The optic vesicle is composed of neural ectoderm and is surrounded by surface ectoderm (see Fig. 1). At about the 5-mm stage, both vesicles invaginate, and the outer wall of each becomes the inner wall of the newly formed concavity, the optic cup (Fig. 2). This inner wall of the optic cup (the former outer wall of the optic vesicle) gives rise to the retina, and the outer wall of the optic cup forms the retinal pigment epithelium (RPE).

As the optic vesicles invaginate to form the optic cups, a groove remains open on the inferior aspect of each (see Fig. 2). Known as the embryonic fissure, this opening is the pathway by which the mesodermal tissue, which gives rise to the intraocular vascular supply, enters the globe. Mesodermal tissue also surrounds the optic vesicles and eventually forms the choroid. Apparently, the choroid develops only in areas where the mesoderm is in contact with the RPE. This concept is supported by the clinical fact that in eyes with a retinochoroidal coloboma secondary to faulty closure of the embryonic fissure, the choroid, as well as the RPE, fails to develop properly. Closure of the embryonic fissure begins centrally and is normally complete at about the 13-mm stage (5 to 6 weeks).

The earliest recognizable structure associated with the optic disc is the primitive epithelial papilla. This is simply an accumulation of cells from the inner layer of the optic cup that surrounds the superior end of the embryonic fissure. At or about the 17-mm stage, nerve fibers grow from the retinal ganglion cells through the primitive epithelial papilla into the optic stalk, and the optic nerve is thus formed.

The first vascular supply to the globe enters through the embryonic fissure as the hyaloid artery at about the 5-mm stage. Derived from the carotid artery, this vessel forms a network (vasa hyaloidea propria) that vascularizes the primary vitreous. The vasa hyaloidea propria is maximally developed at about the 40-mm stage (third month of gestation) and regresses, until even the intraocular hyaloid artery itself usually is gone at about the eighth month of gestation. The portion of the hyaloid artery running within the optic nerve becomes the central retinal artery within the nerve.

Developmentally, the retinal vascular system does not appear to arise directly from the hyaloid artery. The most widely accepted concept has been summarized by Ashton, who states that at about 15 to 16 weeks of gestation (100-mm stage), mesenchymal cells appear on the optic disc adjacent to the hyaloid artery.³ Cords of these cells invade the superficial retina and differentiate into endothelial cells, which form capillaries. At this time, it is not possible to make a distinction between arteries and veins. In turn, the capillaries undergo a process of remodeling, and the retinal arteries and veins are formed.

PREPAPILLARY VASCULAR LOOPS

Prepapillary vascular loops are blood vessels that project from the optic disc into the vitreous cavity and then return to the disc to continue their natural course. First described by Liebrich in 1871,⁴ over 90 cases have since been reported.⁵ The loops have at least one ascending and one descending limb, and 85% to 95% are arterial in origin. Occasionally, an arterial loop projects from the disc and returns to the retina, whereas its venous counterpart may arise from the retina and exit into the disc. Rarely, a loop arises from the retina and returns to the retina; this particular anomaly has been termed a preretinal vascular loop.⁶

The vessels may appear as simple hairpin loops (180° turns), in a figure eight, or in a corkscrew configuration. In about 30% of cases, the loop is surrounded by a white, glial-appearing sheath⁷ (Fig. 3). The average arterial loop extends approximately 1.5 mm into the vitreous cavity, probably within Cloquet's canal; the largest loops reach about 5 mm in height.⁸ Venous prepapillary loops usually are less elevated.⁹ In contrast to persistent hyaloid arteries, prepapillary vascular loops have not been observed to extend as far anteriorly as the posterior lens capsule.

Embryologically, prepapillary loops are thought to occur at about the 100-mm stage, when the retinal vessels are developing. For an unknown reason, a vessel probably grows into Bergmeister's papilla, which is maximally developed at about the 180-mm stage, and then returns to the retina. It has been proposed that the loop requires Bergmeister's papilla as a scaffold for growth. Thus, its growth is limited, since Bergmeister's papilla usually does not extend more than one third of the distance into the vitreous cavity.

Prepapillary loops are rare; the incidence ranges from 1 in 2000 to 1 in 9000 patients.^8,10 Bilaterality occurs in about 9% to 17% of cases of arterial loops, but the percentage with venous loops is uncertain. Arterial prepapillary loops most commonly supply the inferior retinal vascular system, in contrast to venous prepapillary loops, which usually drain the superior retinal vascular system.¹¹

On fluorescein angiography, prepapillary loops demonstrate a rapid flow. However, there may be a sector delay in filling of the optic disc or the area of retina supplied by the loop caused by the increased distance that blood must travel through the loop. Cilioretinal arteries have been seen in up to 75% of eyes with prepapillary loops.⁸

Ocular complications associated with prepapillary vascular loops include branch retinal artery obstruction in the area of retina supplied by the loop,^8,12 amaurosis fugax, and vitreous hemorrhage.^8,13,14 Presumably, kinking of the loop and impairment of blood flow dynamics in some way contributes to the obstruction. Why vitreous hemorrhage occurs is uncertain, although we have noted it to occur in conjunction with acute posterior vitreous detachment. No consistently associated systemic abnormalities have been found in conjunction with prepapillary loops.

