Nancy M. Holekamp,
Lawrence S. Halperin,
Levent Akduman,
R. Joseph Olk
The ocular histoplasmosis syndrome (OHS) causes permanent loss of central vision in 2000 young adults per year. The organism Histoplasma capsulatum has been suspected as a cause of granulomatous uveitis for many years. In 1951, Krause and Hopkins[1] reported a patient with atrophic chorioretinal lesions with pigment change and hemorrhage. A histoplasmin skin test result was positive, and a chest radiograph film showed calcified lung nodules. In 1960, Woods and Wahlen[2] published a report of a collection of patients who were residents of an area endemic for histoplasmosis and had clear vitreous, peripheral atrophic spots, disciform macular lesions, positive histoplasmin skin test results, and pulmonary calcifications.
The four signs of OHS are peripheral punched-out chorioretinal lesions, juxtapapillary atrophic pigmentary changes, disciform macular changes, and a clear vitreous.
This chapter reviews the epidemiology, clinical findings, evaluation, and treatment of OHS.
EPIDEMIOLOGY
Most individuals with OHS are between 30 and 40 years of age. Fundus scars may occur with equal frequency among blacks and whites, although maculopathy is very rare in blacks. Baskin and associates[3]reported six blacks with OHS and macular lesions, five of whom had positive skin test results.
EPIDEMIOLOGIC STUDIES
The epidemiology of OHS has been studied by many investigators and yet the relationship between H. capsulatum infection and the manifestations of ocular disease remains an enigma. A review of several of these reports provides varying aspects of the debate.
Braunstein and co-workers[4] reported 15 individuals in the United Kingdom who had the clinical findings of OHS but in whom all skin test results were negative. These investigators concluded that there could be a different causative factor in the United Kingdom.
Ellis and Schlaegel[5] found the Mississippi and Ohio river valleys to be highly infected; 80% of the adult population had positive skin test results. This area includes 80 million individuals, involving Missouri, Illinois, Indiana, Kentucky, Tennessee, and Mississippi (Fig. 153.1). Wheat and colleagues[6] collected worldwide patterns of skin sensitivity to histoplasmin. Feman and associates[7] noted that 60% of the Tennessee population had positive skin test results, but only 44 new cases of visual loss resulting from OHS occurred in a 6 month period. Smith and Ganley and co-workers[8-10] studied 842 individuals in Walkersville, Maryland, of whom 60% had positive skin test results. One-hundred percent of patients with highly suspicious lesions had positive skin test results, but only 4.4% of those who had positive results had typical fundus lesions. Only one individual had a disciform macular lesion. We conclude that OHS is relatively uncommon, even in endemic areas. Typically, 2-12% of the population in an endemic area has ocular findings consistent with OHS, and only 1 in 1000 experiences maculopathy.
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FIGURE 153.1 This world map demonstrates areas where histoplasmosis infection is endemic. |
Davidorf and Anderson[11] examined 353 school-aged children after an acute epidemic infection on Earth Day in 1970. Forty-one percent of the children became acutely ill from histoplasmosis infection, and 85% had elevated serum titers, compared with 10% of controls. Two years later, all children who had the infection had a positive skin test result, compared with 23.4% of controls. However, the incidence of fundus lesions was similar in infected children when compared with controls, and this brought the association of histoplasmosis infection and OHS into question. A more likely explanation is that a 2 year period after exposure to histoplasmosis is not sufficient time to assess the occurrence of OHS lesions. Anand and colleagues reported observation of active and inactive retinal lesions during an outbreak of histoplasmosis (Anand R, Luby JP, Metrikin D, et al: Acquired histoplasma chorioretinitis. Paper presented at the Annual Meeting of the Retina Society, Santa Fe, NM, 6-10 Sep 1995).
Feman and Tilford[12] found that six of eight patients with positive systemic histoplasmosis cultures had chorioretinal scars consistent with OHS. This again lends support to the concept that H. capsulatumcauses OHS.
FELLOW EYE
Patients with a disciform process in one eye have posterior atrophic lesions in the fellow eye ~25-59% of the time.[13,14] If one eye has a choroidal neovascular membrane (CNVM), and a focal atrophic spot in the posterior pole is present in the second eye, that eye has between 8% and 27% chance of acquiring a CNVM in 3 years.[13-17] More histoplasmosis spots in the posterior pole may lead to increased chances of activation. If no macular atrophic spot is present in the posterior pole of the second eye, there is less than 5% chance of a CNVM developing in 5 years; however, new spots may develop. Close follow-up is needed for the fellow eye, especially if posterior histoplasmosis spots are present. An individual with bilateral macular histoplasmosis spots has 5% chance of a CNVM developing in one eye within 5 years.
The macular photocoagulation study (MPS) showed that there is 9% risk of CNVM formation in 5 years in the fellow eye if a patient with OHS has an extrafoveal or juxtafoveal CNVM in one eye.[18] The study also showed that histo spots of any type in the macula tripled the risk for later development of CNVM. CNVMs were preceded by an atypical histo spot in the macula in more than 75% of the cases. Eighty-one percent of all patients in the MPS retained 20/20 vision in at least one eye in 5 years and risk of legal blindness was very low (8% in bilateral and 1% in unilateral patients).
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HISTOPATHOLOGIC FEATURES
ORGANISM AND SYSTEMIC INFECTION
H. capsulatum is a fungus that is present in its yeast form. The fungus is carried and deposited by droppings from chickens, pigeons, blackbirds, and bats. The birds are not infected but carry the fungus on their feathers. Bats, however, are infected.
In humans, the fungus is first inhaled into the lungs and is then disseminated into the blood stream. Acute pneumonitis with fever may ensue and an acute, life-threatening disease may rarely occur. Pulmonary granulomas form and heal with calcification, and these may be seen on chest radiography. The systemic forms of disease rarely have ocular manifestations.
