15.4  Age-Related Choroidal Atrophy

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pressure inflating the vascular structure of the autopsy eyes. There are several possible reasons for the decreases in choroidal thickness with age, including loss of the choriocapillaris, a decrease in the diameter of the choriocapillary vessels, decrease in luminal diameter of blood vessels, and in some cases, a diminution of the middle layer of the choroids [18–20].

15.4  Age-Related Choroidal Atrophy

A relatively common condition affecting the choroid in older adults is age-related choroidal atrophy or ARCA [21]. The choroid becomes increasingly thin in people with age,

Summary for the Clinician

■The mean subfoveal choroidal thickness in a group of normal eyes was 287 µm

■The mean choroidal thickness at 3 mm nasal to the fovea was 145 µm

■The choroidal thickness showed a statistically significant inverse correlation with age at all measured positions

but people with ARCA have an exaggerated thinning of the choroid such that they have recognizable fundus changes associated with characteristic visual complaints. It is common for patients with ARCA to have numerous visual complaints, despite what seems to be relatively good Snellen acuities. These complaints frequently involve difficulty reading. Ophthalmic examination of the fundus in these patients shows several common findings: the larger choroidal vessels are easily discerned, many of the visible choroidal vessels do not appear to be red, but are yellow or white, there are few visible vessels of any size in the central macula, there may be pigment aggregates in the macular region, there can be peripapillary atrophy despite the absence of myopia, and there often is mild optic nerve pallor (Figs. 15.8 and 15.9). The EDI OCT shows marked loss of thickness of the choroid in these patients. There appears to be loss of the choroidal vessels such that the remaining larger choroidal vessels can fill the entire thickness of the choroid. Given that ARCA happens in older adults, it is not surprising that some of these may also have concurrent late age-related macular degeneration (AMD). Choroidal neovascularization (CNV) in ARCA patients does not appear to be as aggressive, and seems to show a longer-term response per injection of anti­ -VEGF agents than does CNV in other forms of AMD (Figs. 15.10 and 15.11).

Histopathologic analysis of the eyes with what has been termed “senile choroidal sclerosis” has shown atrophy of the choroid with the loss of small and medium vessels to the point that Bruch’s membrane was immediately contiguous with the sclera in areas, and the remaining larger vessels of the choroid occupied the fullthickness of the remaining choroid in others [22]. There was a loss of the expected pigmented cells in the choroid with clumping of preserved pigmented cells in various regions in the choroid. In a series of patients with ARCA, approximately 1/3 had glaucoma [21]. The prelaminar portion of the optic nerve is supplied by the choroid. The

contribution of vascular abnormalities to the development and progression of glaucoma is not known, but it is conceivable that patients with poor blood supply to the optic nerve may be at higher risk for glaucoma, all other things being equal. An association suggested in an older publication was that patients with choroidal sclerosis may develop a particular type of glaucoma called “senile sclerotic glaucoma” [23], a term used at the time of publication of that article. The use of EDI OCT allows for actual quantification of choroidal changes and may help elucidate the interaction between the choroid and glaucoma in the future.

Summary for Clinicians

■Some patients have remarkable thinning of the choroid with advanced age

■These patients can have numerous complaints despite relatively good visual acuity measure­ ments

■This condition is known as age-related choroidal atrophy or ARCA, and is common

■Patients with ARCA can develop late AMD

■Patients with ARCA seem to have a high prevalence of glaucoma

15.5  Choroid in High Myopia

High myopia associated with excessive and progressive elongation of the globe results in a variety of fundus changes that lead to visual impairment, including lacquer cracks in Bruch’s membrane, CNV, and chorioretinal

atrophy [7, 9, 23–35]. There is evidence that axial elongation of the globe leads to reduced retinal function [7, 9, 24, 28, 32, 36]. If the visual dysfunction in the absence of CNV was solely due to retinal stretching, visual function would be expected to correlate with the amount of myopia, regardless of the patient’s age. However, visual function tends to be normal in highly myopic young people, irrespective of the amount of myopia and worsens with age [31, 34, 35]. Histologic studies of older eyes have demonstrated choroidal thinning in high myopia, with a lack of vessels in some areas and pronounced thinning of the choriocapillaris in others [23, 29]. Animal models of myopia reported decreased choriocapillaris density and diameter [26]. Studies using ICG angiography [37, 38], color Doppler ultrasonography [39], and ocular pulse amplitude [40] have also shown that choroidal circulation is decreased in myopic eyes. As the choroid supplies oxygen and nutrition to the retinal pigment epithelial cells and the outer retina [41], compromised choroidal circulation may account, in part, for the retinal dysfunction and vision loss that is seen in high myopia.

