15 Miscellaneous Macular Degenerations
15.1 Pathologic Myopia
Pathologic myopia is one of the leading causes of blindness in the world. In the United States and Europe, it ranks seventh among all the diseases that cause significant, uncorrectable visual loss. 1 Loss of visual acuity is caused by either exudative or progressively atrophic macular degeneration. In general, affected individuals have at least 6 diopters of myopia. Progressive myopia is the hallmark of the condition and is attributed to progressive elongation of the eye. 2 The prevalence of pathologic myopia varies among different races and ethnic groups, and appears to be more common in women than men. In the United States, the condition is found in 2.1% of 17-year-olds. 1 In comparison, the prevalence elsewhere has been reported to be as low as 0.2% in Egypt and as high as 9.6% in Spain. 3
15.1.1 Clinical Features
The clinical findings in pathologic myopia are believed to be the result of progressive elongation of the eye. Some of these features may be present in patients with low to moderate degrees of myopia (less than 6 diopters of myopia), whereas some patients with high degrees of myopia may demonstrate a relatively normal fundus.
The hallmark ophthalmoscopic finding is a peripapillary “myopic” crescent (Fig. 15-1). It usually appears as a hypopigmented, sharply defined area on the temporal aspect of the optic disc, where there is attenuation of the retinal pigment epithelium (RPE), smaller choroidal vessels, and a scleral shell. The borders of the crescent may extend superiorly and nasally and are commonly irregularly delineated by clumps of pigment. Occasionally the myopic crescent extends into the macula and through fixation. Uncommonly, it is located only on the nasal side (myopia inversus). The presence of the crescent correlates with axial length but not with overall total refractive error, as the latter is also influenced by corneal and lenticular factors. Commonly, the optic disc is vertically elongated and may be tilted, with a flattened temporal side. This optic nerve head configuration can make it difficult to assess the degree of cupping when glaucoma is suspected.
Posterior pole staphylomas may also be observed and are characterized by well-circumscribed, nummular areas of chorioretinal atrophy that are white in appearance (Fig. 15-2). When these lesions enlarge and extend into the central macula, loss of vision can follow. The prevalence of staphyloma is also related to increasing axial length.
Less dramatic but important fundus features may be observed in eyes with pathologic myopia. The RPE of the macula may demonstrate varying degrees of mottling. Yellow, linear, subretinal streaks in the macula are known as lacquer cracks and are observed in 4% of highly myopic eyes. 4 They correspond to disruptions in Bruch’s membrane, and because they herald subsequent widespread chorioretinal degeneration, they are a poor visual prognostic sign (Fig. 15-1). 5 Fuchs’ spots are round or oval areas of subretinal hyperpigmentation, which may be found in up to 10% of individuals with pathologic myopia, typically after the age of 30 years (Fig. 15-3). These spots are bilateral in 40% of the patients, with the second eye being involved within 5 years. 5 Fuchs’ spots are believed to be the sequelae of previous subretinal hemorrhage or choroidal neovascularization (CNV). They may have a surrounding area of depigmented atrophy and can significantly affect vision if close to the fovea.
Most patients with pathologic myopia slowly lose central vision because of the progressive atrophic, degenerative changes described earlier. Sudden and often more severe loss of visual acuity is typically a consequence of superimposed, subretinal exudative changes resulting from CNV (Fig. 15-4). 6 The exudative changes consist primarily of subretinal hemorrhage and fluid. There may be an associated elevation of the RPE that can be seen on spectral-domain optical coherence tomography (SD-OCT). SD-OCT can also identify subretinal and intraretinal hemorrhage or fluid. Fluorescein angiography (FA) usually reveals well-delineated, typically classic CNV lesions located near or beneath the fovea (Fig. 15-5). Overall, the neovascular process tends to be less extensive and less aggressive than that found in age-related macular degeneration (AMD), with much less subretinal fluid or macular edema.
