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Physician presents refresher on retinopathy of prematurity

Part 1 of a two-part series explores the pathogenesis, stages and treatments of ROP.

Retinal vascularization commences at 16 weeks of gestation and finishes around 36 weeks nasally and 40 to 45 weeks temporally. When an infant is born prematurely, retinal vascularization is not yet complete and the infant is predisposed to developing retinopathy of prematurity. The infants most at risk for developing ROP are those born sooner than 30 weeks’ gestational age and less than 1,500 grams. Therefore, the American Academy of Pediatrics and the American Association for Pediatric Ophthalmology and Strabismus, along with the American Academy of Ophthalmology, have devised a protocol for screening at-risk infants for ROP.

Pathogenesis and stages

The pathogenesis of ROP involves two phases. Phase one begins with delayed vasculogenesis after premature birth, resulting in vaso-obliteration when exposed to higher than in utero oxygen concentrations. The levels of VEGF and insulin-like growth factor (IGF) initially fall as the infant is exposed to this hyperoxic environment and lack of maternal factors. The resulting avascular retina leads to phase two, with the rise of VEGF and IGF to create an ischemic phase and abnormal angiogenesis.

Christin L. Sylvester

 

ROP consists of five stages. Stage 1 is a demarcation line between vascular and avascular retina. Stage 2 is when the demarcation line turns into a ridge. Stage 3 is neovascularization of the ridge. Stage 4a is a partial retinal detachment with the fovea attached, and stage 4b is a partial retinal detachment with the fovea detached. Stage 5 is a total retinal detachment that can be classified as an open or closed funnel. Plus disease, which is an indicator of severe ROP, is defined as dilated and tortuous vessels at the optic nerve in two quadrants. ROP is also defined by location of the disease, which is divided into three zones. Zone 1 is the most posterior zone encircling the disc and macula by twice the distance from the disc to the macula. Zone 2 includes the peripheral retina extending to the ora serrata nasally. The final zone, zone 3, includes the remaining temporal crescent.

The outcomes of the CRYO-ROP study determined that infants with severe ROP in zone 1 continued to have poor outcomes. Therefore, the Early Treatment for Retinopathy of Prematurity study was completed to revise the treatment criteria and decrease the incidence of poor outcomes. Two types of ROP exist: type 1 high-risk ROP and type 2 low-risk ROP. Type 1 ROP includes those infants with stage 1, 2 or 3 ROP with plus disease or stage 3 ROP without plus disease in zone 1. These infants are considered at high risk, and treatment is recommended. The more mild stages of ROP are considered low risk, and observation for 1 or 2 weeks is recommended, depending on the stage of disease.

Cryotherapy and laser

The gold standard treatment for ROP has been cryotherapy or laser photocoagulation to the avascular retina. Cryotherapy may be used but is often more challenging for posterior disease. It is useful for anterior disease that may be difficult to reach with an indirect laser. Consequently, laser photocoagulation has largely replaced cryotherapy. Laser photocoagulation is portable and more convenient and yields better visual outcomes compared with cryotherapy. Treatment is often performed either in the NICU at bedside with monitored sedation and laser protocol or in the operating room with general anesthesia.

The laser used for ROP treatment is an indirect infrared 810 nm diode laser. As opposed to panretinal laser photocoagulation for diabetic retinopathy, the laser application for ROP is confluent or near-confluent, often requiring 800 to 2,000 spots per eye. Confluent laser patterns and early re-treatment have been proven to aid in decreasing the rate of disease progression, 3.6% compared with 29.4% with less confluent treatment. The entire avascular retina is treated 360° from the ridge to the ora serrata to decrease the continued growth factor production. The typical power setting is 200 mW to 400 mW for a duration of 0.1 to 0.3 seconds, titrating up as necessary to produce a moderately white burn. A thorough inspection of the avascular retina is necessary to ensure that any inadvertently skipped areas are filled in.

