Angiography of Optic Nerve Diseases

The diagnosis of optic nerve disease is usually made by clinical history and ophthalmoscopic features. Fluorescein angiography (FA) and indocyanine green videoangiography (ICGV) findings are not pathognomonic for any optic nerve condition. However, there are some instances in which FA can be helpful in making a diagnosis. Furthermore, in some cases, FA may shed light on the pathophysiology of an unknown disease. Indocyanine green videoangiography may be useful in confirming the diagnosis of choroidal hemangioma, and defining occult choroidal neovascularization and chorioretinal inflammatory diseases. Generally speaking, ICGV is not very helpful in the evaluation and diagnosis of optic nerve diseases.

This chapter focuses on the fluorescein angiographic features of optic nerve diseases.

Blood Supply to the Anterior Optic Nerve

The anterior portion of the optic nerve may be divided into four lamellar regions, each with its own unique microvascular features: the superficial nerve fiber layer, the prelaminar region, the laminar region, and the retrolaminar region (Fig. 7.1).

The superficial nerve fiber layer is supplied principally from the arterioles in the adjacent retina. Most of these vessels are capillaries originating in the peripapillary nerve fiber layer. Emanating from the retinal arterioles at the disc are the radial papillary capillaries. These capillaries are rather straight and long, have few anastomoses, and lie in the superficial portion of the peripapillary nerve fiber layer. These vessels, as with all capillary beds within the optic nerve, are not fenestrated, and the tight junctions between their endothelial cells constitute the blood–ocular barrier. The temporal nerve fiber layer may have an additional arterial contribution from a cilioretinal artery when present. No direct choroidal contribution is observed in the superficial nerve fiber layer region.

In the prelaminar zone, the branches of the arterioles and capillaries form a diffuse network around and within the nerve bundles. The prelaminar capillaries anastomose freely with one another and arise primarily from the short posterior

ciliary arteries and peripapillary choroid. Hayreh1 believes that the central retinal artery does not supply the laminar and prelaminar zones. The anterior pial vessels do not seem to course directly into the prelaminar zone but probably anastomose with the deeper ramifications of the prelaminar capillary network.2

In the laminar zone a similar anastomotic net is formed by branches from the choroid and the short posterior ciliary arteries. As the laminar zone merges with the postlaminar zone, the choroidal supply decreases and is replaced by the pial vessels peripherally and branches of the central retinal artery axially.

The vascular pattern in the postlaminar area is like that of the remainder of the anterior aspect of the intraorbital optic nerve. The main blood supply to the intraorbital portion of the optic nerve is derived from the vessels of the pia mater. The pia of the intraorbital portion of the optic nerve derives its blood supply from the ophthalmic artery. Controversy exists about the blood supply of the axial anterior orbital portion of the optic nerve. At present, most investigators endorse the observations of Hayreh.1 According to his findings, the axial vascular system of the nerve anterior to the entrance of the central retinal artery arises partly from this vessel, as there is no central artery of the optic nerve. The pial arterioles become capillaries as they pass through the pial septa into the axial portion of the nerve.2

The microvascular structure of the optic disc is continuous with the peripapillary retinal capillaries and with the optic nerve capillaries behind the eye. Ultrastructurally, all these vascular channels resemble those of the central nervous system. They are not fenestrated. They have tight junctions and abundant intramural pericytes. They do not leak fluorescein or other tracers despite the fact that many of them are derived from the posterior ciliary arteries, which also supply branches to the peripapillary choriocapillaris. In contrast, the choriocapillaris has a fenestrated endothelium and few pericytes, and it leaks fluorescein. A cuff of nonfenestrated capillaries lies within the choroid at the boundary of the peripapillary choroid and optic nerve head (ONH). Thus, although the vascular

FIG. 7.1. Schematic representation of the blood supply of the optic nerve. R, retina; C, choroid; S, sclera; PCA, posterior ciliary artery; SAS, subarachnoid space; D, dura; A, arachnoid; CAR, central artery of the retina; ZH, Zinn-Haller ring; PAA, pial arteries anastomosis.

bed of the disc is mostly derived from the vessels supplying the choroid, its ultrastructure resembles more the retina–optic nerve vascular system.3

The blood from the prelaminar region of the optic nerve and its overlying nerve fiber layer drains mainly into the central retinal vein. Only a small proportion of this blood is drained into the choroidal circulation through small venous capillaries. These small channels represent potential bypass vessels that dilate when blood is directed away from a chronically constricted or occluded central retinal venous system into the choroidal veins, as occurs in optic nerve sheath meningiomas (ONSMs). These venous capillaries under normal conditions are ophthalmoscopically invisible since they are empty of blood. They are empty because the pressure in the retinal and choroidal veins is the same. When the central retinal vein is chronically compressed and venous pressure in the eye rises, blood is diverted through the lower pressure system, the retinochoroidal capillary system. As it fills, the capillaries become visible ophthalmoscopically. Some authors mistakenly call them opticociliary shunts, a misnomer because they are not true shunts (defined as a congenital artery that empties into a vein and that skips the capillary bed, sometimes part of the Wyburn-Mason syndrome), and they are not optic because they emanate from the retina. Most accurately they should be called retinovenous or ciliovenous collaterals.

Normal Papillary Fluorescein Angiogram

Figure 7.2 is an example of a normal papillary FA.

Preinjection

Given its whiteness, the optic disc is a tissue that intensely reflects light. Hence it can display pseudofluorescence. This is evident when a picture is taken under blue light prior to the administration of fluorescein.