The differential diagnosis of arterial prepapillary loops includes persistent hyaloid artery. However, the latter is only a single vessel, without ascending and descending branches. Congenital venous prepapillary loops must be differentiated from the acquired variety.¹⁵ Congenital loops usually are single and unassociated with other ocular abnormalities, whereas acquired venous loops often are multiple and seen with disease entities such as retinal venous obstruction and optic nerve tumors.¹⁶

PERSISTENT HYALOID ARTERY

The hyaloid artery enters the globe through the embryonic fissure at about the 5-mm gestational stage. It branches throughout the vitreous cavity to form the vasa hyaloidea propria, the vascular supply of the primary vitreous. Additionally, it contributes to the tunica vasculosa lentis to supply blood to the developing lens.¹⁷ Maximally developed at about the 40-mm stage (9 weeks), the vasa hyaloidea propria begins to regress at the 60-mm stage (11 weeks). The hyaloid artery becomes impervious to blood at about 7 months, and the end of the involutional process usually occurs during the eighth month of fetal life, at which time the intravitreal artery becomes atrophic.¹⁸ The sequence of regression is such that the vasa hyaloidea propria regresses first, followed in turn by the capillaries of the tunica vasculosa lentis and then the hyaloid artery.¹⁹

The hyaloid artery can be seen in premature infants, and occasionally the vessel persists into adult life. Ophthalmoscopically, a persistent hyaloid artery appears as a single vessel extending from the optic disc anteriorly through Cloquet's canal. It may be filled with blood but usually is bloodless after birth and can extend as far anteriorly as the posterior capsule of the lens (Fig. 4). Usually, the insertion on the posterior capsule is located inferonasal to the visual axis. Occasionally, after the vessel has regressed, only the circular point of insertion remains; this is known as a Mittendorf dot.

A persistent hyaloid artery may be found in association with persistent hyperplastic primary vitreous^20,21 and should be considered a possible complicating factor during surgery.²² Indeed, intraoperative diathermy of a persistent hyaloid artery has been reported to result in a branch retinal artery occlusion.²³ A persistent hyaloid vascular system also has been reported to occur in association with retinopathy of prematurity, potentially complicating surgical repair.^24,25 Prepapillary and vitreous hemorrhage has been seen in association with persistent hyaloid arteries.^22,26–28 Aside from those cases associated with ocular trauma, the mechanism of hemorrhage is unknown.²⁹

RETINAL MACROVESSELS

Retinal macrovessels are abnormally large single blood vessels, usually veins, which traverse the macular region and supply or drain the retina both inferior to and superior to the horizontal raphe (Fig. 5). This aspect of blood supply or drainage is unusual because only about 1% of eyes have a retinal vessel that extends to any degree on both sides of the horizontal raphe.³⁰ Relatively large branches from these vessels may penetrate the foveal region, and small branches occasionally are seen traversing the foveal avascular zone. The aberrant retinal vessel is congenital and usually unilateral. Surprisingly, most eyes with this abnormality have normal visual acuity and are detected on routine examination.^31,32

On fluorescein angiography, small arteriovenous communications have been noted in some eyes with macrovessels.^31,33 Archer and associates refer to such eyes as having a group I, or mild, arteriovenous communication.³³ Patients classified as group II have a more pronounced communication, with large vessels both entering and leaving the optic disc, and in group III the malformation is so pronounced that visual acuity is decreased (Fig. 6). The abnormalities seen in groups II and III usually are referred to as racemose angiomas rather than macrovessels. Patients with anomalies of the character of these latter two groups, in association with vascular malformations of the skull or central nervous system, are considered to have the Wyburn-Mason syndrome.³⁴ However, eyes with congenital retinal macrovessels do not necessarily have arteriovenous communications, and systemic abnormalities have not been associated with these milder vascular abnormalities. Whereas the earlier described arteriovenous anomalies are thought to be congenital, remodeling of some of the more bizarre malformations (group III) has been observed.³⁵

Fluorescein angiography of congenital retinal macrovessels (group I) commonly demonstrates small areas of retinal capillary nonperfusion.³¹ These may be located in the foveal region or in a perivascular distribution surrounding the abnormal vessel. Flow through the vessels appears to be rapid, although delayed emptying of dye may be observed.^31,32 Permeability alterations of the anomalous vessel is not a feature of this disorder.³⁶

Foveal cysts have been seen in association with congenital macrovessels, but these usually decrease the vision minimally, if at all. Other ocular abnormalities include a poor foveal reflex, minor displacement of the fovea, and retinal pigment epithelial mottling.^31,37,38 Gass describes one patient with congenital retinal macroveins who had similar vascular anomalies of the conjunctiva and tongue.³⁶

Embryologically, macrovessels are thought to develop during the remodeling phase of retinal vascular development, but the stimulus for their development is unknown.

