Presumed ocular histoplasmosis syndrome (POHS) is a distinct clinical entity that is characterized by peripheral atrophic chorioretinal scars, peripapillary scarring, and maculopathy. 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).
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. 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.
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.
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.
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.
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. Three cases of POHS were recently described in India.
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. 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.
POHS is an uncommon cause of visual loss.
The incidence and the prevalence in the blind population in Tennessee were reported to be 2.8% and 0.5%, respectively.
Histoplasmin skin testing reveals that African Americans and Caucasians living in endemic areas are infected equally by H capsulatum. No difference is apparent between the prevalence of peripheral histo spots between these 2 groups. Caucasian patients are more likely than African Americans to develop macular CNV.
Some reports suggest an increased prevalence of POHS in patients with human leukocyte antigen B7 (HLA-B7) and human leukocyte antigen DRw2 (HLA-DRw2). Patients with HLA-DRw2 are more likely to have peripheral histo spots and disciform scarring, whereas patients with HLA-B7 are more likely to have peripheral histo spots.
No apparent gender predilection exists in the Midwest and the mid-Atlantic series according to Smith et al.
In the series from the Netherlands by Suttorp-Schulten et al and in the series from the Pacific Northwest by Watzke et al, women seemed to be affected to a greater degree.[11, 8]
Presumed ocular histoplasmosis syndrome usually affects patients aged 20-50 years; the average age is 35 years.
Both the vitreous and the anterior chamber are typically clear because of a lack of intraocular inflammation.
Punched-out chorioretinal scars (smaller in size than the optic nerve) are called histo spots. Black pigment may appear within or at the margins of these lesions. Linear streaks of atrophic scars in the mid periphery are observed in about 5% of patients with POHS.
Peripapillary chorioretinal scarring is present.
Macular CNV usually is observed as a gray-green subretinal lesion that is surrounded by subretinal blood and leads to a serous or hemorrhagic macular detachment. CNV is estimated to occur in 5% of eyes affected with POHS.
Although the diagnosis of presumed ocular histoplasmosis syndrome is clinical, certain ancillary tests help in confirming it. Other than fluorescein angiography (FA), most patients do not require ancillary testing.
HLA typing B7 and DRw2 may be indicated.
Complement fixing antibodies are only positive in 16-68% of patients with POHS.
Lymphocyte stimulation assay by Histoplasma antigens may be indicated.
Focal calcifications in the liver or the spleen may be present.
FA is essential in diagnosing and managing the maculopathy associated with POHS with photodynamic therapy or laser photocoagulation. The typical angiographic pattern is early hyperfluorescence with late leakage. According to its location relative to the center of the fovea, CNV has been classified as extrafoveal (200-1500 µm), juxtafoveal (1-199 µm), and subfoveal (under the center of the fovea).
Since the advent of anti-VEGF therapy for CNV secondary to the POHS, optical coherence tomography imaging is of paramount importance in the diagnosis and follow-up. Any signs of continued exudation, such as intraretinal or subretinal fluid, is usually an indication for continued anti-VEGF treatment.
Chest radiography findings usually reveal calcifications of the hilar areas.
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.
A few anecdotal cases of oral steroids inducing involution of recent-onset subfoveal CNV have been reported.
A small series reported on the benefits of an intravitreal injection of 4 mg of triamcinolone acetonide in eyes with subfoveal or juxtafoveal CNV secondary to POHS.
Sustained-release steroid implants have been used on a compassionate basis in refractory patients with stabilization or improvement of vision in 6 of 7 cases. However, concomitant submacular surgery was performed in 4 cases.
Antifungals are not beneficial.
Vascular endothelial growth factor (VEGF) has been shown to be a key molecular player in the pathogenesis of CNV. In the current era of anti-VEGF therapy, the extraordinary results obtained in CNV secondary to age-related macular degeneration have been extrapolated to other causes of CNV with apparent good results.[18, 19] Currently available anti-VEGF agents include bevacizumab, ranibizumab, and pegaptanib sodium.
In a small retrospective case series of 28 eyes with a relatively short follow-up of 22 weeks, intravitreal bevacizumab was shown to improve the visual acuity in 71% of eyes. In 14%, the visual acuity remained the same, and, in another 14%, the visual acuity decreased despite treatment.
A large retrospective comparative case series compared intravitreal bevacizumab (117 eyes) with combination therapy consisting of intravitreal bevacizumab and verteporfin photodynamic therapy (34 eyes). At the end of 2 years of follow up, no difference in visual outcome was noted between the treatment strategies. Approximately 30% of eyes gained at least 3 lines of best-corrected visual acuity over baseline. Subgroup analysis revealed that in juxtafoveal CNV, no difference in the burden of injections was noted between the groups. However, in the subfoveal group, there were statistically significantly fewer injections in the combination group.
