Retinopathy of Prematurity

Retinopathy of prematurity (ROP) is a retinal vascular disorder that affects severely premature babies, resulting from incomplete peripheral vascularization at birth followed by abnormal vascularization in the subsequent weeks to months. Abnormal proliferation of blood vessels can lead to fibrovascular networks that exert traction on the retina and may progress to retinal detachment and blindness in the most advanced cases. There are many risk factors for the development of ROP, which include low birth weight, low gestational age, supplemental oxygen therapy, and a possible genetic component. Screening guidelines vary in different parts of the world based upon the characteristics of the premature population and practice patterns of neonatal intensive care units. In the United States, retinal screening is recommended for all babies weighing 1500 grams and/or born before 30 weeks gestational age. In general, the smaller and more premature the baby, the higher the risk for developing ROP. Treatment in the United States, when deemed necessary, consists of panretinal photocoagulation to the areas of avascular retina; however, ROP regresses without treatment in over 90% of cases. More recently intravitreal anti-VEGF therapy has been suggested as primary treatment or as a supplement to laser therapy. Multiple studies have demonstrated efficacy in inducing regression of neovascularization especially in more advanced disease. However the optimal treatment indications, timing, dosage, and follow-up are yet to be determined and therefore this treatment remains off-label in the United States.

Stage I

In stage I, there is a fine, thin demarcation line between the vascular and avascular region in the peripheral retina. The junction is flat.

Courtesy of Earl A. Palmer, Casey Eye Institute

Stage II

In stage II, a broad, thick ridge clearly separates the vascular from the avascular retina.

Stage III

In stage III, neovascularization is present on the posterior edge of the ridge, which has an indistinct, velvety appearance and a ragged border.

Stage IV-A

In stage IV-A, there is a subtotal retinal detachment beginning at the fibrovascular ridge. The retina is under traction anteriorly, beginning at the ridge, and the fovea is uninvolved. Subretinal fluid may also be seen.

Image courtesy of Audina M. Berrocal, MD and Ditte Hesse, CRA, FOPS

Stage IV-B

In Stage IV-B a subtotal retinal detachment is present but the fovea is involved.

Image courtesy of Audina M. Berrocal, MD and Ditte Hesse, CRA, FOPS

Stage V

In stage V-A, there is a total retinal detachment that may eventually evolve into the shape of an open funnel seen below in the left image. Stage V-B is classified as a closed funnel, seen below in the right image.

Images courtesy of Audina M. Berrocal, MD and Ditte Hesse, CRA, FOPS

Plus Disease

Plus disease is characterized by arteriolar tortuosity and venous engorgement in the posterior pole and indicates an especially aggressive form of ischemic disease with a poor prognosis and the need for early aggressive treatment. Iris vascular engorgement, pupillary rigidity, and vitreous haze may also be part of this classification; the latter is a poor prognostic finding.

In the case of aggressive posterior ROP, flat neovascularization and pre-retinal hemorrhage are seen around a posterior ridge. Prominently dilated and tortuous retinal vessels (Plus disease) involving all 12 clock hour positions are also seen.

Spectrum of ROP

This patient demonstrates the clinical presentation in ROP with advanced severity. There is a large retinal fold and peripheral dragging of the retinal vasculature.

The histopathological image shows the nature of the retinal fold and endothelial proliferation extending into the vitreous (arrow).

In these patients with ROP there is an elevated ridge of fibrovascular proliferation bordered posteriorly by prominent vessels (Plus disease). There is evidence of nodular, endothelial cell proliferation posterior to the ridge referred to as “popcorn lesions.” These lesions may represent isolated tufts of extraretinal fibrovascular proliferation left behind as a ridge regresses more anteriorly, or conversely they may represent nascent fibrovascular proliferation that grow to become confluent with a progressing ridge.

ROP “Popcorn Lesions”

These images demonstrate the so-called “popcorn lesions” or nodular endothelial proliferation that is seen at the posterior ridge of fibrovascular proliferation in ROP. Note that the “popcorn lesions” hyperfluoresce, but do not leak very intensely. The neovascularization at the anterior edge of the vasculopathy does leak intensely, although this active permeability regresses as the fibrovascular proliferation consolidates.

