BASICS
DESCRIPTION
- Proliferative disorder of the retinal blood vessels in premature infants: The normal retinal vascularization occurs nasally at ~36 weeks ' gestational age and temporally at ~40 weeks ' gestational age.
- System(s) affected: nervous
- Synonym(s): ROP; retrolental fibroplasia
EPIDEMIOLOGY
Incidence
- 65.8% of infants weighing <1,251 g at birth and 81.6% of those weighing <1,000 g
- Predominant age: premature infants
- Predominant sex: male = female
ETIOLOGY AND PATHOPHYSIOLOGY
Oxidative processes (influenced by high levels of arterial oxygen) in immature retina may be an important causative factor. ‚
Genetics
African American infants appear less susceptible. ‚
RISK FACTORS
- Low birth weight
- Poor postnatal weight gain
- Prematurity
- Supplemental oxygen; once the retina becomes fully vascularized, oxygen does not affect the retina.
- Supplemental oxygen given to premature infants with moderate ROP will not make the retinopathy worse.
COMMONLY ASSOCIATED CONDITIONS
Neonatal respiratory distress syndrome ‚
DIAGNOSIS
PHYSICAL EXAM
- Acute ROP classification
- Location
- Zone I: posterior retina within a 60-degree circle centered on the optic nerve
- Zone II: extends from the edge of zone I to the nasal ora anteriorly
- Zone III: the residual temporal crescent of retina anterior to zone II
- Extent: number of clock hours involved
- Degree of abnormal vascular response observed the following:
- Stage 1: the development of a demarcation line between the vascularized and nonvascularized retina
- Stage 2: the presence of a demarcation line that extends out of the plane of the retina (ridge)
- Stage 3: a ridge with extraretinal fibrovascular proliferation
- Stage 4: subtotal retinal detachment
- Stage 5: total retinal detachment
- Plus disease is characterized by the tortuosity of the retinal vasculature in the posterior fundus. Preplus disease denotes retinal vascular abnormalities not of sufficient degree for plus disease but demonstrating more arterial tortuosity and more venous dilatation than normal (1).
- Aggressive posterior ROP (AP-ROP) represents an uncommon, aggressive posterior ROP that is rapidly progressive (1).
- AP-ROP characterized by severe plus disease, flat neovascularization in zone 1 or posterior zone 2
- The most significant risk factors for retinal detachment in AP-ROP are a gestational age <29.5 weeks, posterior zone 1 disease, and preretinal hemorrhages before laser treatment (2)[B].
DIFFERENTIAL DIAGNOSIS
- Retinoblastoma
- Congenital cataracts
- Norrie disease
- Incontinentia pigmenti
- Familial exudative vitreoretinopathy
- Ocular toxocariasis
- Coats disease
- Persistent hyperplastic primary vitreous
- X-linked retinoschisis
DIAGNOSTIC TESTS & INTERPRETATION
Spectral-domain optical coherence tomography (SD-OCT) imaging frequently demonstrates cystoid macular edema in premature infants screened for ROP before 37 weeks ' postmenstrual age. ‚
Diagnostic Procedures/Other
- Infants with a birth weight <1,500 g or gestational age ≤30 weeks and selected infants with birth weight 1,500 to 2,000 g or gestational age >30 weeks with an unstable clinical course should have screening exams performed after pupillary dilation using binocular indirect ophthalmoscopy (3)[A].
- Analysis of the natural history data from the Multicenter Trial of Cryotherapy for Retinopathy of Prematurity (CRYO-ROP) and the Light Reduction in Retinopathy Study provided evidenced-based screening criteria and the following updated recommendations:
- Eye exams for infants at risk for ROP should commence at 31 weeks ' postmenstrual age (gestational age at birth plus chronologic age) for infants with a gestational age of <27 weeks and at 4 weeks ' chronologic (postnatal) age for infants with a gestational age of ≥27 weeks
- Infants born at 25 weeks ' gestational age or earlier: Consider beginning the screening examination no later than 29 weeks ' postmenstrual age (4)[C].
- Findings that suggest that acute-phase ROP screening may be curtailed include the following:
- Infant 's attainment of 50 weeks ' postmenstrual age without the development of prethreshold ROP or worse
- Progression of retinal vascularization into zone III without previous zone I or zone II ROP
- Full retinal vascularization
- Regression of ROP (3)[A]
- Longitudinal assessment of postnatal weight gain may help predict severity of ROP. Infants can be entered into a computer-based surveillance system weight, insulin-like growth factor, neonatal ROP (WINROP) to help predict the risk of developing ROP.
- Poor weight gain during the 1st week of life is a risk factor for the development of severe ROP (5)[A].
- Follow-up exams are performed until the retina is fully vascularized.
- Telemedicine using the RetCam may be more cost-effective than standard ophthalmoscopy for ROP management.
