Presumed Ocular Histoplasmosis Syndrome

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Background

Presumed ocular histoplasmosis syndrome (POHS) is a distinct clinical entity that is characterized by peripheral atrophic chorioretinal scars, peripapillary scarring, and maculopathy.[1] This condition is believed to be secondary to exposure to Histoplasma capsulatum, although this fungus rarely has been isolated or cultured from an eye with the typically associated clinical findings.

Epidemiologic findings link the fungus to this condition. Based on skin tests in the United States, a similar geographic distribution of the fungal infection and POHS exists. Histoplasmin skin testing may exacerbate the ocular condition. Visual loss in POHS is secondary to the development of macular choroidal neovascularization (CNV).

Pathophysiology

H capsulatum is a dimorphic pathogenic fungus that often grows in soil around old chicken houses and areas harboring bats, such as caves. Large numbers of spores are dispersed into the air when contaminated soil is disturbed (eg, spelunking, raking). Exposure occurs when spores are inhaled.

In a normal host, the initial infection is usually asymptomatic or feels like influenza. In a few patients, a chronic cavitary pulmonary disease may follow. In immunocompromised patients, a progressive, life-threatening, disseminated form can occur. Following initial infection, hematogenous spread to the rest of the body, including the eye, can occur. A focal granulomatous choroiditis is thought to occur. This phase seldom is observed in humans.

In an experimental nonhuman primate model, inoculation of the organism via the carotid artery results in an active choroiditis. These foci are observed as discrete, round, yellowish choroidal lesions. Six weeks following inoculation of the organisms, isolating the organisms by any histologic techniques was not possible. The inflammatory response probably destroyed the invading organisms. With time, the lesions resolve, leaving the typical "punched-out" atrophic scars that disrupt the Bruch membrane (see Physical). Reexposure to the histoplasmin antigen may account for the enlargement of old scars and the emergence of new scars.

Visual loss in POHS is secondary to the development of CNV. Pigment epithelium derived factor (PEDF) was found to have an inhibitory effect on ocular neovascularization. Another peptide, vascular endothelium growth factor (VEGF), is a well-known ocular angiogenic factor. The balance between antiangiogenic factors (eg, PEDF) and angiogenic factors (eg, VEGF) may determine the growth of CNV. This CNV usually grows in the subretinal space in a sheetlike fashion, not in the sub–retinal pigment epithelium (RPE) space. As the CNV grows, reactive hyperplastic RPE tries to surround and envelop the CNV. If successful, the CNV usually involutes.

Why CNV arises is unclear. Based on a case of a pregnant woman who developed a macular detachment during the third trimester, some propose that a type of vascular decompensation caused the CNV.[2] A lymphocytic choroidal infiltrate usually is found near histo spots. Some hypothesize that an allergic reaction to Histoplasma antigens is an important stimulus for CNV growth. A few propose that the infectious granuloma secondary to the fungus is responsible for CNV growth. Others state that damage to the Bruch membrane by itself is a strong stimulus for CNV.

Epidemiology

Frequency

United States

Presumed ocular histoplasmosis syndrome occurs in endemic areas of the United States, including the Ohio and Mississippi River Valleys (Indiana, Ohio, Illinois, Kentucky, Tennessee, and Mississippi) and parts of the mid-Atlantic region (Maryland, West Virginia, and Virginia). Approximately, 200,000-500,000 new infections occur annually.[3]

In an endemic area, 90% of patients with POHS had a positive histoplasmin skin test. In Maryland, 4% of those infected with histoplasmosis had POHS.[4, 5, 6]

Peripheral atrophic scars were present in 2% of people living in endemic areas; disciform scars were found in 0.1% of people.[7]

A clinical entity indistinguishable from POHS has been reported in a series of 10 patients from a nonendemic area, the Pacific Northwest. These patients tested negative to a lymphocyte stimulation assay with H capsulatum. Unlike series from the Midwest, all patients were female; 50% of them were myopic. The authors speculate that an atypical mycobacteria might be responsible for this entity.[8]