ROP and Fibrous Scarring

In these 4 cases, there has been extensive peripheral treatment of the ROP with ablative modalities such as photocoagulation and cryotherapy. There is extensive fibrosis in the posterior pole of each eye and the tractional extension of vessels from the nerve to the periphery.

Trypsin digest preparations show intraretinal neovascularization resembling a sea-fan like configuration in ROP.

Persistent Fetal Vasculature Syndrome (Persistent Hyperplastic Primary Vitreous)

During embryogenesis, the developing structures of the eye are fed by the hyaloid artery, which emerges from the optic nerve head and extends to a network of vessels surrounding the lens collectively referred to as the tunica vasculosa lentis. This fetal vascular system typically regresses by apoptotic mechanisms; however, in some patients it fails to involute, resulting in persistent vascular elements in the posterior segment. This is termed persistent fetal vasculature syndrome (PFVS).

PFVS has a spectrum of presentations depending upon the extent of involution of the hyaloid artery and tunica vasculosa lentis. The retrolental fibrovascular tissue may obstruct the visual axis or cause early cataract. Contraction of the hyaloid fibrovascular remnants can lead to recurrent retinal and vitreous hemorrhages and even tractional retinal detachments. PFVS may also be associated with a variable degree of retinal dysplasia, optic nerve hypoplasia, and fibrovascular proliferation.

PFVS is typically unilateral. When bilateral PFVS is present, the possibility of Norrie disease must be ruled out, as it may mimic PFVS, but with more severe hemorrhagic and dysplastic retinal manifestations.

These images show vascular changes at the optic nerve. They represent the proximal portion of the hyaloidal vasculature. On the far left is a tortuous fibrotic remnant (arrow), which is also referred to as a Bergmeister papilla. A prepapillary arteriolar vascular loop is associated with an inferior branch retinal artery occlusion ( arrows, second image ) and associated with vitreous hemorrhage ( arrow, third image ), which can be seen in such congenital vascular loops. The image on the far right is a congenital venular loop, which is less common.

Far left image courtesy of Dr. David Abramson

These patients have PFVS with variable degrees of incomplete regression of the posterior hyaloid. A fibrous stalk of vasculature is present in both patients and associated with one or more prominent retinal folds (left, arrows) . Bleeding into the vitreous has occurred in the patient on the right (arrows) .

A remnant of the hyaloid vasculature with associated fibrovascular proliferation extends from the optic nerve to the posterior lens capsule in the left eye of this 9-month-old patient with PFVS.

Courtesy of Dr. Mort Goldberg

Note the variation in the clinical presentation of the persistent posterior hyaloid. Some clinical cases appear to be primarily associated with dysplastic changes ( middle row, right ). B-scan ultrasonography illustrates the hyaloid artery ( arrow ) and associated tractional retinal detachment ( arrowhead ).

This image shows the delicate persistent tunica vasculosa lentis in communication with the persistent hyaloidal artery.

Courtesy of Dr. Mort Goldberg

These patients have persistence of the anterior tunica vasculosa lentis, which extends into the margins of the iris and is seen best with fluorescein angiography.

PFVS involving the anterior tunica vasculosa lentis has resulted in dense cataract formation in these two patients. These eyes are microphthalmic as well.