Choroidal Phase

Initially a light diffuse fluorescence appears deep in the sectors corresponding to the areas where the choroid fluoresces. This fluorescence is due to the filling of the capillaries situated at the lamina cribrosa and behind it. These capillaries depend on the choroidal peripapillary vessels, which are branches of the short posterior ciliary arteries. Normally the nasal and temporal sectors of the choroid and the disc fluoresce first followed by the superior and inferior sectors, which acquire a diffuse fluorescence. If a cilioretinal artery is present, the temporal sector will begin to fluoresce. This artery can irrigate up to a third of the disc. One second later, fluorescence increases and it acquires a capillary shape due to filling of the prelaminar plexus or prepapillary racemose capillaries, made up of sinuous capillaries that irrigate all the disc area.

Arterial Phase

During this phase, fluorescence increases, given the presence of more fluorescein in the plexus mentioned before.

Arteriovenous Phase

In the early arteriovenous time, the fluorescence increases, taking advantage of the filling of a superficial capillary plexus (Fig. 7.2B). This plexus is made up of straight capillaries that come out of the disc in radial form, expanding up to a disc diameter. They are called radial epipapillary capillaries. These capillaries are of a venous nature and they act as drainage channels from the peripapillary region. They fluoresce as they get fluorescein from the retinal arterioles. In most cases, fluorescence initiates at the superior and inferior peripapillary regions followed by the nasal and temporary regions. In the venous phase, the disc fluorescence decreases due to a decreased amount of fluorescein in the disc capillaries. At the same time the fluorescence acquires an annular shape (Fig. 7.2C).

Late Phase

The disc has become fluorescent and it contrasts with the rest of the ocular fundus. The annular fluorescence decreases in intensity toward the center because the fluorescein filters from the borders of the choriocapillaris that surrounds the disc (Fig. 7.2D).

Normal Papillary Indocyanine Green

Videoangiography

Figure 7.3 is an example of a normal papillary ICGV. Indocyanine green videoangiography is not very helpful for the diagnosis of optic nerve diseases. During the first second, the choroidal arteries fill rapidly beneath the peripapillary area toward the periphery. Within the first 2 seconds, the posterior pole appears partially uniform with areas of delayed filling that are filled approximately 2 seconds after the dye first enters the eye. Most areas of the periphery become filled at this point. As the fluorescence from the choroidal arteries fade, between

2 and 5 seconds, the silhouette of the large choroidal veins may be easily seen. After 5 seconds, the choroidal fluorescence progressively diminishes. The optic nerve finally becomes dark after several minutes.

Abnormal Fluorescein Angiogram

of the Optic Disc

Hypofluorescence

The first step in the diagnosis of optic nerve diseases based on FA is to recognize areas of abnormal fluorescence and

determine if they are hypofluorescent or hyperfluorescent. Hypofluorescence refers to any abnormally dark area on the positive print of an angiogram. There are two possible causes of hypofluorescence: blocked fluorescence or a vascular filling defect.

Fluorescein is present but cannot be seen in blocked fluorescence. For example, blood in the vitreous or a layer of blood in front of the retina obscures the view of the underlying retinal, choroidal, or disc circulations. With vascular filling defects, fluorescein cannot be seen because it is not present. The key in differentiating blocked fluorescence from vascular filling defects is to correlate the hypofluorescence on the angiogram with the ophthalmoscopic findings. If there is a lesion that is ophthalmoscopically visible that corresponds in size, shape, and location to the hypofluorescence on the angiogram, then blocked fluorescence is present. If there is no corresponding ophthalmoscopic lesion, then it must be assumed that fluorescein has not perfused the vessels and that the hypofluorescence is caused by a vascular filling defect.

Vascular filling defects of the disc occur because the capillaries of the optic nerve head fail to fill. This failure can be caused by optic atrophy, vascular occlusion such as in cases of ischemic optic neuropathy, and congenital absence of disc tissue as in an optic pit or optic nerve head coloboma. Each one of these conditions is characterized by early hypofluorescence caused by nonfilling and late hyperfluorescence resulting from staining of the involved tissue.

Hypofluorescence by Congenital Absence of Disc Tissue

Congenital cavitary anomalies of the optic nerve that may be associated with serous detachments of the macula include optic disc pit, optic nerve coloboma, and morning glory disc

anomaly. The origin of the fluid and precise pathogenesis of the macular detachment associated with cavitary optic disc anomalies remains unclear but probably they all share the same mechanism.

Congenital Pits of the Optic Nerve Head

Congenital pits of the optic nerve head are rare abnormalities that are attributed to imperfect closure of the embryogenic fissure. They occur in approximately 1 in 11,000 patients.4 The pit may be bilateral, slit-like or oval in shape, and may vary from yellow to black in color. Typically, they are located in the temporal aspect of the optic disc, although they may occur elsewhere (Fig. 7.4).5 Visual acuity is usually unaffected unless the pit is complicated by a serous macular retinal detachment, which develops in 25% to 75% of cases.4,5 Considerable controversy exists regarding the pathogenesis and pathologic nature of the macular detachments associated with optic nerve pits. Given that an increase in vascular permeability is not demonstrable by FA, most authors agree that the submacular fluid originates from either the vitreous or cerebrospinal fluid (CSF).6,7 Experimental evidence favors liquid vitreous as the fluid source. In collie dogs, India ink passes into the subretinal space when injected intrathecally.8 However, in a single human subject, intrathecally administered fluorescein failed to be visualized in the subretinal space by fluoroscopy. 9 On the other hand, rare cases of subretinal migration of vitreous substitutes (gas and silicone oil) through anomalous disc excavations have been reported. Furthermore, intraoperative drainage of subretinal fluid through cavitary disc anomalies is possible.8 Regardless of the presumed source, most authors previously assumed that macular detachments were a result of fluid entering directly into the subretinal space by way of a defect at the site of the pit.6,7,9 In 1988, Lincoff et al.10

FIG. 7.4. (A) Color fundus photo showing two yellow-gray oval pits located in the temporal and nasal aspect of the optic disc (arrowheads). Notice a large excavation with a defect in the neural rim inferiorly.

