Ophthalmology

Retinopathy of Prematurity

Definition

Retinopathy of prematurity (ROP), the 2nd most common cause of blindness in the United States, is a disorder of the developing retinal vasculature that occurs with interruption of the forming retinal vessels. Constriction and obliteration of the advancing capillary bed are followed by neovascularization of the retina, which can extend into the vitreous. The most serious and feared complication of ROP is retinal detachment. ROP has previously been known as retrolental fibroplasia (RLF), a very advanced form of ROP with end stage fibrosis and scarring behind the lens.

 

Incidence

The Cryotherapy for ROP trial, a prospective cohort study that observed 4000 infants with birth weight <1251g, demonstrated that ROP occurred in 47% of infants weighing 1000-1251g, in 78% of infants weighing 750-999g, and in 90% of infants weighing <750g. 6-10% of all infants with ROP will develop severe vision loss or blindness. 

 

Risk Factors

  • Extreme prematurity and low birth weight
    • Infants born at <28 weeks gestational age have increased risk of ROP
    • Infants with birth weight <1250g have a 65% risk of developing ROP
    • Infants with birth weight <1000g at birth have an 81% risk of ROP
  • Possibly supplemental oxygen administration

Other possible risk factors: apnea, sepsis, hypoxia, hyper or hypocapnia, IVH, Caucasian race, assisted ventilation >1week, surfactant therapy, high volume blood transfusions, severity of comorbid illnesses, BPD, early administration of EPO, low serum concentrations of IGF-1.

 

Pathophysiology

It is postulated that there are two causal events:

  1. Vasoconstriction and obliteration of the capillary network in response to a vascular insult (possibly high supplemental O2 concentration)
  2. Vasoproliferation possibly a response by the hypoxic retina to an angiogenic factor released by the initial insult. It is believed that hypoxia can cause an overexpression of vascular endothelial growth factor (VEGF) that can induce abnormal retinal angiogenesis. Abnormal fibrovascular tissue can develop with the new vessels and then retract causing retina tension, distortion and possible detachment.

 

Etiology

The exact etiology of ROP is unknown but is likely multifactorial.

Oxygen administration originally was thought to contribute to the development of ROP. This is now being debated. The STOP ROP (Supplemental Therapeutic Oxygen to Prevent ROP) study investigated whether supplemental therapeutic oxygen for premature infants reduced the proportion of infants that progressed to threshold ROP. The study found that the more liberal use of oxygen actually decreased the risk of progression to threshold ROP in these infants from 48% to 41%. Threshold ROP is defined as disease progression to the point of necessitating peripheral retinal ablation therapy.

 

International Classification of ROP

Three components used to determine the extent of disease: 1) the zone in which ROP occurs, 2) the stage of ROP, and 3) the presence or absence of plus disease.

375px-ROP_zones.jpg
Zones of the retina in ROP https://en.wikipedia.org/wiki/Retinopathy_of_prematurity

Zones:

  • Zone 1- the most posterior — an area within twice the distance from the optic nerve head to the fovea
  • Zone 2- ROP outside of zone 1
  • Zone 3- ROP only present on the temporal side of the eye

Stages:

  • Stage 1- a line of demarcation develops from the vascularized region of the retina and the avascular zone
  • Stage 2- the line becomes a ridge that protrudes into the vitreous. Histological evidence of an A-V shunt
  • Stage 3- Extra-retinal vascular proliferation occurs with the ridge. Neovascular tufts can be found posterior to the ridge.
  • Stage 4- Scarring and fibrosis can occur when the neovascularization extends into the vitreous. This can cause traction on the retina, leading to retinal detachment.
  • Stage 5- Indicates total retinal detachment.

Plus Disease — can occur when vessels posterior to the ridge become dilated and tortuous. It often rapidly progresses to retinal detachment.
 

Image of Plus Disease

 

Diagnosis

National recommendations for ROP screening exams in premature infants:

  1. Infants <1500 g or < 28 weeks, or > 1500g with poor clinical course should receive dilated eye exams at 4-6 weeks of age. Exams are to continue every 2-4 weeks until retinal maturity is reached.
  2. Infants with ROP or immature retinal vessels are to have exams every 1-2 weeks until vessels are mature.

 

Treatment

Treatment is initiated when there is ROP in zone I or II, with five contiguous or eight cumulative clock hours of stage 3, and with plus disease — where severe visual loss occurs approximately 50% of the time (threshold retinopathy).

  1. Cryotherapy – an attempt to prevent further progression of the disease by destroying the cells that may release angiogenic factors. If both eyes have threshold ROP, only one eye is treated due to the risk of vitreous hemorrhage. If there is a very high risk of bilateral retinal detachment, the procedure can be performed in both eyes.
  2. Photocoagulation — laser photocoagulation procedure done to destroy cells that could lead to disease progression. In a meta analysis of four photocoagulation trials, this procedure was found to be at least as effective as cryotherapy.
  3. Retinal reattachment — an attempt to treat stage 5 disease, has a low success rate.
  4. Anti-VGEF (bevacizumab) administered in the vitrea – promising but still under investigation. Bevacizumab was FDA approved for treatment of metastatic colon cancer, but is used off-label to treat multiple retinal diseases with abnormal vascular proliferation.

 

Prognosis

90% of Stage 1 and Stage 2 disease regresses spontaneously. Approximately 50% of Stage 3 disease can regress spontaneously. Prognosis for stage 4 and 5 disease is poor, with a high incidence of visual problems and retinal detachment.

 

References

  1.  An International Classification of Retinopathy of Prematurity. The Committee for the Classification of Retinopathy of Prematurity. Archives of Opthalmology 1984; 102: 1130.
  2.  Gomella, Ed., Retinopathy of Prematurity, Neonatology, 520-524, 1999, A & L.
  3.  Good, W, Gendron, RL, Retinopathy of Prematurity Opthalmology Clinics of North America, 2001; Vol 14, No. 3
  4.  Palmer, EA, Flynn, Jt, Hardy RJ et al. Incidence and early course of retinopathy of prematurity. The Cryotherapy for Retinopathy of Prematurity Cooperative Group. Opthalmology 1991; 981:628.
  5.  Screening examination of premature infants for retinopathy of prematurity. A joint statement by the American Academy of Pediatrics, the American Association for Pediatric Opthalmology and Strabismus, and the American Academy of Opthalmology. Pediatrics 1997; 100:273.
  6.  Supplemental Theraputic Oxygen for Prethreshold Retinopathy of Prematurity (STOP ROP), a randomized, controlled trial. I: primary outcomes. Pediatrics 2000; 105:295.
  7.  Yanoff, Opthalmology 1st ed., Vascular Disorders — Retinopathy of Prematurity. Section 8, 19.1-19.7, 1999, Mosby International.
  8. Mintz-Hintner HA et al.  Efficacy of Intravitreal Bevacizumab for Stage 3 Retinopathy of Prematurity NEJM Feb 17, 2011
  9. “Retinopathy of Prematurity” on UpToDate. Updated Oct 11, 2011.
  10. Hartnett M, Penn J.  Mechanism and Mangement of Retinopatjy of Prematurity.  New England Journal of Medicine.  Dec 27, 2012