CILIORETINAL ARTERY

Cilioretinal arteries are vessels that supply the retina but are derived from the short posterior ciliary arteries and, rarely, directly from the choroidal vessels rather than from the central retinal artery.³⁹ Anastomoses between cilioretinal- and central-retinal-derived circulations are minimal. Typically, cilioretinal arteries appear to emerge from the optic disc or disc margin separately from the central retinal artery. A characteristic hook, which has been likened to a walking stick handle, is another helpful ophthalmoscopic sign⁴⁰ (Fig. 7). Fluorescein angiography demonstrates that cilioretinal arteries are present in about 32% of eyes.⁴¹ Usually, a cilioretinal artery fills with the choroidal circulation 1 to 2 seconds before the appearance of dye within the retinal arterial system. With ophthalmoscopy alone, cilioretinal arteries have been noted in about 20% of eyes.^42–44

Cilioretinal arteries usually supply only a small portion of the fundus and are mostly confined to the macula. In about 1 eye in 2900, a cilioretinal artery may supply a major part of the fundus.⁴⁵ However, when prepapillary arterial loops are present, prominent cilioretinal circulations are commonly seen.^8,46 Cilioretinal arteries supply the foveal region in about 10% of eyes.⁴⁷ This is clinically relevant in that such a cilioretinal vessel may preserve central vision in eyes that sustain a central retinal artery obstruction.⁴⁷ The presence of a temporal cilioretinal artery also has been correlated with increased retention of central visual field and visual acuity in eyes with advanced open-angle glaucoma.⁴⁸ Conversely, cilioretinal arteries also may become obstructed and produce a central field defect.⁴⁹ In general, isolated cilioretinal artery obstruction carries a favorable visual prognosis with 90% of eyes achieving a visual acuity of 20/40 or better.⁵⁰

Cilioretinal artery obstruction also may occur in association with central retinal venous obstruction or ischemic optic neuropathy.^50,51 Central retinal vein occlusion is thought to raise intraluminal resistance in the cilioretinal artery and subsequently cause occlusion.^52,53 Other investigators have documented abnormal central retinal artery inflow by intravenous fluorescein angiography in patients with this disorder.⁵⁴ These eyes have a less favorable prognosis, with 70% of eyes achieving a visual acuity of 20/40 or better.⁵⁰ A cilioretinal artery obstruction occurring in the setting of ischemic optic neuropathy may be explained by the shared origin of their vascular supply.⁵¹ These eyes have the worst prognosis, with no eyes achieving better than 20/40 visual acuity.⁵⁰ Cilioretinal artery obstructions account for about 5% of arterial obstructions in the retina.^47,55

CONGENITAL OPTIC PITS

Congenital pits of the optic nerve head appear as round or oval localized depressions within the optic disc (Fig. 8). Over one half are positioned temporally on the nerve head, whereas about one third are located more centrally on the disc.⁵ In 95% of eyes with noncentrally located pits, peripapillary chorioretinal disturbances are seen adjacent to the anomaly.⁵⁶ Optic pits range from 0.1 to 0.7 disc diameters along their widest dimensions and may be as deep as 25 diopters (D), although the mean depth is about 5 D.⁵⁶ Bilateral involvement is seen in about 15% of patients. In those with unilateral pits, the optic disc itself is larger in the affected eye about 80% of the time.⁵⁶

Petersen probably was the first to realize that the association between congenital optic pits and serous retinal detachment was more than coincidental.⁵⁷ The serous retinal detachment usually is confined to the macular region and rarely exceeds 1.5 mm in height. About 40% of pits reported have been noted to have such a nonrhegmatogenous detachment.⁵ Most detachments are seen in eyes with temporally located pits, and the mean age at onset is about 30 years.⁵⁶ Cystic changes are prominent in many of the associated retinal detachments, and in about 25% of eyes with a detachment a lamellar, outer layer macular hole develops.^56,58 Approximately one third of these eyes have subretinal precipitates on the outer surface of the detached retina. In some eyes, a larger, less sharply demarcated area of elevation of the inner retinal surface is present overlying the retinal detachment.^59,60 Although this area appears clinically similar to retinoschisis, the expected complete loss of retinal function in the affected area is not seen.⁶¹ Evaluation with optical coherence tomography has led several investigators to speculate that the subretinal fluid originates from these schisis-like cavities in the inner retina, which communicate with optic nerve pit.^58,62

