Retinopathy of Prematurity – A Brave New World

Retinopathy of Prematurity is a vasoproliferative disorder of the premature retina that continues to be one of the leading causes of blindness in children of both the modern and developing worlds.

Increasing rates of premature birth have led to increases in the prevalence of retinopathy of prematurity (ROP). As the incidence of ROP rises, so too does the need for cost-effective screening and timely treatment to improve visual outcomes. Much of this management is performed by ophthalmologists in the inpatient setting in neonatal intensive care units.

However, a child with treated ROP still requires diligent long-term follow up in the community. Potential sequelae from ROP including refractive error (particularly myopia); amblyopia; and strabismus can result in significant visual morbidity. Neurological abnormality resulting from complications of preterm birth can cause cortical (or cerebral) visual impairment and significant visual morbidity. Optometrists will be involved in the management of these children as they progress to adulthood. Being able to identify complications from ROP and make an early referral to an ophthalmologist for treatment is paramount in the management of these children.

Potential sequelae from ROP including refractive error, particularly myopia; amblyopia; and strabismus can result in significant visual morbidity

AETIOLOGY OF ROP

ROP is essentially a disorder of angiogenesis. The disease primarily occurs in infants with the following risk factors: low birth weight (<1250g); young gestational age (<30weeks); and severity of illness (eg. respiratory distress syndrome; sepsis; bronchopulmonary dysplasia; poor weight gain). It is said that the smallest, sickest and most immature infants are at the highest risk of the disease.¹ It has long been known that excess oxygen administration greatly increases the risk of developing severe ROP.

In order to understand ROP we need to appreciate the normal development of the retinal vasculature. This begins during the fourth month of pregnancy and reaches completion at 38-40 weeks. Human retinal vessels spread over the inner retina in four lobes that correspond to the major vascular arcades seen in a mature retina.^2,3 The development of these vessels is the result of a chemical gradient of factors that promote vessel growth that is ultimately driven by the increasing oxygen requirement of the peripheral avascular retina.³ There is significant remodelling of the developing vascular system that gives rise the arterioles, venules and capillary network of the mature retina. Premature birth may result in the disruption of normal vascular maturation. Exposure of premature infants to relative tissue hyperoxia downregulates vascular endothelial growth factor (VEGF), blood vessels constrict and become obliterated (abnormal remodelling). This may then be followed by retinal hypoxia and resultant vessel proliferation mediated by increased VEGF and insulin like growth factor (IGF1).^3,4

CLASSIFICATION OF ROP

The international classification of ROP (ICROP) was originally published in 1984 and revised in 2005.^4,5

This international classification defines ROP by the location of the disease, the number of clock hours involved, severity or staging of the disease, and the presence of vascular tortuosity or ‘plus disease’.

The retina is divided into three zones, all centered on the optic nerve, to specify the location of the disease.

Zone one is defined as a diameter twice the distance between the fovea and the center of the optic nerve. Clinically, this is approximately the area of the retina seen through a 28D lens when the view is centred on the optic nerve. Zone two is a circle that extends from the nasal ora serrata toward the temporal ora serrata. Zone three is a crescent encompassing the temporal area of the retina to the temporal ora serrata that is not included in zone two (see Figure 1).

Severity of the disease is described by stages (see Table 1). Plus disease is defined as marked vascular dilatation and tortuosity of posterior pole vessels that meets the amount seen in a standard photograph used in the Cryotherapy for Retinopathy of Prematurity Cooperative Group (CRYO-ROP) study.⁶ More recently, ICROP II has included widefield digital photographs in the description of plus disease (see Figure 2).

An uncommon, rapidly progressing, severe form of ROP called aggressive posterior retinopathy of prematurity (AP-ROP) was later added to the classification. It is characterised by its posterior location, prominence of plus disease and the unpredictable nature of the retinopathy. Eyes with AP-ROP require prompt treatment due to its rapid progression.⁷

MANAGEMENT OF ROP: INPATIENT TREATMENT

Treatment of ROP

How ROP is treated depends on its severity. Previously, eyes were treated when they exhibited ‘threshold disease’, defined as five contiguous or eight clock hours of stage three in zone one or two with plus disease. The ET-ROP study trial has shifted that practice to instituting early treatment at ‘pre-threshold’ levels.^8,9 The ET-ROP study classified ‘pre-threshold’ disease Type one and Type two ROP (Table 2). Type one ROP requires urgent treatment while type two disease can safely be observed.

