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06-14-2012, 06:18 PM
Presumed Ocular Histoplasmosis (POHS):

30 year-old male with blurred central vision

Alex W. Cohen, MD, PhD and Jordan M. Graff, MD
March 9, 2008
Chief Complaint: Blurred central vision in the left eye.
History of Present Illness: A 30 year-old white male noticed central visual distortion and loss of vision in the left eye (OS) over the past few weeks. His local optometrist referred him to the University of Iowa Department of Ophthalmology and Visual Sciences for further evaluation.
Past Ocular History: None.
Medical History: The patient reported no prior systemic diseases or illnesses.
Medications: None.
Family History: No familial eye diseases and otherwise noncontributory.
Social History: Married, lives with his wife. He works as a computer programmer. The patient has lived in the Mississippi River Valley for his entire life.
Ocular Exam:

Visual Acuity, without correction: Right eye (OD)--20/20; OS--20/40
Motility: Full, both eyes (OU)
Intraocular pressure: OD -- 15 mmHg; OS -- 16 mmHg
Pupils: Equally reactive to light. No relative afferent pupillary defect (RAPD)
Confrontation visual fields (CVF): Full, OU
External and anterior segment examination: Normal, OU
Dilated fundus exam (DFE):

OD: Clear vitreous and healthy optic nerve with no pallor or edema. There is peripapillary atrophy and dark pigmentation. Normal macula and vessels. In the periphery there are a few "punched out" chorioretinal scars.
OS: Clear vitreous with absolutely no cells or signs of inflammation. The optic nerve head is healthy with no pallor or edema. There is peripapillary atrophy and increased pigmentation. Within the macula, there is a raised yellowish subretinal lesion (see Figures 1 and 2).