Controversy exists as to the etiology of the subretinal fluid. Possible sources include (1) vitreous fluid by way of the pit or a macular hole, (2) leakage from vessels within the pit, (3) leakage from choroidal vessels, and (4) cerebrospinal fluid. In collie dogs, a direct communication has been demonstrated between the vitreous cavity and the subretinal space by way of the pit, but human clinical or histopathologic confirmation of a similar pathway is lacking.^62–64 Although fluorescein angiography reveals leakage originating from vessels within the pit more commonly in eyes with a serous retinal detachment,⁶⁵ many eyes with leakage do not have subretinal fluid. The presence of cilioretinal arteries, which are present in 60% of eyes with optic nerve pits, also are associated with leakage of intravenous fluorescein dye.^56,66 The theory that the subretinal fluid may be derived from cerebrospinal fluid has not been confirmed in human or experimental animal studies.^63,64,67 However, because optical coherence tomography has been unable to demonstrate a communication between the optic pit and the vitreous cavity, some investigators maintain that the cerebrospinal fluid is the most likely source.⁶² Recently, it has been proposed that vitreoretinal traction may contribute to the development of macular detachment in this condition. This theory is supported by the findings in one case where a macular break developed after minor head trauma in a patient with an optic nerve pit and serous macular detachment.⁶⁸ In addition, alleviating the vitreoretinal traction by pars plana vitrectomy or posterior scleral buckling without the use of laser retinopexy has resulted in resolution of the subretinal fluid.^69,70

Fluorescein angiography usually demonstrates early hypofluorescence of a pit, and 50% progress to hyperfluorescence as the study continues (Fig. 9). Visual fields are abnormal in about 60% of eyes with pits; arcuate scotomas are the most commonly encountered defect.⁵⁶

Without treatment, the visual prognosis is poor in patients with an optic nerve pit and serous detachment of the macula.^56,71,72 One study found that over 50% of eyes with retinal detachment and a minimum follow-up of 1 year have an acuity of 20/100 (6/30) or worse. These findings were confirmed in a study where 80% of eyes with an optic nerve pit and serous macular detachment had a visual acuity of 20/200 or worse after an average follow-up period of 9 years.⁷² The visual loss occurred within 6 months of the development of the serous macular detachment.

Laser photocoagulation to the peripapillary retina adjacent to the pit has been advocated for the treatment of associated macular retinal detachment.^73–76 Whereas this therapy probably promotes resolution of the subretinal fluid, it is uncertain whether the visual acuity improves compared with the natural course of the disease.⁵ Pars plana vitrectomy and intraocular gas tamponade with or without laser treatment has been advocated for the treatment of serous macular detachment secondary to optic nerve pits.^69,77–82

No consistent systemic abnormalities have been associated with pits, but the occurrence of a basal encephalocele and agenesis of the corpus callosum in a patient with a pit has been noted.^83,84 Although no definite inheritance pattern has been identified for pits, familial cases, autosomal dominant cases, and cases occurring in monozygotic twins have been seen.^85–87

Embryologically, congenital optic pits probably arise from defective formation of the primitive epithelial papilla. However, in some cases, a pit is located inferiorly and is associated with a retinochoroidal coloboma. In these latter instances, it may arise from defective closure of the superior aspect of the embryonic fissure.⁶⁴

OPTIC NERVE HYPOPLASIA AND APLASIA

There is probably a spectrum of hypoplasia ranging from mild hypoplasia of the optic nerve head to absence of the nerve and retinal vessels (aplasia). Typically, a hypoplastic optic disc appears small and pale and is partially or totally surrounded by a yellow-white ring that may be variably pigmented (Fig. 10). Because of the encircling ring, these eyes have been referred to as having the double-ring sign.⁸⁸ The outer border of the yellow-white ring denotes the juncture of the sclera with the lamina cribrosa and typically corresponds to the size of a normal optic nerve head. The retinal vessels usually are of normal caliber. Histopathologic examination shows a diminished nerve fiber layer in most eyes and usually a reduced number of ganglion cells.^88,89 The outer retinal layers appear normal. An unusual variant of optic nerve hypoplasia occurs in children with periventricular leukomalacia and is associated with a normal-sized optic disc with a large cup.⁹⁰

