AUTHOR AND EDITOR INFORMATION

Section 1 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

INTRODUCTION

Section 2 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

Background

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).

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. Recently, 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.

Frequency

United States

This condition 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.

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.

International

H capsulatum is endemic in the Caribbean and Central and South America. No reports of POHS from these areas have appeared in the literature.

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.²⁶ Given that H capsulatum is not found in Europe, some European colleagues have proposed to change the name from POHS to multifocal choroidopathy.

Mortality/Morbidity

• 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.

Race

• 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.

Sex

• No apparent gender predilection exists in the Midwest and the mid-Atlantic series according to Smith et al.²⁵
• 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.^{26, 27}

Age

• This condition usually affects patients aged 20-50 years; the average age is 35 years.

CLINICAL

Section 3 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

History

• Residents or visitors to endemic areas
• Prior exposure to chickens, parakeets, or pigeons
• Distorted vision
• Sudden, painless loss of central visual acuity
• Micropsia
• Positive scotoma
• Asymptomatic

Physical

• 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.

Causes

The cause of this condition is H capsulatum.

DIFFERENTIALS

Section 4 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

Other Problems to be Considered

Birdshot chorioretinopathy
Punctate inner choroidopathy
Coccidioidomycosis
Multifocal choroiditis
Idiopathic choroidal neovascular membranes

WORKUP

Section 5 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

Lab Studies

• Although the diagnosis 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.

Imaging Studies

• FA is essential in diagnosing and managing the maculopathy associated with POHS.
  
  
  • 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).
• Chest x-ray film findings usually reveal calcifications of the hilar areas.

Other Tests

• Skin testing should not be performed on patients with a maculopathy; some report that it may exacerbate this condition.

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.

TREATMENT

Section 6 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

Medical Care

• Corticosteroids
  
  
  • 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.

Surgical Care

• Laser photocoagulation
  
  
  • 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.
• Submacular surgery
  
  
  • 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), recently reported on the modest benefit in eyes with CNV secondary to POHS with a baseline visual acuity of 20/100 or worse.
• Macular translocation: Macular translocation surgery is another experimental surgical option to treat subfoveal CNV.
• Photocoagulating atrophic scars to prevent CNV formation is not recommended.

Consultations

• Refer to a vitreoretinal specialist.

MEDICATION

Section 7 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

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

Drug Category: Corticosteroids

Anecdotal, controversial evidence suggests efficacy in treating subfoveal CNV.

Drug Category: Photosensitizers for photodynamic therapy

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

FOLLOW-UP

Section 8 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

Further Outpatient Care

• Most persistent and recurrent leakage occurs during the first 18 months following laser treatment.
• Clinical examination cannot replace FA during the first 18 months following laser treatment.
• Two weeks following laser photocoagulation, monitor a patient with a repeat FA.
• • Pay special attention to the borders of the laser treatment zone to detect any persistence.
  • If no leakage is detected, repeat the FA 4 weeks later.
  • If no leakage is detected again, obtain another FA 4-6 weeks later.

Complications

• 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.
• • 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 44% of cases.
  • How to effectively manage these recurrences is unclear.

Prognosis

• 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.
• 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.⁷ 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.

Patient Education

• Once diagnosed with a maculopathy secondary to POHS, the patient is asked to self-monitor each eye with a near card and an Amsler grid.
• If a disturbance is detected, prompt examination is encouraged.

