Presumed Ocular Histoplasmosis Syndrome

From EyeWiki
Original article contributed by: Judy E. Kim, MD
All contributors: Brad H. Feldman, M.D., Judy E. Kim, MD, Vinay A. Shah M.D. and Wen-Shi Shieh
Assigned editor: Judy E. Kim, MD
Review: Assigned status Update Pending by Vinay A. Shah M.D. on December 21, 2014.



Presumed Ocular Histoplasmosis Syndrome
Classification and external resources
DiseasesDB 31279


Disease Entity[edit | edit source]

Disease[edit | edit source]

Presumed ocular histoplasmosis syndrome (POHS) occurs secondary to infection with the yeast form of Histoplasma capsulatum. The disease is characterized by atrophic chorioretinal scars (Figure 1), peripapillary atrophy (PPA) (Figure 2), and the absence of vitritis. POHS is asymptomatic until choroidal neovascularization (CNV) or sequelae such as disciform scars develop (Figure 3)[1].

Etiology[edit | edit source]

There is considerable controversy over the cause of POHS. Classically, POHS is causedby infection with the yeast form of H. capsulatum, which is a dimorphic fungus that lives in the soil[2]. It is endemic to states that contain the Ohio and Mississippi river valleys. Although distributed worldwide, POHS has only been reported in a few non-U.S. countries including Mexico, India, the United Kingdom and the Netherlands.[1][3][4][5]It is carried on the feathers of chickens, pigeons, and blackbirds as well as in the droppings from infected bats.[1] Infection in humans occurs after inhalation of the spore or conidia form, followed by hematogenous spread of the organism to the choroid.[2] The link between H. capsulatum and POHS comes from epidemiological studies where POHS was linked to a positive histoplasmin skin antigen test.[6] However, a study in the Netherlands found that all patients with clinical POHS were histoplasmin skin antigen test negative.[7]

Since POHS is linked to HLA haplotypes DRw2 and B7, some hypothesize that it could also represent an autoimmune inflammatory reaction triggered by certain organisms, including H. capsulatum.[6]  HLA DRw2 has been found in higher concentrations in patients with disciform and peripheral scars compared to the normal population.[8][9] Similarly, nearly 78% of patients with clinical POHS and macular disciformm scars in at least one eye are positive for HLA-B7.[8][10] The absence of vitritis in the clinical criteria for POHS also supports an inflammatory rather than an active infectious etiology.

Risk Factors[edit | edit source]

POHS is more common in patients who live in areas endemic to H. capsulatum, including the Ohio and Mississippi river valleys. It is estimated that 60% of the adult population test positive to histoplasmin by skin antigen test, yet only 1.5% of those patients demonstrate the typical chorioretinal lesions.[2] Of those patients with typical chorioretinal lesions, only 3.8% of patients progress to CNV.[11]

General Pathology[edit | edit source]

Evaluation of typical chorioretinal lesions by light microscopy demonstrates no fungal elements, however immunohistopathologic stains are positive for Histoplasma antigens at sites choroidal infiltration, where lymphocytes predominate. In addition to loss of outer retinal layers and the retinal pigment epithelium, adhesions between the outer retina and choroidal lesions have been found.[6][12]

Pathophysiology[edit | edit source]

Hematogenous spread of H. capsulatum to the choroid causes an inflammatory reaction and invasion of the choroid, leading to a chorioretinal atrophic scar. These chorioretinal scars have breaks in Bruch’s membrane. If the chorioretinal scar is in the macula or peripapillary region, it is predisposed to CNV. Fibrovascular tissue invades the break in Bruch’s membrane, causing an infiltrate that includes vascular endothelium, retinal pigment epithelium, photoreceptors, and inflammatory cells between the retinal pigment epithelium and Bruch’s membrane. This fibrovascular membrane comprises vision-threatening CNV.[6]

Primary prevention[edit | edit source]

No primary prevention is possible for POHS. Monitoring for signs and symptoms of CNV from POHS can be accomplished through amsler grid screening and routine dilated fundoscopic exam of both eyes.