OCULAR HISTOPATHOLOGIC FEATURES
There are several reports of H. capsulatum in eyes with OHS.[19,20] However, Roth's[20] report was refuted by Gass and Zimmerman.[21]
Ocular histopathologic studies have shown H. capsulatum in disseminated histoplasmosis, often in immunocompromised hosts (Fig. 153.2).[22-26] Some of these patients exhibited clinical signs of OHS as well.[20,27] These cases and others have been well summarized.[26]
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FIGURE 153.2 Histopathology of histoplasmosis infection, demonstrating organisms present in the cytoplasm of endothelial cells using different staining techniques. (a) phase-contrast, (b) periodic acid Schiff, (c) higher power of b, (d) Gomori methanamine silver, (e) Gomori methanamine silver with 90 minute exposure. |
Meredith and associates[28] reported cracks in Bruch's membrane related to the growth of choroidal blood vessels into the subretinal space. The overlying retina showed loss of outer layers and cystic degeneration. The retinal pigment epithelium (RPE) was lacking in the center of the lesion but was clumped at the edges. Subretinal pigment epithelium neovascularization extended beyond the disciform process. The juxtapapillary changes resulted from loss of RPE, loss of photoreceptors, and discontinuities in Bruch's membrane. The peripheral lesions showed loss of the RPE, scarring, and occasional lymphocytic infiltration (Fig. 153.3).
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FIGURE 153.3 Histopathologic specimen from a case of ocular histoplasmosis syndrome (OHS). Discontinuities in Bruch's membrane (between arrows in bottom figure) allow choroidal vessels (asterisk in bottom figure) to grow in the subretinal or subretinal pigment epithelial space. |
Pavan and Margo[29] reported a patient with fundus findings suggestive of OHS in which histopathologic examination of the excised membrane revealed the following: intense staining with visible edges in the late phases of fluorescein angiography and a well-circumscribed granuloma containing some eosinophiles.
EXPERIMENTAL ANIMAL MODEL
Smith and co-workers developed an experimental animal model involving the injection of live fungus via the carotid artery.[30-32] Most animals had positive skin test results and early acute choroiditis resulting from mononuclear cell and macrophage infiltration with phagocytosis of yeast. Lymphocytes were found in the choroid, and damage to Bruch's membrane occurred. Six weeks later, yeast was rarely found. Atrophic lesions resulted from loss of RPE associated with altered Bruch's membrane and lymphocytes in the choroid. Subclinical lesions occurred in areas that were not detectable by clinical examination or fluorescein angiography, but lymphocytes were seen under the retina and RPE. Disappearing lesions occurred where lesions were at one time visible but became invisible. There were lymphocytes in the choroid, but the RPE and retina were normal. Chronic choroiditis occurred, with organisms disappearing in 6 weeks. This may be why amphotericin B has no effect on the disease. No macular disciform lesions developed. These laboratory data support clinical findings. Disseminated histoplasmosis causes acute lesions with yeast particles. Later, chronic OHS shows lesions without yeast, but inflammatory cells may still be present. Doubts concerning the cause and effect of H. capsulatum and OHS could be explained by these experimental data.
IMMUNOLOGY
Several theories exist that attempt to explain the pathogenesis of OHS, including the following:
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Immunologic responses to previous infection causes OHS. The macular lesion may be a hypersensitivity reaction to dead organisms elsewhere in the eye. |
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Macular disease in OHS is the result of re-infection with histoplasmosis. |
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Some vascular decompensation in the choroid is responsible for the findings in OHS. |
LYMPHOCYTE HYPERREACTIVITY
Schlaegel and colleagues[33] found altered skin test reactivity to certain antigens in patients with OHS. Lymphocytes are hyperreactive in patients with disciform lesions in OHS, and some investigators believe there is an increased rate of macular subretinal hemorrhage after histoplasmin skin testing. Others[34,35] found that lymphocyte transformation may correlate with OHS activity. Patients with disciform lesions have stimulated lymphocytes in comparison with patients with only peripheral scars and controls. Brahmi and associates[36] found acute histoplasmin infection to be different from OHS in terms of T-cell studies. Lymphocyte marker CD38 was significantly higher than controls in four patients with OHS-like syndrome from the United Kingdom, which may correlate with poor T-cell function in making these patients more susceptible to various stimuli.[37]
HISTOCOMPATIBILITY ANTIGENS
Meredith and co-workers,[38] in the Walkersville study, found no increase in human leukocyte antigen (HLA)-B7 for peripheral lesions only but did find an association with HLA-DRw2. There was a definite association between HLA-B7 and macular lesions. Braley and colleagues[39] found that 78% of patients with OHS and macular disciform lesions were HLA-B7-positive compared with 20% of controls. Godfrey and associates[40] found that 54.8% of macular lesions were HLA-B7 positive.
All these studies support the concept that OHS is an immunologic disorder. Interestingly, lymphocytes are found in scars and lesions in OHS and they also are found in disciform lesions of age-related macular degeneration. Age-related macular degeneration is increasingly being thought of as arising from an underlying chronic inflammatory disorder. Unfortunately, there is no animal model for macular lesions in OHS to study these questions further.
CLINICAL CHARACTERISTICS
See Table 153.1 for a listing of clinical characteristics of the ocular histoplasmosis syndrome.
TABLE 153.1 -- Clinical Characteristics of the Ocular Histoplasmosis Syndrome
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Punched-out chorioretinal lesions |
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Juxtapapillary chorioretinal atrophy |
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Choroidal neovascularization |
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No vitritis |
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No pigment epithelial detachment |
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Disseminated choroiditis - rare |
PUNCHED-OUT CHORIORETINAL LESIONS
Smith and co-workers[41] found one to four punched-out chorioretinal lesions per eye, juxtapapillary changes in 28% of eyes, and bilateral changes in 62% of patients with OHS. Macular lesions are rare but more visually devastating.
The atrophic spots are small, irregular, roundish lesions in the midperiphery and posterior pole. They may have pigment on the edge or in the center and range from 0.3 to 0.7 disk diameter. Choroidal vessels may be seen throughout the atrophic lesions (Fig. 153.4). Watzke and Claussen[42] found that atrophic lesions change shape, size, and pigmentation over time.
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FIGURE 153.4 (a) Fundus photograph of peripheral, punched-out lesions typical of OHS. (b) Fundus photograph of atrophic macular lesions. |
Linear streaks of chorioretinal lesions of variable length, width, and pigmentation may form (Fig. 153.5). They are usually equatorial, parallel to the ora, and average 3 clock hours in length. Bottoni and colleagues[43] found streaks in five patients who also had CNVMs. Fountain and Schlaegel[44] found streaks in 5% of their patients with OHS, but this was a skewed population.
