In 1942, Terry discovered it in infants and young children who were examined due to leukocoria and poor vision. At that time, it was speculated that this fibrous membrane behind the lens was a remnant of the congenital vascular membrane of the lens, called retrolental fibroplasia. In 1949, Owens confirmed through clinical observation that this disease had an active phase before the formation of the fibrous membrane and was not a congenital anomaly. In 1950, Heath named it premature labor infant retinal membrane disease.

bubble_chart Etiology

There is usually a history of excessive oxygen exposure in an incubator after birth. The longer the duration of oxygen exposure, the higher the incidence of the disease. However, some believe it is caused by the rapid cessation of high-concentration oxygen therapy, leading to relative tissue hypoxia, and is unrelated to the duration of oxygen exposure (Jacobson, 1992). Even without a history of oxygen exposure, the disease can occur due to a sudden rise in fetal hemoglobin oxygen saturation, the abrupt transition from fetal PO₂ to neonatal PO₂, and other factors. Additionally, maternal anemia and multiple pregnancies are also among the causes of this condition.

In the early fetal stage, the retina membrane develops with the vitreous stirred pulse and is nourished by the choroid membrane. At 100mm of embryonic development, vitreous blood vessels pass through the optic disc, with small branches extending from the optic disc to the peripheral retina membrane. Initially, these vessels are only visible in the nerve fiber layer, reaching deeper layers in the advanced stage. In normal fetuses, significant vascular proliferation occurs at 6–7 months. In premature infants, the retina membrane is not fully developed, with the peripheral areas being the most immature. In a high-oxygen environment, retinal blood vessels constrict and become obstructed, leading to local ischemia and hypoxia, which triggers abnormal proliferation of retinal blood vessels. This results in a series of changes such as exudation, hemorrhage, and fibrosis. The abnormally proliferated retinal blood vessels penetrate the inner limiting membrane, extending to the retinal surface and into the vitreous. Due to exudation and fibrosis of the intra-vitreous blood vessels, a connective tissue membrane forms behind the lens, and traction may also lead to retinal detachment.

Commonly seen 3-6 weeks after birth, clinically divided into active stage and fibrous membrane formation stage (Reese, 1953).

1. Active stage Divided into five phases:

(1) Vascular change phase: Seen in the early course of the disease. Both arteries and veins exhibit tortuous dilation. The diameter of veins may sometimes be 3-4 times larger than normal. Brush-like capillaries can be observed at the peripheral ends of retinal vessels.

(2) Retinal lesion phase: As the disease progresses, vitreous opacity appears, and the fundus becomes more blurred. New blood vessels proliferate in the retina, mostly near the equator, but can also be seen anterior to the equator or at the posterior pole. The affected retinal area is significantly elevated with vessels crawling on its surface, often accompanied by retinal hemorrhages of varying sizes.

(3) Early proliferation phase: Proliferative vascular strands appear at the aforementioned localized retinal elevations and extend into the vitreous, causing small-range retinal detachment in the peripheral fundus (most cases) or posterior pole (few cases).

(4) Grade II proliferation phase: The detachment expands to involve more than half of the retina.

(5) Extreme proliferation phase: Complete retinal detachment occurs. Sometimes, massive hemorrhage in the vitreous cavity can be observed.

The active stage lasts 3-5 months. Not all cases progress through all five phases; about one-third stop at phase 1, one-fourth at phase 2, and the remainder halt at phases 3, 4, or 5 before entering the fibrous membrane formation stage.

2. Fibrous membrane formation stage Cases that do not resolve spontaneously during the active stage eventually scar and form fibrous membranes, classified from mild to severe into grades 1-5:

Grade II: Organized masses appear at the peripheral retina, pulling the optic disc and retinal vessels to one side. The opposite disc margin shows pigment arcs, and the disc becomes pale.

Grade III: Fibrous proliferative membranes pull the retina to form one or several folds, each connected to membrane-like organized masses at the peripheral retina. Folds are mostly temporal (905) or nasal (105); superior or inferior temporal folds are rare. Unlike congenital retinal folds, retinal vessels do not follow these folds.

