Retinopathy of prematurity

Detailed Slides on ROP definitions, screening, diagnosis and managment

1. RETINOPATHY OF PREMATURITY Dr. LOKANADHA REDDY Fellow in Neonatology OVUM Hospitals Bangalore

2. DEFINITION Retinopathy of prematurity (ROP) is a multifactorial vasoproliferative retinal disorder that increases in incidence with decreasing gestational age It’s a disease of developing retinal vasculature

3. DEFINITION Retinopathy  Affects retinal vasculature Prematurity  typically in <30 weeks or <1500gm Prevalence: 65% of newborns with B.wt <1,250g and 80% of newborns with a B.wt <1,000 g will develop some degree of ROP

4. NORMAL RETINAL DEVELOPMENT

5. NORMAL RETINAL DEVELOPMENT Sclera  Choroid  Retina Retinal layers: Nerve fibers, ganglion cells, photoreceptors migrate from center of optic disc to the periphery By 28 weeks: The photoreceptors migrate 80% of the distance towards ora - serrata Before the retinal vessels develop the avascular retina receives oxygen by diffusion from the choroid vessels

6. NORMAL RETINAL DEVELOPMENT 16 weeks  Retinal vessels arise from hyaloid vessels at optic disc and begin to migrate outwards 36 weeks  Migration is complete on nasal side 40 weeks  Migration is complete on temporal side

7. PATHOGENESIS

8. PATHOGENESIS

9. CLASSIFICATION – ICROP 2005 I-ANTERIOR-POSTERIOR LOCATION ZONE I: Centre: Optic disc Radius: 2 x Disc- foveal distance Boundaries: Completely surrounded by Zone II ZONE II: Centre: Optic disc Radius: Distance from optic disc to nasal ora-serrata Boundaries: Inner-Zone I, Outer-Zone-III temporally ZONE III: a crescent-shaped retinal area extending beyond zone-II to the temporal ora-serrata

10. CLASSIFICATION – ICROP 2005 II SEVERITY – STAGING OF ROP STAGE-1: a thin, sharp line of demarcation between vascularized central retina and more peripheral avascular retina STAGE-2: an intraretinal elevation ( ridge of fibrovascular tissue) at the junction between vascularized and avascular retina STAGE-3: a ridge with extra-retinal fibrovascular extension into the vitreous

11. CLASSIFICATION – ICROP 2005 STAGE-4: Partial retinal detachment ( fibrovascular tissue pulls the retina) 4A: does not involve the fovea (better vision) 4B : involves the fovea (poor vision) STAGE-5: Total retinal detachment (funnel shaped retina) III-EXTENT Number of clock hours of ROP along the circumference of the vascularized retina No longer used for treatment decisions

12. CLASSIFICATION – ICROP 2005 IV-POSTERIOR POLE VASCULAR ABNORMALITIES PLUS DISEASE: Presence of dilated and tortuous vessels of the posterior pole present in ≥2 quadrants PRE-PLUS DISEASE: Abnormal vascular dilation and tortuosity that is insufficient for diagnosis of plus disease Aggressive posterior ROP recognized by: Marked dilation and tortuosity of posterior pole vessels(plus disease out of proportion) Difficulty in documenting the stage of ROP at junction between vascularized and avascular retina Occurs in zone I or posterior zone II Stage 3 with APROP can progress to stage 5 directly

13. CLASSIFICATION – ICROP 2005 Threshold ROP: ≥ 5 contiguous or 8 cumulative clock hours (30-degree sectors) of stage 3 with plus disease in either zone 1 or 2. This is the level of ROP at which the risk of blindness is predicted to be at least 50% and at which the CRYO-ROP study showed that the risk of blindness could be reduced to approximately 25% with appropriate treatment.