Identified risk factors for developing CNV in POHS include smoking, low levels of formal education, and increasing age.[13][14] Studies have shown that former or current smokers are nearly three times more likely to develop a CNVthan controls.[13] The association between low educational level and higher likelihood of developing CNV is likely related  to greater exposure to secondhand smoke. The strong association between increased  age and CNV formation has been attributed to the longer duration for CNV development, weaker integrity of Bruch’s membrane,  and a decreased potential for DNA repair.[13][14] Patients with PPA have a CNV risk of 4% compared to 25% for macular histo spots.[1]

Diagnosis[edit | edit source]

The diagnosis of POHS is based upon fundoscopic exam for the four cardinal features and fluorescein angiography for characterization of CNV.

History[edit | edit source]

Patients typically present in their 2nd to 5th decade of life. There is no gender predisposition to POHS.[6] Many case reports have demonstrated that clinical findings of POHS are more common in Caucasian patients compared with black or Hispanic patients. [15][16][17][18][19] It is pertinent to ask where the patient has lived, especially with regards to the Mississippi and Ohio river valley region.

Physical examination[edit | edit source]

Slit lamp examination and dilated fundoscopic exam are necessary for diagnosis.

Signs[edit | edit source]

Three characteristic findings of POHS are typically found on fundoscopic exam: multiple white atrophic chorioretinal scars or histo spots (Figure 1), PPA (Figure 2), and the absence of vitritis. These findings may or may not be associated with CNV (Figure 3)[1], which often appears as greenish-yellow subretinal discoloration with a surrounding pigmented ring at the macula. Confluent atrophic chorioretinal scars in a linear or curvilinear pattern of variable length, width, and pigmentation can be found in the mid-periphery in approximately 5% of patients[20] (Figure 4). In advanced cases, CNV can progress to a disciform scar with subretinal fibrovascular tissue.[2] POHS changes can be found bilaterally in up to 60% of cases.[1]

Symptoms[edit | edit source]

Prior to CNV development, POHS is asymptomatic. POHS often presents with the classic symptoms of CNV, including painless vision loss, metamorphopsia, blurred central vision, and central or paracentral scotomas.[2]

Diagnostic procedures[edit | edit source]

Fluorescein angiography (FA) can assist in the diagnosis of POHS. Peripapillary and chorioretinal atrophy can be identified with a window defect pattern of hyperfluorescence. CNV as a result of POHS will demonstrate the same patterns on FA as other etiologies of choroidal neovascularization, with leakage of fluorescein dye that increases in intensity with expanding borders.[21] Indocyanine green angiography (ICG) can be helpful for elucidating occult CNV. On early ICG, there will be increased hyperfluorescencee as a result of new, disorganized choriocapillaris.[21]

Optical coherence tomography provides additional information regarding the location and extent of CNV as well as a modality to monitor disease activity. On spectral-domain optical coherence tomography (SD-OCT), histo spots correspond to focal areas of outer retinal atrophy. There is disorganization of the outer retinal hyperreflective bands as compared with normal surrounding retina. Similar findings are observed in patients with PPA.[21]

With regards to infrared imaging, PPA appears as a hyperreflective irregular halo around the optic nerve head. Disciform scars and macular histo spots also appear as hyper-reflective and irregular areas. Fundus autofluorescence can aid in detection of small, nonpigmented macular chorioretinal scars, which are round and hypoautofluorescent in appearance.[21]

Laboratory test[edit | edit source]

The histoplasmin skin antigen test can help to identify if a patient has been exposed to H. capsulatum. However, based upon the study from the Netherlands cohort as previously discussed, exposure to H. capsulatum is not necessary for the clinical findings of POHS.[7] Furthermore, if the retinal findings are classic, histoplasmin testing is not performed routinely.

Differential diagnosis[edit | edit source]

The differential diagnosis of POHS includes other causes of CNV including age-related macular degeneration (AMD), degenerative myopia, angioid streaks, vitelliform macular dystrophy, and idiopathic CNV. The differential diagnosis also includes other causes of chorioretinitis including multifocal chorioretinitis, serpiginous choroiditis, bird shot chorioretinopathy, multiple evansescent white dot syndrome, acute multifocal plaquoid pigment epitheliopathy, toxoplasmosis, toxocariasis, rubella, Vogt-Koyanagi-Harada syndrome, and Behcet syndrome.[1]

Management[edit | edit source]

General treatment[edit | edit source]

POHS without CNV is observed and counseling for monitoring of CNV. Because POHS is not truly an infectious process, early attempts at anti-fungal therapy yielded no benefit.[22] Treatment is generally guided toward early detection of CNV via amsler grid screening and routine dilated fundoscopic exam. Once CNV develops, the approach is similar to the treatment of AMD.

