This document summarizes a presentation on the case of a premature infant with retinopathy of prematurity (ROP) involving both eyes. The infant showed slow progression of extraretinal fibrovascular proliferation (ERP) in multiple parallel arcs. Treatment options were discussed, including treating the right eye and monitoring the left eye. The presence of isolated neovascular tufts ("popcorn") was noted to potentially increase risk of progression. Costs of treatment and hospitalization were also reviewed.

1. Grand Rounds Michael Rubin, MD Department of Ophthalmology and Visual Science The University of Chicago May 18, 2005

2. Baby’s profile NICU Consultation for evaluation of girl: Birthdate: 12.24.2004 Gestational age: 24 weeks Birth weight: 638 grams Co-Morbidities: NEC Mother: No PMH, first pregnancy and delivery, no complications

3. Left Eye 03/31/05

4. LE 04/15/05

6. Right Eye 03/31/05

7. Right Eye 04/14/05

8. Chronology 9-10 Weeks: First noted to have ROP bilaterally in posterior zone 2. 11-12 weeks: We first documented extra retinal growth, in both eyes, right worse than left. This appeared to be originating posterior to and clearly separated from the ridge, in discrete sectors superonasally (2-3 hours) and temporally (1-2 hours), and not entirely continuous within each sector. Posterior vessel changes were present but definitely did not meet plus criterion.

9. Slow Progression We have followed this baby very closely over the month of April, and have documented slow progression in both eyes with the unusual pattern of multiple parallel arcs, as documented in the images. In some areas these arcs have become confluent with each other and with the ridge, but mostly they remain discrete. Circumferential extent has increased very slowly (with filling in of some of the gaps originally present)

10. Prior to Treatment At the time of treatment there was 6 hours total (4-5 continuous in the superonasal sector) for the RE, 4 hours total (3 continuous superonasal) for the LE of ERP. Posterior vessel changes were close to plus in the RE, definitely still less than plus in the LE. If the ridge was moving anteriorly in either eye, it was happening very slowly. It is my sense that the ridge wasn’t moving anteriorly. Most of zone 2 remained avascular in both eyes.

11. Dilemma The ERP seems almost entirely to represent "popcorn" proliferation, and therefore questionably qualifiying for stage 3 status, yet progression has been continuing and this is clearly a high risk infant. She is close to but still a bit short of meeting strict treatment criteria in the right eye. Comfortably short of that point in the LE by Dr. Greenwald’s assessment. The required extent of laser application would be quite large. The situation is complicated by the fact that the baby's mother lives in Iowa and wants her transferred to a hospital in Dubuque ASAP; the NICU staff here have no problem with that provided her eye condition is judged to be acceptable for transfer by us.

12. Treatment Should we treat the RE now, and hold off on the LE pending further observation over a couple of weeks to confirm a positive response in the RE and continuing progression in the LE?

13. Stage 1 Stage 1: A fine, thin demarcation line between the vascular and avascular region is present. This line has no height and no thickness.

14. Stage 2 Stage 2: A broad, thick ridge clearly separates the vascular from the avascular retina. In zone 1, if there is any hint of pink or red in the ridge, this is an ominous sign. If there is any vessel engorgement, the disease should be considered threshold and treatment commenced within 72 hours. In zone 2, if there are no vascular changes and the ridge has no engorgement, the eye should be examined within 2 weeks. Prethreshold is defined as stage 2 with plus disease. In zone 3, examination every 3-4 weeks should be sufficient, unless of course there is any vascular tortuosity or straightening of the vascular arcades.

15. Stage 3 Stage 3: The extraretinal fibrovascular proliferation (neovascularization) may be present on the ridge, on the posterior surface of the ridge or anteriorly toward the vitreous cavity. The neovascularization gives the ridge a velvety appearance, a ragged border. In zone 1, if there is any neovascularization, it is serious and requires treatment. In zone 2, prethreshold is defined as stage 3 without plus disease, or stage 3 with less than 5 contiguous or 8 noncontiguous hours. Threshold is stage 3 with at least 5 contiguous or 8 noncontiguous hours and plus disease. In zone 3, examination every 2-3 weeks should be sufficient, unless there is any vascular tortuosity or straightening of the vascular arcades.

16. Stage 2 or 3? “ Small isolated tufts of new vessels lying on the surface of the retina may be seen posterior to the ridge structure. Such lesions do not constitute the fibrovascular growth that is a necessary condition for stage 3.” Committee for Classification of Retinopathy of Prematurity. An international classification of retinopathy of prematurity. Arch Ophthalmol 1984;102:1130-4.