The available treatments for ROP are listed in Table 3.

Peripheral retinal laser photocoagulation is currently the gold standard of treatment and has a long safety and efficacy profile. Prior to this, cryotherapy was used effectively. Laser photocoagulation has been reported to be less traumatic and has achieved better structural and functional outcomes compared with cryotherapy in threshold disease.⁹ The 10-year outcomes of the CRYO-ROP study demonstrated the long-term benefit of cryotherapy on eyes with threshold ROP.

ROP in zone one is the most difficult to treat due to the highest risk of recurrence. The Early Treatment for ROP (ET-ROP) study reported greater than 50 per cent favourable outcomes (visual acuity using grating acuity and structural retinal appearance) following retinal laser in zone one disease.⁹

Laser therapy in ROP is applied to all peripheral avascular retina, avoiding any gaps in the laser, and often some laser is also applied to some vascular areas of retina to aid in regression of the abnormal new vessels. The laser therapy covers a larger area and is confluent, unlike laser seen in proliferative diabetic retinopathy. The procedure can take two hours or more, as the pre-term infant may need to undergo general anaesthesia, be examined and documented thoroughly, and the treatment is often applied to both eyes (Figure 3a and b).

 

If infants progress to Stage four or Stage five ROP, with an associated retinal detachment, then vitreoretinal surgery is the next step. In most of these infants, the detachment is due to the traction from their abnormal new vessels, rather than a tear in the retina (Figure 4). The primary goal in the surgery is to relieve the traction, and depending on extent and severity of detachment, this may be done with a scleral buckle alone, or with a vitrectomy and combined lensectomy.

Are Newer Treatments, Such as Anti- VEGF, Surpassing Laser Treatment?

In contrast to conventional laser, which destroys peripheral retina, anti-VEGF is an option.

The efficacy of Intravitreal Bevacizumab (Avastin) for stage three+ ROP in zone one (BEAT-ROP) study initially reported six years ago, reported a significantly higher recurrence in zone one in eyes treated with laser compared to intravitreal injection of Bevacizumab. The recurrence rates in the conventional laser group were 6.2 +/- 5.7 weeks compared to 16 +/-4.6 weeks in the bevacizumab group with some recurrences in this group occurring at 54 weeks.¹⁰ Also of note from the BEAT-ROP study was that the peripheral retina continued to vascularise post injection of anti-VEGF.

The BEAT-ROP studies had been criticised for several inconsistencies in the study design, follow up duration and overall higher failure rates of laser compared to previous studies, making interpretation and applicability of these results to high risk ROP infants controversial.^11,12

A systematic review of the use of all anti-VEGF medications in the treatment of ROP reveals variability in the use of this treatment modality (see Table 4). The management varied between studies from dosing, timing of treatment and the need for adjunctive ‘rescue’ laser treatment. There were also mixed outcomes for treatment of stage four disease, with some eyes showing resolution of detached retina but others requiring surgery. All anti- VEGFs are known to increase the risk of traction retinal detachment so it must be used with caution.

For high res. table click here

None of the studies reported any systemic or local side effects but most were not adequately powered to assess safety.

Advantages of Anti-VEGF in Treating ROP

The most consistent evidenced-based advantage of use of anti-VEGF over retinal laser in treating ROP is the lower rate of myopic shifts as well as potential sparing of peripheral retina and therefore visual field. Other technical advantages of anti-VEGF use include ease of administration, especially in the setting of hazy ocular media where retinal laser may be challenging; the ability to perform the procedure without sedation, especially in critically ill neonates; and the availability of anti-VEGF versus laser in the clinical setting.^13,14 Furthermore, anti- VEGF may be beneficial in sparing foveal destruction in patients with aggressive APROP as it is associated with rapid resolution of ROP, which would otherwise again need challenging posterior laser application.¹⁵

Implications of Anti-VEGF Treatment for ROP

There are several concerns relating to anti- VEGF use in treatment of this disease. With retinal laser treatment, the peripheral retina is ablated, and once the ROP regresses, it can be safe to monitor peripherally. However, with anti-VEGF treatments, several issues of concern arise. For example, the retinopathy may not fully regress or can re-develop months after the initial treatment; also the persistence of peripheral retinal avascular zones requires ongoing reviews. Additionally, the threat of late reactivation of ROP has implications for follow-up.