Unilateral and bilateral involvement occur with almost equal frequency, and in bilateral cases there is no apparent sex predilection.^91,92 However, in unilateral cases, over three fourths of patients are men.⁹³ Visual acuity in involved eyes may range from normal to no light perception, although most reported cases have been in the counting-fingers to light-perception range.^91–93 Despite this fact, a trial of occlusion therapy is warranted in cases of unilateral hypoplasia associated with strabismus.⁹³ Strabismus often is seen in unilateral cases, usually in the form of an esotropic deviation.^91,92,94 It also may be found in bilateral cases, but in these eyes, a pendular nystagmus is more frequently encountered because of poor visual acuity.^91,92 Careful retinoscopy and refraction is essential in these patients because high rates of astigmatism have been found in affected eyes.^95,96 Electroretinography usually is normal in eyes with this disorder.⁹⁷

Calculation of the disc-macula: disc diameter ratio has been recommended to establish the diagnosis of optic nerve hypoplasia.⁹⁸ A ratio of 3.0 or higher has been found to be correlated with the diagnosis of optic nerve hypoplasia.⁹⁹ Magnetic resonance imaging and B-scan ultrasonography also can demonstrate a small optic nerve in affected individuals.^100,101 Systemic abnormalities that may be associated with optic nerve hypoplasia include anencephaly and hydranencephaly and an entity known as septooptic dysplasia (DeMorsier syndrome).^88,89,92,102 DeMorsier initially described the association of optic nerve hypoplasia and absence of the septum pellucidum,¹⁰³ and later it was realized that pituitary dwarfism and diabetes insipidus¹⁰⁵ also could be seen with the syndrome. At least one quarter of patients with bilateral optic nerve hypoplasia have hypothalamic-pituitary endocrine dysfunction, and 11.5% have DeMorsier syndrome.^106,107 Magnetic resonance imaging of affected individuals can provide prognostic information regarding the likelihood of neurodevelopmental deficits and hypothalamic-pituitary dysfunction.^96,108–110

The etiology of optic nerve hypoplasia is uncertain in most cases. However, certain prenatal insults have been linked to its development. These include young maternal age^109,111,112; maternal ingestion of anticonvulsant medications,^113,114 alcohol,^90,115 and quinine¹¹⁶; maternal diabetes^94,117,118; and congenital cytomegalovirus infection.¹¹⁹ Intracranial cysts and tumors also have been associated with optic nerve hypoplasia.^96,120,121 Initially, the most widely accepted embryologic theory was that the condition resulted from partial failure of development of the retinal ganglion cells.¹²² Normally, these cells are apparent at the 17-mm stage and their axons grow through the primitive optic papilla into the optic stalk to form the optic nerve. A decrease in the number of ganglion cells would subsequently lead to decreased nerve fibers and a smaller optic nerve. However, other investigators propose that the disorder results from a supranormal regression of optic nerve axons in utero^123,124 or to a vascular disruption sequence involving the proximal trunk of the anterior cerebral artery.^88,112,125

Optic nerve aplasia lies at the end of the spectrum with the more severe forms of hypoplasia. However, in contrast, it connotes total absence of the optic nerve, ganglion cells, and retinal blood vessels.^89,126 It may occur as an isolated finding¹²⁷ or in combination with severe defects, such as partial agenesis of the central nervous system.^128,129 Involved eyes have no light perception and usually are microphthalmic.¹³⁰ It has been speculated that the condition arises from severe failure of ganglion cell development^89,128 or absence of mesodermal ingrowth into the globe,¹²² but exact embryologic origins are uncertain.

MORNING GLORY DISC ANOMALY

The morning glory optic disc anomaly appears ophthalmoscopically as an enlarged excavated disc with white, fibroglial-appearing tissue located at its center; an elevated, subretinal peripapillary annulus of chorioretinal pigmentary changes encircles the disc (Fig. 11). This congenital abnormality has been likened to the morning glory flower, from which it derives its name.¹³¹ Most cases are unilateral, and visual acuity most often falls into the 20/100 (6/30) to hand-motion range.^131,132 Retinal detachment is seen in over one third of cases, the etiology of which is uncertain.^132,133 These detachments connect to the optic nerve head and usually are confined to the posterior pole.^131,134 The mechanism may involve a retinal break in the tissue within the optic disc anomaly, which provides a communication for fluid between the vitreous cavity and the subretinal space,^135–137 or from an abnormal communication between the subarachnoid space surrounding the optic nerve and the subretinal space.^133,138 Most cases are managed with plana vitrectomy, laser photocoagulation, and intravitreal gas or silicone oil tamponade.^135,137,139

No hereditary tendency is evident, and no associated intrauterine insults have been identified. Basal encephalocele and pituitary hormone disturbances have been described in conjunction with the abnormality.^140–143 The etiology of the anomaly is uncertain, although the association of a morning glory optic disc with persistent hyperplastic primary vitreous has been noted.^144,145

Optic nerve dysplasia is the term that has been applied to the morning glory disc anomaly when the center is elevated rather than excavated. This variant also has been associated with basal encephalocele.¹⁴⁶

PERSISTENT BERGMEISTER'S PAPILLA

Bergmeister's papilla arises from the cells that constitute the primitive epithelial papilla. These neuroectodermal cells proliferate until they are maximally developed, at about the 180-mm stage (5 to 6 months). At this time, they form a glial sheath around the proximal one third of the hyaloid artery. The sheath begins to atrophy during the seventh month of intrauterine life, and the point to which it regresses determines the character of the physiologic cup. Failure of complete regression produces a persistent Bergmeister's papilla.

