Retinopathy of Prematurity – Causes, Symptoms, Diagnosis, Treatment and Ongoing care

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): Retinopathy of prematurity (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

Risk Factors

  • Low birth weight
  • 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.

Genetics

African American infants appear less susceptible.

Etiology

Oxidative processes (influenced by high levels of arterial oxygen) in immature retina may be an important causative factor.

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:
      • 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. Pre-plus 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).

Diagnostic Tests & Interpretation

Lab

Possible serum markers to monitor ROP include insulinlike growth factor 1 and insulinlike growth factor–binding protein 3.

Diagnostic Procedures/Surgery

  • Infants with a birth weight <1,500 g or gestational age ≤30 weeks (as defined by the attending neonatologist) and selected infants with birth weight between 1,500 and 2,000 g or gestational age >30 weeks with an unstable clinical course, including those requiring cardiorespiratory support and who are believed by their attending pediatrician or neonatologist to be at high risk, should have retinal screening examinations performed after pupillary dilation using binocular indirect ophthalmoscopy (2)[A].
  • The American Academy of Pediatrics, the American Association for Pediatric Ophthalmology and Strabismus, and the American Academy of Ophthalmology produced a joint statement recommending the initial eye examination be performed between 4 and 6 weeks of chronologic age or between 31 and 33 weeks of postconceptional age (gestational age at birth plus chronologic age) (3)[A].
  • The preceding joint statement had its limitations, and some patients would have been diagnosed with threshold disease at their initial examination if postconceptional age criteria from the joint statement had been followed. 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 examinations for infants at risk for ROP should commence at 31 weeks’ postmenstrual age (gestational age at birth plus chronological age) for infants with a gestational age of less than 27 weeks and at 4 weeks’ chronologic (postnatal) age for infants with a gestational age of 27 weeks or greater (4)[A].
    • Findings that suggest that acute-phase ROP screening may be curtailed include the following:
      • Infant’s attainment of 45 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 (2)[A]
  • Longitudinal assessment of postnatal weight gain may help predict severity of ROP. Infants entered into a computer-based surveillance system, WINROP (weight, insulinlike growth factor, neonatal ROP). A persistent reduction in insulinlike growth factor (IGF-1) is associated with reduced postnatal weight gain and the subsequent development of ROP (5)[A].
  • Follow-up examinations are performed until the retina is fully vascularized.
  • Telemedicine using the RetCam may be more cost-effective than standard ophthalmoscopy for ROP management.

Pathological Findings

  • Peripheral retinal nonperfusion
  • Retinal neovascularization
  • Retinal hemorrhages
  • Retinal detachment

Differential Diagnosis

  • Retinoblastoma
  • Congenital cataracts
  • Norrie disease
  • Incontinentia pigmenti
  • Familial exudative vitreoretinopathy
  • Ocular toxocariasis
  • Coats disease
  • Persistent hyperplastic primary vitreous
  • X-linked retinoschisis

Treatment

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.
  • There are case reports of the off-label intravitreal administration of Avastin in the treatment of ROP.

Additional Treatment

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General Measures

  • The CRYO-ROP study demonstrated a favorable outcome for eyes treated at threshold vs 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 1 eye within 72 h 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]. The eyes assigned to early treatment had a significantly reduced likelihood of poor vision, from 19.5–14.5%, at ∼1 year of age:
    • 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.
  • Serial examinations should be performed on eyes with prethreshold type 2 ROP, which is 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 2–4 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 less than 7 days is greatest between 33 and 36 weeks postmenstrual age, regardless of zone of retinopathy (7)[A].

Surgery/Other Procedures

  • Trans-scleral cryotherapy to the avascular retina when applied to high-risk eyes may reduce the incidence of sight-threatening complications. The CRYO-ROP study has shown that treatment of high-risk eyes reduces the incidence of unfavorable outcomes by 46%.
  • The results at 1 year from CRYO-ROP demonstrated an unfavorable outcome in 25.7% of eyes that received cryotherapy compared with 47.4% of control eyes.
  • The results at 15 years from CRYO-ROP for retinopathy of prematurity demonstrated the following: Vision rated 20/200 or worse occurred in 44.7% of treated eyes vs 64.3% of control eyes, and an unfavorable outcome for fundus status was found in 30% of treated eyes vs 51.9% of control eyes.
  • Laser treatment applied to the avascular retina in high-risk eyes may reduce the incidence of sight-threatening complications; cataract formation and serous retinal detachment are possible complications of laser treatment.
  • Diode laser treatment is becoming the primary treatment modality because it may be better tolerated and probably results in better vision, less myopia, and less retinal dragging compared with eyes treated with cryotherapy.
  • 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 vs a less-dense pattern of diode laser treatment.
  • IV fentanyl is a good analgesic agent to use when performing laser treatment with scleral depression on preterm infants.
  • After 10 years of follow-up, 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 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 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.

