This article is from March 2008 and may contain outdated material.
Classically described as endemic to a geographic belt in the central United States that includes the Ohio River Valley and the Mississippi River Valley, Histoplasma capsulatum, a dimorphic mold, can affect the eye in multiple ways. Ocular histoplasmosis syndrome (OHS) refers to a spectrum of disease extending from granulomatous fundus lesions to the development of choroidal neovascularization (CNV) and resultant disciform scarring. CNV resulting from OHS can cause severe vision loss in a relatively young demographic—usually during the third or fourth decade of life.
The route of inoculation with H. capsulatum is typically respiratory, and patients may develop characteristic chorioretinal scars during a self-limited systemic infection, which is verified after the fact by positive skin antigen testing. That said, the antigen-disease relationship is still not clearly defined, with some patients showing worsening of their ocular disease after a positive antigen test result. It has been postulated that the fraction of patients with OHS who go on to develop the macular findings associated with significant vision loss may be genetically predisposed. Certain human leukocyte antigens, such as HLA-B7 and HLA-DRw2, are more common in patients with peripapillary CNV or submacular hemorrhage.1
OHS is a clinical diagnosis with a classic triad of punched-out peripheral choroidal scars, peripapillary pigmented degeneration, and macular CNV or disciform scarring. The differential diagnosis includes multifocal choroiditis, sarcoidosis, cryptococcosis, tuberculosis, coccidioidomycosis, pathologic myopia, punctate inner choroidopathy and age-related macular degeneration. The absence of vitritis in OHS helps to distinguish it from other mycotic etiologies. Age, absence of drusen and history differentiate it from macular degeneration. Refraction, absence of peripapillary scleral show and absence of lacquer cracks distinguish it from pathologic myopia. Peripapillary pigmentation and/or atrophy is often found in individuals without any visual complaints. The chorioretinal scars seen in OHS are oval-shaped, “punched out” lesions often seen near the posterior pole. Occasionally a linear streak of pigmented lesions also is seen near the equator.1While asymptomatic characteristic chorioretinal scarring may be seen on routine examination, presentation with subretinal hemorrhage, retinal pigment epithelium detachment, subretinal fluid or disciform scarring may confirm a more debilitating form of ocular histoplasmosis. The presence and location of active CNV can be confirmed with a combination of optical coherence tomography and fluorescein angiography that reveals signs of early leakage, as well as by evaluation by a retina specialist.
Characteristics of Ocular Histoplasmosis Syndrome
Resident of histoplasmosis belt of the United States
Caucasian; 20 to 50 years of age
- Multiple choroidal spots (“histo” spots)
- Peripapillary changes
- CNV or disciform scar
No vitreous inflammatory disease
HLA-B7 positivity (macular disease)
SOURCE: Nussenblatt, R. B. “Ocular Histoplasmosis,” in Uveitis: Fundamentals and Clinical Practice, ed. R. B. Nussenblatt and S. M. Whitcup (Philadelphia: Mosby, 2004), 235–242.
Fortunately, most patients with chorioretinal findings of OHS are asymptomatic and do not require any treatment. In those who develop associated CNV, prognosis and treatment options differ depending on the location of the membrane—peripapillary, extrafoveal, juxtafoveal or subfoveal.
Peripapillary. Peripapillary pigmented degeneration, one of the characteristic fundus findings in histoplasmosis, may be the site of new CNV. Photodynamic therapy, while having benefit for subfoveal lesions, carries the risk of optic nerve damage when used to treat peripapillary CNV. Thermal laser may be a useful option but is associated with a risk of optic nerve damage from heat transfer. Intravitreal corticosteroids have been shown to be effective with these lesions but are associated with risk of cataract and secondary glaucoma. The use of anti-VEGF drugs may be successful in treating peripapillary lesions, but such usage is not FDA-approved.