Ophthalmoscopically, a persistent Bergmeister's papilla appears as minimally clustered white tissue overlying the optic disc. It may be associated with absence of the physiologic cup and with congenital anomalies such as prepapillary vascular loops.

COLOBOMA

Colobomas are congenital or acquired notches, fissures, or defects that are found in the eye. Most commonly, they are congenital and occur secondary to faulty closure of the embryonic fissure. The optic nerve alone may be involved, or, more often, the anomaly may be of the retinochoroidal variety. Isolated optic nerve colobomas appear as excavations within the nerve head and can range up to 25 D in depth and 0.9 disc diameters across.¹⁴⁷ They may be unilateral or bilateral, and an autosomal dominant heredity pattern has been described in some patients.¹⁴⁷ Despite their presence, visual acuity may be good. However, there is an associated nonrhegmatogenous retinal detachment in 8% to 50% of patients, and this can substantially decrease the vision.^147,148

Some optic nerve colobomas have glial tissue filling the cup, similar to the morning glory anomaly.¹⁴⁷ Whether some morning glory discs represent an aberrant form of optic disc coloboma is uncertain.^149–151

Retinochoroidal colobomas are glistening white or yellow defects with distinct borders that occur inferior or inferonasal to the optic disc (Fig. 12). They may extend up to and involve the optic disc (Fig. 13), or they may be seen as isolated chorioretinal defects. The margins of the coloboma often are pigmented, and the defect is filled with abnormal retinal tissue. Anteriorly, the defect can extend as far as the iris and produce an inferonasal gap (Fig. 14). These anomalies may occur in otherwise normal persons or in association with chromosomal abnormalities or multisystem diseases, such as trisomy 13, the Aicardi syndrome, Goldenhar's syndrome, and the CHARGE association.^148,152,153 Occasionally, autosomal dominant or recessive inheritance patterns are found, but often none are evident.¹⁵² In families with autosomal dominant inheritance, variable expression of the genetic trait makes genetic counseling difficult.¹⁵⁴

Embryologically, retinochoroidal colobomas arise from failure of the embryonic fissure to close. Consequently, the inner and outer layers of the optic cup are abnormal in this region. The inner layer (sensory retina) usually is present as a membrane of undifferentiated retina that may have blood vessels going through it (see Figs. 12 and 13). The outer layer (RPE) is absent, and since the choroid is dependent on the RPE for its development, it also is lacking.

Ocular associations with retinochoroidal colobomas include orbital cysts, in severe cases,¹⁵⁵ and retinal dysplasia.¹⁵² Retinal detachment can be seen in conjunction with these defects, probably because of retinal breaks within the colobomatous area, which are difficult to visualize.^139,156 Vitrectomy with air-gas/fluid exchange has been advocated for repair of retinal detachments associated with retinochoroidal colobomas when no retinal break is visible.¹⁵⁷

INFERIORLY TILTED DISC

Ophthalmoscopically, an inferiorly tilted optic disc appears to be longer horizontally than vertically. It usually is accompanied by an inferonasal crescent, and the fundus in the inferonasal quadrant may be less pigmented than the reminder of the fundus (Fig. 15). The tilted disc may be associated with an outpouching of the globe in the quadrant where the crescent is located, and this has been referred to as nasal fundus ectasia.¹⁵⁸ Fuchs' coloboma, inverse myopia, and dysversion of the optic disc are other names that have been applied to the entity.¹⁵⁹

Visual acuity in eyes with tilted discs often is mildly decreased, and in those with fundus ectasia, relative temporal field defects may be seen. In bilateral cases, these abnormalities may produce bitemporal hemianopia, and unless the clinician is aware of this fact, the patient may undergo unnecessary diagnostic and therapeutic procedures for a suspected pituitary tumor.¹⁶⁰ When the refractive error in the ectatic area in these cases is corrected with lenses, the field defect usually is reduced or disappears.¹⁵⁸ Eyes with diabetic retinopathy may have less severe retinopathy in the affected retinal quadrant.¹⁶¹

PERIPAPILLARY STAPHYLOMA

A peripapillary staphyloma is a staphylomatous excavation, generally of -8 to -20 D, surrounding the optic nerve.^162,163 Although the visual acuity often is decreased with this usually unilateral defect,^163,164 normal vision has been reported.¹⁶⁵ Most often, the optic nerve head itself appears relatively normal, and atrophic choroidal changes are present surrounding the defect (Fig. 16).