14. CLASSIFICATION – ICROP 2005 Pre-Threshold ROP : Type 1 In zone 1, any ROP and plus disease or stage 3 with or without plus disease In zone 2, stage 2 or 3 ROP with plus disease Type 2 In zone 1, stage 1 or 2 ROP, without plus disease In zone 2, stage 3 ROP without plus disease

15. CLASSIFICATION – ICROP 2005 Status of ROP is determined by Highest stage Mild to moderate – Stage I & II More serious - Stage III Emergency – Stage IV & V Lowest zone Mild – Zone III Most severe – Zone I & Posterior Zone II Most common – Zone II Plus disease - more serious Additional serious signs – Vitreous haze, iris vascular engorgement, pupillary rigidity

16. NATURAL HISTORY Begins at 31-33 weeks GA Progresses over next 2-5 weeks Spontaneous regression – Stage I&II and Early stage III Blindness or severe visual impairment – Retinal detachment or severe distortion of posterior retina

17. RISK FACTORS Low gestational age – single most important risk factor Low birth weight Poor postnatal weight gain/delay in return to B.wt in 14 days Mechanical ventilation Lability in oxygen requirement(hypoxia- hyperoxia ) Prolonged oxygen exposure Hypercarbia Males>Females IVH Anemia Blood transfusion( HbA -> more oxygen delivery) Exposure to light Unstable clinical course Late onset sepsis/Candida sepsis Hypotension Acidosis Vitamin E defeciency

18. PREVENTION OF ROP DO’S AND DON’TS TO PREVENT ROP Avoid iatrogenic premature births Stringent regulated use of oxygen Use a pulse- oximeter Soon after the birth During resuscitation Transport to NICU Transport to another facility During NICU stay

19. PREVENTION OF ROP Attach pulse- oximeter preferably to RUL after birth Remember SpO2 takes 3-5 minutes to increase after birth. Avoid oxygen administration if baby has good respiratory efforts FiO2 recommendation for resuscitation of preterm infants: 30-90% only If using BMV for PPV remove reservoir and ventilate. This will ensure FiO2 < 40% If using Neopuff for PPV use oxygen-air blender and start with 30% FiO2. Adjust based on SPO2 readings

20. PREVENTION OF ROP Target SPO2 of 88-92% always(resuscitation/NICU/transport) Avoid large changes in FiO2 during desaturation episodes n NICU. Increase or decrease by 5% at a time and evaluate each time Have a display of Oxygen saturation recommendation on a wall in NICU Remember: Sicker the baby, higher is the risk of developing ROP

21. PREVENTION OF ROP Aggressive Nutrition Poor postnatal weight gain is a risk factor for ROP Use TPN for all babies <31 weeks / <1250gm Start enteral feeds early or as soon as baby is hemodynamically stable Avoid Hypotension Target Mean BP as per norms for GA

22. PREVENTION OF ROP Prevent Late Onset Sepsis Strict asepsis precautions Contact isolation for all babies Strict sterile precautions while preparing and starting IVF. Two health care professionals should prepare the fluids ideally. Discard any leftover IVF bottle 24 hours after it is opened Avoid interrupting IV infusion lines once initiated

23. PREVENTION OF ROP - STUDIES Lower or more tightly controlled oxygen saturation limits early in the neonatal course reduce severity of ROP without any adverse effects on mortality, BPD & neurological sequelae . Antenatal Steroids & Surfactant : Decrease RDS and hence may decrease serious ROP Prophylactic Vitamin E: Till now no benefit was shown in the trials but further research is warranted Reduction in light exposure : No clear benefit Administration of penicillamine : No clear benefit

24. PREVENTION OF ROP - STUDIES In some studies Insulin-like growth factor-1 (IGF-1) was deficient in premature infants almost immediately after birth, and they observed that children who were slow to recover to normal serum levels of IGF-1 were more likely to develop ROP ( Hellstrom et al, 2001 ). In several careful follow-up studies, these investigators demonstrated that determining the rate of weight gain , essentially a noninvasive surrogate for growth hormone level, was effective in stratifying the risk of developing serious ROP even before the retinopathy is manifest

