Retinopathy of Prematurity

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Retinopathy of Prematurity
Classification and external resources
ICD-10 H35.1
DiseasesDB 11442


Disease Entity

Retinopathy of prematurity (ROP), initially described as retrolental fibroplasia by Terry in 1942 was the leading cause of blindness in children in the United States.[1] Despite advances in diagnosis and treatment, as medicine and technology advances and premature infants are surviving at earlier gestational ages, ROP continues to be a significant problem. ROP results in disorganized growth of retinal blood vessels, which may lead to scarring and retinal detachment.

Etiology

ROP occurs in premature infants who are born before the retinal vessels complete their normal growth. Local ischemia plays a role, just as in other proliferative retinopathies like diabetic retinopathy and sickle cell retinopathy. Its incidence varies inversely with birth weight and gestational age. Oxygen has long been known to have a role in the disease process. Excessive oxygen can cause vaso-obliteration in the immature retina. Studies have shown that keeping the oxygen saturation at a lower level from birth can reduce the rate of advanced ROP. [2]

Risk Factors

Key risk factors

  • Low birthweight (less than 1500 grams)
  • Gestational age (32 weeks or less)
  • Extended supplemental oxygen, although the exact role is not fully understood

Suggested risk factors

  • Intraventricular hemorrhage, respiratory distress syndrome, sepsis, white race, and multiple births. [3][4]

General Pathology

In histological studies of infants with ROP, the earliest lesions seen in acute phase were arteriovenous shunts. Other lesions include neovascularization that may penetrate the vitreous, microvascular changes including tufting, and obliteration of capillaries around arteries and veins. [5]

Pathophysiology

In utero, the fetus is in a hypoxic state in contrast to after birth. When infants are born prematurely, the growth of retinal vessels is stimulated by vascular endothelial growth factor (VEGF). However if the immature retina is exposed to ongoing hyperoxia, the vessels will stop growing. Over time, the avascular retina becomes ischemic and stimulates VEGF in some cases leading to arterial venous shunts and neovascularization.

Primary prevention

Screenings of infants at risk with appropriate timing of exams and follow up is essential in identifying infants in need of treatment.[4]

Table: Recommended Timing of First Exam Based on Gestational Age
Gestational Age at Birth Postmenstrual (weeks) Chronologic (weeks)
23 weeks 31 8
24 weeks 31 7
25 weeks 31 6
26 weeks 31 5
27 weeks 31 4
28 weeks 32 4
29 weeks 33 4
30 weeks 34 4
31 weeks 35 4
32 weeks 36 4

Diagnosis

The International Committee for Classification of Retinopathy of Prematurity developed a diagnostic classification in 1984, and since has been further refined.[6][7][8] It is defined by location, stage and extent.

Location

For the purpose of defining the location, three concentric zones were defined. Since retinal vascular development proceeds from the optic nerve to the ora serrata, the zones are centered on the optic disc rather than the macula. Zone I is a circle, the radius of which extends from the center of the optic disc to twice the distance from the center of the optic disc to the center of the macula. Zone II extends centrifugally from the edge of zone I to the nasal ora serrata. Zone III is the residual crescent of retina anterior to zone II. By convention, zones II and III are considered to be mutually exclusive.

Staging

Prior to the development of ROP in the premature infant, vascularization of the retina is incomplete or "immature".

Stage 1: Demarcation Line This line is a thin but definite structure that separates the avascular retina anteriorly from the vascularized retina posteriorly. There is abnormal branching or arcading of vessels leading up to the demarcation line that is relatively flat, white, and lies within the plane of the retina.

Stage 2: Ridge The ridge arises from the demarcation line and has height and width, which extends above the plane of the retina. The ridge may change from white to pink and vessels may leave the plane of the retina posterior to the ridge to enter it. Small isolated tufts of neovascular tissue lying on the surface of the retina, commonly called "popcorn" may be seen posterior to this ridge structure and do not constitute the degree of fibrovascular growth that is a necessary condition for stage 3.

Stage 3: Extraretinal Fibrovascular Proliferation Neovascularization extends from the ridge into the vitreous. This extraretinal proliferating tissue is continuous with the posterior aspect of the ridge, causing a ragged appearance as the proliferation becomes more extensive.

Stage 4: Partial Retinal Detachment Stage 4, in the initial classification was the final stage and initially known as the cicatricial phase.[6] It was later divided into extrafoveal (stage 4A) and foveal (stage 4B) partial retinal detachments. Stage 4 retinal detachments are generally concave and most are circumferentially oriented. Retinal detachments usually begin at the point of fibrovascular attachment to the vascularized retina and the extent of detachment depends on the amount of neovascularization present.[7]

Stage 5: Total Retinal Detachment Retinal detachments are generally tractional and usually funnel shaped. The configuration of the funnel itself is used for subdivision of this stage depending if the anterior and posterior portions are open or narrowed.[7] More than one stage may be present in the same eye, staging for the eye as a whole is determined by the most severe stage present.