Myopic macular hemorrhage demonstrates a variable visual prognosis. For subfoveal hemorrhage associated with CNV, anti–vascular endothelial growth factor (anti-VEGF) treatment has emerged as the treatment of choice.
Of note is that some patients who present with new macular hemorrhages in the setting of pathologic myopia may not have evidence of CNV on FA (Fig. 15-1). In this situation, neovascularization is either occult (obscured by the hemorrhage) or not present. Regardless of the source, submacular hemorrhages in eyes with pathologic myopia are associated with a variable visual prognosis depending on proximity to the fovea, and it is important to realize that many patients with extrafoveal lesions can retain excellent central visual acuity. However, in patients with subfoveal or juxtafoveal lesions, treatment with photodynamic therapy (PDT) and anti-VEGF agents has been investigated.
The peripheral retina of patients with pathologic myopia generally demonstrates diffuse pigmentary alterations and often has a tigroid appearance. Patchy or diffuse areas of atrophy of the retina and choroid are often observed. Patients with pathologic myopia are at increased risk for retinal tears and retinal detachment.
The diagnosis of pathologic myopia is suggested by the history of requiring correction for high refractive error and, occasionally, by family history. The axial length of the eye is typically greater than 26 mm. The diagnosis is then confirmed by observing the constellation of fundus features described earlier.
The differential diagnosis varies depending on the predominant clinical features. Patients with anomalous, tilted discs usually demonstrate an inferior scleral crescent with an irregular vascular pattern emanating from the optic nerve head and an area of fundus ectasia inferotemporally. The myopic crescent is more commonly located temporally. The presumed ocular histoplasmosis syndrome (POHS) demonstrates peripapillary pigmentary alterations, scattered “punched-out” chorioretinal atrophic lesions, and macular CNV. This syndrome, however, has no predilection for patients with high myopic refractive errors. Macular conditions that manifest serous or serosanguinous exudations, such as AMD or central serous chorioretinopathy, may be confused with myopic macular degeneration when incidental myopia and peripapillary pigmentary changes are present. Gyrate atrophy is an uncommon autosomal recessive condition characterized by multiple, sharply demarcated areas of geographic chorioretinal atrophy beginning in the midperipheral fundus in childhood and then coalescing to involve larger portions of the fundus with increasing age. These patients are often highly myopic, and if this precocious pattern of degeneration is observed, gyrate atrophy should be considered in the differential diagnosis (see ¦Chapter 22¦).
15.1.3 Pathogenesis and Histopathology
The pathogenesis of the macular degenerative changes in highly myopic eyes is not well understood, although they are believed to be influenced in part by genetic factors. Progressive axial elongation distends the ocular coats and causes the peripapillary, retinal, choroidal, and scleral degenerative changes. Resultant abnormalities at the level of Bruch’s membrane probably underlie the predisposition to CNV, as is the case with the other diseases discussed in this chapter.
Histopathologically, the sclera is thin, with areas of corresponding changes in the architecture of its collagen bundles. Degenerative changes involving the choriocapillaris, Bruch’s membrane, and the RPE are also observed, with thinning of the choroid and an absence of vasculature in some areas. 7 The RPE cells appear flatter and larger than usual. Bruch’s membrane is thinned and areas of dehiscences can be observed. There is also an associated thinning of the neurosensory retina, particularly in areas overlying choroidal atrophy. The thickness of the neurosensory macula is reduced partially because of thinning of the ganglion cell layer.
15.1.4 Management and Course
At this time, there are no proven therapies to prevent progressive elongation of the globe in pathologic myopia. In the hope of slowing down or preventing significant atrophic macular degeneration, scleral resection and reinforcement procedures have been performed. Limited reports indicate achievement of some degree of axial length or staphyloma stabilization. 8 , 9 However, beneficial effects on the visual outcome have never been demonstrated definitively.