Although uncommon, the complications of laser photocoagulation can include serous choroidal effusions, inflammation, cataracts, iris or corneal damage, vitreous hemorrhages and anterior segment ischemia. The cataracts associated with laser surgery are often transient and will spontaneously resolve, although more severe cataract formation has been described. More common complications include undertreatment with disease progression and myopia. Myopia can occur due to the laser ablative therapy itself or from anterior segment growth arrest and resultant anterior lens displacement.

Laser photocoagulation to the avascular retina in type 1 high-risk ROP reduces blindness, although many patients may end up with poor visual acuity. A better understanding of the pathogenesis of ROP has resulted in treatment modalities that are aimed at suppression of VEGF and normalization of serum IGF-1 or that may reduce the risk factors associated with premature birth.

In part 2 of this column in the March 10 issue, I will describe treatment options for ROP.

Visit UPMCPhysicianResources.com/Ocular to learn more about ROP. You can also submit clinical questions or read the most recent questions asked of the UPMC Eye Center’s ophthalmology experts.

References:
Banach MJ, et al. Ophthalmology. 2000;doi:10.1016/S0161-6420(99)00042-1.
Fierson WM, et al. Pediatrics. 2013;doi:10.1542/peds.2012-2996.
Good WV, et al. Trans Am Ophthalmol Soc. 2004;102:233-248; discussion 248-250.
Hellström A, et a. Lancet. 2013;doi:10.1016/S0140-6736(13)60178-6.
Houston SK, et al. Lasers Med Sci. 2013;doi:10.1007/s10103-011-1021-z.
Lambert SR, et al. Am J Ophthalmol. 2001;doi:10.1016/S0002-9394(99)00475-4.
Ng EY, et al. Ophthalmology. 2002;doi:10.1016/S0161-6420(01)01017-X.
For more information:
Christin L. Sylvester, DO, is a clinical assistant professor of ophthalmology at UPMC and the University of Pittsburgh. She can be reached at Children’s Hospital of Pittsburgh of UPMC, Children’s Hospital Drive, 45th and Penn Ave., CHP Faculty Pavilion, Suite 5000, Pittsburgh, PA 15201; email: sylvestercl@upmc.edu.
Disclosure: Sylvester has no relevant financial disclosures.

Retinal vascularization commences at 16 weeks of gestation and finishes around 36 weeks nasally and 40 to 45 weeks temporally. When an infant is born prematurely, retinal vascularization is not yet complete and the infant is predisposed to developing retinopathy of prematurity. The infants most at risk for developing ROP are those born sooner than 30 weeks’ gestational age and less than 1,500 grams. Therefore, the American Academy of Pediatrics and the American Association for Pediatric Ophthalmology and Strabismus, along with the American Academy of Ophthalmology, have devised a protocol for screening at-risk infants for ROP.

Pathogenesis and stages

The pathogenesis of ROP involves two phases. Phase one begins with delayed vasculogenesis after premature birth, resulting in vaso-obliteration when exposed to higher than in utero oxygen concentrations. The levels of VEGF and insulin-like growth factor (IGF) initially fall as the infant is exposed to this hyperoxic environment and lack of maternal factors. The resulting avascular retina leads to phase two, with the rise of VEGF and IGF to create an ischemic phase and abnormal angiogenesis.

Christin L. Sylvester

 

ROP consists of five stages. Stage 1 is a demarcation line between vascular and avascular retina. Stage 2 is when the demarcation line turns into a ridge. Stage 3 is neovascularization of the ridge. Stage 4a is a partial retinal detachment with the fovea attached, and stage 4b is a partial retinal detachment with the fovea detached. Stage 5 is a total retinal detachment that can be classified as an open or closed funnel. Plus disease, which is an indicator of severe ROP, is defined as dilated and tortuous vessels at the optic nerve in two quadrants. ROP is also defined by location of the disease, which is divided into three zones. Zone 1 is the most posterior zone encircling the disc and macula by twice the distance from the disc to the macula. Zone 2 includes the peripheral retina extending to the ora serrata nasally. The final zone, zone 3, includes the remaining temporal crescent.