(B) Fluorescein angiography showing hypofluorescence through all the times of the angiogram in the area of the optic disc pits.

proposed that fluid typically enters the neurosensory retina directly from the pit, separating the inner retinal layers to produce a primary schisis-like macular elevation. In contrast to earlier theories, they hypothesized that macular detachments are a secondary phenomenon that start in the macula and may persist without communication with the pit due to the development of an outer lamellar macular hole. Several years later, optical coherence tomography (OCT) showed that the schisis-like separation precedes macular detachment and that it invariably communicates with the optic disc, even when the associated macular detachment does not.8,11 Several authors have suggested that CSF from the perineural subarachnoid space may be responsible for the maculopathy complicating optic pits and related anomalies. Furthermore, communications between the subarachnoid space and subretinal space and between the subarachnoid space and vitreous cavity have been proven clinically. As Irvine et al.12 suggested, the vitreous, subarachnoid, and subretinal spaces may all be variably interconnected since the herniated tissues composing the optic nerve anomaly remain porous in nature due to its incomplete differentiation. It follows that the subretinal fluid in a given case might be vitreous fluid, CSF, or a mixture of both fluids. This anatomic factor and the transmission of intracranial pressure fluctuations to the pit via the perineural subarachnoid space may be responsible in part for the pathogenesis of macular detachments associated with optic nerve pits.8

Fluorescein Angiographic Findings

Fluorescein angiography showed early hypofluorescence (Fig. 7.5) and late staining in the area of the optic disc pit. More precisely, at the midphases of the angiogram, the optic disc pit showed a slight staining of the pit margin, which gradually increased during the subsequent phases. At the late stages of the examination, lesser or greater hyperfluorescent

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of the optic disc pit can be noted. Fluorescein angiography shows a well-delineated round or oval area of late hyperfluorescence corresponding to the area of macular elevation. In the early FA phases, the appearance of fluorescein dye in the area of the macular elevation is evident (Fig. 7.5). The dye increases in intensity during the late phases of the procedure. The hyperfluorescence, which is more intense in the papillomacular bundle region adjacent to the optic disc, does not have the typical appearance of choroidal transmission fluorescence. The hyperfluorescence is localized under the level of the retinal vasculature and seems to be caused by leakage of the dye into the schisis cavity and subretinal fluid. Theodossiadis et al.13 hypothesized that the dye passes through the optic pit into the fluid of the schisis cavity first. Afterward it flows into the subretinal fluid through the existing outer layer lamellar macular hole. The well-delineated area of hyperfluorescence corresponds exactly with the macular elevation. The authors postulated that the halo of hyperfluorescence could be attributed to the more intense concentration of dye at the limits of the macular elevation. The intensity of the hyperfluorescence of the elevated macula, which varies in each individual case, could be related to the degree of fluid viscosity within the schisis cavity.

Optic Disc Coloboma and Morning

Glory Syndrome

The morning glory syndrome is a congenital optic nerve anomaly that has received scant attention since it was first described by Handmann in 1929. There have been documented variations of the syndrome. The syndrome is usually unilateral, hereditary, and associated with other congenital anomalies. The majority of patients have a visual acuity between 20/200 and counting fingers in the affected eye, although cases with 20/20 vision and no light perception have been reported. The anomaly is usually limited to the eye, and the retrobulbar nerve and brain appear normal, as documented by ultrasound and computed tomography. However, the syndrome may be associated with basal encephalocele in patients with midline facial defects. Surprisingly, increasing fibrovascular tissue produces traction on the disc substance and vasculature, vitreous, macula, and peripapillary retina. These findings may place these patients within a spectrum of congenital optic nerve anomalies ranging from staphylomata to posterior persistent hyperplastic primary vitreous.14 The morning glory anomaly usually presents itself as leukokoria in the first months or years of life. On funduscopic examination, a funnel-shaped excavation of the optic disc and peripapillary retina is seen. The disc is enlarged and has indistinct borders, which are surrounded by depigmented areas. A white, elevated, hyperplastic glial tissue occupies the central disc, obscuring the central retinal vessels. Abnormally narrow, straight vessels radiate from the disc margins

J.F. Arevalo et al.

FIG. 7.6. On funduscopic view, the morning glory anomaly is characterized by an enlarged optic disc with indistinct border surrounded by depigmented areas, white, elevated, hyperplastic glial tissue that occupy the central disc and obscures the central retinal vessels, and abnormally narrow, straight vessels radiated from the disc margins.

(Fig. 7.6). There is an increased risk of non-rhegmatogenous serous retinal detachment in eyes with the morning glory syndrome.

Fluorescein Angiographic Findings

Fluorescein angiography shows hypofluorescence at the center of the disc, and numerous radial vessels are seen around this central hypofluorescent glial tissue. Peripapillary changes around the disc cause a mottled fluorescence. Exudative changes from accumulation of subarachnoid fluid or a small retinal break in the abnormal retina adjacent to the disc anomaly are responsible for the retinal detachment, which is present in one third of cases.

