Presumed Ocular Histoplasmosis Syndrome
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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 (Figure 2), and the absence of vitritis. POHS is asymptomatic until choroidal neovascularization (CNV) develops (Figure 3)1.
There is considerable controversy over the cause of POHS. Classically POHS is caused by infection with the yeast form of Histoplasma capsulatum. Histoplasma capsulatum is a dimorphic fungus that lives in the soil2. It is endemic to states that contain the Ohio and Mississippi river valleys. It is carried on the feathers of chickens, pigeons, and blackbirds as well as in the droppings from infected bats1. Infection in humans occurs after inhalation of the yeast, followed by hematogenous spread of the organism to the choroid2. The link between Histoplasma capsulatum and OHS comes from epidemiological studies where OHS was linked to a positive histoplasmin skin antigen test3. However, a study in the Netherlands found that all patients with clinical POHS were histoplasmin skin antigen test negative4. Since OHS is linked to HLA haplotypes DRw2 and B7, it is hypothesized that POHS could also represent an autoimmune inflammatory reaction triggered by certain organisms, including Histoplasma capsulatum3. The absence of vitritis in the clinical criteria for OHS supports an inflammatory rather than an active infectious etiology.
POHS is more common in patients who live in areas endemic to Histoplasma capsulatum, including the Ohio and Mississippi river valleys. It is estimated that 60% of the adult population test positive to histoplasmin by skin antigen test3. However, only 1.5% of those patients who test positive for histoplasmin demonstrate the typical chorioretinal lesions. Of those patients with typical chorioretinal lesions, only 3.8% of patients progress to CNV. OHS is also linked to HLA haplotypes DRw2 and B73.
Evaluation of typical chorioretinal lesions by light microscopy demonstrates no fungal elements. Instead, a mixed population of inflammatory cells were found in the choroidal infiltrates. Additionally, loss of retinal pigment epithelium and adhesion between the outer retina and choroidal lesion was found3.
Hematogenous spread of Histoplasma 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 CNV3.
No primary prevention is possible for POHS. Monitoring for symptoms and signs of CNV from POHS is available via amsler grid screening and routine dilated fundoscopic exam of both eyes. Patients with peripapillary atrophy have a CNV risk of 4% compared to 25% for macular histo spots5.
The diagnosis of OHS is based upon fundoscopic exam for the four cardinal features and fluorscein angiography for characterization of CNV.
Patients typically present in their 2nd to 5th decade of life. There is no gender predisposition to POHS3. It is important to ask where the patient has lived, specifically regarding the Mississippi and Ohio river valleys.
Slit lamp examination and dilated fundoscopic exam are necessary to make the diagnosis. Particular attention should be paid to identify if vitritis is present (it is absent in OHS), the peripheral retina for white atrophic chorioretinal lesions, and the macula to detect CNV. Examination of both eyes is necessary because changes are bilateral in 60% of cases1.
On fundoscopic exam, three classic signs of POHS are found: multiple white atrophic chorioretinal scars (histo spots, Figure 1), peripapillary atrophy (Figure 2), and the absence of vitritis. These findings may or may not be associated with a fourth sign: CNV (Figure 3)1. CNV typically appears as a green-yellow subretinal discoloration with a surrounding pigmented ring at the macula. Confluent atrophic chorioretinal scars in a linear or curvilinear pattern can sometimes be found in the mid-periphery (Figure 4). In advanced cases, CNV can progress to a disciform scar with subretinal fibrovascular tissue2. In the fellow eye, POHS changes are found in 60% of cases1.
Prior to CNV development, POHS is asymptomatic. POHS presents to the clinic with classic symptoms of CNV, including painless vision loss, metamorphopsia, blurred central vision, and (para)central scotoma2.
The clinical diagnosis of POHS is based upon identification of its four cardinal features on slip lamp examination and indirect ophthalmoscopy: multiple white atrophic chorioretinal scars (histo spots), peripapillary atrophy, the absence of vitritis, and CNV in the macula.
Fluorescein angiography can assist in the diagnosis of POHS. Staining and window defect will be identified in areas of chorioretinal atrophy. CNV will demonstrate late leakage1.