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FIGURE 153.5 Fundus photograph shows the peripheral linear streak of histoplasmosis spots. |
New lesions may form in areas previously seen to be normal on clinical examination and fluorescein angiography. Schlaegel and associates[45] said 26% of spots were newly developed over 5 years of follow-up, whereas other studies cited 9% and 16.6%.[13,42,46] Gass and Wilkinson[47] found only 1 out of 81 patients in whom a new peripheral lesion developed, but Lewis and Schiffman[14] re-evaluated 99 of their patients with longer follow-up and found that 19% acquired new lesions, suggesting that longer follow-up leads to identification of more new lesions.
JUXTAPAPILLARY CHORIORETINAL ATROPHY
The juxtapapillary changes in OHS are probably due to juxtapapillary choroiditis that goes unrecognized, and this leads to chorioretinal changes around the disk (Fig. 153.6). Various investigators have found that 85-94% of patients with OHS have juxtapapillary changes.[13,33,48] The atrophic juxtapapillary changes may lead to choroidal neovascularization that can decrease central vision (Fig. 153.7).[49] Lewis and co-workers[48] found that 3.8% of patients with juxtapapillary changes experienced a juxtapapillary CNVM, and Cantrill and Burgess[50] found that 15% of patients with symptoms from a juxtapapillary CNVM in one eye had a juxtapapillary CNVM in the fellow eye. Gass and Wilkinson[47] found that 10% of all CNVMs in OHS were juxtapapillary. Gutman[13] reported that 58% of patients with these types of lesions had visual acuity of 20/200 or worse, indicating that juxtapapillary CNVM may lead to significant central vision loss.
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FIGURE 153.6 Juxtapapillary changes include retinal pigment epithelial hypertrophy and atrophy. |
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FIGURE 153.7 In this eye, juxtapapillary changes led to the development of choroidal neovascular membrane (CNVM). (a) The fundus photograph shows evidence of gray subretinal lesions along with subretinal blood, both of which are signs of CNVM. (b) An early frame of a fluorescein angiogram shows early hyperfluorescence. (c) A later frame shows massive leakage from the new vessel membrane. (d) In another patient, a juxtapapillary CNVM causes extensive retinal striae. |
MACULAR LESION
The classic macular lesion associated with OHS is a well-defined CNVM with serous detachment of the retina, a small amount of subretinal hemorrhage and hard lipid exudate, and a pigment halo surrounding the active lesion (Fig. 153.8).
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FIGURE 153.8 Macular lesion of OHS. (a) Fundus photograph of a CNVM, with a gray membrane, subretinal hemorrhage, subretinal fluid, and pigment ring. (b) An early frame of a fluorescein angiogram with early hyperfluorescence demonstrates a juxtafoveal CNVM. |
Symptoms of a CNVM include decreased vision, metamorphopsia, and blurring. Micropsia occasionally may be a subjective complaint.
Generally, the CNVM occurs at the edge of an old healed chorioretinal scar in the macula, termed a 'histo spot'. Melberg and colleagues have identified this scar as the 'ingrowth site' of the neovascularization as it is associated with a discontinuity in Bruch's membrane on histopathologic examination.[51,52] Macular lesions can develop in previously normal retina. It is more common, however, that reactivation of old lesions accounts for new CNVMs, with a 20-23% activation rate.[47,48]
CNVMs are classified by their location in relation to the center of the foveal avascular zone (FAZ). The designations of extrafoveal, juxtafoveal, and subfoveal are described.
Extrafoveal CNVMs
Extrafoveal CNVMs have an edge of hyperfluorescence or blockage of fluorescence, as shown on fluorescein angiography, between 200 and 2500 ?m from the center of the FAZ. Lewis and co-workers[48]found that 69% of patients with extrafoveal CNVMs had visual acuity of 20/40 or better at presentation.
Juxtafoveal CNVMs
Juxtafoveal CNVMs have either a hyperfluorescent edge 1-200 ?m from the center of the FAZ, with or without block-age (blood, pigment) through the center of the FAZ, or a CNVM 200-2500 ?m from the center, with blood or blocked fluorescence within 200 ?m of the center. Lewis and co-workers[48] found that 71% of patients with juxtafoveal CNVMs from OHS had visual acuity measuring 20/200 or worse. Gutman[13] found that if the CNVM was inside the FAZ, there was a 63% chance that visual acuity would be less than 20/200, but a 25% chance if the CNVM was outside the FAZ. Olk and co-workers[17]found that 65% of patients with juxtafoveal membranes had a visual outcome of 20/200 or worse. Poor prognostic clinical signs include subretinal blood, poor initial vision, membrane close to the center of the FAZ, and large CNVM size. Steroids have no effect on juxtafoveal lesions.
Subfoveal CNVMs
Subfoveal CNVMs have active leakage under the center of the FAZ. Fourteen to sixteen percent of these patients recover visual acuity of 20/40 spontaneously without laser treatment,[17,48,53] and laser treatment through the center of the FAZ would almost certainly decrease visual acuity to the 20/200 level immediately. A pilot study of laser treatment for subfoveal neovascular membranes in OHS has shown no benefit from the laser treatment in eyes with new or recurrent subfoveal CNVMs that are 3.5 disc areas or less in size and with vision between 20/40 and 20/320.[54] Therefore, these patients should not be considered for thermal laser treatment. However, untreated 50% or more of these eyes end up with very poor vision.[17,47,55] A favorable natural history has been predicted by the following: age less than 30 years, small CNVM, and good fellow eye. A Poor prognosis untreated has been found in eyes with initially excellent vision and a CNVM that involved more than 50% of the FAZ. Thirty-six percent of patients less than 30 years of age had visual acuity of 20/40 or better, establishing that the greater the area of FAZ covered by the CNVM, or the further the CNVM is beyond the center of the FAZ, the worse the prognosis.
VITRITIS AND OHS
The presence of vitritis almost always rules out the diagnosis of OHS. Any time vitreous cells are present, entities other than OHS must be considered.
PIGMENT EPITHELIAL DETACHMENTS
Gass[56] and others believe that pigment epithelial detachments are very rare in OHS. Occult and minimally classic CNVM are also rare. The most prevalent type of CNVM in OHS is predominantly classic. There may be surrounding atrophy of the RPE, thought to be due to chronic fluid accumulation in untreated cases.
DISSEMINATED CHOROIDITIS
Disseminated choroiditis usually occurs in immunocompromised patients. The lesions present as yellow, circumscribed, elevated choroidal infiltrates with fuzzy edges and a surrounding ring of pigment (Fig. 153.9). The foci of choroiditis may develop into a CNVM, with serous retinal detachment, hemorrhage, and retinal striae. Conway and colleagues[57] have shown that 93% of patients with macular histochoroiditis were at least stabilized with systemic steroids.