In-Patient Considerations

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 2–4 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 examinations:
    • 1-week or less follow-up:
      • Stage 1 or 2 ROP: Zone l
      • Stage 3 ROP: Zone ll
    • 1- to 2-week follow-up:
      • Immature vascularization: Zone l, no ROP
      • Stage 2 ROP: Zone ll
      • Regressing ROP: Zone l
    • 2-week follow-up:
      • Stage 1 ROP: Zone ll
      • Regressing ROP: Zone ll
    • 2- to 3-week follow-up:
      • Immature vascularization: Zone ll, no ROP
      • Stage 1 or 2 ROP: Zone lll
      • Regressing ROP: Zone lll (2)[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 midteens; long-term follow-up of ROP cicatricial patients is indicated.

Prognosis

  • Spontaneous regression occurs over a period of weeks or months in most cases; occurs in ∼85% of eyes.
  • The earliest sign of regression is the growth of blood vessels beyond the demarcation line into previously avascular retina.
  • Some cases of ROP do not regress spontaneously without sequelae but rather progress. A gradual transition then occurs from active ROP to cicatricial ROP, which is associated with varying degrees of fibrosis and vitreoretinal traction that may lead to retinal detachment.

Complications

  • Retinal detachment
  • Retinal fold involving the macula
  • Vitreous hemorrhage
  • Angle-closure glaucoma
  • Amblyopia
  • Strabismus
  • Myopia

References

1. International Committee for the Classification of Retinopathy of Prematurity. The International Classification of Retinopathy of Prematurity revisited. Arch Ophthalmol. 2005;123:991–9.

2. Section on Ophthalmology American Academy of Pediatrics, American Academy of Ophthalmology, American Association for Pediatric Ophthalmology and Strabismus. Screening examination of premature infants for retinopathy of prematurity. Pediatrics. 2006;117:572–6. Erratum in: Pediatrics 2006; 118:1324.

3. Screening examination of premature infants for retinopathy of prematurity: A joint statement of the American Academy of Pediatrics, the American Association for Pediatric Ophthalmology and Strabismus, and the American Academy of Ophthalmology. Ophthalmol. 1997;104:888–9.

4. Reynolds JD, Dobson V, Quinn GE, et al. Evidence-based screening criteria for retinopathy of prematurity: natural history data from the CRYO-ROP and LIGHT-ROP studies. Arch Ophthalmol. 2002;120:1470–6.

5. Wu C, Vanderveen DK, Hellström A, Löfqvist C, Smith LE et al. Longitudinal postnatal weight measurements for the prediction of retinopathy of prematurity.Arch. Ophthalmol. 2010;128:443–7.

6. 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;121:1684–94.

7. Christiansen SP, Dobson V, el al. Progression of type 2 to type 1 retinopathy of prematurity in the Early Treatment for Retinopathy of Prematurity Study.Arch Ophthalmol. 2010;128:461–465.

Codes

ICD9

  • 362.20 Retinopathy of prematurity, unspecified
  • 362.21 Retrolental fibroplasia
  • 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
  • 362.29 Other nondiabetic proliferative retinopathy

Snomed

  • 415297005 retinopathy of prematurity (disorder)
  • 408847006 retinopathy of prematurity stage 1 – demarcation line (disorder)
  • 408848001 retinopathy of prematurity stage 2 – intraretinal ridge (disorder)
  • 408849009 retinopathy of prematurity stage 3 – ridge with extraretinal fibrovascular proliferation (disorder)
  • 408850009 retinopathy of prematurity stage 4 – subtotal retinal detachment (disorder)
  • 408851008 retinopathy of prematurity stage 5 – total retinal detachment (disorder)

Clinical Pearls

  • Infants with birth weight <1,500 g or gestational age ≤ 30 weeks and selected infants with birth weight between 1,500 and 2,000 g or gestational age >30 weeks with an unstable clinical course should have retinal screening examinations performed after pupillary dilation using binocular indirect ophthalmoscopy.
  • Diode laser treatment is becoming 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.

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