Persistence of Fetal Vasculature

The spectrum of persistence of fetal vasculature (posterior persistent hyperplastic primary vitreous) includes persistence of the hyaloid artery, Bergmeister’s papilla, nonattachment of the retina, retinal folds, macular hypoplasia, and optic nerve head hypoplasia. In Bergmeister’s papilla (Fig. 7.7), white intravitreal membranes can attach to the optic nerve, distorting its margins and obscuring its cup. Fluorescein angiography demonstrates hypofluorescence of the white intravitreal membranes. The membranes are associated with retinal folds in two thirds of cases and usually with tortuosity of peripapillary vessels.

Tilted Disc Syndrome

The association between tilted disc and optic pit has been described, as well as the relationship among optic pit, optic coloboma, and morning glory syndrome.15 These conditions represent different degrees of dysplasia in the spectrum of optic nerve malformations related to faulty closure of the embryonic (fetal) fissure of the optic stalk and cup.16

Tilted disc syndrome is a relatively common congenital anomaly, occurring in 1% to 2% of the population. It is characterized by an inferonasal “tilting” of the disc, with the upper and temporal portion of the disc lying anterior to the inferonasal portion (Fig. 7.8). Associated findings typically include an obliquely directed long axis of the disc, an inferonasal crescent, a posterior staphyloma of the affected inferonasal region of the fundus, and situs inversus. Situs inversus is characterized by the emergence of the retinal vessels from the upper

and temporal sides rather than from the nasal side.17 The most important of these associations is myopic astigmatism, which happens to be most pronounced in the region of the staphyloma. Superotemporal or bitemporal visual field depression is another important associated finding.17 Macular pigmentary changes have been reported in up to 11% of eyes with tilted disc syndrome,18 but these are usually asymptomatic. Visual loss may be caused by choroidal neovascularization.19

In 1998, Cohen et al.20 described a previously unreported complication of tilted disc syndrome: serous retinal detachment. It is caused by subretinal leakage that mimics chronic idiopathic central serous chorioretinopathy (ICSCR). In their cases, the site of leakage was at the edge of the staphyloma in an area of retinal pigment epithelium (RPE) changes. The staphyloma corresponds to an area of scleral ectasia but also to choriocapillaris rarefaction and RPE hypopigmentation. The leakage could be caused by anatomic factors. They hypothesized

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that the junctional area between the staphyloma and normal fundus corresponds to a region in which mechanical forces or hemodynamic changes, or both, facilitate the development of subretinal leakage. Although it is not possible to rule out a coincidental association of ICSC and tilted disc syndrome, the constant location of the leakage site in a particular anatomic area strongly suggests a specific pathogenesis, although it is unclear at this time. In 1999, Tosti21 confirmed the presence of this association and added three cases to the initial report of five affected eyes. He suggested that anomalies at the junction between the altered disc margin and the peripapillary retina may play a role, similar to what happens in optic pit syndrome. However, we recently saw a 39-year-old woman with the site of leakage at the edge of the staphyloma in an area of diffuse atrophy of the RPE. Multiple OCT scans over the temporal margin of the optic disc in our case failed to demonstrate anomalies at the junction between the altered disc margin and the peripapillary retina (Fig. 7.9).

Leys and Cohen22 reported the ophthalmoscopic and fluorescein angiographic features of this association. They demonstrated linear pigmentary changes at the border of the staphyloma with one or more leaking or staining sites. In several patients, the leaking sites changed at different visits, some having disappeared and new ones appearing. A longstanding or recent neurosensory detachment was identified. Retinal pigment epithelium changes caused by chronic retinal detachment or serous elevation with or without subretinal exudates were observed clinically and documented by FA. In eyes with chronic disease, they noted deep atrophy at the sites of subretinal leakage and large atrophic tracts due to chronic serous retinal detachment.

In our case (Fig. 7.9), the site of leakage was apparent at the edge of the staphyloma in an area of diffuse atrophy of the RPE. We concur with Cohen et al.20 in believing that the staphyloma associated with the tilted disc syndrome represents the major cause of leakage. In addition, an ICGV performed 2 months before the development of the active leakage site enabled the observation of dilated choroidal vessels. The hyperfluorescent areas corresponded with choroidal hyperpermeability and was observed in the same area of the venous dilatation as was reported previously by Giovannini et al.23 in ICSC. Although it may not be possible to rule out a coincidental association of ICSC and tilted disc syndrome or myopic staphyloma, maybe this particular anatomic alteration predisposes to increased venous pressure that causes venous choroidal congestion and increased choroidal permeability, thus giving rise to a picture indistinguishable from ICSC in these cases.

There are a few cases of subretinal neovascular membranes associated with tilted disc syndrome (Fig. 7.10). Stur24 in 1988 fist reported a case with this association. The pathogenesis of subretinal neovascular membranes and tilted disc syndrome remains unclear. Prost and De Laey25 suggest that a combination of factors that include associated RPE disturbances adjacent to both a break in Bruch’s membrane and an abnormal choriocapillaris contribute to the pathogenesis of the subretinal

J.F. Arevalo et al.

membranes in this condition. In addition, the superotemporal elevation of a tilted optic disc could lead to mechanical disruption of peripapillary tissue, creating a pathway for the ingrowth of neovascular tissue analogous to peripapillary subretinal neovascular membranes described in association with optic nerve drusen.19

Peripapillary Atrophy

Peripapillary atrophy can be defined as an inner crescent area of chorioretinal atrophy where the sclera and choroidal vessels are visible. It is also characterized by an outer irregular area of hypopigmentation and hyperpigmentation located outside the scleral ring of Elschnig. It is seen not only in progressive glaucoma but also in patients with nonprogressive glaucoma, ocular hypertensives, and normal individuals. There may also be some alterations in parapapillary tissue when there is a progressive axial enlargement producing myopia. Jonas and coworkers26,27 divided peripapillary atrophy into two zones:

(1) a peripheral “alpha” zone with irregular hyperpigmentation and hypopigmentation, and (2) a central “beta” zone characterized by marked chorioretinal atrophy with visible large choroidal vessels and sclera. Both zones were significantly larger and more frequent in eyes with glaucoma than in normal subjects (Fig. 7.11).