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FIGURE 153.9 (a) Histoplasmic choroiditis causes yellow choroidal infiltrates with a surrounding pigment ring. Fluorescein angiography demonstrates early blocked fluorescence (b) and the intermediate (c) and late (d) staining of the lesion. These lesions can become atrophic with time (e) and ultimately may develop secondary reactive hyperplasia of the retinal pigment epithelium (f). |
OPTIC DISC EDEMA
Optic disc edema occurs rarely in patients with OHS.[58,59] The juxtapapillary findings in OHS may originate from undetected, transient papillitis.
EXOGENOUS HISTOPLASMIC ENDOPHTHALMITIS
One case of exogenous histoplasmic endophthalmitis after cataract extraction has been reported.[60]
VITREOUS HEMORRHAGE
There has been one report of a patient with OHS in whom a CNVM developed and resulted in breakthrough vitreous hemorrhage.[61] OHS can be considered in the differential diagnosis of vitreous hemorrhage.
SUBRETINAL HEMORRHAGE
Subretinal hemorrhage from CNVM due to OHS tends to be smaller than similar lesions from age-related macular degeneration. Generally, they can be observed and will undergo spontaneous resorbtion. However, subretinal hemorrhage from a CNVM due to OHS requiring evacuation has been reported.[62]
FLUORESCEIN ANGIOGRAPHY
INDICATIONS
Patients with no subjective complaints or findings of peripheral or macular chorioretinal scars do not require fluorescein angiography. The indications for fluorescein angiography include symptoms of a CNVM, such as visual loss, metamorphopsia, or blurring; clinical signs of CNVM; and the need to evaluate the fellow eye of a patient with OHS to check for the presence of macular chorioretinal scars that would indicate an increased risk to that eye (Table 153.2). It is vital to obtain a fluorescein angiogram in any patient with new symptoms.
TABLE 153.2 -- Symptoms and Signs of Choroidal Neovascularization
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Metamorphopsia |
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Visual blurring |
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Serous detachment of retina |
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Subretinal hemorrhage |
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Hard lipid exudate |
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Pigment halo surrounding lesion |
FINDINGS
The histoplasmosis 'spots' show early hypofluorescence with faint late staining (Fig. 153.10). These areas can change to early staining with late leakage over time. Gass[56] believes the punched-out lesions fluoresce but that this is due to scleral reflection and not actual leakage of dye. The RPE and choriocapillaris between the histoplasmosis lesions are normal (this is not the case in age-related macular degeneration).
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FIGURE 153.10 (a) Fundus photograph of a CNVM (inferior to the fovea) and histoplasmosis spots (superior to the fovea). (b) and (c) Fluorescein angiograms of histoplasmosis spots. (b) shows early hypofluorescence and (c) shows late staining. Note how the new vessel membrane leaks fluorescein dye and develops fuzzy margins late in the study. The histoplasmosis spots show staining of the sclera but stay sharply demarcated. |
Acute, yellow choroidal lesions stain with fluorescein.[56]
CNVM stains early in a lacy pattern and leaks late, with the margins of the lesion becoming blurred. Subretinal fluid may collect dye late in the study. Subretinal blood allows fluorescence of retinal vessels but blocks fluorescence of the choroidal vessels and CNVM. There may be a halo of hypofluorescence around the CNVM which corresponds to a reactive layer of RPE cells trying to contain or 'cocoon' the neovascular tissue.
DIFFERENTIAL DIAGNOSIS
The types of differential diagnoses are listed in Table 153.3.
TABLE 153.3 -- Differential Diagnosis of the Ocular Histoplasmosis Syndrome
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Multifocal choroiditis and panuveitis |
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Birdshot choroidopathy |
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Diffuse unilateral subacute neuroretinopathy |
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Acute posterior multifocal placoid pigment epitheliopathy |
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Vogt-Koyanagi syndrome |
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Behçet's disease |
MULTIFOCAL CHOROIDITIS AND PANUVEITIS (PSEUDO-PRESUMED OHS)
Dreyer and Gass[63] reported on 28 patients with multifocal choroiditis, old punched-out lesions, juxtapapillary atrophic changes, and CNVMs. Most patients were from nonendemic areas and had vitritis and decreased electroretinogram signals. Of 16 patients who underwent skin testing, only 5 tested positive for histoplasmosis. This syndrome is especially difficult to differentiate from birdshot choroidopathy and diffuse unilateral subacute neuroretinopathy. Deutsch and Tessler[64] reported similar findings, however 43% of their patients were black. The choroidal punched-out lesions in pseudo-presumed OHS are smaller than those in OHS, some of the spots represent an active choroiditis, and vitritis may be present. Systemic steroids may help the active lesions in pseudo-presumed OHS.
BIRDSHOT (VITILIGINOUS) CHOROIDOPATHY
Birdshot choroidopathy presents in an older age group than does OHS. Choroidal lesions are creamy, active spots without atrophy or pigmentation, and there are no juxtapapillary changes. Optic disc pallor occurs, but choroidal neovascularization is rare. The electroretinogram is depressed, and fluorescein angiography shows disc leakage and cystoid macular edema.
DIFFUSE UNILATERAL SUBACUTE NEURORETINOPATHY
Diffuse unilateral subacute neuroretinopathy is a unilateral parasitic infestation. Early in the disease, there are clusters of white spots, vitritis, and RPE changes between white lesions. The lesions are evanescent and change with the location of the parasite. Late in its course, optic atrophy and arterial narrowing develop.
ACUTE POSTERIOR MULTIFOCAL PLACOID PIGMENT EPITHELIOPATHY
Usually occurring after upper respiratory infection, acute posterior multifocal placoid pigment epitheliopathy leads to clustered lesions in the posterior pole, often with severe loss of vision. The lesions disappear after a brief period, usually with return of good vision.
VOGT-KOYANAGI SYNDROME
The Vogt-Koyanagi syndrome is a granulomatous uveitis with infiltrative choroidal lesions. Exudative retinal detachment is frequently present. Systemic symptoms such as tinnitus, deafness, poliosis, vitiligo, and headache occur.
BEHÇET'S DISEASE
Behçet's disease includes severe vasculitis with panuveitis. Aphthous oral ulcers and genital lesions usually accompany the attacks of uveitis.