Medical therapy[edit | edit source]

The Macular Photocoagulation Study (MPS) evaluated laser photocoagulation forextrafoveal, juxtafoveal, and peripapillary CNV. The MPS found that laser photocoagulation decreased the risk of severe vision loss from 44% to 9% at 5 year follow-up for extrafoveal CNV and 28% to 12% for juxtafoveal CNV.[23][24]The major complication of this treatment is the permanent scotoma caused by laser photocoagulation, limiting its utility in subfoveal CNV. This concern was addressed by the Verteporfin for Ocular Histoplasmosis trial that evaluated photodynamic therapy (PDT) for subfoveal CNV. The authors found that 45% of patients had improved vision, while 9% suffered severe vision loss after 2 years of follow-up.[25]

With the recent breakthrough using anti-vascular endothelial growth factor (VEGF) therapy for AMD, many case reports and case series have investigated anti-VEGF therapy for CNV from OHS. A large retrospective study found that average visual acuity (VA) improved from 20/53 to 20/26 in 54 eyes treated over a 26 months period with either intravitreal bevacizumab or ranibizumab. The average number of injections required was 4.5 per year of treatment.[26]

Multiple studies have looked at the effect of bevacizumab alone in CNV for patients with POHS.[27][28][29] One such case series retrospectively evaluated VA in 28 eyes with subfoveal or juxtafoveal POHS-related CNV treated with intravitreal bevacizumab. Of these eyes, 16 had PDT failures, 5 received bevacizumab within two weeks of PDT (combination treatment), and 7 were PDT-naive. Seventy-one percent of patients showed VA improvement, while 14% stabilized and the remaining 14% had decreased VA after a mean follow-up of 11 weeks and an average of 1.8 injections. Of note, the 14% with decreased vision were PDT failures with progressive vision loss.[30] A separate study evaluated the effect of intravitreal bevacizumab in 24 treatment-naive eyes with subfoveal or juxtafoveal CNVs secondary to POHS.[31] After following patients for 12 months, VA was found to improve from 0.86±0.35 to 0.34±0.33 logMAR units, with an average of 6.8 injections per year. Over 50% of eyes had a final VA of 20/40 or better.

With regards to the efficacy of intravitreal ranibizumab, a randomized study investigated the benefit of monthly ranibizumab injections versus three monthly doses followed by “as needed” injections in patients with non-AMD related CNV.[32] Of the 30 enrolled patients, 9 had a diagnosis of OHS. Although the study did not stratify results based on diagnosis, it reported a gain of 15 or more letters in VA at 6 and 12 months for 66.7% of patients in the monthly injection group and similar gains in 64.3% and 57.1% of patients in the as needed group at 6 and 12 months, respectively.

Lastly, a retrospective study investigated the effect of intravitreal triamcinolone for CNV resulting from OHS.[33]  Five patients received 0.1 mg of triamcinolone for subfoveal CNVs and 5 patients received the same dosing for juxtafoveal CNVs. The results showed that 30% gained ≥5 ETDRS letters, 20% lost ≥5 ETDRS letters, and 50% remained stable after a median of 17 months follow-up. Although transient increases in intraocular pressure (4 of 9 patients) and progression of cataracts (4 out of 9 phakic patients) were reported, the study concluded that intravitreal triamcinolone was a relatively safe treatment option. However, the small study size and reported adverse events render these conclusions difficult to generalize.

Currently, there are two clinical trials in the recruiting phase that are geared toward investigating the effect of intravitreal aflibercept for the treatment of CNVs secondary to POHS (HANDLE study, clinical trial #NCT01790893; and Treatment of CNV Secondary to Presumed Ocular Histoplasmosis With EYLEA 2.0 mg, clinical trial#NCT01578720).[21] Even though the use of intravitreal anti-VEGF therapy in treating OHS CNV is considered off-label, it has become first line treatment based on its availability and studies demonstrating efficacy and safety. 

