage Second stage

16. 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.

17. 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 

18. International classification of ROP 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.

19. Retinal zones

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

21. B. Stage II : The line develops into a ridge and protruding into vitreous. C lassification of ROP (cont..)

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

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

24. Stage 4

25. 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 C lassification of ROP (cont..)

26. STAGE 5 : TOTAL RETINAL DETACHMENT

27. 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. C lassification of ROP (cont..)

28. Composite Categories of ROP Aggressive posterior ROP ( AP-ROP) Pre-threshold ROP Threshold ROP

29. 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

30. 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

31. 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

32. 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

33. 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.

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

35. 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

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

37. 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 .

38. 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.

39. 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.

40. 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

41. 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

42. 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.

43. 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

44. 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 Vitrectomy with or without lensectomy membrane peeling, if necessary

45. 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

46. 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:

47. 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

48. 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.

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

50. 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

51. 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

52. 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.

53. 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

54. 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

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

56. 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

57. THANK YOU