Part 4 • Infectious Uveitic Conditions

Chapter 15 Ocular Histoplasmosis

such as natural killer cell activity and helper/suppressor cell ratios, were different between these groups.

With use of HLA typing, a potential immunogenetic predisposition to the development of the macular lesions appears to have been identified. Godfrey and coworkers42 and Braley and colleagues43 found an association between HLA-B7 and the macular lesions of this syndrome, giving a calculated relative risk of 11.8. This association has not been noted with those patients manifesting only peripheral retinal lesions. Spaide and colleagues44 found an absence of HLA-DR2 in 17 patients with multifocal choroiditis and panuveitis, whereas this antigen was found in 17 patients with subretinal neovascularization associated with the ocular histoplasmosis syndrome. The authors believed these data suggested that despite the ocular fundus similarities of these two entities, the disorders appear to have differing genetic dispositions. Ongkosuwito and colleagues,45 analyzing DR sequencing, have suggested that isoleucine at amino acid 67 was most strongly associated with the ocular histoplasmosis syndrome.

Many questions remain concerning the underlying mechanism of this entity. Many years ago, Richard O’Connor, who at that time was at the University of California, San Francisco, studied patients in whom typical lesions of ocular histoplasmosis developed several decades after they left an endemic area. Several explanations for this can be given. It may be that genetically prone persons are unable to clear the organism and that they continuously ‘shed’ antigen from a site, such as the spleen. Once the organism has lodged in the eye, the low-grade inflammatory response in the choroid occurs again. Another possibility is that molecular mimicry may be the reason for repeated attacks (see Chapter 1). A third possibility is that in genetically prone persons the fungal antigen acts as an adjuvant to induce an inflammatory response wherever it lodges, for example in the choroid (Fig. 15-4). Ongkosuwito and colleagues46 studied 23 patients in The Netherlands with peripapillary atrophy, punched-out retinal lesions, and macular disciform scars but no cells in the vitreous. None had antibodies to H. capsulatum, nor could any other risk factors be identified.

The subretinal membranes resulting from the ocular histoplasmosis syndrome have been studied. In one study reported by Grossniklaus and colleagues47 17 ocular histoplasmosis membranes were evaluated. All were fibrovas­ cular, and some showed hemorrhage. The most common cellular elements were vascular endothelium and retinal pigment epithelium. It should be added that in one report, Mann and colleagues48 reported a granulomatous inflammation. The membranes in this disorder were thinner and smaller in diameter, and photoreceptors were less likely to be found than in membranes removed from eyes with agerelated macular degeneration.47

Nonsurgical therapies

Amphotericin B has no role in the treatment of ocular histoplasmosis. Not only is it ineffective, it also exposes the patient to a medication with serious secondary effects.

Corticosteroids can be given for the acute macular lesion that causes a sudden drop in visual acuity or in preparation for laser therapy. Patients with macular lesions, particularly

Activation

Visible elevated lesion

Figure 15-4.  Scheme showing the presence of ‘invisible’ lesions in the choroid. Histoplasma antigen may be present, inducing a minimal inflammatory response, and therefore is not seen. If more antigen is released from distant site and lodges in the same area, or if Histoplasma antigen already there acts as adjuvant, more pronounced inflammatory response will occur, which now can be visualized as ‘active’ lesion.

those with one eye already visually handicapped because of the disease, may consider carrying prednisone with them and checking daily for any changes in vision or distortions that occur as noted on an Amsler grid. Short-term corticosteroid therapy should be given in high doses (60 mg daily, 50–120 mg every other day) to effect a change. The chronicity of the disorder (at least 2 years) suggests that a long-term therapeutic commitment must be made by both patient and physician. The final visual outcome when subretinal neovascular nets encroach on the foveal and juxtafoveal region is not affected by corticosteroid therapy;49 with a follow-up of 39 months on average, 81% of eyes had visual acuities worse than 6/12, and almost 70% of these were 6/60 or worse using this form of therapy.

Steroids, given locally and systemically, have been used as antiangiogenic agents. In one study, 18 patients with ocular histoplasmosis were treated with either oral prednisone for 4–6 weeks (n = 10) or a single sub-Tenon’s injection of triamcinolone (n = 8).50 Oral prednisone resulted in short-term improvement in visual acuity and stabilization of the lesion. Intraocular steroid has also been used. Rechtman and colleagues51 reported the use of intraocular triamcin­ olone injections for 10 ocular histoplasmosis patients with subfoveal or juxtafoveal choroidal neovascular lesions. They reported that three had an improvement in visual acuity, two

had a loss, and five had no change in visual acuity. This was with an average follow-up of 17 months (6–41 months). Increased intraocular pressure and ‘mild’ cataract development were noted as adverse effects. Continued intraocular injections of steroid would theoretically be necessary to effect a long-term result.

Holekamp and colleagues52 reported the use of either a 2-mg or a 6-mg fluocinolone acetonide implant in 14 eyes with choroidal neovascularization not due to AMD, seven of them being due to ocular histoplasmosis. Ten of the 14 eyes saw an involution of the CNV, but interestingly four, all of whom were receiving the 2 mg implant, had recurrence of their lesions. The authors report ‘significant’ complications with the device.

Antiangiogenic therapies, particularly the intravitreal injection of anti-VEGF agents, have provided the practitioner with a new approach to ocular neovascular lesions. Adan and colleagues53 reported a case of a juxtafoveal CNV responding well in the short term to an injection of bevaczumab. Schadlu et al.54 performed a retrospective chart review of 28 eyes in 28 patients who received intravitreal injections of bevacizumab for CNV secondary to ocular

histoplasmosis. The follow-up was a mean of 22 weeks and patients received an average of almost two injections. Twenty of the eyes followed had an improvement in central visual acuity, four eyes stayed unchanged, and four had a decrease in vision. The real question is the long-term stability of these observations or whether continued injections of an anti-VEGF agent are needed (Fig. 15-5).

Laser therapy

Maumenee35 first suggested the use of laser photocoagulation to treat the ocular histoplasmosis syndrome. The results of a randomized clinical trial evaluating the effectiveness of argon laser photocoagulation for choroidal neovascular membranes have shown this approach to be the treatment of choice until now.55 After an 18-month follow-up, 34% (39 of 114) of untreated eyes versus 9.4% (11 of 117) of treated eyes lost six lines or more of visual acuity from baseline. In 1991 the Macular Photocoagulation Study Group56 published their 5-year results of three randomized studies using argon laser photocoagulation in the treatment of extrafoveal choroidal neovascularization due to various