Test Interpretation
- Peripheral retinal nonperfusion
- Retinal neovascularization
- Retinal hemorrhages
- Retinal detachment
TREATMENT
GENERAL MEASURES
- The CRYO-ROP study demonstrated a favorable outcome for eyes treated at threshold versus control eyes. Threshold ROP is defined as zone I or II, stage 3 ( ≥5 contiguous or 8 total clock hours with plus disease).
- Stage 3 retinopathy is defined as a ridge of extraretinal fibrovascular proliferation.
- A plus sign is added to the ROP stage number when retinal vascular tortuosity is noted in the posterior fundus.
- Threshold disease was defined as at least 5 contiguous or 8 cumulative clock hours of stage 3 associated with retinal vascular tortuosity in the posterior segment of the eye (plus disease) in zone I or II.
- When threshold disease is detected in infants, ablative therapy should be considered in at least one eye within 72 hours of diagnosis.
- The Early Treatment for Retinopathy of Prematurity (ETROP) study demonstrated that premature infants at high risk of vision loss from ROP retain better vision when therapy is administered early than when treatment is held until the traditional threshold (6)[A].
- In the ETROP study, patients received treatment with laser therapy, but cryotherapy also was allowed.
- Eyes with high-risk prethreshold ROP or type 1 ROP were treated. Type 1 ROP was defined as zone I with any stage of ROP with plus disease (dilatation and tortuosity of posterior pole retinal vessels in at least 2 quadrants, usually ≥6 clock hours); zone I, stage 3 ROP without plus disease; or zone II, stage 2 or 3 ROP with plus disease.
- Eyes with high-risk prethreshold ROP are at risk for developing glaucoma during the first 6 years of life (7)[A].
- Serial exams should be performed on eyes with prethreshold type 2 ROP, defined as zone I, stage 1 or 2 ROP without plus disease or zone II, stage 3 ROP without plus disease. Treatment should be considered for an eye with prethreshold type 2 ROP when progression to high-risk prethreshold type 1 ROP or threshold ROP occurs. Eyes with low-risk prethreshold type 2 ROP receive follow-up every 2 to 4 days for at least 2 weeks until the ROP regresses or progresses to high-risk prethreshold disease.
- The risk of progression from type 2 ROP to type 1 ROP in <7 days is greatest between 33 and 36 weeks ' postmenstrual age, regardless of zone of retinopathy (8)[A].
MEDICATION
Vascular endothelial growth factor (VEGF) has been demonstrated in the subretinal fluid of patients with advanced ROP: ‚
- Bevacizumab (Avastin) is a full-length antibody to VEGF that inhibits VEGF.
- The off-label administration of intravitreal bevacizumab demonstrated a significant benefit over conventional laser therapy for the treatment of stage 3+ ROP with zone I involvement (9)[C].
- ROP recurred in 4% of the bevacizumab-treated eyes and in 22% of eyes receiving standard laser treatment. The difference was statistically significant for zone I ROP but not for zone II disease.
- In addition, peripheral retinal vessel development continued after bevacizumab administration; in contrast, there was permanent destruction of the peripheral retina with conventional laser therapy.
- Treatment of ROP with intravitreal bevacizumab as compared to laser treatment led to less myopia and astigmatism (10)[C].
- The effect of intravitreal bevacizumab for the treatment of ROP may be transient and recurrences of the disease are possible (11)[C].
SURGERY/OTHER PROCEDURES
- Transscleral cryotherapy to the avascular retina when applied to high-risk eyes may reduce sight-threatening complications. The CRYO-ROP study showed that treatment of high-risk eyes reduces unfavorable outcomes by 46%.
- The results at 15 years from CRYO-ROP for ROP demonstrated that vision rated 20/200 or worse occurred in 44.7% of treated eyes versus 64.3% of controls, and an unfavorable outcome for fundus status was found in 30% of treated eyes versus 51.9% of controls.
- Diode laser treatment applied to the avascular retina is the primary treatment modality because it is better tolerated and results in better vision, less myopia, and less retinal dragging compared with cryotherapy.
- Cataract formation and serous retinal detachment are possible complications of laser treatment.
- Threshold ROP had a reduced rate of progression in eyes with zone 2 disease when a dense, near-confluent pattern of diode laser treatment was applied versus a less dense pattern of diode laser treatment.
- After 10 years, eyes treated with laser were 5.2 times more likely to have 20/50 or better vision than eyes treated with cryotherapy.
- Scleral buckling may reduce progression from stage 4 to stage 5 ROP. The encircling 240-degree band can be divided at 3 months after surgery if it is felt that the retina will remain attached.