A group of 31 patients (55 eyes) with a mean age of 59.7 ± years and a mean refractive error of −11.9 ± 3.7 diopters was evaluated with EDI OCT [18]. The mean subfoveal choroidal thickness was 93.2 (±62.5) mm, and was negatively correlated with age (p = 0.006) (Fig. 15.12), refractive error (p < 0.001) (Fig. 15.13), and history of CNV (p = 0.013). Regression analysis suggested that subfoveal choroidal thickness decreased by 12.7 µm for each decade of life, and by 8.7 µm for each diopter of myopia. The choroid in areas of peripapillary atrophy was exceedingly thin or not visualizable, as would be

expected, but the choroid in pigmented areas adjacent to the peripapillary­ atrophy was markedly attenuated in thickness (Figs. 15.14 and 15.15). Glaucoma was present in 21.8% of the eyes. A prior history of CNV was present in 19 eyes. For those with no history of CNV, a linear regression of explanatory variables with subfoveal choroidal thickness as the dependent variable reduced to a model containing age in years and refraction in spherical equivalent diopters. For those with CNV, linear regression did not find any significant explanatory variables associated with subfoveal choroidal thickness.

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The age-dependent decrease in choroidal thickness suggests that in addition to undergoing choroidal thinning due to progressive stretching from increasing axial elongation, highly myopic eyes also experience the same age-related choroidal attenuation that affect normal eyes. Since both the choroid and the retina are stretched in highly myopic eyes, the choroid - although thinner than

Fig. 15.15  Peripapillary atrophy as compared with the choroidal thickness in high myopia. (a) Note that this patient with high myopia has the so-called peripapillary atrophy. (b) The EDI OCT image shows the choroid to be very thin (arrowheads) with no sharp transition to where the clinically observed “peripapillary” atrophy starts (which is shown by the arrow)

normal - may still be able to supply the proportionally thin retina with necessary oxygen and nutrients. This is consistent with the fairly normal visual function in adolescents and young adults with high myopia. The relatively thin choroids seen in younger myopes may be physiologically sufficient even if the same thickness of choroid found in an eye without myopia may be considered pathologic. As such, these patients have what could be termed myopic choroidal thinning. However, as the choroid undergoes age-related attenuation, the available supply may not be sufficient to support the outer retina, the RPE, and even the choroid itself. At some point, the thickness of the choroid seems to make a transition from myopic choroidal thinning to frank myopic choroidal atrophy. The transition point has not been defined at present, but it is possible that functional features such as threshold sensitivities or visual acuity may be part of the definition rather than just choroidal thickness alone. Patients with the loss of the choroid from myopia and age, who have decreased visual function as a consequence, are observed to have what could be termed myopic choroidal atrophy [42].

Summary for Clinicians

■The choroidal thickness in high myopia is inversely proportional to the diopters of myopia and age

■The choroid in the peripapillary region was exceptionally thin, possibly explaining peripapillary atrophy in myopes

■Myopic choroidal thinning occurs with increasing amounts of myopia, and myopic choroidal atrophy occurs when age-related processes cause the choroid to decrease in thickness sufficient to cause visual dysfunction