Occasionally, the walls of a peripapillary staphyloma can be observed to contract.^162,166,167 The reason for this phenomenon is uncertain, although intrascleral smooth muscle has been described in an eye with a congenital coloboma of the optic disc and surrounding staphylomatous defect.¹⁶⁸ Pulsations also have been observed in synchrony with respiration.^163,169

The anomaly is thought to most likely arise from failure of development of the posterior sclera.¹⁶²

CONGENITAL HYPERTROPHY OF THE RETINAL PIGMENT EPITHELIUM

Congenital hypertrophy of the RPE occurs as a flat, round, usually hyperpigmented fundus lesion (Fig. 17). Often, a thin hypopigmented ring comprises the border of the abnormality. In contrast to inflammatory diseases, which produce RPE hyperplasia with rough edges, the margins of congenital hypertrophy of the RPE are well delineated (Fig. 18A). Commonly, depigmented lacunae can be seen within the confines of the lesion (see Fig. 17).

Histologically, congenital hypertrophy of the RPE is characterized by a monolayer of large RPE cells containing larger-than-normal pigment granules (Fig. 19; see Fig. 18B through E). Overlying photoreceptor elements have been shown to be degenerated, which explains the localized visual field defects corresponding to these areas.¹⁷⁰

Congenital hypertrophy of the RPE usually is asymptomatic and is observed as an incidental finding on fundus examination. It has no malignant potential and should not be confused with choroidal nevi ormelanomas because congenital hypertrophy is flat, is usually black, and has sharp borders.

GROUPED HYPERTROPHY OF THE RETINAL PIGMENT EPITHELIUM

Grouped hypertrophy of the RPE, also known as “bear tracks,” is a multifocal variant of congenital hypertrophy of the RPE and consists of several well-delineated, pigmented, flat lesions, usually in one sector of the fundus (Fig. 20). The lesions range from 0.1 to 3.0 mm in diameter and are most often larger peripherally than posteriorly.¹⁷¹

Histologically, the involved RPE cells are taller and contain a greater concentration of pigment granules (which may be enlarged) than normal RPE (Fig. 21). The overlying retina has been shown to be unaffected in one patient.¹⁷¹

Congenital hypertrophy of the RPE and grouped pigmentation of the retina may be different expressions of a similar condition, the latter being multifocal, rather than unifocal.¹⁷² Both conditions are asymptomatic and, probably rarely, if ever, affect the central visual acuity. A variant of grouped hypertrophy of the RPE has been associated with familial adenomatous polyposis and Gardner's syndrome.^173,174 This entity is similar to grouped hypertrophy of the RPE except that the lesions are more likely to be bilateral, randomly distributed throughout the fundus, and have irregular borders.¹⁷⁵

ALBINISM

Albinism is a congenital condition characterized by faulty development of melanin pigment. It can occur as oculocutaneous (generalized) albinism, in which the skin, hair, and eyes are affected, or as ocular albinism, in which only the eye is involved.

Generalized albinism occurs in about 1 in 20,000 people.¹⁷⁶ It is thought to be an autosomal recessive disorder and can be seen in tyrosinase-negative and tyrosinase-positive forms. However, normal offspring have been described from parents who both have oculocutaneous albinism.¹⁷⁷

Normally, tyrosine is converted to dopa in the pathway of melanin biosynthesis. Tyrosinase is an essential enzyme that catalyzes several steps in this conversion. In the tyrosinase-deficient form of albinism, hair bulbs incubated with tyrosine cannot form melanin, implying that the abnormality occurs secondary to a deficient catalytic activity of tyrosinase.¹⁷⁸ In the tyrosinase-positive variety, melanin can be formed by incubation of hair bulbs with tyrosine. Tyrosinase is present in this variety, and the defect is thought to result from abnormalities of the “P” polypeptide, a melanosomal tyrosine transporter.¹⁷⁸

Tyrosinase-negative albinism affects visual acuity most severely, with most patients falling into the 20/200 to 20/400 (6/60 to 6/120) range. These patients usually have photophobia, nystagmus, no fundus pigment, and light irides that transilluminate (Fig. 22). The tyrosinase-positive form is less severe; these patients also have nystagmus and photophobia, but visual acuity may be better, and some pigmentation may be present.^179,180