Figure 1 A: 30-degree fundus photo, OD. Note the peripapillary atrophic changes. B: 30-degree fundus photo, OS. Similary peripapillary atrophic and pigment changes are evident. Note the chorioretinal "histospot" within the macula and the absence of any vitreous inflammation. http://webeye.ophth.uiowa.edu/eyeforum/cases-i/case83/POHS_Fig1A.jpg http://webeye.ophth.uiowa.edu/eyeforum/cases-i/case83/POHS_Fig1B.jpg
Figure 2: Magnified image of the chorioretinal scars shown in Figure 1B. Note the elevation and softened edge surrounding the lesion near the fovea (arrow) and the presence of a minute amount or subretinal hemorrhage. http://webeye.ophth.uiowa.edu/eyeforum/cases-i/case83/POHS_Fig2.jpg
Figure 3A: Optical Coherence Tomography (OCT) scans of both eyes shows an increase in central macular thickness (CMT) OS (295Ám) compared to OD (205Ám). A).
B: Note the presence of subretinal fluid and distortion of the foveal depression, OS. http://webeye.ophth.uiowa.edu/eyeforum/cases-i/case83/POHS_Fig3A.jpghttp://webeye.ophth.uiowa.edu/eyeforum/cases-i/case83/POHS_Fig3B.jpg
Course: This patient has a history and clinical appearance strongly suggestive of the presumed ocular histoplasmosis syndrome (POHS). While his thick, yellow macular lesion is not perfectly classic (see Figure 5 and Discussion below), all indications suggest that a choroidal neovascular membrane (CNVM) has developed in this left macula at the site of a chorioretinal scar. We discussed at length with the patients the options for treatment, including established clinical studies for macular laser or photodynamic therapy (PDT) to the lesion. Additionally, the patient was informed about early results in the literature and personal experience suggesting good results with the off-label use of intravitreal bevacizumab (Avastin). The patient chose intravitreal injection, which was accomplished without complication. He was seen again at four weeks following the injection by which time his vision had improved to 20/20 and the retinal lesion was dry both clinically and by OCT (Figure 4).
Figure 4: OCT scan of the left eye 4 weeks after a single intravitreal injection of bevacizumab (Avastin) showing resolution of the subretinal fluid (CMT, 210 Ám) and restoration of the normal foveal contour.http://webeye.ophth.uiowa.edu/eyeforum/cases-i/case83/POHS_Fig4.jpg
Discussion: Presumed Ocular Histoplasmosis Syndrome (POHS) is a clinical diagnosis made based on a constellation of ocular findings that were originally described in 1960. The syndrome is an inflammatory disorder that has been postulated to result from systemic infection with the dimorphic fungi Histoplasma capsulatum. There have however, been no confirmatory studies which directly implicate this fungus in the pathogenesis of the disease. Rather, epidemiological data suggests that the prevalence of POHS is greatly increased in areas that are endemic to the Histoplasma organisms. Classically, people living in the Ohio and Mississippi River Valleys are known to have as high as a70% rate of positive skin test for exposure to H.capsulatum. Indeed, the vast majority of patients with POHS react positively to this skin test. However, only about 4.4% of patients with a positive skin test have evidence of POHS. Therefore, the relationship between H. capsulatum and POHS remains presumed.
Of note, patients with POHS are often young and otherwise healthy and the retinal lesions can produce significant functional visual loss in this working age population.
The diagnosis of POHS is made based upon the identification of classic fundus findings. These are the presence of peripapillary atrophy or pigmentation, the presence of characteristic "punched-out" chorioretinal atrophic lesions, and the absence of overlying vitreous involvement. The peripapillary changes are thought to represent a regressed choroidal neovascular membrane (CNVM), and the "punched-out" lesions are thought to represent areas of hematogenous seeding of H. capsulatum to the retina. It should be noted that many of the peripheral "punched-out" chorioretinal scars may well be associated with small CNVMs as well that are not brought to attention clinically and regress spontaneously. Classic examples of these lesions can be seen in Figure 5. Often times, as in the case presented here, POHS will present to the attention of the ophthalmologist with a symptomatic CNVM involving the macula or fovea. In this case, the macular lesion was somewhat unusual with a thick yellow substance to it, whereas the CNVM in POHS is often a gray-green lacy net arising from a chorioretinal scar (see Figure 6) that is defined early in the angiogram and leaks late.
Figure 5A: POHS in a patient with significant peripapillary atrophy and pigment change, demonstrating the appearance of a regressed peripapillary CNVM that has been postulated as the source of these lesions. B: Peripheral chorioretinal scars in a patient with POHS. http://webeye.ophth.uiowa.edu/eyeforum/cases-i/case83/POHS_Fig5A.jpghttp://webeye.ophth.uiowa.edu/eyeforum/cases-i/case83/POHS_Fig5B.jpg
Figure 6A: Gray-green macular CNVM in a patient with POHS B: Fluorescein angiogram of the patient in Figure 6A demonstrates classic leakage pattern associated with CNVM in patient with POHS. http://webeye.ophth.uiowa.edu/eyeforum/cases-i/case83/POHS_Fig6A.jpghttp://webeye.ophth.uiowa.edu/eyeforum/cases-i/case83/POHS_Fig6B.jpg
The pathogenesis of the CNVM is unknown; however, several authors have suggested that following hematogenous spread of the organisms to the retina, areas of focal inflammation occur, leading to a disruption in Bruch's membrane, and thus predisposing to CNVM formation. POHS has also been postulated to result from autoimmune trigger, which is spurned by the presence of the infectious organism. In any case, patients are usually either identified while asymptomatic (minority) or come to the attention of an ophthalmologist with complaints of decreased vision.
The treatment of POHS has evolved over the past several years, and while there is no direct therapy to target the organism, several modalities have been identified as beneficial in the treatment of the accompanying CNVM. Historically, laser photocoagulation showed that inhibition of well-defined, classic extrafoveal, juxtafoveal, and peripapillary lesions in POHS could be achieve. However, the resultant central scotoma was sometimes unacceptable in lieu of newer therapeutic options. Photodynamic therapy (PDT) with verteporfin was approved by the FDA for the treatment of CNVM related to POHS in late 2001. Since that time, numerous studies have shown that PDT constitutes a safe and effective means for treating the disease. The treatment of subfoveal CNVM with PDT has also been evaluated and in uncontrolled clinical trials has been shown to be beneficial and likely safe over relatively short follow up periods. More recently, the anti-VEGF treatments (bevacizumab and ranibizumab) have been found to be of potential benefit in the treatment of POHS-related CNVM. These molecules have been proven to be extremely effective in treatment of CNVM related to AMD and the recent literature is replete with case reports of its success in the treatment of CNVMs associated with other conditions, including POHS. Still, the safety and efficacy of this therapy has not been evaluated over a long period of follow-up.
Diagnosis: Presumed Ocular Histoplasmosis Syndrome (POHS) with CNVM
EPIDEMIOLOGY