15.6  Pigment Epithelial Detachment in

Age-Related Macular Degeneration

Although detachment of the RPE associated with AMD 15  is common, theories about the formation of pigment epithelial detachments (PEDs) are remarkably divergent. RPE detachment was described first by Gass and coworkers [43] in 1966, and in 1972, Gass [44] further hypothesized that PEDs occurred in AMD secondary to either serous exudation from choriocapillaris hyperpermeability through an intact Bruch’s membrane or by neovascular ingrowth with subsequent exudation from the new vessels directly into the sub-RPE space. Gass thought exudation from neovascularization spread laterally, lifting the surrounding RPE monolayer by hydrostatic dissection up around the leaking vessels. Bird and Marshall [45] proposed that instead of choriocapillaris hyperpermeability or neovascularization, there is increasing deposition of lipid materials into Bruch’s membrane with age that rendered it progressively more hydrophobic and impermeable [46]. Pumping of fluid by the RPE toward the hydrophobic Bruch’s membrane would cause this fluid to accumulate under the RPE above Bruch’s membrane to create a PED, instead of passing through Bruch’s membrane. Bird proposed that CNV, if it occurred at all, was an event that occurred secondary to the PED [47]. Kuhn and associates[48] and Slakter and coworkers [49] identified a peculiar vascular configuration, the anastomosis of retinal vessels with underlying CNV, as a risk factor for the development for PED. Hartnett and coworkers, in two publications[50, 51], demonstrated that retinal vessels could grow down to the deep retina and lead to a PED, and they called the vascular change a “deep retinal vascular anomaly”. Years later, another group renamed this entity, retinal angiomatous proliferation (RAP), and proposed a staging system [52]. However, Gass and coworkers subsequently disagreed with this hypothesis and staging system [53].

Instead, Gass proposed that patients who appeared to have RAP actually had an early sign of occult chorioretinal anastomosis with occult CNV [53]. The outer retina and the RPE were thought to degenerate, and eventually because of this degeneration, the retinal vessels and the CNV came closer together. Solely on the basis of the proximity, the vessels of the retina were theorized to become anastomotic with those of the CNV. In this new theory, Gass retained his older idea that exudation from occult CNV extended laterally with the development of an adjacent PED.

One of the chief difficulties with PEDs is the difficulty of visualizing their contents [54]. It is difficult to image the contents of PEDs by fluorescein angiography because

of light absorption and scattering by the RPE and because fluorescein dye leaks into any potential spaces under the RPE to mask the deeper contents. Conventional OCT has poor ability to image structures under the RPE and consequently, many PEDs look hollow. However, these OCT scans do not image the underlying choroid, so one cannot be certain if deeper portions within the PED are filled with fluid with no reflectivity or just are not imaged in the first place. Using OCT with enhanced imaging of the contents of the PED, as evidenced by imaging of the complete thickness of the choroid in a series of patients, led to interesting findings.

After a series of anti-VEGF injections, some patients can appear to retain PEDs that appear to be “hollow” by conventional OCT. A small series examined with EDI OCT showed that these PEDs were filled with lamellar hyperreflective material (Fig. 15.16). Histologic examination of excised CNV following anti-VEGF treatment showed paucicellular fibrotic scarring [53] with a cross-sectional appearance similar to what was seen by EDI OCT examination. Other patients, those with serous detachment of the RPE, appeared to have collections of material along the back surface of the RPE (Figs. 15.17 and 15.18). Areas of hotspots seen during angiography, suggestive of RAP vs. occult retinal choroidal anastomosis, had spider-like projections extending into the contents of the PED. Anti-VEGF injections were associated with contraction of this material, such that the material could form sheets across the inner chord diameter of the PED. The contracture of the material has been associated with tears of the RPE (Figs. 15.19–15.21).

Angiographic correlation of the material showed that areas of collection of the sub-RPE material was associated with increased fluorescence and late staining, suggesting that the material is composed, at least in part, of fibrovascular proliferation. Hotspots in PEDs colocalized with what appeared to be retinal choroidal anastomosis. However, the appearance of the retina was different from what Gass and coworkers proposed. Gass thought the anastomosis occurred because there was degeneration of the RPE as well as the outer retina such that the retinal vessels came into close contact with the vessels of the CNV [53]. Because of their physical proximity, the vessels were supposed to have become anastomotic. In EDI OCT scans, the outer retina does not appear to be degenerated and autofluorescence shows an intact RPE. This implies that there must be some other mechanism leading to anastomotic connections between the retina and CNV. CNV has been proposed to grow because of increased VEGF levels under the RPE; and by extension, retinal vessel growth from the inner to the outer retina was proposed