17. Stage 4 and 5 Stage 4: This stage is a subtotal retinal detachment beginning at the ridge. The retina is pulled anteriorly into the vitreous by the fibrovascular ridge. Stage 4A does not involve the fovea. Stage 4B involves the fovea. Stage 5: This stage is a total retinal detachment in the shape of a funnel. Stage 5A is an open funnel. Stage 5B is a closed funnel.

18. Plus Plus disease is defined as dilation and tortuosity of the peripheral retinal vessels, iris vascular engorgement, pupillary rigidity, and vitreous haze, which are part of the subclassification given to the above stages.

19. Popcorn Study Significance of isolated neovascular tufts ("Popcorn") in retinopathy of prematurity David K. Wallace MD, Jan A. Kylstra MD, David B. Greenman BA, and Sharon F. Freedman MD b

20. Study Design The significance of isolated neovascular tufts ("popcorn") occurring in association with stage 2 retinopathy of prematurity (ROP) has not been studied. The authors retrospectively reviewed the clinical courses and outcomes of all patients with zone II, stage 2 ROP with popcorn examined over the past 3 years at one institution. Eyes with zone I disease, plus disease, or stage 3 at the initial appearance of popcorn were excluded. The study group was compared with a control group of patients of similar birth weight and gestational age with zone II, stage 2 ROP without popcorn.

21. Results Popcorn first appeared at a mean age of 36.4 (±2.2) weeks after conception in 26 patients. Of these, 17 patients (65%) progressed to stage 3, 10 (38%) had plus disease, 6 (23%) reached threshold, and 9 (35%) required laser treatment. Of 19 control patients, 4 (21%) progressed to stage 3, 1 (5%) had plus disease, 1 (5%) reached threshold, and 1 (5%) required laser treatment. The popcorn group had a significantly higher incidence of progression to stage 3 ( p <0.005), plus disease ( p <0.025), and laser treatment ( p <0.025). All eyes of both groups had complete regression of disease.

22. Conclusion of Study The presence of popcorn significantly increases the risk that an eye with zone II, stage 2 ROP will progress to stage 3, develop plus disease, and require laser treatment. Patients with popcorn and coexistent mild vascular dilation or tortuosity insufficient for plus disease are at particularly high risk for disease progression.

23. Popcorn Small isolated tufts of new blood vessels, commonly referred to as “popcorn,” may be seen posterior to a stage 2 ridge. Although they represent extraretinal fibrovascular proliferation, they do not constitute the fibrovascular growth that is required to diagnose stage 3 ROP.

24. Study Definition Study defined popcorn as one or more areas of isolated tufts of fibrovascular tissue located posterior to, and not contiguous with, a stage 2 ridge.

25. Regression?? Significance of popcorn is not well known, although traditionally it has been thought of as a sign of disease regression, developing as a stage 2 ridge advances anteriorly.

26. …or Progression? It has been reported that isolated tufts of neovascular tissue can occur early or late in the course of active ROP and in association with either progressing or regressing disease.

27. Characteristics Popcorn can be single or multiple, in one or more quadrants, and located posterior to the ridge, or a great distance from it.

28. Predictor of Progression? It is now believed that the presence of popcorn represents a predictor of disease progression. We know that the major prognostic factors in ROP are zone, plus disease, and stage.

29. ? 2 types of popcorn 1. Assoicated with an increased risk of disease progression 2. One that occurs later in the disease process as an advancing stage 2 ridge leaves behind benign tufts of neovascular tissue.

30. Aggressive? In this study, all patients in the control and popcorn group regressed prior to indication for treatment. Is it the case that patients in whom popcorn develops before state 3 may have a more benign, slowly progressive form of ROP?

31. Application to Practice Likely 2 forms of “Popcorn.” Early Form: Follow closely, will likely lead to definitive stage 3 disease. Late Form: May be sign of regression, as the ridge is scooting anteriorly. Do we need to revamp the classification system? Any suggestions?

32. Patient visit pricing Initial ROP Consult: Billed: $300 Collected: $60 Follow up ROP visits (per visit): Billed: $80 Collected: $25 Billed: $2080 Collected: $624

33. Laser Cost Laser Cost Right Eye: $2200 Collected: $350 Left Eye: $2200 Collected: $350

34. Inpatient Costs NICU Stay (per day): Billed: $3343.00 Medicaid Pays: $2005.80 Step Down (per day): Billed: $2389.00 Medicaid Pays: $1433.40

35. Total Costs Total Inpatient Costs: Billed: $491,890 Collected: $295,134 Average NICU stay costs: $58,000

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