Extent

The extent of disease is recorded as hours of the clock or as 30° sectors. As the observer looks at each eye, the 3-o’clock position is to the right and nasal in the right eye and temporal in the left eye, and the 9-o’clock position is to the left and temporal in the right eye and nasal in the left eye.[6]

Plus disease

Additional signs of increased venous dilatation and arteriolar tortuosity of the posterior retinal vessels which can increase in severity to include iris vascular engorgement, poor pupillary dilatation, and vitreous haze was referred to as plus disease in the original classification. [6] Subsequent clinical trials have used a "standard" photograph to define the minimum amount of vascular dilatation and tortuosity required making the diagnosis of plus disease.[9]

Pre-Plus disease

There is a spectrum of abnormal dilatation and tortuosity of which Plus disease is the severe form. A pre-plus disease was later described as vascular abnormalities of the posterior pole that are insufficient for the diagnosis of plus disease but that demonstrate more arterial tortuosity and more venous dilatation than normal.[8]

Aggressive Posterior ROP (AP-ROP)

An uncommon, rapidly progressing, severe form of ROP is designated AP-ROP was later added to the classification. [8] Characteristic features of this type of ROP are a posterior location, plus disease, and the ill-defined nature of the retinopathy, which usually progresses to stage 5 if untreated. This rapidly progressing has also been referred to as "type II ROP" and "Rush disease".

Diagnostic procedures

Following pupillary dilation using eye drops, the retina is examined using an indirect ophthalmoscope. The peripheral portions of the retina are pushed into view using scleral depression.

Differential diagnosis

  • Familal Exudative Vitreoretinopathy is a genetic disorder that appears similar to ROP but occurs in full-term infants.
  • Persistent Fetal Vascular can cause a traction retinal detachment difficult to differentiate but typically unilateral and does not have a correlation to prematurity.

Management

Ophthalmologists with adequate knowledge of ROP should perform retinal exams in preterm infants. The initial exam should be based on the infant’s age (see table1). Follow up recommendations were updated in 2006 by the American Academy of Pediatrics and depend on the location and stage. [10]

Follow up of 1 week or less:

  • Stage 1 or 2 ROP in zone I
  • Stage 3 ROP in zone II


Follow up of 1 to 2-weeks:

  • Stage 2 ROP in zone II
  • Regressing ROP in zone I
  • Immature vessels in zone I


Follow up of 2-weeks:

  • Stage 1 ROP in Zone II
  • Regressing ROP in zone II


Follow up of 2 to 3-weeks:

  • Immature vessels in zone II
  • Stage 1 or 2 in zone III
  • Regressing ROP in zone III

Surgery

The first surgical treatment for ROP accepted to be safe and effective was cryotherapy to the avascular retina as designated by the CRYO- ROP study in 1986. This produced a reduction in unfavorable outcomes in eyes with threshold ROP. [3] Subsequently, argon and diode lasers have been used similarly to treat the avascular retina to reduce unfavorable outcomes. The laser units are preferred because they are more portable and better tolerated by patients. [11]


Surgical treatment is currently recommended for the following:

  • Zone I ROP: any stage with plus disease
  • Zone I ROP: stage 3 – no plus disease
  • Zone II ROP: stage 2 or 3 with plus
  • The number of clock hours of disease is no longer the determining factor
  • Eyes meeting these criteria should be treated within 72 hours.

Surgical follow up

Surgically treated eyes must be watched carefully for regression. Despite treatment, some eyes will progress to retinal detachment. In the CRYO-ROP study, approximately 30% of eyes progressed to posterior pole macular fold or retinal detachment.[9]These eyes may need vitreoretinal surgery.

Complications

The most feared complication in ROP is retinal detachment or macular folds. There are a number of other complications related to this disease that can effect visual development. Myopia is a common finding in premature infants with our without ROP. Infants with regressed ROP also have an increased incidence of strabismus, amblyopia, and anisometropia.

Prognosis

If ROP progresses leading to retinal detachment, the outcome is visually devastating. The CRYO-ROP study showed that treatment reduces the risk of unfavorable outcome from 51% to 31%. The same study showed improved outcomes in the treated group for visual acuity at the 3-year and 10-year follow up.

Additional Resources

References

  1. Terry TL. Retrolental fibroplasia. J Pediatr. 1946 Dec; 29:770-3.
  2. Chow LC, Wright KW, Sola A, CSMC Oxygen Administration Study Group. Can changes in clinical practice decrease the incidence of severe retinopathy of prematurity in very low birth weight infants? Pediatrics 2003 ;111:339-45.
  3. 3.0 3.1 Cryotherapy for Retinopathy of Prematurity Cooperative Group. Multicenter trial of cryotherapy for retinopathy of prematurity: preliminary results. Arch Ophthalmol. 1988;106:471-479.
  4. 4.0 4.1 Charles BJ, Ganthier R, Appiah AA. Incidence and characteristics of ROP in low-income inner city population. Ophthalmology 1991; 98:14-17.
  5. Kushner BJ, Essner D, Cohen IJ, Flynn JT. Retrolental Fibroplasia: Pathologic correlation. Arch Ophthalmol. 1977 Jan;95(1):29-38.
  6. 6.0 6.1 6.2 6.3 Committee for the Classification of Retinopathy of Prematurity. An International Classification of Retinopathy of Prematurity. Arch Ophthalmol. 1984;102:1130-1134.
  7. 7.0 7.1 7.2 ICROP Committee for Classification of Late Stages ROP. An international classification of retinopathy of prematurity, II: the classification of retinal detachment. Arch Ophthalmol. 1987;105:906-912
  8. 8.0 8.1 8.2 International Committee for the Classification of Retinopathy of Prematurity. The International Classification of Retinopathy of Prematurity revisited. Arch Ophthalmol. 2005 Jul;123(7):991-9.
  9. 9.0 9.1 Cryotherapy for Retinopathy of Prematurity Cooperative Group. The natural ocular outcome of premature birth and retinopathy. Arch Ophthalmol. 1994;112:903-912.
  10. 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 Feb;117(2):572-6.
  11. Hunter DG, Repka MX. Diode laser photocoagulation for threshold retinopathy of prematurity. A randomized study. Ophthalmology 1993;100:238-244.