Grade IV: Fibrous membranes or detached portions of organized retina are visible behind the lens, obscuring the pupillary area. Unobstructed areas show fundus red reflex on ophthalmoscopy.

Grade V: The entire area behind the lens is covered by fibrous membranes or detached organized retina. On dilated examination, elongated ciliary processes with serrated edges are visible at the pupillary periphery. The anterior chamber is very shallow, often with anterior/posterior synechiae. Secondary glaucoma or extensive anterior synechiae may cause corneal opacity. The eyeball is smaller than normal, with inward invasion.

bubble_chart Treatment Measures

If synechiae of the iris have already formed and are extensive, glaucoma surgery may be considered.

bubble_chart Prognosis

The prognosis of vision in this disease varies depending on the severity during the active phase and the extent of residual fibrous membrane. If the condition spontaneously stops at stages 1-2 during the active phase, vision is not significantly impaired. Even with residual fibrous membrane, if the macula is not affected, relatively good vision can be preserved. When fibrous membrane formation reaches grades 4-5, vision is severely compromised.

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Strictly limiting oxygen use for premature infants is the only effective preventive measure. Oxygen at a concentration of 40% should only be administered when life-threatening cyanosis occurs, and the duration should not be too long. Additionally, early high-dose application of vitamin E may have some preventive effect. Early detection and timely application of cryotherapy or laser photocoagulation have been reported to successfully prevent further deterioration of the condition.

To prevent the occurrence of secondary glaucoma, active and severe cases must frequently receive mydriasis to avoid posterior synechia of the iris. A 2% homatropine solution is preferred as the mydriatic agent, as it can avoid atropine poisoning and prevent peripheral anterior synechia of the iris caused by prolonged and persistent pupil dilation.

bubble_chart Differentiation

The vast majority of this disease occurs in premature infants with a history of excessive oxygen exposure in incubators. Based on this, a diagnosis can be made. In addition to differentiating it from congenital retinal folds, Coats disease, retinoblastoma, suppurative endophthalmitis, and organized vitreous hemorrhage, the following diseases should also be considered for differential diagnosis:

(1) Bloch-Sülzberger syndrome (incontinentia pigmenti) This syndrome is a disorder of ectodermal tissue occurring at birth or shortly after, with a family history. A few cases are associated with posterior lens fibrous atrophy, which differs from this disease.

(2) Retinal dysplasia This condition also involves the presence of a posterior lens fibrous membrane. However, it is characterized by bilateral microphthalmia at birth, posterior synechiae of the iris, along with a family history, intellectual disability, poor physical development, cerebral edema, cardiovascular disease, polydactyly, and other systemic disorders, distinguishing it from this disease.

(3) Congenital encephalo-ophthalmic dysplasia This disease is also seen in premature infants and involves posterior lens fibrous membranes, as well as retinal dysplasia and detachment. However, it is accompanied by cerebral edema, ptosis, and developmental abnormalities of the cerebrum and cerebellum, which help differentiate it from this disease.

(4) Persistent hyperplastic primary vitreous (PHPV) and fibrous chronic pseudophakia The former is also known as persistent posterior fetal fibrovascular sheath of the lens. The lens vascular membrane should completely disappear by the 8.5th month of fetal development. If this process is disrupted, leading to permanent retention, it results in congenital posterior lens vascular membrane persistence. Although it may also present with microphthalmia and secondary glaucoma, this condition occurs in full-term infants without significant weight deficiency, is unilateral, and involves pupillary and lens displacement, among other differences that distinguish it from this disease.

When the posterior lens vascular membrane proliferates excessively and ruptures, causing leukocoria, mesodermal tissue invades as the cortex is absorbed, forming a connective tissue membrane, known as fibrous pseudophakia.

(5) Familial exudative vitreoretinopathy (FEVR) The fundus findings of this condition resemble those of this disease. However, it is typically inherited in an autosomal dominant pattern, occurs in full-term newborns delivered normally, and lacks a history of oxygen exposure, distinguishing it from this disease.