TREATMENT
STEROIDS
No controlled trial has proven the efficacy of steroids in OHS. Many years ago, Schlaegel and colleagues[45] considered systemic steroids to be appropriate for acute flare-ups and possibly for long-term use to prevent visual loss. Schlaegel[65,66] believed that steroids, if used, should be given in high doses (prednisone 60-100 mg/day) and tapered very slowly over 1-2 yr. Makley and co-workers[67] found some benefit if steroids were used early in the course of macular lesions. These studies were performed before other treatment alternatives were available. Today, steroids are rarely used for CNVM. However, some early cases of OHS may present with choroditis at the site of a macular 'histo spot' without concomitant CNVM. It can be reasonable to try local corticosteroids (subtenon or intravitreal) or a short course of systemic corticosteroids in these cases, with close follow-up looking for the development of CNVM.
DESENSITIZATION
Schlaegel and associates[45] desensitized OHS patients by giving small doses of histoplasmin antigen subcutaneously. They found that there was no difference between treated and control groups. Some investigators report that skin testing or desensitization may exacerbate macular lesions in OHS.
LASER TREATMENT OF INACTIVE MACULAR LESIONS
Gitter and Cohen[68] attempted to prevent CNVM formation in fellow eyes by laser treatment of inactive macular lesions. Their study contained no controls, but no complications were reported. Later, one of the patients experienced a CNVM in a treated scar. Others have reported similar cases.[69,70] Prophylactic laser photocoagulation is not recommended, as it is not useful in preventing CNVM formation.
AMPHOTERICIN B
Amphotericin B has been tried in the past in an attempt to obliterate a histoplasmosis infection. Makley and co-workers[67] found no treatment benefit. Most investigators believe that OHS lesions are probably sterile, inflammatory lesions containing no organisms, and therefore, antifungal agents play no role in the treatment of OHS.
ANTIHISTAMINES
Antihistamines were at one time thought to play a regulatory role for choroidal capillaries and have been tried in OHS macular disciform lesions but without success.
6-MERCAPTOPURINE
6-Mercaptopurine has been tried, but with no benefit.
MACULAR PHOTOCOAGULATION STUDY - OHS AND EXTRAFOVEAL CNVM
The ocular histoplasmosis section of the MPS was a multicenter, controlled clinical study, designed to answer specific questions concerning whether laser treatment would prevent visual loss from CNVMs. The CNVM includes hyperfluorescence, blood, pigment, and blocked fluorescence on fluorescein angiography. Extrafoveal CNVMs are defined as having hyperfluorescence on fluorescein angiography 200-2500 ?m from the center of the FAZ (Fig. 153.11). The diagnosis of OHS requires at least one atrophic chorioretinal scar. Entrance into the MPS required visual acuity of 20/100 or better. Juxtapapillary CNVMs were included in the study only if treatment would spare at least 1.5 clock hours of nerve fiber layer in the maculopapular bundle.
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FIGURE 153.11 (a) Schematic representation of an extrafoveal CNVM demonstrates the measurement from the center of the foveal avascular zone to the edge of the CNVM, in this case 200 ?m away. (b) Fundus photograph of a CNVM. (c) Fluorescein angiogram demonstrates early, lacy hyperfluorescence. (d) Middle frame of the angiogram shows leakage of dye. (e) Posttreatment photograph. (f) Fluorescein angiogram shows obliteration of the new vessel membrane. Note normal hyperfluorescence at the edge of a laser scar. |
Results of the MPS[71] showed that at 24 months, a 6 line visual loss had occurred in 50% of the group receiving no treatment and in 22% of the treated group. At 36 months, the results were 45% for the group receiving no treatment and 10% for the treated group.[72] The effectiveness of laser treatment when compared with controls was present in all subgroups at all stages of follow-up. Burgess[73]concluded that any CNVM completely outside the FAZ should be treated with laser.
Brown and colleagues performed an analysis of the cost-effectiveness of laser photocoagulation for extrafoveal CNVM due to OHS and found it to be highly cost-effective from a patient preference-based point of view.[74]
MACULAR PHOTOCOAGULATION STUDY - OHS (SUMMARY)
The current recommendation for the evaluation and treatment of extrafoveal, juxtafoveal, and peripapillary (nonsubfoveal) CNVMs resulting from OHS is to follow the guidelines from the MPS trial. Juxtafoveal CNVMs should be treated according to the MPS guidelines as long as a good margin of laser (>100 mm) can be applied on the foveal edge without involving the center of the fovea. Juxtafoveal CNVMs that would require laser treatment into the center of the fovea should be con-sidered for alternative treatments generally considered for subfoveal CNVM as discussed below. CNVMs on the nasal side of the optic nerve rarely need treatment, since they usually undergo spontaneous involution. The most common complication of laser photocoagulation for CNVM due to OHS is recurrence, usually attributable to inadequate coverage or intensity of the treatment. Other complications are rare (Table 153.4). Because the recurrence rate exceeds 30% CNVMs treated with laser photocoagulation should be followed with frequent examination and daily home use of the Amsler grid.
TABLE 153.4 -- Complications of Laser Treatment
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Recurrence of choroidal neovascular membrane |
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Retinal pigment epithelial rips |
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Acute choroidal hemorrhage |
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Nerve fiber layer field defects |
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Premacular fibroplasia |
LASER TREATMENT TECHNIQUE
GENERAL GUIDELINES
There are some general rules that may guide laser photocoagulation of choroidal neovascular membranes.
The role of anesthesia in laser photocoagulation of CNVMs is to provide comfort during the procedure and to increase the margin of safety when treating near the fovea. Topical anesthesia may be adequate for treatment in the cooperative patient with an extrafoveal CNVM. For juxtafoveal CNVMs, we recommend retrobulbar anesthesia in all but the most cooperative patients. If the patient squeezes the lids, Bell's phenomenon can move the eye superiorly, thereby risking photocoagulation of the fovea during treatment of a CNVM superior to fixation. Further, juxtafoveal CNVMs should be treated with krypton red or diode laser (805 nm), and this frequently causes some discomfort if local anesthesia is not given.
A recent fluorescein angiogram is essential for adequate treatment. It has been shown that CNVMs may grow, especially those closer to the fovea, in the course of several days. The fluorescein angiogram being used to guide treatment should be less than 72 h old, especially with juxtafoveal lesions. More latitude may be taken with extrafoveal CNVMs that are greater than 200 ?m from the center of the FAZ.