25. SCREENING OF ROP (KIDROP) WHOM TO SCREEN? All preterm infants with B.Wt <1750 gm (mandatory) or <2000gm(preferred) GA <34 weeks Up to 36 weeks with risk factors Do not exclude any baby based on the absence of risk factors if they are eligible by weight or prematurity Remember even if you don’t give an ounce of oxygen, ROP can still develop Screening to continue till 44 weeks of GA

26. SCREENING OF ROP (KIDROP) WHEN TO SCREEN? Before 30 days of life Best practice: Between 3 rd &4 th week of life irrespective of GA Between 2 nd &3 rd week of life for babies <1200gm or <28 weeks 2 weeks for <28 weekers and 3 weeks for >28 weekers Initiating timely screening is the responsibility of the neonatologist Delay in screening is liable to medico legal scrutiny A sick child is more likely to develop ROP. Don’t delay

27. SCREENING OF ROP (KIDROP) PRECAUTIONS AND PROCEDURE FOR SCREENING Best performed in the presence of neonatologist Step-down room of NICU is ideal Last feed approximately 1 our prior to examination Pupillary dilatation: Phenylephrine 2.5% and Cyclopentolate 0.5% ( Auropent plus eye drops) One drop in each eye, 2-3 times, 15 min apart Wipe off excess drops from the cheeks, blocking punctum also advisable Poor dilatation may be an indicator of severe disease DONOT over administer eye drops, wait for ophthalmologist to opine

28. SCREENING OF ROP (KIDROP) PRECAUTIONS AND PROCEDURE FOR SCREENING Swaddle the baby with warm linen wraps Procedure: Indirect ophthalmoscopy using a 20 D or 28 D lens or with RETCAM imaging Peripheral scleral depression with an infant depressor and a infant wire speculum are required Failure to depress may risk missing peripheral disease Monitor for apnea and bradycardia For analgesia 10%Dextrose/24% sucrose can be used A resuscitation kit must be accessible and functional

29. SCREENING OF ROP (KIDROP) SCHEDULE AND DOCUMENTATION Maintain a fixed day, fixed time each week Avoid ROP screening on ad-hoc basis Details of dilatation, schedule and list of babies to screen must be printed and displayed in NICU Documentation should be according to ICROP classification Parents should be given a card with diagnosis and follow up date Counseling the parents about the disease and need for follow up is the key to improve compliance

30. SCREENING OF ROP (KIDROP) SCHEDULE AND DOCUMENTATION Inform the neonatologist about the baby status If your hospital has no ROP specialist, arrange for the nearest doctor to visit your facility Photo-documentation on wide-field digital imaging is better for documentation, medico-legal evidence and does not miss even peripheral and minimal disease Baby can have multiple retinal findings besides ROP. Digital imaging is best for this

31. TELEMEDICINE KIDROP-KARNATAKA INTERNET ASSISTED DIAGNOSIS OF ROP Started by Narayana Nethralaya in 2008 in Karnataka Uses RETCAM shuttle – widefield digital imaging technology to send images to be analyzed by the experts at the centre Triple T philosophy T: Tele ROP T: Training of peripheral ophthalmologists and ophthalmic assistants T: Talking to neonatologist

32. TIMING OF TREATMENT Current recommendations are to consider treatment for eyes with type 1 prethreshold ROP based on the Early Treatment for ROP (ETROP) randomized trial that showed a significant benefit for treatment of eyes with type 1 ROP Close observation is currently recommended for type 2 prethreshold ROP Treatment should be considered for an eye with type 2 ROP when progression to type 1 status or threshold ROP occurs. Approximately 15% of type 2 eyes progress to type 1 ROP.