International

H capsulatum is endemic in the Caribbean, Central America, and South America. No reports of POHS from these areas have appeared in the literature. However, certain areas of India are endemic for systemic histoplasmosis.[9] Three cases of POHS were recently described in India.[10]

Patients with clinical findings indistinguishable from POHS have been reported in areas where H capsulatum is not found. These reports suggest that other agents can cause similar fundus findings as POHS. In the Netherlands and the United Kingdom, a clinical syndrome indistinguishable from POHS has been described. In the Dutch series by Suttorp-Schulten et al, a large number of female and myopic patients were reported.[11] Given that H capsulatum is not found in Europe, some European colleagues have proposed to change the name from POHS to multifocal choroidopathy. Other cases from Brazil have also been described.[12]

Mortality/Morbidity

Race

Sex

Age

History

Physical

Causes

The cause of presumed ocular histoplasmosis syndrome is H capsulatum.

Smoking

A retrospective case control study has recently identified smoking as an important risk factor (odds ratio, 2.83) for the development of CNV secondary to POHS.[14]

Laboratory Studies

Imaging Studies

Other Tests

Histologic Findings

Few cases report H capsulatum isolated from the human eye. In most cases, isolation of the organism in either atrophic scars or CNV is not possible. Histologically, the peripapillary and peripheral spots are seen as areas where there is partial loss of the RPE and the photoreceptor cell layer. The Bruch membrane often presents with focal breaks in it. Sometimes, the overlying inner retina shows cystic degeneration. These areas often are surrounded by a lymphocytic choroidal infiltrate.

In the macular area, most CNV develops adjacent to an atrophic histo spot, although de novo neovascularization can occur. The new capillaries and fibroblasts originate from the choroid and grow through a defect in the Bruch membrane into the subretinal space, not the sub-RPE space (type 2 CNV). Reactive hyperplastic RPE is present at the advancing edge of CNV.

Specimens obtained during surgical excision of CNV reveal that the most common cellular components are vascular endothelium and RPE; they were present in more than 85% of samples. Fibrocytes and macrophages have been identified in more than 50% of specimens. Extracellular components include collagen and fibrin.

Medical Care

Surgical Care

Consultations

Medication Summary

Antifungals, such as amphotericin B, are not helpful. Steroids anecdotally have been used in subfoveal CNV by a few observers.

Prednisone (Deltasone, Orasone)

Clinical Context:  May decrease inflammation by reversing increased capillary permeability and suppressing PMN activity.

Triamcinolone (Kenalog)

Clinical Context:  Off-label use of triamcinolone.

Class Summary

Anecdotal, controversial evidence suggests efficacy in treating subfoveal CNV.

Verteporfin (Visudyne)

Clinical Context:  A benzoporphyrin derivative monoacid (BPD-MA), consists of equally active isomers BPD-MAC and BPD-MAD, which can be activated by low-intensity, nonthermal light of 689-nm wavelength. After activation with light and in presence of oxygen, verteporfin forms cytotoxic oxygen free radicals and singlet oxygen. Singlet oxygen causes damage to biological structures within range of diffusion. This leads to local vascular occlusion, cell damage, and cell death. In plasma, verteporfin is transported primarily by low-density lipoproteins (LDL). Tumor and neovascular endothelial cells have increased specificity and uptake of verteporfin because of their high expression of LDL receptors. Effect can be enhanced by use of liposomal formulation.

Class Summary

Reduction of leakage from abnormal, neovascular vessels, resulting in reduced visual loss.

Pegaptanib (Macugen)

Clinical Context:  Selective vascular endothelial growth factor (VEGF) antagonist that promotes vision stability and reduces visual-acuity loss and progression to legal blindness. VEGF causes angiogenesis and increases vascular permeability and inflammation.