- Vitrectomy and/or scleral buckling may be used to treat retinal detachment associated with ROP. Lens-sparing vitrectomy (LSV) may be used to treat stage 4 ROP. Emphasis should be placed on prevention of retinal detachment in premature infants because of the poor visual outcome after a lensectomy/vitrectomy procedure for retinal detachment due to ROP.
- Lens clarity is observed in most eyes after LSV surgery for advanced ROP for the patient 's childhood (12)[B].
- Early vitreous surgery before the fibrovascular tissue reaches the vitreous base may be beneficial for AP-ROP (13)[C].
- The off-label use of microplasmin (ocriplasmin) as a surgical adjunct to pediatric vitreoretinal surgery is being investigated (14)[C].
INPATIENT CONSIDERATIONS
Admission Criteria/Initial Stabilization
Treatment usually is performed in the neonatal ICU or as an outpatient or inpatient as the child grows older. ‚
ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
Patient Monitoring
- Close follow-up of patients with ROP is required.
- Eyes with low-risk prethreshold type 2 ROP receive follow-up every 2 to 4 days for at least 2 weeks until the ROP regresses or progresses to high-risk prethreshold type 1 ROP (6)[A].
- Schedule for follow-up exams.
- ≤1-week follow-up
- Stage 1 or 2 ROP: zone l
- Stage 3 ROP: zone ll
- Immature vascularization: zone I, no ROP
- Immature retina extends into posterior zone II, near the boundary of zone I.
- The presence or suspected presence of AP-ROP
- 1- to 2-week follow-up
- Immature vascularization: zone l, no ROP
- Immature vascularization; posterior zone II
- Stage 2 ROP: zone ll
- Regressing ROP: zone l
- 2-week follow-up
- Stage 1 ROP: zone ll
- Regressing ROP: zone ll
- Immature vascularization: zone II, no ROP
- 2- to 3-week follow-up
- Stage 1 or 2 ROP: zone lll
- Regressing ROP: zone lll (3)[A]
- In some cases of regressed ROP, cicatrization may develop and is associated with variable degrees of fibrosis. This may lead to vitreoretinal traction and subsequent retinal detachment from formation of a retinal hole.
- Retinal detachment secondary to cicatricial ROP may occur during the mid-teens; long-term follow-up of ROP cicatricial patients is indicated.
PROGNOSIS
- Spontaneous regression occurs over a period of weeks or months in most cases.
- Some cases of ROP do progress. A gradual transition then occurs from active to cicatricial ROP, which is associated with varying degrees of fibrosis and vitreoretinal traction that may lead to retinal detachment.
- When compared to conventional management, early treatment for type 1 high-risk prethreshold eyes in subjects at 6 years of age had improved visual acuity outcomes (15)[A].
COMPLICATIONS
- Retinal detachment
- Retinal fold involving the macula
- Vitreous hemorrhage
- Angle-closure glaucoma
- Amblyopia
- Strabismus
- Myopia
REFERENCES
11 International Committee for the Classification of Retinopathy of Prematurity. The International Classification of Retinopathy of Prematurity revisited. Arch Ophthalmol. 2005;123(7):991 " “999.22 Sanghi ‚ G, Dogra ‚ MR, Katoch ‚ D, et al. Aggressive posterior retinopathy of prematurity: risk factors for retinal detachment despite confluent laser photocoagulation. Am J Ophthalmol. 2013;155(1):159.e2 " “164.e2.33 Fierson ‚ WM. Screening examination of premature infants for retinopathy of prematurity. Pediatrics. 2013;131(1):189 " “195.44 Kishore ‚ K, Macwan ‚ KS. Need for revised screening protocol for early detection of retinopathy of prematurity in infants born before 25 weeks. JAMA Ophthalmol. 2013;131(4):546 " “547.55 Wu ‚ C, L ƒ ¶fqvist ‚ C, Smith ‚ LE, et al. Importance of early postnatal weight gain for normal retinal angiogenesis in very preterm infants: a multicenter study analyzing weight velocity deviations for the prediction of retinopathy of prematurity. Arch Ophthalmol. 2012;130(8):992 " “999.66 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;121(12):1684 " “1694.77 Bremer ‚ DL, Rogers ‚ DL, Good ‚ WV, et al. Glaucoma in the Early Treatment for Retinopathy of Prematurity (ETROP) study. J AAPOS. 2012;16(5):449 " “452.88 Christiansen ‚ SP, Dobson ‚ V, Quinn ‚ GE, et al. Progression of type 2 to type 1 retinopathy of prematurity in the Early Treatment for Retinopathy of Prematurity Study. Arch Ophthalmol. 2010;128(4):461 " “465.99 Mintz-Hittner ‚ HA, Kennedy ‚ KA, Chuang ‚ AZ. Efficacy of intravitreal bevacizumab for stage 3+ retinopathy of prematurity. N Engl J Med. 2011;364(7):603 " “615.1010 Harder ‚ BC, Schlichtenbrede ‚ FC, von Baltz ‚ S, et al. Intravitreal bevacizumab for retinopathy of prematurity: refractive error results. Am J Ophthalmol. 2013;155(6):1119.e1 " “1124.e1.1111 Hu ‚ J, Blair ‚ MP, Shapiro ‚ MJ, et al. Reactivation of retinopathy of prematurity after bevacizumab injection. Arch Ophthalmol. 2012;130(8):1000 " “1006.1212 Nudleman ‚ E, Robinson ‚ J, Rao ‚ P, et al. Long-term outcomes on lens clarity after lens-sparing vitrectomy for retinopathy of prematurity. Ophthalmology. 2015;122(4):755 " “759.1313 Azuma ‚ N, Ito ‚ M, Yokoi ‚ T, et al. Visual outcomes after early vitreous surgery for aggressive posterior retinopathy of prematurity. JAMA Ophthalmol. 2013;131(10):1309 " “1313.1414 Wong ‚ SC, Capone ‚ AJr. Microplasmin (ocriplasmin) in pediatric vitreoretinal surgery: update and review. Retina. 2013;33(2):339 " “348.1515 Good ‚ WV, Hardy ‚ RJ, Dobson ‚ V, et al. Final visual acuity results in the early treatment for retinopathy of prematurity study. Arch Ophthalmol. 2010;128(6):663 " “671.