The peripapillary blood flow is directed away from the optic disc margin toward the peripheral choroid. At the prelaminar and laminar levels of the optic nerve, the only vessels between the optic nerve and the peripapillary choroid are the small arterial and venous connections. There is a conspicuous absence of the capillary bed in this area. Since arteriolar blood flow is directed away from the peripapillary region, either toward the choroid or the central optic nerve, and the peripapillary region is likely a low-pressure system as compared to the rest of the choroid,28 the area between the optic nerve head and the peripapillary choroid may act as a “watershed zone.” This region may be susceptible to localized ischemia during periods of decreased arterial perfusion. If this concept is combined with the vertically oriented watershed zones, the peripapillary region certainly becomes a potential site for ischemic damage, especially at the superior and inferior temporal regions. During periods of decreased systemic blood pressure or increased intraocular pressure, localized hypoperfusion may occur in these regions.29

During clinical examinations, parapapillary atrophy may range from irregular pigmentation to severe loss of the RPE that results in visualizing bare sclera and the large choroidal vessels at the parapapillary area. Tezel et al.30 observed that the severity of parapapillary atrophy may increase in ocular hypertensive eyes as assessed by the conversion of the alpha zone to the beta zone in some of their study eyes. These observations correlate with the histopathologic findings that the alpha zone of parapapillary atrophy represents pigmentary and structural changes of the RPE and the beta zone represents more

advanced damage of the parapapillary tissues with a complete loss of RPE cells, adjacent photoreceptors, and choriocapillaris (Fig. 7.11). Tezel et al. found an important association between a larger baseline size of parapapillary atrophy, especially beta zone, and its subsequent progressive changes. Because healthy RPE modulates the structure and function of the choriocapillaris, its destruction causes choriocapillary atrophy. The larger area and extension of parapapillary atrophy may signify a greater susceptibility of the parapapillary tissues to injury.29 In patients with ocular hypertension, progressive changes in parapapillary atrophy might occur before clinically noticeable optic disc or

visual field defects. These changes have a 49% sensitivity and a 90% specificity. Alpha and beta zones have to be differentiated from the scleral crescent in highly myopic eyes and from the inferior scleral crescent in eyes with “tilted optic discs.”29

Peripapillary crescents surrounding the optic disc are a hallmark of eyes with a highly myopic refractive error. In the early FA phase usually there is consistent hypofluorescence across the entire crescent. In the late phases, the crescent can be divided into a hyperfluorescent outer zone and a hypofluorescent inner zone. Differential fluorescence between the outer and inner myopic crescent occurs only in the late-phase FAs. The outer zone

7. Angiography of Optic Nerve Diseases

represents delayed choroidal filling. In contrast, the inner zone represents the complete loss of choroidal vessels.

Peripapillary atrophy in glaucoma is divided into a central beta zone and a peripheral alpha zone. According to Funaki et al.,31 the alpha zone demonstrates hyperfluorescence secondary to a window defect. The beta zone remains consistently hypofluorescent by FA (Fig. 7.11). Comparison of these angiographic features indicates that the beta zone in glaucomatous eyes and the inner zone in highly myopic eyes had the same FA features. The outer zone of the myopic crescents was hypofluorescent in the early phase and became hyperfluorescent in the late phase in contrast with the consistent hyperfluorescence of the alpha zone in glaucomatous eyes. Based on their FA findings, Yasuzumi et al.32 reported that the Zinn-Haller ring was dislocated at the border between the outer and inner zones. Dislocation of the ring might be caused by mechanical stretching around the optic disc, suggesting that the inner zone of the myopic crescent also develops as a result of mechanical stretching around the optic disc. During follow-up, 60 of their 88 study eyes (68.2%) had significant enlargement of the myopic crescent. Further analysis revealed that in most of these eyes only the outer zone enlarged significantly. The outer zone might represent choroidal circulatory disturbances, as well as mechanical stretching. These two factors contribute to crescent enlargement in highly myopic eyes.32

Choroidal occlusions are more clearly demonstrated on ICGV than retinal vascular defects, the opposite of what is observed with FA. Atrophy of the vascular bed occurs in a variety of conditions. During the late-phase ICGV, pathologic myo-

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pia with a posterior staphyloma usually shows peripapillary hypofluorescence caused by extensive choriocapillaris atrophy.

Nonarteritic Anterior Ischemic

Optic Neuropathy

This common form of optic neuropathy typically occurs in adults between the ages of 50 and 70 years. It is usually an isolated event without associated arteritis, evidence of ocular inflammation, or laboratory evidence of a systemic arteritis. It most often occurs in healthy individuals but has been reported in association with systemic hypertension, diabetes mellitus, blood loss, recent intraocular surgery, and increased intraocular pressure. Nonarteritic anterior ischemic optic neuropathy (NAION) is usually manifested by an abrupt, painless, unilateral loss of central or peripheral vision. The peripheral visual loss most frequently involves the inferior visual field in the form of an altitudinal or arcuate defect (Fig. 7.12). Upper field defects are also commonly seen (Fig. 7.13). This loss is accompanied by a relative afferent pupillary defect and dyschromatopsia. In at least 40% of patients, the fellow eye may also develop NAION. Repeated episodes in the same eye are reported to be infrequent.

The optic nerve head characteristically undergoes sectorial swelling with initial hyperemia and superficial nerve fiber layer hemorrhage at the disc margin. Shortly thereafter the disc edema resolves and is followed by pallor in the involved sector.