33. TREATMENT 1. LASER PHOTOCOAGULATION THERAPY Preferred initial treatment in most centers. D elivered through an indirect ophthalmoscope and is applied to the avascular retina anterior to the ridge of extraretinal 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

34. TREATMENT 1. LASER PHOTOCOAGULATION THERAPY Performed in the NICU and usually can be performed with local anesthesia and sedation Laser therapy is at least as effective as cryotherapy in achieving favorable visual outcomes Adverse effects: cataracts, glaucoma, or anterior segment ischemia

35. TREATMENT 2. CRYOTHERAPY Indications: special cases, such as when there is poor pupillary dilation or vitreous hemorrhage, which prevent adequate delivery of laser therapy Procedure: A cryoprobe is applied to the 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 are made in each eye Usually done under general anesthesia . Cryotherapy causes more inflammation and requires more analgesia than laser therapy Adverse effects: cataracts , glaucoma, or anterior segment ischemia

36. TREATMENT 3. ANTI-VEGF THERAPY Intravitreal injection of VEGF inhibitors( Bevacizumab ) has been offered for ROP treatment in many centers , particularly for cases of zone 1 or aggressive posterior ROP, as salvage treatment after laser therapy or in conjunction with vitreoretinal surgery Although use of these agents for ROP treatment is off-label, at least two randomized trials and multiple small case series have shown the efficacy of this treatment However , some concerns remain about dosing and safety because systemic absorption may result in reduced VEGF and vascularization of other organ systems.

37. TREATMENT 3. ANTI-VEGF THERAPY The ocular safety profile is reasonably good, although endophthalmitis is a rare but potentially devastating complication Advantages: potentially less stress for the infant (because the procedure time is short and only requires topical anesthesia); less destruction of the retina (because laser and cryotherapy are ablative procedures); and longterm , lower rates of very severe myopia

38. TREATMENT 4. RETINAL REATTACHMENT Once the macula detaches in stage 4B or 5 ROP , retinal surgery may be performed in an attempt to reattach the retina . Vitrectomy with or without lensectomy , and membrane peeling if necessary, is performed to remove tractional forces causing the retinal detachment. A scleral buckling procedure may be useful for more peripheral detachments, with drainage of subretinal fluid for effusional detachments.

39. TREATMENT 4. RETINAL REATTACHMENT Repeat operations for redetachment of the retina are common Even if the retina can be successfully attached, with rare exception, the visual outcome is in the range of legal blindness. Despite the measurement of low visual acuity, children find any amount of vision useful, and 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

40. PROGNOSIS – SHORT TERM Risk factors for ROP requiring treatment include posterior location (zone 1 or posterior zone 2 ) presence of ROP on the first examination increasing severity of stage circumferential involvement plus disease & rapid progression Most infants with stage 1 or 2 ROP will experience spontaneous regression . If prethreshold ROP develops 77 % of type 2 eyes regress 32 % of type 1 eyes regress

41. PROGNOSIS – SHORT TERM In ETROP, early treatment for type 1 ROP reduced unfavorable visual outcomes from 33% to 25% . Unfortunately, only 35% of patients maintained visual acuity at 6 years of age of 20/40 or better, suggesting more work to prevent development of ROP is needed. Any zone 3 disease has an excellent prognosis for complete recovery

42. PROGNOSIS - LONG TERM Infants with significant ROP have an increased risk of Myopia Anisometropia Astigmatism Strabismus Amblyopia L ate retinal detachment G laucoma . Cicatricial disease refers to residual scarring in the retina and may be associated with retinal detachment years later

43. PROGNOSIS - LONG TERM S tage 4 ROP : prognosis depends on the involvement of the macula ; the chance for good vision is greater when the macula is not involved . Retinal detachment(stage 5) : the prognosis for good vision is poor even with surgical reattachment , although some useful vision may be preserved .

44. PROGNOSIS - LONG TERM All premature infants who meet screening criteria regardless of the diagnosis of ROP are at risk for long-term vision problems , from either ocular or neurologic abnormalities A follow-up evaluation is recommended by an ophthalmologist with expertise in neonatal sequelae at approximately 1 year of age or sooner if ocular or visual abnormalities have been noted

45. REFERENCES AVERY’S 9 TH EDITION CLOHERTY 8 TH EDITION KIDROP-KARNATAKA INTERNET ASSISTED DIAGNOSIS OF ROP