The fluorescein angiogram is essential for mapping the FAZ as well as the CNVM. The use of the aiming beam to map fixation is not a reliable way to define the FAZ. Because of eccentric fixation or distortion of the fovea, one may be fooled into treating the fovea if the aiming beam is used to determine fixation.
The following procedural details may be helpful. Both the surgeon and the patient should be seated comfortably at the laser. An elbow rest should be used to stabilize the surgeon's arm. A fixation light for the patient's fellow eye helps to stabilize the treatment eye. The patient should be introduced to the sound of the laser before treatment actually begins. Treatment should be guided by an early frame of a recent fluorescein angiogram. One should use a computer monitor (for digital angiograms), a table-top viewer (for film angiograms) adjacent to the laser slit lamp.
Various fundus contact lenses are available for macular treatment. It must be remembered that some lenses reverse and invert the surgeon's view of the fundus (Mainster, Rodenstock). The fluorescein angiogram must be properly oriented so that the surgeon does not confuse the anatomy.
If bleeding occurs during the laser treatment, intraocular pressure should be increased with the contact lens and then laser treatment applied over the bleeding site, preferably with argon green.
Klein and colleagues[81] did not avoid retinal vessels in the treatment area. However, it is generally recommended that heavy, long-duration burns not be placed directly over retinal vessels, especially if the vessel supplies the central fovea.
Sabates and colleagues[82] found that hemorrhage obscures the complete extent of the CNVM and absorbs the laser energy, thus sparing the CNVM. Intense treatment over areas of subretinal hemorrhage is not indicated, as energy absorption is quite superficial and will cause damage to the retina.
ARGON GREEN LASER FOR EXTRAFOVEAL CNVM
First, the CNVM is outlined with burns of 100 ?m size and 0.1 s duration. Gass[83] recommends covering any pigment ring and choroidal neovascularization as shown by an early frame of the fluorescein angiogram. On the foveal side, 100-200 ?m spots of 0.2 s duration are delivered in a confluent fashion. These should be heavy white spots. The remainder of the lesion is covered confluently with heavy laser burns of 200-500 ?m spots and 0.5 s duration. The CNVM should be covered 100 ?m past the edge of the CNVM. On the foveal side, if the treatment will not enter the FAZ, the treatment should extend 100 ?m. If the edge of the CNVM is close to the edge of the FAZ, coverage of the CNVM by a full 100 ?m beyond the edge is not required (Fig. 153.13).
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FIGURE 153.13 (a-c) Schematic representation of the treatment of an extrafoveal CNVM. |
KRYPTON RED LASER FOR JUXTAFOVEAL CNVM
The krypton red laser should be used with large spots (at least 200 ?m) and long-duration (at least 0.2 s) to decrease the chance of rupturing Bruch's membrane. The retina will whiten less with krypton red than with argon green. It is not necessary to treat blood or blocked fluorescence (Fig. 153.14).
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FIGURE 153.14 (a and b) Schematic representation of the treatment of a juxtafoveal CNVM. |
First, the foveal side of the lesion is treated with 200 ?m spots of 0.2 s duration. The remainder of the lesion is treated with 200-500 ?m confluent burns of 0.5 s duration.
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If hyperfluorescence is more than 100 ?m from the center of the FAZ, and if blood or blocked fluorescence is present, treatment extends 100 ?m into the blocked fluorescence, but the center of the FAZ is not treated. |
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If hyperfluorescence is within 200 ?m and if no blocked fluorescence is present, laser treatment should cover the hyperfluorescence, and treatment does not need to extend 100 ?m past the edge. |
RECURRENT CNVM IN OHS FOLLOWING LASER PHOTOCOAGULATION
DEFINITION
After laser photocoagulation, interpretation of the posttreatment angiogram can be one of the most challenging facets in the treatment of macular disease.[84] A persistent CNVM shows hyperfluorescence (representing choroidal neovascularization) within 6 weeks of treatment. A recurrent CNVM is defined as leakage adjacent to or within the laser scar occurring more than 6 weeks after treatment.
INCIDENCE
The MPS reviewed the incidence of recurrent CNVMs.[85,86] In the OHS-juxtafoveal segment of the study, 31% of the treated eyes had recurrent CNVMs, and 65% of these recurrences were amenable to further treatment. The remainder were not retreatable because of subfoveal extension of the CNVM. This compares with 59% of treated eyes with age-related macular degeneration and 33% of eyes with idiopathic CNVM.
Recurrence after surgical removal of CNVM in OHS has been reported between 38 to 44%.[87,88] Two-thirds of recurrences were subfoveal and were either observed or surgically removed. The remaining third was amenable to laser photocoagulation (i.e., extrafoveal or juxtafoveal) and did much better than those observed or surgically removed.
TIME COURSE
Most recurrences were noted within 12 months after treatment, with the majority occurring within the first 6 months.
CAUSE
Several factors may contribute to the recurrence of CNVMs after treatment: inadequate coverage or intensity of treatment, the presence of blood or pigment within 200 ?m of the center of the FAZ, and location of the CNVM less than 200 ?m from the center. Further, the growth of an independent CNVM may occur during the posttreatment follow-up period. This is believed to be unrelated to treatment. Several risk factors have been statistically associated with recurrences, including hypertension, cigarette smoking, proximity to fovea, young age, and female gender.
In relation to the original CNVM, recurrences can occur on the margin of the treatment, in the center of the treatment scar, contiguous to the scar, from a feeder vessel originating from the original CNVM, or as a completely new lesion greater than 250 ?m from the margin of the laser scar (Fig. 153.15). Ninety percent of marginal recurrences are on the foveal side of the treatment, indicating that recurrences are largely responsible for visual loss from OHS after laser treatment.
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FIGURE 153.15 Schematic examples of locations of recurrent CNVMs. |
TREATMENT OF SUBFOVEAL CNVM
Laser photocoagulation of subfoveal CNVMs has been shown to be of no benefit in a pilot study.[54] Therefore, subfoveal laser treatment of CNVMs is contraindicated.
MANAGEMENT OF SUBFOVEAL CNVM
Subfoveal CNVM has active leakage under the center of the FAZ. Natural history studies suggest that only 14-16% of these patients recover visual acuity of 20/40 spontaneously without treatment.[17,50,53]Laser photocoagulation is contraindicated. Fortunately, there has been a rapid advance in recent years of new, alternative treatments for subfoveal CNVM.