Patients with NAION often have optic discs that appear small and “crowded” (“disc at risk”) with inconspicuous or absent physiologic excavations and increased numbers of branches of the central retinal vessels within the disc (Fig. 7.13B). The eyes tend to be more hypermetropic. The small size of the optic cup may indirectly reflect the small size of the scleral canal, which has been considered to be the anatomically determining element for the increased risk of NAION.

The pathogenesis of NAION is multifactorial and includes structural and blood flow abnormalities. Olver et al.33 proposed that reduced perfusion pressure in the region of the paraoptic branches of the short posterior ciliary arteries results in optic disc hypoperfusion. In vivo, the posterior ciliary arteries behave physiologically as end arteries. The position and extent of the watershed zone in relation to the optic nerve head vary greatly, being located anywhere between the fovea and the nasal peripapillary choroid. It has been suggested that the disc is more vulnerable to ischemia when the watershed zone is located at the peripapillary choroid.34

There are three angiographic features that are well studied in NAION:

1.Peripapillary choroidal delay or choroidal dye filling delay: Early reports on angiography in NAION emphasized delayed filling of the disc and peripapillary choroid. However, recent angiographic studies have revealed a generalized choroidal filling delay only in arteritic disease. Patients with nonarteritic disease demonstrate only a focal delay (with filling times similar to those of controls).35 Hayreh36 described massive choroidal nonperfusion in patients with

arteritic anterior ischemic optic neuropathy (AAION). He suggested that such choroidal abnormalities are extremely rare in NAION. Similarly, comparative analysis from ICGV and FA techniques did not show a statistically significant increase in the frequency of the peripapillary choroidal watershed zone filling delay in NAION.37

2.Leakage from the disc: FA can show hyperfluorescence due to diffuse or focal leakage from the disc. ICGV is unable to demonstrate optic disc leakage.

3.Disc filling defects: FA demonstrates hypofluorescent areas encircled by hyperfluorescence. The hypofluorescence is due to segmental optic disc ischemia. Hyperfluorescence occurs secondary to leakage from the edematous disc (Figs. 7.12 and 7.13).

Arteritic vs. Nonarteritic Anterior Ischemic Optic Neuropathy

Patients with giant-cell arteritis may also develop ischemic optic neuropathy as a consequence of acute occlusion of the posterior ciliary arteries. These patients are usually 60 years of age or older and may have systemic symptoms of cranial arteritis. The sedimentation rate is typically elevated. During the acute phase of the disease, the entire choroid supplied by the occluded posterior ciliary artery does not fill on FA during its early phases. By the late retinal venous phase the occluded choroid starts to fill in a retrograde fashion from the vortex veins.37 The blood in the vortex vein has a very high concentration of

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oxygen, which prevents the development of choroidal infarcts and parapapillary atrophy in most AAION eyes. Moreover, within a few days, the occluded choroid starts to establish a collateral circulation and the filling on FA normalizes.38

Very importantly, in AAION there is a total infarction of the involved part of the ONH caused by permanent thrombotic occlusion of the posterior ciliary arteries by giant cell arteritis. This results in massive loss of not only the axons but also the other tissues in the involved part of the ONH. Some time later fibrosis of the longitudinal septa in the retrolaminar region develops. Hayreh et al39 reported angiographic and clinical findings of about 1000 patients with NAION. In contrast to the situation in AAION, none of the eyes developed an occlusion of the posterior ciliary arteries with the exception of an extremely rare case with embolic occlusion of the posterior ciliary artery. Instead, they only found evidence of a transient hypoperfusion or nonperfusion of the ONH during sleep caused by a fall of perfusion pressure in the ONH capillaries secondary to a nocturnal fall of blood pressure. This is indicated by the fact that angiography does not reveal any evidence of posterior ciliary artery occlusion. Furthermore, at least three quarters of the patients with NAION discover the visual loss on waking up from sleep. Finally, the visual loss in NAION is usually not as marked as in AAION. Thus the severity, duration, and extent of ischemia are far greater in one type of AION than in the other. Consequently, the extent and severity of ONH damages is entirely different in AAION and NAION. In this connection it should be noted that contrary to popular belief, neural ischemia is not an “all-or-none phenomenon” but there is an entire spectrum of ischemia varying from subclinical to most severe. The ischemia of the ONH is most severe in AAION and only transient in nature, and mild to moderate in NAION.40

Siatkowski et al.35 found in eyes with AAION a delayed dye appearance in the retina with consecutive delayed laminar flow and venous filling. Valmaggia et al.41 attempted to see the value of an ICGV in the management of patients with AAION and NAION by comparing ICGV with FA. They found that the angiographic temporal features such as choroidal dye appearance, retinal dye appearance, laminar flow, venous filling, or complete choroidal filling were not significantly different between the two types of angiography in both diseases. Therefore, ICGV does not provide any additional useful information with respect to FA when evaluating AAION and NAION.

Hyperfluorescence at the Optic Disc

Hyperfluorescence refers to any abnormally light area on the positive print of an angiogram, that is, an area showing fluorescence in excess of what would be expected on a normal angiogram. Hyperfluorescence at the optic disc depends in part on the relationship of its appearance to the timing of the fluorescein injection. Depending on the angiographic phase, it is termed autofluorescence or early or late hyperfluorescence.

167

Autofluorescence is the emission of fluorescent light from ocular structures in the absence of sodium fluorescein. Conditions that cause autofluorescence are optic nerve head drusen and astrocytic hamartoma. Indocyanine green videoangiography is not helpful in conditions such as optic nerve head drusen and optic disc edema, the opposite of what may be observed with some intraocular tumors. Details of ICGV features of intraocular tumors are discussed in Chapter 8.