The Macular Photocoagulation Study (MPS), a multicenter prospective randomized clinical trial, demonstrated that laser photocoagulation is indicated in the treatment of extrafoveal and juxtafoveal CNV secondary to POHS.
The goal of treatment is to obliterate the entire area of CNV.
Prior to laser treatment, a fluorescein angiogram that shows the exact borders of the lesion is essential.
Despite its marginal benefits, the MPS recommended laser treatment of peripapillary CNV. Alternatively, pars plana vitrectomy and excision of the peripapillary CNV may be considered. Most surgeons recommend removal of recent subfoveal CNV but not peripapillary lesions.
Pilot studies of laser photocoagulation of subfoveal CNV were inconclusive.
Photodynamic therapy (PDT): Subfoveal CNV secondary to POHS is a labeled indication for PDT by the US Food and Drug Administration. An open-label, uncontrolled clinical study reported the median improvement of visual acuity of 6 letters after a mean of 3.9 PDT treatments in a 2-year follow-up with no serious ocular or systemic effects reported.
Given that most CNV secondary to POHS grow in the subretinal space, uncontrolled studies have recommended surgical excision of subfoveal CNV via pars plana vitrectomy. The goal is to remove the CNV but to leave the underlying RPE and choriocapillaris intact.
The Submacular Surgery Trial (SST), a randomized multicenter prospective trial sponsored by the National Eye Institute (NEI), reported on the modest benefit in eyes with CNV secondary to POHS with a baseline visual acuity of 20/100 or worse.
A case series of 45 eyes with extensive peripapillary CNV that were ineligible for laser photocoagulation by the Macular Photocoagulation Study criteria underwent surgical removal. Of these 45 eyes, in 23 eyes the CNV extended subfoveally. In this subgroup, the median visual acuity improved from 20/200 to 20/50. Almost 80% (18/23) of eyes achieved stable or improved visual acuity from baseline. Only 22% (5/23) of eyes experienced a loss of more than 2 lines of visual acuity from baseline. Close to 50% (11/23) of eyes achieved a visual acuity of ≥ 20/40. In the remaining 17 eyes where CNV remained extrafoveal, 88% (15/17) of eyes had an improvement or stability in visual acuity. Only 12% (2/17) of eyes showed a loss of ≥ 2 lines of visual acuity. The median visual acuity improved from 20/60 to 20/20. This suggests that surgical extraction in selected cases of extensive peripapillary CNV secondary to POHS might be beneficial.
Macular translocation: Macular translocation surgery is another experimental surgical option to treat subfoveal CNV.
Photocoagulating atrophic scars to prevent CNV formation is not recommended.
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.
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.
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.
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.
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.
After 5 years of follow-up care, the MPS reported that 26% and 33% of patients had recurrent or persistent CNV following laser photocoagulation to an extrafoveal or juxtafoveal CNV, respectively.[21, 25]
These recurrences tended to be toward the foveal side and were associated with visual loss.
In most cases, photocoagulation of recurrent CNV is indicated.
Laser treatment of peripapillary CNV may be complicated by thermal damage to the papillomacular bundle.
Surgical excision of CNV may be complicated by retinal detachment, postvitrectomy cataract, macular pucker, and macular hole.
Recurrence of CNV following excision is observed in 58% of cases by 24 months of follow-up.
How to effectively manage these recurrences is unclear.
The average interval from the onset of symptoms between the first eye and the fellow eye was 4 years. According to the MPS, 2% per year risk of developing CNV in the fellow eye exists. The risk depends on whether the fellow eye has peripapillary scarring (4% risk) or a macular atrophic spot (20-24% risk).
The visual prognosis for patients with POHS depends on the development of CNV and its location with respect to the center of the fovea.
The MPS has shown that after 5 years of follow-up care, 12% of eyes with extrafoveal CNV that were photocoagulated had severe visual loss (loss of 6 lines or more) compared to 42% of eyes that were observed.[21, 25]
Of eyes with juxtafoveal CNV, 12% had severe visual loss compared to 28% of eyes that were observed.
In the MPS, photocoagulation of peripapillary CNV reduced severe visual loss from 26% of control eyes to 14% of treated eyes.
Pilot studies of photocoagulation of subfoveal CNV by Fine et al were inconclusive. The natural history of untreated subfoveal CNV shows that 14-23% of patients retain 20/40 or better visual acuity. Eyes with subfoveal CNV undergoing surgical excision were more likely to gain 20/40 if the preoperative vision was 20/100 or better.
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
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
Almony A, Thomas MA, Atebara NH, Holekamp NM, Del Priore LV. Long-term follow-up of surgical removal of extensive peripapillary choroidal neovascularization in presumed ocular histoplasmosis syndrome. Ophthalmology. 2008;115(3):540-545.e5.