Ocular histoplasmosis syndrome (OHS) is a multifocal chorioretinitis presumed to be caused by infection with Histoplasma capsulatum, a dimorphic fungus with both yeast and filamentous forms early in life. The yeast form is the cause of both systemic and ocular disease; primary infection occurs after inhalation of the fungal spores into the lungs. Ocular disease is thought to arise as a consequence of hematogenous dissemination of the organism to the spleen, liver, and choroid following the initial pulmonary infection. Acquired histoplasmosis is usually asymptomatic or may result in a benign illness, typically during childhood.
OHS is most frequently found in endemic areas of the United States such as the Ohio and Mississippi River valleys, where 60% of individuals react positively to histoplasmin skin testing. However, OHS has also been reported in nonendemic areas in this country (Maryland) and sporadically throughout Europe (the United Kingdom and Netherlands). Although no serologic confirmation of histoplasmosis infection in patients with OHS has been reported, a causal relationship is strongly suggested by epidemiologic evidence linking an increased prevalence of ocular disease among patients who live or formerly resided in endemic areas. Furthermore, H capsulatum DNA has been detected in chronic choroidal lesions of a patient with OHS, and individuals with disciform scars are more likely than control subjects to react positively to histoplasmin skin testing. Men and women are affected equally, and the vast majority of patients are of northern European extraction.
The diagnosis of OHS is based on the clinical triad of multiple white, atrophic choroidal scars (so-called histo spots); peripapillary pigment changes; and a maculopathy caused by CNV in the absence of vitreous cells. Histo spots may appear in the macula or periphery, are discrete and punched out (arising from a variable degree of scarring in the choroid and adjacent outer retina), and are typically asymptomatic (Fig 7-19). Approximately 1.5% of patients from endemic areas exhibit typical peripheral histo spots, first appearing during adolescence. Linear equatorial streaks can be seen in 5% of patients (Fig 7-20). In contrast, metamorphopsia and a profound reduction in central vision herald macular involvement from CNV and bring the patient to the attention of the ophthalmologist. The mean age of patients presenting with vision-threatening maculopathy is 41 years. Funduscopy of active neovascular lesions reveals a yellow-green subretinal membrane typically surrounded by a pigment ring; overlying neurosensory detachment; and subretinal hemorrhage, frequently arising at the border of a histo scar in the disc–macula area. Cicatricial changes characterize advanced disease, with subretinal fibrosis and disciform scarring of the macula.
The pathogenesis of OHS is thought to involve a focal infection of the choroid at the time of initial systemic infection. This choroiditis may subside and leave an atrophic scar and depigmentation of the RPE, or it may result in disruption of the Bruch membrane, choriocapillaris, and RPE, with subsequent proliferation of subretinal vessels originating from the choroid. Lacking tight junctions, these neovascular complexes leak fluid, lipid, and blood, resulting in loss of macular function. The initiating stimulus for the growth of new subretinal vessels is unknown; however, immune mechanisms in patients with an underlying genetic predisposition for the development of this disease have been implicated. HLA-DRw2 is twice as common among patients with histo spots alone, whereas both HLA-B7 and HLA-DRw2 are 2 to 4 times more common among patients with disciform scars caused by OHS as compared to control subjects. Similarly, HLA-DR2 was absent in a group of patients with MCP, a disease that simulates OHS in many respects, whereas the antigen was present among those with CNV due to OHS.
The differential diagnosis includes entities other than age-related macular degeneration (AMD) that are frequently associated with CNV, including angioid streaks, choroidal rupture, idiopathic CNV, MCP, punctate inner choroidopathy, and granulomatous fundus lesions that may mimic the scarring seen in OHS (as in toxoplasmosis, tuberculosis, coccidioidomycosis, syphilis, sarcoidosis, and toxocariasis). The atrophic spots and maculopathy of myopic degeneration and disciform scarring in AMD may also be confused with OHS.
Over time, new choroidal scars develop in more than 20% of patients; however, only 3.8% of these progress to CNV. If histo spots appear in the macular area, the patient has a 25% chance of developing maculopathy within 3 years; if no spots are observed, the chances fall to 2%. The risk of developing CNV in the contralateral eye is high, ranging from 8% to 24% over a 3-year period. Massive subretinal exudation and hemorrhagic retinal detachments may occur and result in permanent loss of macular function. Although some cases of spontaneous resolution with a return to normal vision have been reported, the visual prognosis of untreated OHS-associated CNV is poor, with 75% of eyes reaching a final visual acuity of 20/100 or worse over a 3-year period.