Optic Nerve Head Drusen

Drusen of the optic disc may be easily diagnosed when glowing yellow hyaline bodies are visible on ophthalmoscopy. However, diagnostic difficulties may be encountered when drusen are buried deep within the nerve tissue in the optic nerve head. In these circumstances, they can resemble true optic disc swelling based on the ophthalmoscopic appearance alone. According to Kurz-Levin and Landau,42 the most useful and sensitive diagnostic technique for the diagnosis of optic disc drusen is ultrasonography. After comparing B-scan echography, orbital computed tomography (CT) scan, and preinjection control photography for detection of autofluorescence, almost half of their cases were detected only by B-scan echography and by no other diagnostic method. Although CT scan also images calcium deposits, evaluation by this method missed a substantial number of cases of drusen of the optic nerve head. This is because the slice viewed in the region of the optic nerve head and bone windows is routinely 1.5 mm thick, which might not be small enough for detecting smaller drusen. Computed tomography has the advantage over ultrasonography of providing simultaneous images of the brain. For this reason authors differ as to which imaging method is preferable.

Alternatively, photographs taken with the filters normally used for FA in place, but without the injection of fluorescein dye, show that superficial disc drusen often demonstrate the phenomenon of autofluorescence.42 This method is suitable for confirming visible drusen of the optic disc but not reliable in detecting drusen that are buried deep in the disc tissue. Preinjection control photography detected superficial drusen of the optic disc in over 96% of the eyes diagnosed. In contrast, only 27% of the eyes diagnosed with buried drusen were detected with this method. The overlying tissue might cause attenuation of the underlying autofluorescence that is emitted by the deeply situated optic nerve head drusen. Such attenuated autofluorescence might be too weak to be detected by preinjection control photography.42 After intravenous fluorescein injection, drusen exhibit a nodular hyperfluorescence that corresponds to the location of the visible drusen.41 The late phases may be characterized by some minimal blurring of the drusen that may either fade or maintain fluorescence (Fig. 7.14).43 Unlike papilledema, there is no visible leakage along the major vessels. Venous anomalies (venous stasis, venous convolutions, and retinociliary venous communications) and staining of the peripapillary vein walls occasionally are seen in

eyes with optic disc drusen.43 Finally, FA is helpful in identifying subretinal neovascularization associated with drusen (Fig. 7.15). We have not found this technique helpful in detecting drusen that were not visible biomicroscopically.

Papilledema and Optic Disc Edema

The difference between normal and abnormal leakage at the disc may be subtle. In both papilledema (Fig. 7.16) and optic

disc edema (Fig. 7.17), the capillaries of the optic nerve are dilated and leak fluorescein. Because the fluorescein picture is not specific to these conditions, the diagnosis is made by the clinical history and ophthalmoscopic findings. The angiogram is similar in each case, demonstrating leakage associated with swelling of the optic nerve head. In the early phases of the angiogram, dilation of the capillaries on the optic nerve head may be seen. In the late phases of the angiogram, the dilated vessels leak, resulting in a fuzzy fluorescence of the disc margin.44

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Ocular Tumors

Melanocytoma of the Optic Nerve

Melanocytoma of the optic nerve commonly occurs in black patients. It is a variant of a melanocytic nevus (Fig. 7.18). The main clinical significance of a melanocytoma of the optic nerve lies in the differentiation from malignant melanoma. The melanocytoma may be confined to the disc itself or have contiguous involvement of the choroid or sensory retina. It may cause disc edema, vascular obstruction, and field loss. It should be recognized as a black lesion on the disc. In 75% of cases there is a fibrillated margin, reflecting involvement of the peripapillary nerve fiber layer of the retina.45 Although melanocytomas tend to be circumscribed tumors, they can occasionally show small degrees of growth. Finally, malignant transformation of melanocytoma of the optic disc is very rare (Fig. 7.19).

Clinical features such as the deep black pigmentation, the fibrillated margin, the commonly occurrence in black patients, nonprogressive growth, and no visual loss can help in making the diagnosis of a melanocytoma. Fluorescein angiography can provide further information regarding the extent of the tumor. In most cases, FA of a melanocytoma of the optic nerve demonstrates hypofluorescence throughout the angiogram. This is presumably because of the deeply pigmented, densely packed cells, which have little vascularity. In the late phases the disc margin can stain (Fig. 7.18). In patients with associated optic disc edema, there is intense hyperfluorescence of the optic disc adjacent to the tumor.45

Peripapillary Choroidal Melanoma

In contrast to retinoblastoma, which has a marked tendency toward neural invasion, most uveal melanomas show little inclination to invade the optic nerve. They occur almost exclusively

J.F. Arevalo et al.

in whites. Even tumors that are adjacent to the optic disc tend to stop abruptly at the disc margin. Some peripapillary diffuse choroidal melanomas, however, show a marked tendency for optic nerve invasion.46

Peripapillary melanoma can occasionally simulate an optic neuritis on direct ophthalmoscopy. Shields et al.47 reviewed the FA pattern of choroidal melanomas. Although fluorescein shows no pattern that is pathognomonic for choroidal melanoma, occasionally it can be helpful in differentiating a melanoma from certain pseudomelanomas (Figs. 7.20 and 7.21). A very small choroidal melanoma occasionally may show no appreciable abnormality with FA. This normal fluorescein pattern has been correlated with an intact RPE over a melanoma composed of rather tightly packed spindle cells.48 A slightly larger melanoma that disrupts the RPE has rather typical angiographic features. In the arterial or early venous phase, there is mottled hyperfluorescence of the tumor. The areas of orange pigment are hypofluorescent at this time. In the venous phase, pinpoint foci of hyperfluorescence often become apparent on the surface of the tumor, particularly near its margins. There is progressive fluorescence of the lesion during the recirculation phase. In the late angiograms, the pinpoint foci of hyperfluorescence remain. The overlying orange pigment either remains hypofluorescent or shows slight hyperfluorescence.48,49 There may be late staining of overlying or adjacent subretinal fluid.