Courtesy of Dr. David Abramson

Chorioretinal Coloboma

Coloboma may involve many ocular structures including the iris, lens, ciliary body, retina, choroid, or optic nerve and result from incomplete fusion of the embryonic fissure. Chorioretinal coloboma are most often located in the inferonasal quadrant as this is the last sector of the embryonic fissure to close during embryogenesis. Size and location of the coloboma can vary and accordingly visual acuity ranges from normal to no light perception depending upon the extent of the lesion and involvement of the optic nerve and macula. Occasionally, chorioretinal coloboma can produce a white pupil (leukocoria) on ophthalmoscopy that may simulate a mass lesion such as a retinoblastoma. Patients with chorioretinal coloboma are at risk of various complications throughout life including rhegmatogenous retinal detachment and choroidal neovascular membrane formation. Macular schisis and detachment may complicate optic nerve coloboma and other congenital optic disc anomalies and this entity is comprehensively reviewed in Chapter 15 . Chorioretinal colobomas may be isolated or can be associated with a number of systemic syndromes including fetal alcohol syndrome, infections (e.g. congenital rubella syndrome), and various genetic syndromes including CHARGE syndrome (coloboma, heart abnormalities, anal atresia, renal abnormalities, genitourinary abnormalities, ear anomalies) associated with CHD7 mutation and papillorenal syndrome (PAX2 mutation), characterized by optic nerve or chorioretinal coloboma in association with congenital kidney disease.

This is a very large coloboma that involves the optic nerve and choroid. There is a staphylomatous abnormality within the central choroidal colobomatous area (arrows). The circular abnormalities within the staphylomatous area (arrowheads) may represent tiny fistulous tracks into the retrobulbar area. A child with such a large coloboma may present with leukocoria simulating a retinoblastoma.

This is a fundus photo and fluorescein angiogram of a macular scar from a 14-month-old boy with congenital toxoplasmosis, which simulates a coloboma. It is excavated, bordered by pigment, and irregular at its edges.

These are two patients with a congenital choroidal coloboma. These are associated with colobomatous changes involving the optic nerve. A zonal area of chorioretinal atrophy and pigment epithelial hyperplasia ( arrows ) is presumed to be the result of an antecedent retinal detachment that has spontaneously resolved.

Courtesy of Ophthalmic Imaging Systems, Inc

This is a large posterior coloboma encompassing the optic nerve and choroid. There is a fibrous membrane overlying the coloboma (arrows). These congenital abnormalities are inferiorly located in the fundus. In addition, the patient harbored an iris coloboma.

Color fundus photograph of a patient with papillorenal syndrome showing a blunted foveal reflex and inferotemporal optic disc coloboma (versus an optic nerve pit) of the right eye (top left) with magnified view of the optic nerve (top middle). Fluorescein angiogram of the right eye highlights the optic nerve coloboma (versus an optic nerve pit) (top right). SD-OCT through the nerve of the right (middle left) and left (middle right) eyes demonstrates the optic nerve colobomas (asterisks) and SD-OCT through the macula (bottom) demonstrates retinoschisis. Genetic testing revealed a heterozygotic mutation in the PAX2 gene. The patient also had hearing loss, which can be characteristic of this disorder.

Images courtesy of Ricardo Japiassú, MD

Congenital Folds

Congenital retinal fold is a rare abnormality consisting of an anomalous fold of retina and associated vessels coursing through the posterior segment from the optic disc to the ora serrata. It is often associated with disorders of the peripheral retinal vasculature such as ROP, familial exudative vitreoretinopathy (FEVR), incontinentia pigmenti, and Norrie disease. It therefore may not represent a separate clinical entity, but instead may exist as part of the spectrum of these diseases. It should, however, be differentiated from a glial mass and from persistent fetal vasculature. In the absence of other ocular disorders and when associated with hyperopia, posterior microphthalmos syndrome should be excluded. Congenital folds are most often found bilaterally and symmetrically and may be associated with visual dysfunction and nystagmus.

This patient demonstrated 18 diopters of hyperopia in each eye. Posterior microphthalmos and bilateral, symmetric congenital retinal folds in the macular region are illustrated.

Courtesy of Dr. Thomas W. Wilson

The color fundus photographs of this patient with posterior microphthalmos demonstrates subtle papillomacular folds, an abnormal foveal reflex, and a crowded disc. SD-OCT demonstrates retinal folds and mild cystoid macular edema. Axial length was measured to be 15.44 mm.