Extrafoveal. The Macular Photocoagulation Study (MPS) Group established a treatment algorithm using argon laser photocoagulation for extrafoveal membranes (greater than 200 µm from the foveal center) associated with OHS after it showed that untreated eyes had three to six times the risk of severe vision loss than treated eyes. The MPS also reported a 26 percent recurrence rate over five years in the treated membranes.2 For extrafoveal lesions, intravitreal injections of anti-VEGF drugs are another accepted option, but they carry the discomfort of repeat injections and the risk of endophthalmitis.
Juxtafoveal. For juxtafoveal lesions, where the lesion edge is less than 200 µm from the foveal center, the MPS showed that those treated with krypton laser were less likely to develop severe vision loss (?6 lines) when compared with observation alone (11 vs. 30 percent).3 Many retina specialists believe that thermal laser can be used to completely treat lesions without infringing on the foveal avascular zone; for lesions closer to the foveal avascular zone, PDT or pharmacotherapy may be preferred. Photodynamic therapy with verteporfin for juxtafoveal lesions avoids the risk of an expanding scar or scotoma associated with thermal laser and has been shown to result in visual improvement in 30 percent of eyes and stabilization in 52 percent of eyes.4 Intravitreal injection of corticosteroid or anti-VEGF medications are additional options, with many patients opting for bevacizumab.
Subfoveal. With its potential to cause greater vision loss, laser treatment is avoided for subfoveal lesions. Physical excision of these membranes did not show a statistically significant improvement in visual outcome in the Submacular Surgery Trial.5 As such, more favorable options for subfoveal lesions caused by OHS that have been used include photodynamic therapy and intravitreal corticosteroid injections. Intravitreal bevacizumab, pegaptanib and ranibizumab are newer options that are currently being used.
It is important to recognize that these drugs, when applied to histoplasmosis, are often not covered under insurance plans. While it is not yet clear whether the benefits of ranibizumab therapy for neovascular AMD as described in the clinical trials extend to other causes of CNV, multiple investigators at the 2007 ARVO annual meeting reported benefits of ranibizumab or bevacizumab injections for OHS.
Watch for endophthalmitis. It is reassuring that most cases of OHS occur in healthy asymptomatic individuals who require only continued monitoring and use of an Amsler grid for signs of CNV. However, it is important to remember that H. capsulatum can also cause an endogenous endophthalmitis. This is more often noted to occur in immunocompromised patients, particularly those with HIV infection.6 Posterior segment findings include multiple, white, creamy foci and a retinochoroiditis. Diagnosis is made based on the presence of active pulmonary or disseminated histoplasmosis and positive cultures from sputum, the anterior chamber or the vitreous cavity. The treatment options for these patients include either systemic liposomal amphotericin B or itraconazole.6
Histoplasmosis, while usually benign, can cause severe vision loss in patients of any age and can demonstrate an aggressive course in the immunocompromised population. The exact mechanism and/or role of H. capsulatum in stimulating an immunologic response and resultant chorioretinal scarring remains unclear at this time.
1 Hawkins, B. S. et al. “Ocular Histoplasmosis,” in Retina, ed. S. J. Ryan et al. (Philadelphia: Mosby, 2006), 1749–1762.
2 Hawkins, B. S. et al. Arch Ophthalmol 1991;109(8):1109–1114.
3 Schachat, A. P. et al. Arch Ophthalmol 1994;112(4):500–509.
4 Shah, G. K. et al. Retina 2005;25(1):26–32.
5 Hawkins, B. S. et al. Arch Ophthalmol 2004;122(11):1616–1628.
6 Moorthy, R. “Histoplasmosis,” in Ophthalmology, ed. M. Yanoff et al. (St. Louis: Mosby, 2004), xxii and 1652.
Dr. Iyengar is a third-year ophthalmology resident at the University of Kansas, and Dr. Dyer is an associate clinical professor of ophthalmology there as well as a retina specialist at Retina Associates in Kansas City, Kan. Neither has related financial interests.