A large dome-shaped melanoma demonstrates mottled hyperfluorescence in the early venous phase with late intense hyperfluorescence of the lesion. During the late arterial or early venous phase, a mushroom-shaped melanoma with prominent blood vessels in the dome of the tumor shows relative hyperfluorescence caused by the presence of fluorescein within their lumina. The simultaneous fluorescence of the retinal and choroidal vessels has been named the “double circulation” pattern, which is highly characteristic of many choroidal melanomas.48,50 During the recirculation phase, the fluorescence of the large vessels begins to fade. Progressive mottled hyperfluorescence of the extravascular portions of the dome becomes apparent. In the

late stages, there is hypofluorescence of the large vessels and hyperfluorescence of the extravascular tissues, causing the large vessels to be silhouetted against the light background. Small areas of hyperfluorescence have been correlated with eventual sites of breaks through Bruch’s membrane.48,51

Retinal Capillary Hemangioma

The peripheral retinal capillary hemangioma is usually so characteristic that the diagnosis can be suspected prior to performing ancillary studies. Fluorescein angiography is a very helpful ancillary study in confirming the diagnosis. In the arterial phase, the tumor fills rapidly by way of the feeding retinal artery and shows numerous fine capillaries within the tumor. In the venous phase, the lesion shows marked hyperfluorescence as the dye leaks from the capillaries. In the late phase, fluorescein leaks from the tumor into the overlying vitreous (see Chapter 8).52

Tumors on the optic disc may sometimes be more difficult to diagnose. Fluorescein angiography is useful in differentiating the lesion from papilledema and optic neuritis. The fine capillaries in the tumor fill rapidly in the arterial phase. The tumor becomes rapidly fluorescent in the venous phase and shows intense late hyperfluorescence with leakage into the overlying vitreous.52

Optic Nerve Sheath Meningioma

and Optociliary Veins

The retinociliary veins may also be found with optic nerve tumors, particularly spheno-orbital meningiomas, optic nerve drusen, glaucoma, papilledema, after central retinal vein occlusion, and many others diseases. These optociliary vessels along with chronic visual loss and optic atrophy constitute the three elements of an optic nerve sheath meningioma

(ONSM), known as the Hoyt-Spencer triad. Optic nerve sheath meningioma is usually so characteristic that the diagnosis can be suspected prior to performing ancillary studies. If there is optic disc edema, the late venous FA shows a hyperfluorescent disc with superficial capillary dilation and collateral retinociliary veins at the margins of the optic disc (Fig. 7.22). In optic atrophy, failure of the capillaries of the optic nerve head to fill is seen. When present, FA allows visualization of retinociliary veins at the margins of the optic disc in the early venous phase of the angiogram in all cases. MuciMendoza et al.53 studied eyes suffering from optociliary veins and ONSM with ICGV, which enabled a better delineation of the optociliary veins from the disc margin to the choroid. Interestingly, they found an inverse relationship between the degree of optic disc edema and the development and ease of visualization of the optociliary veins and their draining course through the choroidal circulation. They believe that sustained pressure around the optic nerve by the tumor progressively destroys axons, and as they grow scarcer the optic disc atrophies. At the same time, this compression obstructs the venous drainage through the central retinal vein, diverting blood toward the ciliary system, establishing an inverse relationship between the severity of the edema and the prominence of optociliary veins.53

Optic Disc Metastasis

Metastasis to the optic disc accounts for 5% of all intraocular metastases. It can occur as invasion from a juxtapapillary choroidal metastasis or as an isolated optic disc metastasis. Breast and lung cancers are the most common primary neoplasms that account for metastasis to the optic disc. The primary site is never determined in 20% of patients. The characteristic clinical features of optic disc metastasis should help differentiate it from other causes of swollen optic disc. In general, during the arterial phase the FA demonstrates relative hypofluorescence of the mass. A gradual hyperfluorescence begins in the late venous phase and turns into a moderate to intense fluorescence of the mass in the late angiogram with slight fluorescence of the overlying vitreous (Figs. 7.23 and 7.24).54

Optic Nerve Phacomas

Astrocytic hamartomas usually appear as sessile white lesions at the level of the retina or protruding above and overlying the optic disc (Fig. 7.25). They tend to occur as part of tuberous sclerosis or neurofibromatosis. They can develop yellow refractile calcifications that can be remembered as a fish-egg

appearance. During the arterial phase of the FA, little tortuous vessels can be seen on the relatively hypofluorescent tumor surface. In the venous phase, the blood vessels usually become more apparent over the tumor. These fine vessels tend to leak during the late venous phase and finally show diffuse homogeneous staining of the mass in the late frames.55

Conclusion

When it comes to diseases of the optic nerve, the clinician bases his correct diagnosis on the unique tools of clinical

history and ophthalmoscopy. Fluorescein angiography and ICGV have been extremely valuable for expanding our knowledge of the anatomy and pathophysiology of some of these diseases.

Acknowledgments

The authors have no proprietary or financial interest in any products or techniques described in this article. This work is supported in part by the Arevalo-Coutinho Foundation for Research in Ophthalmology (FACO), Caracas, Venezuela.

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