Images courtesy of Alan Bird, MD and Philip Hykin, MD

Phakomatoses

This group of disorders arises due to genetic mutations typically involving tumor suppressor genes that result in the development of benign and/or malignant tumors, which classically involve the brain, skin, and eye. Retinal lesions can be the important clue to the diagnosis of the systemic condition that can be fatal if left untreated. Phakomatoses often present during the pediatric years, although lesions may be acquired during the lifetime of the patient. While many of these retinal lesions are more comprehensively discussed in the oncology chapter ( Chapter 8 ), we will briefly review the salient retinal and systemic features in this chapter as these findings are not entirely uncommon in the pediatric population.

Neurofibromatosis Type I

Neurofibromatosis type I (NF1) is an autosomal dominant disease caused by mutation in the NF1 gene on chromosome 17q11.2. NF1 occurs in approximately 1 in 3000 live births, and 50% of cases are secondary to spontaneous mutation. The NF1 gene normally functions as a tumor suppressor, and mutation leads to abnormal proliferation of multiple neural tissues. Diagnosis is based upon the presence of some combination of axillary or inguinal freckling, optic glioma, Lisch nodules, cutaneous neurofibromas, plexiform neurofibromas, certain osseous lesions, and the presence of a first-degree relative with NF1. The most common ophthalmologic finding is the presence of iris Lisch nodules, which affect nearly all patients by the age of 20 years old. More recently choroidal hamartomas consisting of abnormal proliferations of Schwann cells have been described in 78 to 100% of NF1 patients. These lesions are best seen with enhanced depth optical coherence tomography or infrared imaging.

Color fundus photographs of this patient with neurofibromatosis type 1 shows subtle deep hyperpigmented lesions at the level of the choroid, that are made much more apparent by infrared imaging (bottom row). These lesions represent hamartomatous proliferations of Schwann cells similar in histology to neurofibromata of the skin and Lisch nodules.

Neurofibromatosis Type 2

Neurofibromatosis type 2 is a rare hereditary phakomatosis caused by mutation in the NF2 tumor suppressor gene on chromosome 22. It is inherited in an autosomal dominant manner but approximately 50% of cases result from de novo mutations. Clinically, the disease is characterized by bilateral vestibular schwannomas, multiple central nervous system tumors, and several ocular abnormalities, the most frequent of which is posterior subscapular cataract. Posterior manifestations include combined hamartoma of the retina and retinal pigment epithelium and epiretinal membrane (ERM). The ERMs that complicate NF2 may appear similar to the typical ERM of inflammatory etiology, or may have a distinct, scaphoid appearance with edges curled up toward the vitreous. There may be a correlation with the presence of ERM and severity of the systemic disease.

This patient with NF2 was found to have an ERM with the characteristic scaphoid morphology seen in NF2. Color photograph of the patient’s hand and lower leg shows a neurofibroma on the palm and a café au lait spot respectively.

Combined Hamartoma of the Retina and RPE

A hamartoma of the retina may present to the pediatric retinal physician with its characteristic vitreoretinal interface disturbance, prominent retinal vessels, and variably reactive pigment epithelium.

This 17-month-old boy has a characteristic elevated pigmented hamartomatous mass involving both the retina and the retinal pigment epithelium with overlying glial tissue.

Arterial–Venous Malformations (Wyburn Mason Syndrome)

Wyburn Mason syndrome is a rare, nonhereditary phakomatosis consisting of arterial–venous malformations (AVM) of the retina, ipsilateral central nervous system, and face. Retinal angiomas are typically asymptomatic and inert and do not affect vision unless the retinal vascular abnormality is extensive or involves the macula. Rarely leakage and exudation and hemorrhage may develop. Reports of retinal ischemia resulting from retinal arterial shunting exist. Of greater concern are the potential complications of intracranial (typically involving the midbrain) and intraorbital lesions, which if present, may result in compressive optic neuropathy, hemiplegia, or even death from intracranial hemorrhage.

Fluorescein angiography of a patient with Wyburn Mason syndrome demonstrates rapid filling of this type III arteriovenous malformation. No leakage was seen from these vessels in late phases of the study (not shown).

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