SURGICAL REMOVAL OF CNVM
Between 1992 and 1997, there were numerous reports on surgical removal of subfoveal CNVM in OHS.[62,52,89-101] Various series reported initial visual improvement or stabilization of visual acuity in 37-83% of the cases (Fig. 153.16).[90,92,93,98,100,101] Thomas and co-workers[93] reported visual acuity of 20/40 or better in 31% of the cases at 10.5 months follow-up. Macular function after removal of CNVM depends on functional photoreceptors, RPE, and choriocapillaris. Akduman and associates[92] showed that visual improvement correlated with perfusion of subfoveal choriocapillaris after submacular surgery in OHS. Seventy-one percent of the eyes with perfused subfoveal choriocapillaris had visual improvement postoperatively versus only 14% of those not perfused. These initially encouraging case series led to the submacular surgery trial (SST) for OHS.
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FIGURE 153.16 (a and b) Preoperative color photograph and fluorescein angiogram of a patient with subfoveal CNVM secondary to OHS. Preoperative vision is 20/60. (c and d) Postoperative color photograph and fluorescein angiogram of the same patient. Postoperative vision is 20/40. |
THE SUBMACULAR SURGERY TRIALS (GROUP H)
The SSTs were a group of randomized prospective clinical trials funded by the National Institutes of Health whose purpose was to determine if submacular surgery was beneficial for certain types of CNVM. The SST Group H was designed to compare surgical removal versus observation of subfoveal CNVM that were either idiopathic or associated with ocular histoplsmosis.[102] Eligible patients had new or recurrent subfoveal CNVM and visual acuity of 20/50 to 20/800 in the study eye. A successful outcome was defined as a 24 month visual acuity better or no more than one line (seven letters) worse than at baseline.[102]
Of the 225 patients enrolled, 113 were assigned to observation and 112 to surgery. Forty-six percent of the eyes in the observation arm and 55% in the surgery arm had a successful outcome (success ratio 1.18; 95% confidence interval 0.89-1.56). Median visual acuity at the 24 month examination was 20/250 for eyes in the observation arm and 20/160 for eyes in the surgery arm. In a subgroup of eyes with initial visual acuity worse than 20/100, surgery was more successful; 76% of 41 eyes in the surgery arm versus 50% of 40 eyes in the observed arm at the 24 month examination had a successful outcome (success ratio 1.53; 95% confidence interval 1.08-2.16)
Complications were more frequently detected in the eyes undergoing submacular surgery. Four percent of eyes in the surgery arm experienced rhegmatogenous retinal detachment. Twenty-four percent of eyes developed postvitrectomy cataract, all in patient over the age of 50 years. Recurrent CNVM developed in 58% of surgically treated eyes by the 24 month follow-up exam.
The SST Goup H Study Group concluded that the small benefit of submacular surgery for CNVM due to OHS was less than the trial was designed to detect. However, they did recommend submacular surgery for the subgroup of eyes with visual acuity worse than 20/100. Other factors to consider when contemplating submacular surgery include the small risk of retinal detachment, probably cataract among older patients, and the need for additional treatment if recurrent CNVM were to occur.
The SST Group H also examined the health-related quality-of-life outcomes among patients who were randomized to observation or surgical removal of the CNVM.[103] Trained interviewers who were masked to treatment assignment administered three questionnaires by telephone at baseline and 6, 12, and 24 months: The National Eye Insitute Visual Function Questionanaire (NEI-VFQ), the 36-Item Short-Form Health Survey (SF-36), and the Hospital Anxiety and Depression Scale (HADS). Vision-targeted quality of life improved more after submacular surgery than with observation, supporting a possible small overall benefit of surgery.
Submacular surgery techniques have been successfully used to treat nonsubfoveal CNVM due to OHS. Atebara and colleagues[104] studied results of surgical removal of large non-age-related macular degeneration peripapillary CNVM, most of which (17/19) were due to OHS. Seventy-nine percent of those were also subfoveal. These authors reported improvement of preoperative median visual acuity of 20/200 to 20/40 at 7 months follow-up. Submacular surgery has also been employed to remove subfoveal hemorrhage that may occur on rare occasions from CNVM in OHS.[62]
The era of submacular surgery allowed for histopathologic analysis of the CNVM associated with OHS and increased our understanding of the pathogenesis of non-AMD choroidal neovascularization. The excised CNVM consists of similar cellular and extracellular components, namely RPE cells, vascular endothelium, erythrocytes, chronic inflammatory cells, cells resembling fibroblasts, collagen fibrils, fibrin, and fragments of Bruch's membrane, as in CNVMs secondary to other disorders, with the exception of basal laminar drusen seen only in age-related macular degeneration.[95,100] However, clinical correlation with the histopathology in the OHS suggests that the new vessels from the choriocapillaris grow through a focal abnormality in Bruch's membrane and RPE into the subsensory retinal space, unlike age-related macular degeneration in which a diffuse abnormality of RPE is present and the CNVM grows under the RPE.[52] RPE is engulfed by the CNVM in age-related macular degeneration, whereas it partially engulfs and delineates the CNVM in OHS. Therefore, a focal rather than a diffuse abnormality of RPE in OHS may help explain better surgical results in OHS than other disorders associated with CNVM formation.
PHOTODYNAMIC THERAPY FOR SUBFOVEAL CNVM DUE TO OHS
In March 2000, Sickenberg, Schmidt-Erfurth, and Miller published a nonrandomized, multicenter, open-label, dose-escalation Phase I and II clinical trial of single or multiple sessions of photodynamic therapy (PDT) with verteporfin for CNVM due to causes other than AMD.[105] For the 13 patients in the study, underlying etiologies included pathologic myopia, ocular histoplasmosis, angioid streaks, and idiopathic causes. The authors concluded that PDT with verteporfin was well tolerated in non-AMD eyes, and treatment could successfully result in cessation of leakage with one or more sessions. However, a larger, Phase III randomized, prospective, controlled clinical trial on the use of photodynamic therapy for CNVM due to ocular histoplasmosis was never done.
In September 2004, Rosenfeld and colleagues published the 2 year results of a prospective open-label three-center, uncontrolled clinical study of PDT with verteporfin in patients with CNVM due to ocular histoplasmosis.[106] Twenty-six patients with baseline visual acuity between 20/40 and 20/200 were studied. At 24 months, 22 patients were available for examination. Median visual improvement from baseline in visual acuity was 6 letters. Ten patients (45%) gained 7 or more letters of visual acuity while four (18%) patients lost 8 or more letters, including two patients (9%) who lost at least 15 letters. There was no leakage on the fluorescein angiogram in 85% of the evaluable lesions. No serious ocular events were noted.