Furthermore, the use of anti-VEGF in any vasoproliferative retinal disease carries with it a risk of fibrovascular contraction, which can lead to the devastating complication of tractional retinal detachment.

There is also more recently published evidence of persisting fluorescein angiography abnormalities in retinal vasculature including areas of persisting avascular retina in the periphery, vessel leakage, shunts, abnormal vessel branching and vascular ‘tangles’ and hyperfluorescent lesions in the posterior pole with altered foveal avascular zones.¹⁶

As a result, the use of anti-VEGF in treating ROP needs to be undertaken with extreme caution and regular, often weekly, follow up for a prolonged period to detect recurrence and retinal traction. At present there is much uncertainty about when to stop reviewing these children.

The overwhelming controversy surrounds the systemic implications for organogenesis in these premature infants. Some large randomised control studies have demonstrated a higher incidence rate of psychomotor impairment and neurodevelopmental disabilities in the anti- VEGF treated group.¹⁷

MANAGEMENT OF ROP: FOLLOW-UP IN THE COMMUNITY

Individuals with ROP require lifelong follow-up. The most common sequelae are refractive error, amblyopia and strabismus. Even with treatment, however, there is still a risk that a retinal detachment can develop during the patient’s life. Severe ROP, and in rare cases mild ROP, can be associated with other conditions, including glaucoma, cataracts, corneal opacities, microphthalmia, retinal folds, dragging of retinal vessels and macular holes.¹⁸

Optometrists are well placed to co-ordinate this care and be the first to highlight ocular complications including strabismus, high refractive error and amblyopia that will require early management.

In the majority of cases, infants are seen four to six months after they have been released from postoperative care or once the ophthalmologist feels the ROP has regressed fully.

During this initial examination, it is important to get a measurement of visual acuities through age appropriate tests by using Teller cards, fixate and follow, or occlusion preference testing. Evaluating for binocularity with a simple cover test can afford valuable information and hint towards the possible existence of amblyopia. It is just as important to get an assessment of refractive error with a cycloplegic retinoscopy.

Results obtained from this baseline testing will enable early referral if there is suspicion of amblyopia, strabismus etc. The schedule for future examinations can then be established, based on co-managed care between the ophthalmologist and optometrist.

Prematurity alone may be associated with ocular complications, including refractive errors, especially myopia and strabismus. In infants with neurological sequelae, the possibility of cortical vision impairment must be kept in mind.

The role of myopia in low birth weight infants, with and without ROP, has been studied during the last few decades. The development of high myopia (>5.00D) in relation to ROP appears to be more due to changes in the anterior segment than an increase in axial length of the eye.¹⁹

Strabismus is another complication associated with premature birth. Strabismus is seen at a much higher rate in the low birth weight population with or without ROP (3 per cent of children born full term and 20 per cent of those born prematurely).²⁰

From either refractive error, and or strabismus, amblyopia may occur. It is therefore important to monitor these infants closely for early detection and treatment.

Dr. Christolyn Raj is a retinal specialist with Sunbury Eye Surgeons and Vision Eye Institute at Camberwell and Coburg, Victoria. She specialises in medical retina, cataract/refractive surgery and paediatric retinal eye disease. She is an Honorary Senior Lecturer at The University of Melbourne.

Dr. Abhishek Sharma is a retinal specialist at Queensland Eye Institute in Brisbane. His specialties include retinal surgery for macular holes, epiretinal membranes and retinal detachments, as well as treatment for macular degeneration and severe diabetes. He is the author of Mindmaps in Ophthalmology published through CRC Press.

Dr. James Elder is an ophthalmologist at the Royal Children’s Hospital and an Associate Professor in the Department of Paediatrics of the University of Melbourne. He has been involved in the care of infants with ROP for 27 years. His surgical expertise covers most areas of paediatric ophthalmology including: infant cataract, childhood glaucoma, strabismus, oculoplastics and management of retinoblastoma. He is the author of 52 peer reviewed journal articles and 10 book chapters.

References

1. AAP, AAO, and AAPOS. Screening examination of premature infants for retinopathy of prematurity. Pediatrics. 2006 Feb. 117(2):572-6.