The early, acute granulomatous lesions of OHS are rarely observed but may be treated with oral or regional (periocular) corticosteroids (Fig 7-21). In the early stages of FA, foci of active choroiditis block the dye and appear hypofluorescent; later in the study, these lesions stain, becoming hyperfluorescent. In contrast, areas of active CNV appear hyperfluorescent early in the angiogram and leak later in the study. Choroidal neovascular membranes may arise outside the vascular arcades, but typically do not reduce vision and may be safely managed with observation only. Treatment options for vision-threatening juxtafoveal or subfoveal CNV include thermal laser photocoagulation (Fig 7-22), photodynamic therapy (PDT) using verteporfin with or without intravitreal triamcinolone, submacular surgery for membrane removal, and intravitreal injection of anti–vascular endothelial growth factor (anti-VEGF) agents.
The Macular Photocoagulation Study (MPS) group conducted 2 multicenter, randomized, controlled clinical trials that showed a beneficial effect of argon blue-green and krypton red laser photocoagulation for well-defined, classic extrafoveal, juxtafoveal, and peripapillary CNV secondary to OHS (see Fig 7-22). (See BCSC 12, Retina and Vitreous, Chapter 4.) The proportion of eyes experiencing severe visual loss was significantly reduced with photocoagulation. Disease progression was seen in 12% of treated individuals compared with 42% of control patients. A high rate of persistent or recurrent CNV was observed following photocoagulation, in 26% of extrafoveal and in 33% of juxtafoveal lesions. Thermal laser photocoagulation is not used in the treatment of subfoveal CNV in the context of OHS, given the profound and immediate loss of central vision that results from the destructive effects of this modality.
PDT with verteporfin has been advocated for the treatment of subfoveal OHS-associated CNV based on small, prospective, uncontrolled case series. The Verteporfin in Ocular Histoplasmosis study reported that after 2 years, 45% of patients experienced moderate visual gain and 82% avoided visual loss, with an increase in the median contrast sensitivity score of 3.5 letters. There were no serious adverse events. Moreover, at 48 months, 60% of patients gained ≥7 letters from baseline while only 7% lost >15 letters.
Similarly, intravitreal triamcinolone was shown to be relatively safe and effective in the management of OHS-associated juxtafoveal and subfoveal CNV in small retrospective case studies.
A number of anti-VEGF agents currently being used in the management of neovascular AMD are available for the off-label treatment of OHS-associated CNV. These include the ribonucleic acid aptamer pegaptanib; ranibizumab, the active fragment of a humanized anti-VEGF monoclonal antibody; and the related full-length molecule, bevacizumab. Intravitreal anti-VEGF therapy has been shown to be superior to PDT in patients with neovascular AMD in visual acuity outcome, but no such randomized, prospective study comparing these modalities has been conducted in OHS-associated CNV. A recent retrospective study of 24 eyes with OHS-associated CNV treated with intravitreal bevacizumab monotherapy demonstrated that at least 50% of eyes with subfoveal or juxtafoveal CNV experienced ≥3 lines of visual gain and up to 100% patients had improved or stable visual acuity after 3–12 months of follow-up. Final visual acuity was 20/40 or better in 58% of eyes, compared with 21% at baseline. As with neovascular AMD, combination approaches with PDT and intravitreal corticosteroids or anti-VEGF agents may prove fruitful, especially in treating entities with an underlying inflammatory etiology.
Selected patients with an active subretinal neovascular membrane located under the foveal avascular zone may benefit from submacular surgery and removal of the membrane (Fig 7-23). However, although short-term visual outcomes were initially encouraging, longer follow-up and the subsequent publication of the Submacular Surgery Trials (SST) Group H results showing CNV recurrence rates approaching 50% within the first 12 months have muted the enthusiasm for this approach. While the study indicated that surgery may be of benefit for patients with a visual acuity worse than 20/100, a clear recommendation for surgery even for this subgroup may be overshadowed by the not-infrequent occurrence of complications, including intraoperative retinal breaks (12.5% peripheral and 2% posterior pole), cataract (39%), and retinal detachment (4.5%). In selected cases of extensive peripapillary CNV associated with OHS, surgical removal may provide a more definitive visual benefit with low recurrence rates and be preferable to photoablation, given the likelihood of multiple PDT and anti-VEGF treatments. Thermal laser photocoagulation, PDT, anti-VEGF agents, intravitreal corticosteroids, and submacular surgery for the treatment of CNV are discussed in greater detail in BCSC Section 12, Retina and Vitreous.
For a discussion of the ocular manifestations of candidiasis, aspergillosis, cryptococcosis, and coccidioidomycosis and their treatments, please see Chapter 8.
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