The results of the above prospective study corroborated an earlier retrospective review published by Busquets et al in June 2003.[107] Thirty-eight patients with CNVM due to OHS that were treated with PDT using verteporfin were studied. On average, OHS patients who received treatment developed 0.88 line of visual improvement. Visual acuity improved or stayed the same in 69% of eyes, improved by at least two lines in 44%, and improved by more than four lines in 22%. This retrospective series had variable follow-up and included some eyes (38%) that had undergone prior submacular surgery. Nevertheless, the authors concluded that PDT with verteporfin may be beneficial in patients with CNV secondary to OHS.
Colleagues at the same institution then reported the use of PDT with verteporfin for juxtafoveal CNVM due to OHS.[108] Twenty-three eyes were retrospectively studied. With variable follow-up, vision improved by more than 3 Snellen lines in 30%, remained within 2 lines of baseline in 52%, and worsened by 3 lines or more in 18%. Other smaller retrospective case series on PDT with Verteporfin for subfoveal and juxtafoveal CNVM due to OHS suggested similar outcomes.[109,110] In summary, PDT with verteporfin for CNVM due to OHS is a safe and moderately beneficial treatment option.
While PDT combined with intravitreal triamcinolone injection has been suggested to be more beneficial than PDT alone for CNVM due to AMD, there are no published reports in the peer-reviewed literature of this treatment modality for CNVM due to OHS.
INTRAOCULAR CORTICOSTEROIDS FOR CNVM DUE TO OHS
Corticosteroids have some inherent properties which may be considered antiangiogenic. Thus, several investigators have looked at the effect of the intraocular use of corticosteroids for treating CNVM due to OHS. In October 2003, Rechtman and colleagues retrospectively reported their experience with intravitreal triamcinolone acetonide injections for subfoveal and juxtafoveal CNVM.[111] Ten eyes (five subfoveal and five juxtafoveal) with a mean follow-up of 17 months were treated with one or more injections. Thirty percent of eyes gained at least 5 letters, 20% lost 5-14 letters, and 50% maintained stable visual acuity. Interestingly, reported side effects included transient intraocular pressure elevation and mild cataract development, well known complications of intravitreal corticosteroids.
Holekamp and colleagues reported on the use of long-term intraocular delivery of fluocinolone acetonide in treating 14 eyes with non-AMD CNVM.[112] Seven eyes had ocular histoplasmosis. Average follow-up was 33 months. Ten of 14 eyes demonstrated involution of CNVM or inhibition of recurrent CNVM. Ten eyes had stable or improved visual acuity. Median initial visual acuity was 20/64. Median final visual acuity was 20/40. However, all eyes developed elevated intraocular pressure and cataract. Complications required the removal of the drug delivery implant in eight eyes.
Thus, it appears that intraocular corticosteroids potentially offer stabilization and perhaps some improvement in eyes with CNVM and OHS, but the complications of cataract and glaucoma limit the desirability of this treatment.
ANTI-VEGF THERAPY AND CNVM DUE TO OHS
At the time of this writing, there are no published reports of anti-VEGF therapy for CNVM due to ocular histoplasmosis. The authors of this chapter have anecdotal experience with pegaptanib and bevacizumab, and believe that this form of therapy (along with ranibizumab) will likely prove beneficial for this disease. The following case history will serve as an example:
Case #1. A 23-year-old white male presented with blurred vision and distortion of 1 week duration in the left eye. He was known to carry the diagnosis of ocular histoplasmosis. In fact, one year ago, he presented with identical symptoms and was felt to have choroiditis of a juxtafoveal macular histo spot. A short course of oral steroids showed no benefit. He refused thermal laser and subsequently underwent photodynamic therapy with verteporfin. The symptoms resolved completely within 2 weeks.
At this recurrence one year later, visual acuity was 20/25. Again, there was hyperfluorescence of the juxtafoveal macular histo spot (Fig. 153.17). PDT with verteporfin was performed with no improvement. In order to mimic the successful result obtained one year earlier, oral corticosteroids were started and PDT with verteporfin was performed a second time. Because of worsening symptoms and increased fluorecsein angiographic leakage, an intravitreal injection of pegaptanib was given. One week later there was continued worsening of vision and angiographic leakage. Intravitreal bevacizumab was given. There was immediate and complete resolution of symptoms with 6 months follow-up (Fig. 153.18).
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FIGURE 153.17 (a) A 23-year-old patient with ocular histoplasmosis presented with a juxtafoveal CNVM causing metamorphopsia and visual acuity of 20/25. (b) There is late hyperfluorescence on the fluorescein angiogram. |
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FIGURE 153.18 (a) The patient refused thermal laser and failed photodynamic therapy and pegaptanib injection. After one injection of bevacizumab there was complete resolution of symptoms, improvement of vision to 20/15, and inactivity of the CNVM for 6 months. (b) The fluorescein angiogram shows staining of the inactive CNVM, but no leakage. |
CONCLUSION
OHS is a relatively common disease in the endemic areas of the Ohio and Mississippi river valleys. Patients with macular chorioretinal scars are at risk for the development of choroidal neovascularization that can threaten central vision. Individuals with a macular 'histo spots' or a history of CNVM should self-monitor vision regularly with an Amsler grid (Fig. 153.19).
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FIGURE 153.19 (a) An Amsler grid is used for diagnosis of CNVMs. This grid can be used at home by patients at risk for the development of new vessel membranes. (b) An artist's demonstration of metamorphopsia and relative scotoma as seen by a patient with a new CNVM. |
Laser photocoagulation is recommended for extrafoveal and juxtafoveal CNVMs secondary to OHS. Laser photocoagulation is not recommended for subfoveal CNVM in OHS. Submacular surgery appears to be of benefit in eyes with subfoveal CNVM in OHS when visual acuity is less than 20/100. PDT with verteporfin offers the possibility of stabilization and occasional improvement in some eyes, but this has not been shown definitively in a large, randomized clinical trial. Intraocular corticosteroids have a biologic effect on CNVM in OHS, but the complications of glaucoma and cataract make this form of therapy less attractive. Finally, anti-VEGF therapy has not yet been well-studied in this disease, but is a potentially promising treatment for the future.
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