The histoplasmin skin antigen test can help to identify if a patient has been exposed to Histoplasma capsulatum. However, based upon the study from the Netherlands cohort discussed above, exposure to Histoplasma capsulatum is not necessary for the clinical findings of POHS. Furthermore, if the retinal findings are classic, histoplasmin testing is not performed routinely.
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, Behcet syndrome, and others1.
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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 provided no benefit6. Instead, treatment is guided toward early detection of CNV via amsler grid screening and routine dilated fundoscopic exam. Once CNV develops, it is treated similarly to AMD.
The Macular Photocoagulation Study (MPS) evaluated laser photocoagulation for extrafoveal, juxtafoveal, and peripapillary CNV. The MPS found that laser photocoagulation decreased the risk of severe vision loss from 44% to 9% at 5 years follow up for extrafoveal CNV and 28% to 12% for juxtafoveal CNV7, 8. 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 up9. 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 recent larger retrospective study found that average visual acuity improved from 20/53 to 20/26 in 54 eyes treated over a 26 months period10. The average number of injections required was 4.5 per year of treatment. Anti-VEGF therapy is now first line for treatment of CNV secondary to OHS.
Medical follow up
In patients receiving intravitreal anti-VEGF therapy, it is customary for patients to be followed every 4 weeks as injections are 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.
Submacular surgery was investigated prior to the anti-VEGF era for treatment of subfoveal CNV. The studies found no overall consistent benefit of submacular surgery. However, in subgroup analysis of eyes with visual acuity worse than 20/100, a minor, non-statisically significant benefit to surgery was observed. This benefit was outweighed by the risk of cataract, retinal detachment, and recurrence of lesions11. Due to the successful currently available medical treatments using anti-VEGF therapy, submacular surgery is not performed on regular basis for subfoveal CNV.
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.
Patients with no classical signs of OHS in their fellow have a 1% chance of developing CNV. Patients with peripapillary atrophy have a 4% risk to develop CNV. Patients with histo spots in the macula have a 25% risk of CNV development. If CNV is identified early, anti-VEGF medical treatments can maintain visual acuity at roughly 20/25 after 2 years of treatment.
1. Ophthalmology, A.A.o. in Basic and Clinical Sciences Course (Lifelong Education for the Ophthalmologist, San Fransisco, CA, 2006). 2. 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. AAO. in Basic and Clinical Sciences Course (Lifelong Education for the Ophthalmologist, San Fransisco, CA, 2006). 6. Giles, C.L. & Falls, H.F. 1961. Further evaluation of amphotericin-B therapy in presumptive histoplasmosis chorioretinitis. Am J Ophthalmol 51: 588-98. 7. 1983. Argon laser photocoagulation for ocular histoplasmosis. Results of a randomized clinical trial. Arch Ophthalmol 101: 1347-57. 8. 1987. Krypton laser photocoagulation for neovascular lesions of ocular histoplasmosis. Results of a randomized clinical trial. Macular Photocoagulation Study Group. Arch Ophthalmol 105: 1499-507. 9. Rosenfeld, P.J., Saperstein, D.A., Bressler, N.M., Reaves, T.A., Sickenberg, M., Rosa, R.H., Jr., Sternberg, P., Jr., Aaberg, T.M., Sr. & Aaberg, T.M., Jr. 2004. Photodynamic therapy with verteporfin in ocular histoplasmosis: uncontrolled, open-label 2-year study. Ophthalmology 111: 1725-33. 10. Nielsen, J.S., Fick, T.A., Saggau, D.D. & Barnes, C.H. 2011. Intravitreal anti-vascular endothelial growth factor therapy for choroidal neovascularization secondary to ocular histoplasmosis syndrome. Retina 11. Hawkins, B.S., Bressler, N.M., Bressler, S.B., Davidorf, F.H., Hoskins, J.C., Marsh, M.J., Miskala, P.H., Redford, M., Sternberg, P., Jr., Thomas, M.A. & Toth, C.A. 2004. 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 122: 1597-611.