CODES
ICD10
- H35.109 Retinopathy of prematurity, unspecified, unspecified eye
- H35.119 Retinopathy of prematurity, stage 0, unspecified eye
- H35.129 Retinopathy of prematurity, stage 1, unspecified eye
- H35.139 Retinopathy of prematurity, stage 2, unspecified eye
- H35.141 Retinopathy of prematurity, stage 3, right eye
- H35.142 Retinopathy of prematurity, stage 3, left eye
- H35.143 Retinopathy of prematurity, stage 3, bilateral
- H35.149 Retinopathy of prematurity, stage 3, unspecified eye
- H35.151 Retinopathy of prematurity, stage 4, right eye
- H35.153 Retinopathy of prematurity, stage 4, bilateral
- H35.159 Retinopathy of prematurity, stage 4, unspecified eye
- H35.161 Retinopathy of prematurity, stage 5, right eye
- H35.162 Retinopathy of prematurity, stage 5, left eye
- H35.163 Retinopathy of prematurity, stage 5, bilateral
- H35.169 Retinopathy of prematurity, stage 5, unspecified eye
- H35.152 Retinopathy of prematurity, stage 4, left eye
- H35.133 Retinopathy of prematurity, stage 2, bilateral
- H35.132 Retinopathy of prematurity, stage 2, left eye
- H35.131 Retinopathy of prematurity, stage 2, right eye
- H35.123 Retinopathy of prematurity, stage 1, bilateral
- H35.122 Retinopathy of prematurity, stage 1, left eye
- H35.121 Retinopathy of prematurity, stage 1, right eye
- H35.112 Retinopathy of prematurity, stage 0, left eye
- H35.111 Retinopathy of prematurity, stage 0, right eye
- H35.103 Retinopathy of prematurity, unspecified, bilateral
- H35.102 Retinopathy of prematurity, unspecified, left eye
- H35.101 Retinopathy of prematurity, unspecified, right eye
- H35.113 Retinopathy of prematurity, stage 0, bilateral
ICD9
- 362.20 Retinopathy of prematurity, unspecified
- 362.22 Retinopathy of prematurity, stage 0
- 362.23 Retinopathy of prematurity, stage 1
- 362.24 Retinopathy of prematurity, stage 2
- 362.25 Retinopathy of prematurity, stage 3
- 362.26 Retinopathy of prematurity, stage 4
- 362.27 Retinopathy of prematurity, stage 5
SNOMED
- Retinopathy of prematurity (disorder)
- Retinopathy of prematurity stage 0 (finding)
- Retinopathy of prematurity stage 1 - demarcation line (disorder)
- Retinopathy of prematurity stage 2 - intraretinal ridge (disorder)
- Retinopathy of prematurity stage 3 - ridge with extraretinal fibrovascular proliferation (disorder)
- Retinopathy of prematurity stage 4 - subtotal retinal detachment
- Retinopathy of prematurity stage 5 - total retinal detachment
CLINICAL PEARLS
- Infants with birth weight <1,500 g or gestational age ≤30 weeks and selected infants with birth weight 1,500 to 2,000 g or gestational age >30 weeks with an unstable clinical course should have retinal exams performed after pupillary dilation using binocular indirect ophthalmoscopy.
- Diode laser treatment is the primary treatment modality.
- The ETROP study demonstrated that premature infants at high risk of vision loss from ROP retain better vision when therapy is administered early than when treatment is held until the traditional threshold.