2. Selvam, S., et al. (2017). “Retinal vasculature development in health and disease.” Prog Retin Eye Res. epub

3. Lutty, G. A. and D. S. McLeod (2017). “Development of the hyaloid, choroidal and retinal vasculatures in the fetal human eye.” Prog Retin Eye Res. epub

4. Classification of Retinopathy of prematurity. The International Classification of Retinopathy of Prematurity revisited. Arch Ophthalmol. 2005 Jul. 123(7):991-9.

5. Committee for the classification of retinopathy of prematurity. An international classification of retinopathy of prematurity. ArchOphthalmol. 1984 Aug. 102(8):1130-

6. Gelman R, Martinez-Perez ME, Vanderveen DK, Moskowitz A, Fulton AB. Diagnosis of plus disease in retinopathy of prematurity using Retinal Image multiScale Analysis. Invest Ophthalmol Vis Sci. 2005 Dec. 46(12):4734-8.

7. Connolly BP, McNamara JA, Sharma S, et al. A comparison of laser photocoagulation with trans-scleral cryotherapy in the treatment of threshold retinopathy of prematurity. Ophthalmology. 1998 Sep.105(9):1628-31.

8. Cryotherapy for retinopathy of prematurity cooperative group. Multicenter trial of cryotherapy for retinopathy of prematurity: preliminary results. Pediatrics. 1988 May. 81(5):697-706.

9. Early treatment for retinopathy of prematurity cooperative group. Revised indications for the treatment of retinopathy of prematurity: results of the early treatment for retinopathy of prematurity randomized trial. Arch Ophthalmol. 2003 Dec. 121(12):1684-94.

10. Geloneck MM, Chuang AZ, Clark WL, et al; BEATROP Cooperative Group. Refractive outcomes following bevacizumab monotherapy compared with conventional laser treatment: a randomized clinical trial. JAMA Ophthalmol. 2014;132(11):1327-1333.

11. Rao,P , Trese, M. Anti-VEGF in Retinopathy of Prematurity. Retinal Physician, Volume: 14, Issue: September 2017: 25-29

12. Sankar MJ, Sankar J, Mehta M, Bhat V, Srinivas R. Anti-vascular endothelial growth factor (VEGF) drugs for treatment .of retinopathy of prematurity. Cochrane Database Syst Rev. 2016;2.

13. Mintz-Hittner HA, Kuffel RR Jr. Intravitreal injection of bevacizumab (avastin) for treatment of stage 3 retinopathy of prematurity in zone one or posterior zone two. Retina. 2008 Jun. 28(6):831-8.

14. Hwang CK, Hubbard GB, Hutchinson AK, Lambert SR. Outcomes after intravitreal bevacizumab versus laser photocoagulation for retinopathy of prematurity: a 5-year retrospective analysis. Ophthalmology. 2015;122(5):1008- 1015.

15. Travassos A, Teixeira S, Ferreira P, et al. Intravitreal bevacizumab in aggressive posterior retinopathy of prematurity. Ophthalmic Surg Lasers Imaging. 2007 May- Jun. 38(3):233-7.

16. Lepore, D., et al. (2017). “Follow-up to Age 4 Years of Treatment of Type 1 Retinopathy of Prematurity Intravitreal Bevacizumab Injection versus Laser: Fluorescein Angiographic Findings.” Ophthalmology. epub

17. Lien R, Yu MH, Hsu KH, et al. Neurodevelopmental outcomes of infants with retinopathy of prematurity and bevacizumab treatment. PLoS One. 2016;11(1):e0148019.

18. Kennedy JE, Todd DA, John E. Progress in retinopathy of prematurity. Premature birth and retinopathy of prematurity. 1997. 73-5.

19. Quinn GE, Dobson V, Kivlin J, et al. Prevalence of myopia between 3 months and 5 1/2 years in preterm infants with and without retinopathy of prematurity. Cryotherapy for Retinopathy of Prematurity Cooperative Group. Ophthalmology. 1998 Jul. 105(7):1292-300.

20. VanderVeen DK, Coats DK, Dobson V, et al. Prevalence and course of strabismus in the first year of life for infants with prethreshold retinopathy of prematurity: findings from the Early Treatment for Retinopathy of Prematurity study.