Histoplasma capsulatum - endemic organism in the Ohio and Mississippi River Valleys
2000 people per year living in endemic areas will suffer significant vision loss
No Gender or racial prevalence
SIGNS


Diagnosis consisting of the following findings:

punched-out choroidal lesions ("histo-spots")
juxtapapillary atrophic pigmentary changes
choroidal neovascularization
no inflammation of vitreous

SYMPTOMS


In the absence of CNVM affecting central acuity, most patients are asymptomatic
Patient with central chorioretinal scars or CNVM may complain of:

Decreased central vision
Partial or complete central or paracentral scotoma
Metamorphopsia

TREATMENT


Thermal laser for extrafoveal CNVM
Photodynamic therapy (PDT) with verteporfin for extrafoveal, juxtafoveal, peripapillary, and subfoveal CNVM
Early case series and personal experience of POHS with excellent response to anti-VEGF therapy with bevacizumab (Avastin)

Differential Diagnoses for macular chorioretinal scar with associated fluid:


Toxoplasmosis (would have vitreous inflammation)
Myopic degeneration
Angiod streaks
Age-Related Macular Degeneration (AMD)
Central Serous Chorioretinopathy (CSCR)
Punctate Inner Choroidopathy (PIC)
Multifocal Choroiditis (MFC)
Idiopathic CNVM
References

1. Prasad AG, Van Gelder RN. Presumed ocular hisoplasmosis syndrome. Curr Opin Ophthalmol 2005;16:364.
2.Olver A, Ciulla TA, Comer GH. New and classic insights into presumed ocular histoplasmosis syndrome and its treatment. Curr Opin Ophthalmol 2005;16:160.
3. Rosenfeld PJ, Saperstein DA, Bressler NM, Reaves TA, Sickenberg M, Rosa RH Jr, Sternberg P Jr, Aaberg TM Sr, Aaberg TM Jr; Verteporfin in Ocular Histoplasmosis Study Group. Photodynamic therapy with verteporfin in ocular histoplasmosis: uncontrolled, open-label 2-year study. Ophthalmology 2004;111:1725.
4. Adán A, Navarro M, Casaroli-Marano RP, Ortiz S, Molina JJ. Intravitreal bevacizumab as initial treatment for choroidal neovascularization associated with presumed ocular histoplasmosis syndrome. Graefes Arch Clin Exp Ophthalmol. 2007;245:1873.
5. Schadlu R, Blinder KJ, Shah GK, Holekamp NM, Thomas MA, Grand MG, Engelbrecht NE, Apte RS, Joseph DP, Prasad AG, Smith BT, Sheybani A. Intravitreal Bevacizumab for Choroidal Neovascularization in Ocular Histoplasmosis. Am J Ophthalmol. 2008; Mar 3. Epub ahead of print PMID: 18321466.
6. Weingeist TA, Watzke RC. Ocular involvement by histoplasma capsulatum. Int Ophthalmol Clin. 1983;23(2):33-47.