In ocular albinism, the condition usually is transmitted in an X-linked fashion, although an autosomal recessive pattern of inheritance also has been described.¹⁸¹ Compared with the generalized forms, more ocular pigment usually is present with ocular involvement alone, but the visual acuity still may be 20/100 (6/30) or less.¹⁸¹ Mutations in a gene that codes for a membrane glycoprotein localized to melanosomes have been identified in individuals with X-linked ocular albinism.^182,183

A foveal reflex usually is absent in each of the described types of albinism that involve the eye,^181,184 and histologically the fovea may not be identifiable^185,186 (Fig. 23). The demonstration of optic pathway misrouting by visual evoked potential studies is present in most cases and may be a useful diagnostic test to confirm a diagnosis of albinism.^{180,187–189} Finally, recent advances in the understanding of the molecular genetics of these disorders holds potential for confirming the diagnosis, detecting carriers, and enabling prenatal diagnosis.^178,190

Therapy is directed toward correcting refractive errors and lessening the photophobia with dark glasses or tinted contact lenses. Surprisingly, many albinotic children are able to read, probably secondary to their excellent accommodation.¹⁹¹

RUBELLA RETINOPATHY

In 1941, Gregg described the triad of cataracts, deafness, and congenital heart disease in infants born to mothers who had experienced rubella during pregnancy.¹⁹² However, he attributed the first observation of fundus pigmentary changes to Mitchell in 1939. The ocular manifestations usually occur secondary to infection during the first trimester of pregnancy, and it has been estimated that the chances of the fetus being involved secondary to infection at this time are greater than 50%.¹⁹³

Retinopathy is the most common ocular manifestation of congenital rubella, followed in frequency by strabismus and cataract.¹⁹³ It is characterized by a diffuse pigmentary disturbance (salt-and-pepper retinopathy), often more prominent on fluorescein angiography than ophthalmoscopically (Fig. 24). Usually, it is bilateral, but this is not always so.^193,194 The visual acuity in eyes with retinopathy unaccompanied by cataracts or glaucoma usually is 20/20 to 20/60 (6/6 to 6/18), with a median of about 20/25 (6/7.5). Although it was formerly believed that the retinopathy was not progressive and affected the vision only mildly, several cases have been described in which a subretinal neovascular membrane developed and decreased the acuity to the 20/200 to 20/400 (6/60 to 6/120) range.^195–199 In addition, affected eyes should be carefully examined for the signs of late-onset glaucoma.²⁰⁰ Importantly, the electroretinogram usually is normal with this disease.²⁰¹

LEBER'S CONGENITAL AMAUROSIS

Leber's congenital amaurosis accounts for about 10% of congenital blindness and at least 5% of all inherited retinal dystrophies.^202,203 The fundi may be normal in this bilateral disease, but when they are abnormal, they include diffuse pigmentary stippling, pale optic nerves, or both (Fig. 25A through C). Blond fundi also may be seen. Other ocular associations may include cataracts, nystagmus, and hyperopia.^204,205

The children are usually blind, typically with visual acuity ranging from 20/200 (6/60) to hand motions, or become so during the first year of life. Severe night blindness, and occasionally photoaversion, also is present.²⁰⁶ Roving eye movements may be apparent because of the poor visual acuity.

The electroretinogram is crucial for making the diagnosis and is either flat or shows only minimal responses (see Fig. 25D). This disease is autosomal recessive, and it may represent a type of retinitis pigmentosa, since children with a progressive form may develop fundi identical to the typical retinitis pigmentosa fundus by the middle childhood years.^205,207 It is thought that the impaired development or extremely early degeneration of photoreceptors is related to a mutation on chromosome 17, which causes impaired production of a retinal guanylate cyclase.^203,208,209

MYELINATED NERVE FIBERS

Myelinated nerve fibers in the retina appear ophthalmoscopically as superficial yellow or white patches that follow the course of the nerve fiber layer. Usually, the peripheral edges of the lesions are feathery, and they may be connected to the optic disc or more peripheral and separated from it by an area of normal retina (Fig. 26). The anomaly produces localized relative visual field defects, and since it rarely involves the fovea, it usually does not affect visual acuity.²¹⁰ Rarely, unilateral peripapillary myelinated nerve fibers are associated with myopia, strabismus, and amblyopia.^211,212 Although affected eyes have been reported to be refractory to treatment, amblyopia therapy should be considered because some patients respond to therapy.^213,214 Finally, retinal vascular abnormalities ranging from mild telangiectasis to frank neovascularization may develop in a region of myelinated nerve fibers, and these vessels may result in vitreous hemorrhage.^215–218

Normally, medullation of the optic nerve begins just before birth, proceeding anteriorly so that it reaches the lamina cribrosa at or shortly after birth. Thus, myelinated nerve fibers probably develop after birth and are not a true congenital anomaly but rather a postnatal development.⁹

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