REFERENCES

Section 9 of 9

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

1. Alam S, Zawadzki RJ, Choi S, Gerth C, Park SS, Morse L, et al. Clinical application of rapid serial fourier-domain optical coherence tomography for macular imaging. Ophthalmology. Aug 2006;113(8):1425-31. Epub 2006 Jun 12. [Medline].
2. Atebara NH, Thomas MA, Holekamp NM, Mandell BA, Del Priore LV. Surgical removal of extensive peripapillary choroidal neovascularization associated with presumed ocular histoplasmosis syndrome. Ophthalmology. Sep 1998;105(9):1598-605. [Medline].
3. Baskin MA, Jampol LM, Huamonte FU, Rabb MF, Vygantas CM, Wyhinny G. Macular lesions in blacks with the presumed ocular histoplasmosis syndrome. Am J Ophthalmol. Jan 1980;89(1):77-83. [Medline].
4. Berger AS, Conway M, Del Priore LV, Walker RS, Pollack JS, Kaplan HJ. Submacular surgery for subfoveal choroidal neovascular membranes in patients with presumed ocular histoplasmosis. Arch Ophthalmol. Aug 1997;115(8):991-6. [Medline].
5. Callanan D, Fish GE, Anand R. Reactivation of inflammatory lesions in ocular histoplasmosis. Arch Ophthalmol. Apr 1998;116(4):470-4. [Medline].
6. Dawson DW, Volpert OV, Gillis P, Crawford SE, Xu H, Benedict W, et al. Pigment epithelium-derived factor: a potent inhibitor of angiogenesis. Science. Jul 9 1999;285(5425):245-8. [Medline].
7. Fine SL, Wood WJ, Isernhagen RD, Singerman LJ, Bressler NM, Folk JC, et al. Laser treatment for subfoveal neovascular membranes in ocular histoplasmosis syndrome: results of a pilot randomized clinical trial. Arch Ophthalmol. Jan 1993;111(1):19-20. [Medline].
8. Gass JD. Stereoscopic Atlas of Macular Diseases. In: Diagnosis and Treatment. 4^th ed. St Louis: Mosby Year Book Inc; 1997:130-147.
9. Godfrey WA, Sabates R, Cross DE. Association of presumed ocular histoplasmosis with HLA-B7. Am J Ophthalmol. Jun 1978;85(6):854-8. [Medline].
10. Grossniklaus HE, Green WR. Histopathologic and ultrastructural findings of surgically excised choroidal neovascularization. Submacular Surgery Trials Research Group. Arch Ophthalmol. Jun 1998;116(6):745-9. [Medline].
11. Hawkins BS, Bressler NM, Bressler SB, Davidorf FH, Hoskins JC, Marsh MJ, et al. Surgical removal vs observation for subfoveal choroidal neovascularization, either associated with the ocular histoplasmosis syndrome or idiopathic: I. Ophthalmic findings from a randomized clinical trial: Submacular Surgery Trials (SST) Group H Trial: SST Report No. 9. Arch Ophthalmol. Nov 2004;122(11):1597-611. [Medline].
12. Holekamp NM, Thomas MA, Dickinson JD, Valluri S. Surgical removal of subfoveal choroidal neovascularization in presumed ocular histoplasmosis: stability of early visual results. Ophthalmology. Jan 1997;104(1):22-6. [Medline].
13. Holekamp NM, Thomas MA, Pearson A. The safety profile of long-term, high-dose intraocular corticosteroid delivery. Am J Ophthalmol. Mar 2005;139(3):421-8. [Medline].
14. Khalil MK. Histopathology of presumed ocular histoplasmosis. Am J Ophthalmol. Sep 1982;94(3):369-76. [Medline].
15. Macular Photocoagulation Study Group. Five-year follow-up of fellow eyes of individuals with ocular histoplasmosis and unilateral extrafoveal or juxtafoveal choroidal neovascularization. Arch Ophthalmol. Jun 1996;114(6):677-88. [Medline].
16. Melberg NS, Thomas MA, Dickinson JD, Valluri S. Managing recurrent neovascularization after subfoveal surgery in presumed ocular histoplasmosis syndrome. Ophthalmology. Jul 1996;103(7):1064-7;discussion 1067-8. [Medline].
17. Oliver A, Ciulla TA, Comer GM. New and classic insights into presumed ocular histoplasmosis syndrome and its treatment. Curr Opin Ophthalmol. Jun 2005;16(3):160-5. [Medline].
18. Ongkosuwito JV, Kortbeek LM, Van der Lelij A, Molicka E, Kijlstra A, de Smet MD, et al. Aetiological study of the presumed ocular histoplasmosis syndrome in the Netherlands. Br J Ophthalmol. May 1999;83(5):535-9. [Medline].
19. Prasad AG, Van Gelder RN. Presumed ocular histoplasmosis syndrome. Curr Opin Ophthalmol. Dec 2005;16(6):364-8. [Medline].
20. Rechtman E, Allen VD, Danis RP, Pratt LM, Harris A, Speicher MA. Intravitreal triamcinolone for choroidal neovascularization in ocular histoplasmosis syndrome. Am J Ophthalmol. Oct 2003;136(4):739-41. [Medline].
21. Rosenfeld PJ, Saperstein DA, Bressler NM, Reaves TA, Sickenberg M, Rosa RH Jr, et al. Photodynamic therapy with verteporfin in ocular histoplasmosis: uncontrolled, open-label 2-year study. Ophthalmology. Sep 2004;111(9):1725-33. [Medline].
22. Rosenfeld PJ, Saperstein DA, Bressler NM, Reaves TA, Sickenberg M, Rosa RH Jr, et al. Photodynamic therapy with verteporfin in ocular histoplasmosis: uncontrolled, open-label 2-year study. Ophthalmology. Sep 2004;111(9):1725-33. [Medline].
23. Shah GK, Blinder KJ, Hariprasad SM, Thomas MA, Ryan EH Jr, Bakal J, et al. Photodynamic therapy for juxtafoveal choroidal neovascularization due to ocular histoplasmosis syndrome. Retina. Jan 2005;25(1):26-32. [Medline].
24. Smith RE, Dunn S, Jester JV. Natural history of experimental histoplasmic choroiditis in the primate. I. Clinical features. Invest Ophthalmol Vis Sci. Jul 1984;25(7):801-9. [Medline].
25. Smith RE, Ganley JP. An epidemiologic study of presumed ocular histoplasmosis. Trans Am Acad Ophthalmol Otolaryngol. Sep-Oct 1971;75(5):994-1005. [Medline].
26. Suttorp-Schulten MS, Bollemeijer JG, Bos PJ, Rothova A. Presumed ocular histoplasmosis in The Netherlands--an area without histoplasmosis. Br J Ophthalmol. Jan 1997;81(1):7-11. [Medline].
27. Watzke RC, Klein ML, Wener MH. Histoplasmosis-like choroiditis in a nonendemic area: the northwest United States. Retina. 1998;18(3):204-12. [Medline].
28. Woods AC, Whalen HE. The probable role of benign histoplasmosis in the etiology of granulomatous uveitis. Am J Ophthalmol. Feb 1960;49:205-20. [Medline].

Article Last Updated: Jul 24, 2007