Historically, systemic amphotericin-B has been studied as a treatment agent for OHS.[34] A small case series initially reported improvement in the lesions after intravenous amphotericin-B[35], but this was later refuted by a larger study that reported lack of marked VA improvement and potential adverse side effects such as nephrotoxicity.[36] Since inflammation is thought to play a role in pathogenesis of OHS, oral corticosteroids as well as periocular steroids have also been investigated as therapy agents.[37][38]  The existing studies suggest that there is no benefit on final VA outcomes.[39][40][41] Recently, a prospective and interventional study evaluated the effect of fluocinolone acetonide implants in non-AMD CNVs.[42] Seven of the 14 patients had a diagnosis of POHS and were assigned to high-dose sustained delivery devices of either 2 mg or 6 mg dosing. After a 33-month mean follow-up period, 10 eyes demonstrated VA improvement or stabilization. Nevertheless, all patients developed elevated intraocular pressures and cataracts while 4 eyes experienced non-ischemic central retinal vein occlusions.  The relative success of laser photocoagulation and anti-VEGF injections in conjunction with these known side effects of corticosteroid use have discouraged their role in treating POHS.

Medical follow up[edit | edit source]

In patients receiving intravitreal anti-VEGF therapy, it is customary for patients to be followed every 4 weeks as treatment is initiated. Follow-up can then be slowly extended as determined by the response to treatment and the amount of sub-retinal fluid on clinical exam and ancillary optical coherence tomography testing.

Surgery[edit | edit source]

Submacular surgery was investigated prior to the PDT and anti-VEGF era for treatment of subfoveal CNV. The first study to describe a surgical approach to removing subfoveal CNV in POHS showed that 83% of treated eyes had visual acuity improvement or stabilization and a recurrence rate of 37%.[43][44][45] A similar study by the same group demonstrated similar findings with a 44% CNV recurrence rate among 117 POHS patient undergoing subfoveal surgery. However, after a median follow-up period of 13 months, 35% of patients were found to have postoperative VA of 20/40 or better.[46] A separate study followed the surgical results of 17 eyes with POHS and CNV for a duration of 32 months. Seven of the 14 eyes with subfoveal CNV achieved a postoperative VA of 20/40 or better while all three extrafoveal CNVs had a final VA of 20/20 vision.[47]

In the submacular surgery trials (SST), the ninth report investigated the benefit of submacular surgery versus observation in patients with classic subfoveal CNV secondary to POHS or other idiopathic causes.[48] At 24 months, there was no significant difference in median visual acuity between the observation arm (20/250) and the surgery arm (20/160) and 58% of the treated eyes had CNV recurrence. The authors concluded that there was no benefit for submacular surgery unless VA was worse than 20/100. Nevertheless, submacular surgery is not currently performed routinely for subfoveal CNV due to the availability and success of medical treatments using anti-VEGF therapy.

Macular translocation is an alternative surgical intervention that has been studied as a treatment for subfoveal CNV in POHS patients. The procedure involves rotating the macula to a healthier RPE and choroidal bed.[49][50] This approach has been abandoned, however, because studies have shown that VA outcomes are not superior to anti-VEGF injections, Additionally, there are high risks for perioperative complications such as proliferative vitreoretinopathy development.

Complications[edit | edit source]

Complications of CNV associated with POHS includes formation of disciform scar at the macula, resulting in loss of central vision. The complications of intravitreal anti-VEGF therapy are similar to those for AMD. These complications include endophthalmitis, subconjunctival hemorrhage, traumatic cataract formation, retinal tears or detachments, and increased intraocular pressure.

Prognosis[edit | edit source]

Patients with no classical signs of POHS in their fellow eye have a 1% chance of developing CNV. Patients with PPA have a 4% risk to develop CNV. Patients with histo spots in the macula have a 25% risk of CNV development.[1]

Additional Resources[edit | edit source]

References[edit | edit source]

