Presumed Ocular Histoplasmosis Syndrome
Presumed ocular histoplasmosis syndrome (POHS) occurs secondary to infection with the yeast form of Histoplasma capsulatum. The disease is characterized by atrophic chorioretinal scars, peripapillary atrophy (PPA) , and the absence of vitritis. POHS is asymptomatic until choroidal neovascularization (CNV) or sequelae such as disciform scars develop .
There is considerable controversy over the cause of POHS. Classically, POHS is caused by infection with the yeast form of H. capsulatum, which is a dimorphic fungus that lives in the soil. 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.It is carried on the feathers of chickens, pigeons, and blackbirds as well as in the droppings from infected bats. Infection in humans occurs after inhalation of the spore or conidia form, classically associated with cave exploration and exposure to infected bats as well as birds, followed by hematogenous spread of the organism to the choroid. The link between H. capsulatum and POHS comes from epidemiological studies where POHS was linked to a positive histoplasmin skin antigen test. However, a study in the Netherlands found that all patients with clinical POHS were histoplasmin skin antigen test negative. POHS is different from “Disseminated Histoplasmosis” which is the exudative/productive H. capsulatum infection of ocular tissues, seen in immunocompromised adults or infants.
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. HLA DRw2 has been found in higher concentrations in patients with disciform and peripheral scars compared to the normal population. Similarly, nearly 78% of patients with clinical POHS and macular disciformm scars in at least one eye are positive for HLA-B7. The absence of vitritis in the clinical criteria for POHS also supports an inflammatory rather than an active infectious etiology.
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. Of those patients with typical chorioretinal lesions, only 3.8% of patients progress to CNV.
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.
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.
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. Studies have shown that former or current smokers are nearly three times more likely to develop a CNV than controls. The association between low educational level and higher likelihood of developing CNV is likely related to greater exposure to second hand 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. Patients with PPA have a CNV risk of 4% compared to 25% for macular histo spots.
The diagnosis of POHS is based upon fundoscopic exam for the four cardinal features and fluorescein angiography for characterization of CNV.
Patients typically present in their 2nd to 5th decade of life. There is no gender predisposition to POHS. Many case reports have demonstrated that clinical findings of POHS are more common in Caucasian patients compared with black or Hispanic patients.  It is pertinent to ask where the patient has lived, especially with regards to the Mississippi and Ohio river valley region. Though the association with pulmonary H. capsulatum and POHS is unclear, asking about recreational activities, such as cave exploration, as well as animal exposure is important in collecting a thorough history.
Slit lamp examination and dilated fundoscopic exam are necessary for diagnosis.
Three characteristic findings of POHS are typically found on fundoscopic exam: multiple white atrophic chorioretinal scars or histo spots , PPA , and the absence of vitritis. These findings may or may not be associated with CNV , 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. In advanced cases, CNV can progress to a disciform scar with subretinal fibrovascular tissue. POHS changes can be found bilaterally in up to 60% of cases.
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.
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. Indocyanine green angiography (ICG) can be helpful for elucidating occult CNV. On early ICG, there will be increased hypercyanescence as a result of new, disorganized choriocapillaris.
Optical coherence tomography (OCT) 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. OCT angiography (OCT-A) is a new imaging modality that allows for visualization of the retinal and choroidal vasculature changes in POHS. OCT-A has been shown to detect CNV and subtle vascular changes when SD-OCT and FA show stability of these lesions. OCT-A has also been proven to help distinguish between the CNV seen in POHS from other white dot syndromes and age-related macular degeneration (AMD). One study showed the choroidal hypoperfusion of POHS seen on OCT-A correlates well with the clinically observed pathology, while those in other white dot syndromes is not as clear .
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.
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. Furthermore, if the retinal findings are classic, histoplasmin testing is not performed routinely.
The differential diagnosis of POHS includes other causes of CNV including AMD, degenerative myopia, angioid streaks, vitelliform macular dystrophy, and idiopathic CNV. The differential diagnosis also includes other causes of chorioretinitis with multifocal chorioretinal scars including idiopathic multifocal chorioretinitis and panuveitis, sarcoidosis, toxoplasmosis and serpiginous choroiditis. Other conditions that can be considered include birdshot chorioretinopathy, multiple evansescent white dot syndrome, acute multifocal plaqcoid pigment epitheliopathy, , toxocariasis, rubella, Vogt-Koyanagi-Harada syndrome, and Behcet syndrome although the clinical presentation and natural history of these conditions is different from POHS.
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. 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.
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.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.
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 POHS. 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. OCT-A has been shown to be very effective for tracking treatment efficacy of anti-VEGF therapy, similar to neovascular AMD, detecting changes in vascular flow suggestive of CNV where FA and SD-OCT showed stability.
Multiple studies have looked at the effect of bevacizumab alone in CNV for patients with POHS. 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. A separate study evaluated the effect of intravitreal bevacizumab in 24 treatment-naive eyes with subfoveal or juxtafoveal CNVs secondary to POHS. 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. Of the 30 enrolled patients, 9 had a diagnosis of POHS. 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.
A retrospective study investigated the effect of intravitreal triamcinolone for CNV resulting from POHS. 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.
Most recently, the effect of intravitreal aflibercept for the treatment of CNVs secondary to POHS was evaluated in the HANDLE study. In an open-label randomized Phase I/II study thirty-nine eyes from 39 patients were randomized in a 1:1 ratio to 2 groups. The Sustained Group eyes (n = 19) underwent monthly intravitreal aflibercept for 3 months, then mandatory intravitreal aflibercept every 2 months for 12 months (with an option for monthly PRN dosing, if needed). The PRN Group eyes (n = 20) received 1 intravitreal aflibercept at randomization, then monthly PRN for 12 months. At 12-month follow-up, Sustained Group's average visual acuity was 84.9 letters (74-94) and Snellen equivalent was 20/21 (20/13-20/32), indicating an average improvement of 12 letters (6 letters loss to 36 letters gain) (P < 0.01). The PRN Group's 12-month average visual acuity was 80.9 letters (60-94) and Snellen equivalent was 20/26 (20/13-20/63), indicating an average gain of 19 letters (4-75) (P < 0.01). The Sustained Group's mean baseline CST was 383 μm and mean 12-month CST was 268 μm (P < 0.01). Mean baseline CST of the PRN Group was 360.8 μm, with the final mean CST of 260.5 μm (P < 0.01). No reported endophthalmitis, retinal tears, detachments, vitreous hemorrhage, nor adverse thrombotic events were reported. The authors concluded that intravitreal aflibercept resulted in improved visual and anatomical outcomes with a favorable safety profile. PRN intravitreal aflibercept dosing required less injections with similar visual and anatomical outcomes compared with sustained dosing.
Even though the use of intravitreal anti-VEGF therapy in treating POHS 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. A small case series initially reported improvement in the lesions after intravenous amphotericin-B, but this was later refuted by a larger study that reported lack of marked VA improvement and potential adverse side effects such as nephrotoxicity. 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. The existing studies suggest that there is no benefit on final VA outcomes. Recently, a prospective and interventional study evaluated the effect of fluocinolone acetonide implants in non-AMD CNVs. 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
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.
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%. 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. 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.
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. 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. 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 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 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.
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