The outcomes of the CRYO-ROP study determined that infants with severe ROP in zone 1 continued to have poor outcomes. Therefore, the Early Treatment for Retinopathy of Prematurity study was completed to revise the treatment criteria and decrease the incidence of poor outcomes. Two types of ROP exist: type 1 high-risk ROP and type 2 low-risk ROP. Type 1 ROP includes those infants with stage 1, 2 or 3 ROP with plus disease or stage 3 ROP without plus disease in zone 1. These infants are considered at high risk, and treatment is recommended. The more mild stages of ROP are considered low risk, and observation for 1 or 2 weeks is recommended, depending on the stage of disease.

Cryotherapy and laser

The gold standard treatment for ROP has been cryotherapy or laser photocoagulation to the avascular retina. Cryotherapy may be used but is often more challenging for posterior disease. It is useful for anterior disease that may be difficult to reach with an indirect laser. Consequently, laser photocoagulation has largely replaced cryotherapy. Laser photocoagulation is portable and more convenient and yields better visual outcomes compared with cryotherapy. Treatment is often performed either in the NICU at bedside with monitored sedation and laser protocol or in the operating room with general anesthesia.

The laser used for ROP treatment is an indirect infrared 810 nm diode laser. As opposed to panretinal laser photocoagulation for diabetic retinopathy, the laser application for ROP is confluent or near-confluent, often requiring 800 to 2,000 spots per eye. Confluent laser patterns and early re-treatment have been proven to aid in decreasing the rate of disease progression, 3.6% compared with 29.4% with less confluent treatment. The entire avascular retina is treated 360° from the ridge to the ora serrata to decrease the continued growth factor production. The typical power setting is 200 mW to 400 mW for a duration of 0.1 to 0.3 seconds, titrating up as necessary to produce a moderately white burn. A thorough inspection of the avascular retina is necessary to ensure that any inadvertently skipped areas are filled in.

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Although uncommon, the complications of laser photocoagulation can include serous choroidal effusions, inflammation, cataracts, iris or corneal damage, vitreous hemorrhages and anterior segment ischemia. The cataracts associated with laser surgery are often transient and will spontaneously resolve, although more severe cataract formation has been described. More common complications include undertreatment with disease progression and myopia. Myopia can occur due to the laser ablative therapy itself or from anterior segment growth arrest and resultant anterior lens displacement.

Laser photocoagulation to the avascular retina in type 1 high-risk ROP reduces blindness, although many patients may end up with poor visual acuity. A better understanding of the pathogenesis of ROP has resulted in treatment modalities that are aimed at suppression of VEGF and normalization of serum IGF-1 or that may reduce the risk factors associated with premature birth.

In part 2 of this column in the March 10 issue, I will describe treatment options for ROP.

Visit UPMCPhysicianResources.com/Ocular to learn more about ROP. You can also submit clinical questions or read the most recent questions asked of the UPMC Eye Center’s ophthalmology experts.

References:
Banach MJ, et al. Ophthalmology. 2000;doi:10.1016/S0161-6420(99)00042-1.
Fierson WM, et al. Pediatrics. 2013;doi:10.1542/peds.2012-2996.
Good WV, et al. Trans Am Ophthalmol Soc. 2004;102:233-248; discussion 248-250.
Hellström A, et a. Lancet. 2013;doi:10.1016/S0140-6736(13)60178-6.
Houston SK, et al. Lasers Med Sci. 2013;doi:10.1007/s10103-011-1021-z.
Lambert SR, et al. Am J Ophthalmol. 2001;doi:10.1016/S0002-9394(99)00475-4.
Ng EY, et al. Ophthalmology. 2002;doi:10.1016/S0161-6420(01)01017-X.
For more information:
Christin L. Sylvester, DO, is a clinical assistant professor of ophthalmology at UPMC and the University of Pittsburgh. She can be reached at Children’s Hospital of Pittsburgh of UPMC, Children’s Hospital Drive, 45th and Penn Ave., CHP Faculty Pavilion, Suite 5000, Pittsburgh, PA 15201; email: sylvestercl@upmc.edu.
Disclosure: Sylvester has no relevant financial disclosures.