Ranibizumab (Lucentis)

Clinical Context:  Recombinant humanized IgG1-kappa isotype monoclonal antibody fragment designed for intraocular use. Indicated for neovascular (wet) age-related macular degeneration (ARMD). In clinical trials, about one third of patients had improved vision at 12 mo that was maintained by monthly injections. Binds to VEGF-A, including biologically active, cleaved form (ie, (VEGF110). VEGF-A has been shown to cause neovascularization and leakage in ocular angiogenesis models and is thought to contribute to ARMD disease progression. Binding VEGF-A prevents interaction with its receptors (ie, VEGFR1, VEGFR2) on surface of endothelial cells, thereby reducing endothelial cell proliferation, vascular leakage, and new blood vessel formation.

Bevacizumab (Avastin)

Clinical Context:  Murine derived monoclonal antibody that inhibits angiogenesis by targeting and inhibiting vascular endothelial growth factor (VEGF). VEGF causes angiogenesis and increases vascular permeability and inflammation. Nonspecific VEGF inhibitor.

Because ranibizumab ($1950/dose) and bevacizumab ($50-75/dose) have an enormous price differential, yet, as many retina physicians feel, comparable effectiveness, a great deal of interest exists in comparing the 2 medications directly. The National Eye Institute has recently funded a large randomized controlled trial to directly compare the safety and efficacy of bevacizumab and ranibizumab in the Comparison of Age-Related Macular Degeneration Treatment Trials (CATT) that is expected to begin enrollment in early 2008 and be completed by 2011.

Aflibercept (Eylea)

Clinical Context:  Fusion protein of key domains from human VEGF receptors 1 (VEGFR1) and 2 (VEGFR2) with human IgGFc designed for intraocular use. Indicated for neovascular (wet) age-related macular degeneration (ARMD) and macular edema secondary to central retinal vein occlusion. Binds to VEGF-A, including biologically active, cleaved form (ie, (VEGF110) and placental growth factor. VEGF-A has been shown to cause neovascularization and leakage in ocular angiogenesis models and is thought to contribute to ARMD disease progression. Binding VEGF-A prevents interaction with its receptors (ie, VEGFR1, VEGFR2) on surface of endothelial cells, thereby reducing endothelial cell proliferation, vascular leakage, and new blood vessel formation.

Class Summary

These agents are used to neutralize VEGF expression in ocular angiogenesis.

Further Outpatient Care

Complications

Prognosis

Author

Lihteh Wu, MD, Consulting Surgeon, Department of Ophthalmology, Vitreo-Retinal Section, Instituto De Cirugia Ocular, Costa Rica

Disclosure: Heidelberg Engineering Honoraria Speaking and teaching; Bayer Health Honoraria Speaking and teaching; Alcon Labs Honoraria Speaking and teaching

Specialty Editors

Russell P Jayne, MD, Consulting Vitreoretinal Surgeon, The Retina Center at Las Vegas

Disclosure: Nothing to disclose.

Simon K Law, MD, PharmD, Clinical Professor of Health Sciences, Department of Ophthalmology, Jules Stein Eye Institute, University of California, Los Angeles, David Geffen School of Medicine

Disclosure: Nothing to disclose.

Steve Charles, MD, Director of Charles Retina Institute; Clinical Professor, Department of Ophthalmology, University of Tennessee College of Medicine; Adjunct Professor of Ophthalmology, Columbia College of Physicians and Surgeons; Clinical Professor Ophthalmology, Chinese University of Hong Kong

Disclosure: Alcon Laboratories Consulting fee Consulting

Lance L Brown, OD, MD, Ophthalmologist, Affiliated With Freeman Hospital and St John's Hospital, Regional Eye Center, Joplin, Missouri

Disclosure: Nothing to disclose.

Chief Editor

Hampton Roy Sr, MD, Associate Clinical Professor, Department of Ophthalmology, University of Arkansas for Medical Sciences

Disclosure: Nothing to disclose.

Additional Contributors

Teodoro Evans, MD Consulting Surgeon, Vitreo-Retinal Section, Clinica de Ojos, Costa Rica

Disclosure: Nothing to disclose.

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