Efforts have concentrated on CNV detection and treatment. Patients who experience sudden loss of vision and who manifest macular exudative or hemorrhagic changes should have a SD-OCT and an FA to identify and determine the extent of the CNV (Fig. 15-4 and Fig. 15-5). If there is just blocked fluorescence from hemorrhage, indocyanine green angiography (ICG) may help to identify or rule out underlying CNV. Unfortunately, when CNV is identified, it is located under the foveal center in approximately 60 to 75% of cases. 3 , 5 Although the behavior of CNV is not as aggressive as it is in AMD, it is nonetheless associated with a variable degree of central visual loss. 10
For nonsubfoveal CNV in eyes with myopic degeneration, laser photocoagulation has been shown to be effective in preventing visual loss. 11 , 12 However, recurrence rates of CNV can be high, and of particular concern, there can be significant, progressive enlargement of the laser photocoagulation scars with time (Fig. 15-6). 13 As a result, patients with juxtafoveal (within 200 μm from the foveal center) and particularly with subfoveal CNV are not good candidates for laser treatment. Prior to the advent of anti-VEGF agents, PDT was used in the treatment of CNV associated with myopic degeneration. The VIP Study was a randomized, controlled clinical trial investigating the use of verteporfin with PDT versus placebo in the treatment of myopia-associated CNV. The study enrolled 120 patients with subfoveal CNV; approximately 90% had evidence of a classic CNV lesion. The 1-year results showed that PDT with verteporfin was associated with less visual acuity loss compared to placebo. The main outcome measure (proportion of eyes with a visual acuity loss of less than 8 Early Treatment Diabetic Retinopathy Study (ETDRS) letters) was statistically significant between the groups (72 vs. 44%; p < 0.01). In the PDT group, 86% of patients lost less than 15 ETDRS letters of vision, compared to 67% in the control group. In addition, 32% of patients treated with PDT gained at least 5 ETDRS letters compared to 15% in controls. 14 At the 2-year follow-up, the main outcome measure (loss of less than 8 ETDRS letters) was no longer statistically significant (64 vs. 49%; p = 0.11). However, 40% of patients in the PDT group gained 5 or more letters compared to only 13% in the control group. 15 This study led to the adoption of PDT with verteporfin as treatment for subfoveal CNV secondary to myopic degeneration until the use of anti-VEGF agents in 2006. 16 , 17
The use of intravitreal bevacizumab led to a paradigm shift in the management of AMD-associated CNV, with the ANCHOR 18 and MARINA 19 trials showing that anti-VEGF therapy with ranibizumab not only prevented severe visual loss in the majority of patients, but also was associated with a mean gain in visual acuity of 8 to 10 ETDRS letters; almost 40% of patients gained three or more lines of vision (=15 ETDRS letters). Early case series demonstrated the efficacy of intravitreal bevacizumab for the treatment of CNV secondary to myopic degeneration. 16 , 17 A systematic review and meta-analysis demonstrated that anti-VEGF agents were superior to PDT at 2 years in improving visual acuity in eyes with myopia-associated CNV. The pooled data showed that 35% of 513 patients gained three or more lines of visual acuity with an associated decrease in OCT-measured central retinal thickness. 20 Although anti-VEGF therapy has proven efficacy in stabilizing and often improving visual acuity in myopia-associated CNV, optimal treatment protocols have not been determined. Most studies utilize either one injection followed by pro re nata (PRN) treatment based on OCT findings, visual acuity, and clinical examination or three monthly injections followed by PRN treatment. The RADIANCE study 21 was a randomized, double-masked, controlled trial investigating intravitreal ranibizumab versus PDT in the treatment of CNV secondary to pathologic myopia. The study included 277 patients divided into three groups: (1) two initial monthly ranibizumab injections followed by PRN injections based on visual acuity; (2) one initial ranibizumab injection followed by PRN injections based on disease activity; and (3) PDT with verteporfin with rescue ranibizumab after month 3. Intravitreal ranibizumab was found to be superior to PDT with respect to visual acuity outcomes. At month 3, the two ranibizumab groups gained on average 10.5 ETDRS letters compared to 2.2 letters in the PDT group. At month 12, the ranibizumab monotherapy groups gained an average of 13.8 to 14.4 ETDRS letters. The group that received PDT followed by ranibizumab after month 3 gained an average of 9.3 letters compared to baseline but did not catch up to the ranibizumab monotherapy. Both intravitreal ranibizumab treatment protocols were associated with similar visual acuity gains, with group 1 receiving a median of four injections compared to two injections in group 2.