  1. 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 Ophthalmology, A.A.o. in Basic and Clinical Sciences Course (Lifelong Education for the Ophthalmologist, San Fransisco, CA, 2006)
  2. 2.0 2.1 2.2 2.3 2.4 Oliver, A., Ciulla, T.A. & Comer, G.M. 2005. New and classic insights into presumed ocular histoplasmosis syndrome and its treatment. Curr Opin Ophthalmol 16: 160-5.
  3. Prasad, A.G. & Van Gelder, R.N. 2005. Presumed ocular histoplasmosis syndrome. Curr Opin Ophthalmol 16: 364-8.
  4. Ongkosuwito, J.V., Kortbeek, L.M., Van der Lelij, A., Molicka, E., Kijlstra, A., de Smet, M.D. & Suttorp-Schulten, M.S. 1999. Aetiological study of the presumed ocular histoplasmosis syndrome in the Netherlands. Br J Ophthalmol 83: 535-9.
  5. Giles, C.L. & Falls, H.F. 1961. Further evaluation of amphotericin-B therapy in presumptive histoplasmosis chorioretinitis. Am J Ophthalmol 51: 588-98.
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  7. 7.0 7.1 Ongkosuwito JV, Kortbeek LM, Van der Lelij A, et al. Aetiological study of the presumed ocular histoplasmosis syndrome in the Netherlands. Br J Ophthalmol. 1999 May;83(5):535-9.
  8. 8.0 8.1 Meredith TA, Smith RE, Duquesnoy RJ. Association of HLA-DRw2 antigen with presumed ocular histoplasmosis. Am J Ophthalmol. 1980 Jan;89(1):70-6.
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  21. 21.0 21.1 21.2 21.3 21.4 Diaz RI, Sigler EJ, Rafieetary MR. Ocular histoplasmosis syndrome. Surv Ophthalmol. 2015 Jul-Aug;60(4):279-295.
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  29. Nguyen QD, Shah SM, Hafiz G, et al. Intravenous bevacizumab causes regression of choroidal neovascularization secondary to diseases other than age-related macular degeneration. Am J Ophthalmol. 2008;145:257-66.
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  31. Ehrlich R, Ciulla TA, Maturi R, et al. Intravitreal bevacizumab for choroidal neovascularization secondary to presumed ocular histoplasmosis syndrome. Retina. 2009;29:1418-23.
  32. Heier JS, Brown D, Ciulla T, et al. Ranibizumab for choroidal neovascularization secondary to causes other than age-related macular degeneration: a phase I clinical trial. Ophthalmology. 2011;118:111-8.
  33. Rechtman E, Allen VD, Danis RP, et al. Intravitreal triamcinolone for choroidal neovascularization in ocular histoplasmosis syndrome. Am J Ophthalmol. 2003;136:739-41.
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  39. Olk RJ, Burgess DB, McCormick PA. Subfoveal and juxtafoveal subretinal neovascularization in the presumed ocular histoplasmosis syndrome. Visual prognosis. Ophthalmology. 1984;91:1592-602.
  40. Mann ES, Fogarty SJ, Kincaid MC. Choroidal neovascularization with granulomatous inflammation in ocular histoplasmosis syndrome. Am J Ophthalmol. 2000;130:247-50.
  41. Martidis A, Miller DG, Ciulla TA, et al. Corticosteroids as an antiangiogenic agent for histoplasmosis-related subfoveal choroidal neovascularization. J Ocul Pharmacol Ther. 1999;15:425-8.
  42. Holekamp NM, Thomas MA, Pearson A. The safety profile of long-term, high-dose intraocular corticosteroid delivery. Am J Ophthalmol. 2005;139:421-8.
  43. Thomas MA, Dickinson JD, Melberg NS, et al. Visual results after surgical removal of subfoveal choroidal neovascular membranes. Ophthalmology. 1994;101:1384-96.
  44. Thomas MA, Grand MG, Williams DF, et al. Surgical management of subfoveal choroidal neovascularization. Ophthalmology. 1992;99:952-68; discussion 75-6. 
  45. Thomas MA, Kaplan HJ. Surgical removal of subfoveal neovascularization in the presumed ocular histoplasmosis syndrome. Am J Ophthalmol. 1991;111:1-7.
  46. Holekamp NM, Thomas MA, Dickinson JD, et al. Surgical removal of subfoveal choroidal neovascularization in presumed ocular histoplasmosis: stability of early visual results. Ophthalmology. 1997;104:22-6.
  47. Atebara NH, Thomas MA, Holekamp NM, et al. Surgical removal of extensive peripapillary choroidal neovascularization associated with presumed ocular histoplasmosis syndrome. Ophthalmology. 1998;105:1598-605.
  48. Hawkins BS, Bressler NM, Bressler SB, 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. 2004;122:1597-611.
  49. Ehlers JP, Maldonado R, Sarin N, et al. Treatment of non-age-related macular degeneration submacular diseasess with macular translocation surgery. Retina. 2011;31:1337-46.
  50. Ng EW, Fujii GY, Au Eong KG, et al. Macular translocation in patients with recurrent subfoveal choroidal neovascularization after laser photocoagulation for nonsubfoveal choroidal neovascularization. Ophthalmology. 2004;111:1889-93.