Although studies have used both bevacizumab and ranibizumab in the treatment of CNV secondary to pathologic myopia, small case series show similar efficacy between agents 22 and the CATT and IVAN 23 , 24 studies reported similar clinical efficacy between ranibizumab and bevacizumab in eyes with exudative AMD. Despite the efficacy of anti-VEGF therapy in the management of myopia-related CNV, patients need close follow-up after cessation of treatment. Monitoring with a home Amsler grid combined with frequent follow-up including SD-OCT and clinical examination may identify disease reactivation that has been shown to occur in up to 25% of patients. 25 Risk factors for CNV recurrence include increasing age, greater myopia, decreased choroidal thickness, larger CNV lesions, and subfoveal hemorrhage. Lacquer cracks extending through the fovea, baseline visual acuity, and peripapillary choroidal atrophy were prognostic factors for visual acuity after treatment. 26
Intravitreal anti-VEGF therapy has emerged as the standard of care in the treatment of CNV secondary to myopic degeneration. Unlike AMD, myopia-related CNV usually responds to two to four injections with the majority of retina specialists utilizing a PRN treatment approach.
15.2 Presumed Ocular Histoplasmosis Syndrome
Histoplasma capsulatum is a soil mold found predominantly in the central and eastern United States, particularly the Ohio–Mississippi River Valley area. 27 Respiratory tract infections are usually asymptomatic and self-limited. POHS is likely the result of a subclinical systemic infection by this organism many years prior. The clinical syndrome of peripapillary chorioretinal changes, multiple macular and peripheral chorioretinal atrophic lesions, macular CNV, and an absence of inflammation was first described in 1960. 28 It is unusual to have active H. capsulatum intraocular infection. Panuveitis has been described in chronically ill and immunocompromised patients but is not a feature of POHS. 29
15.2.1 Clinical Features
The classic triad of POHS includes peripapillary chorioretinal atrophy, multiple “punched-out” chorioretinal scars, and acute or chronic macular exudative changes from CNV (Fig. 15-7). Patients are often young, usually between 20 and 50 years of age, and have visited or lived in the Ohio–Mississippi River Valley area; the incidence of “histo spots” is estimated to be 2.6% in this endemic area. 30 Prior exposure to pigeons, chickens, or parakeets may be significant.
The peripapillary chorioretinal atrophic changes can vary in degree. A rim of pigment separating the optic disc from the adjacent atrophy may be present. 31 The “punched-out” lesions are scattered throughout the fundus, are typically less than 1 mm in diameter, often have surrounding hyperpigmentation, and do not demonstrate significant elevation. Occasionally, these “histo spots” may form peripheral depigmented linear streaks that suggest a choroidal vascular predilection (Fig. 15-8). 32 The streaks are often equatorial in distribution and may be found in as many as 5% of patients with POHS. An absence of anterior chamber inflammation and vitreous cells is characteristic of POHS.
Patients with POHS are usually asymptomatic, but occasionally they present with sudden visual distortion or loss of vision. Visual symptoms are typically the result of macular CNV with secondary exudative changes (Fig. 15-9 and Fig. 15-10). 33 , 34 , 35 The CNV is often visible ophthalmoscopically and appears under the neurosensory retina as a slightly elevated, gray-green lesion (Fig. 15-9). FA usually shows the CNV to be well delineated, with classic early hyperfluorescence and late leakage. OCT findings may show subretinal or sub-RPE neovascular CNV with exudation as evident by subretinal and intraretinal fluid. The CNV lesions are most commonly classic on FA, and OCT shows type 2 lesions.