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Presumed Ocular Histoplasmosis Syndrome
(POHS)
Amiee Ho, OD
Pacific University College of Optometry
Course Description
• This course focuses on presumed ocular histoplasmosis syndrome; mainly the clinical features, facts and current research findings, and how to diagnosis, properly manage, and when to refer for treatment if needed.
Course objectives
• Understand general background, current facts and research findings of POHS
• Understand importance of monitoring these patients and knowing when to refer immediately
• Know the retinal signs of POHS
• Understand early detection of choroidal neovascularization can help preserve vision
• Knowing the available treatment options
20 y.o. Caucasian female
• POV: General Eye Exam • Last Eye Exam: >5 years • Chief Complaint: No visual complaints with current SV distance Rx • HPI: NONE
– Flashes: none– Floaters: none– Double vision: none– Eye pain: none
• Ocular hx: no ocular diseases injuries, or surgeries • Family Ocular hx: no blindness, glaucoma, or ARMD• Medical hx: None• Current Medications: None• Allergies: NKDA, NKMA• Occupation: Student • Hobbies: Traveling
Exam Findings
• Entering VAs: – Distance: OD: 20/25- OS: 20/25-
– Near: OU: 20/20
• CT with Rx: Ortho at distance/Ortho at near
• Pupils: PERRL, (-)RAPD
• EOMs: SAFE
• Confrontational Visual Field: FTFC both eyes
• Subjective Refraction: – OD: -6.00-1.25x100 20/20-
– OS: -5.75-1.00x100 20/20-
Anterior Segment • Lids/Lashes: 1+ MGD OU
• Conjunctiva: clear and white OU
• Cornea: clear OU
• Angles: 4/4 OU
• A/C: deep and quiet OU
• Iris: flat, (-)TID OU
• Lens: clear OU
• IOP: 15mmHg OU @ 10:50am
DILATE!!
Posterior Segment• ONH:
– c/d: 0.25x0.25 OD, 0.30x0.30 OS– rim: pink and healthy OU– depth: shallow OU– margins: extensive PPA 360 with rim of pigment between disc and
atrophy area OU
• Vessels: AV ratio 2/3 OU• Posterior Pole: multiple round chorioretinal scars of varying sizes
scattered throughout posterior pole OU• Macula: multiple small round chorioretinal scars scattered
throughout macula sparing fovea OU; (+) foveal reflex OU• Vitreous: clear OU, (-) vitritis • Periphery: multiple chorioretinal scars of varying sizes scattered
throughout peripheral retina OU
Presumed Ocular Histoplasmosis Syndrome (POHS)
1. Optic nerve: peripapillary atrophy
2. Posterior pole/periphery: multiple chorioretinal scars
3. Macula: chorioretinal scars
4. No vitritis: (-)inflammation/infection
Diagnosis
Who gets POHS?
• 20-50 years old • People that live or traveled to Ohio-Mississippi River Valley areas
– Currently POHS is the leading cause of severe, irreversiblevision loss in middle-aged adults located in the endemic parts of the US
• No sex or racial preference – Bilateral maculopathy occurs more often in men than women
• Six times more prevalent in white vs black population
Symptoms
• Symptoms: – Often asymptomatic– Decreased/distorted vision (with CNV)
Signs
• Signs: “Classic Triad”
1. “histo spots”: discrete atrophic choroidal scars or punched out lesions anywhere in retina
2. Peripapillary atrophy or scarring
3. Macular CNV or chorioretinal involvement: subretinal blood/exudate or scarring
• Other Signs:
– Bilateral involvement
– Absence of iritis or vitritis: CLEAR vitreous and anterior chamber
– No symptoms unless maculopathy occurs
• Mostly found on routine eye exams
– **5% have linear streak lesions in mid-peripheral retina (1981)
Linear Streaks of the Equator in the Presumed Ocular Histoplasmosis Syndrome (1981)
• Purpose of article:
– In addition to the classic triad…
– A fourth sign: peripheral streak lesions should be added to the common triad of POHS
• Streaks are:– variable in length, width and pigmentation
– almost invariably in equatorial region and oriented parallel to ora serrata
– Found in 5% of POHS patients
Streak Lesion Details
• Streak lesion location: – Generally equatorial
– 61% of streaks were 2DD within an ampullae: • Anterior to ampullae (82%)
– 39% of streaks were in the middle or far periphery
– Quadrant involvement: • Superotemporal: 30%
• Superonasal: 24%
• Inferotemporal: 26%
• Inferonasal: 20%
Streak Lesion Details• Streak pigmentation:
– Variable: usually spotty if pigment present
– Depigmentation (most common): 58%
– Heavy pigmentation: 8%
– Smooth without interruptions: 75%
– Interrupted/broken/row of histo spots: 25%
– Multiple streaks in same eye (parallel to each other and to ora): 8%
Streak Lesion Details
• Streak lesion length:
– Varied: ½ a clock hr – 11 clock hrs
– Avg: 3.3 clock hrs or more than one quadrant
• Streak lesion width:
– One vein width: 125μm
– 150μm - 1500μm
Facts about POHS
• 1942 - POHS was first described as ocular lesions noted by Reid et al in patients with disseminated Histoplasmosis
• 1959 - Woods and Wahlen (and later Schlaegel and Kenney) demonstrated activation of chorioretinal lesions with histoplasmin skin testing, pulmonary calcification and atrophy around the optic nerve head, suggesting link with histoplasmosis– The causative organism: Histoplasma Capsulatum
Facts on Histoplasma CapsulatumGeneral:
• Not normal flora for man
• Dimorphic fungus - either yeast or mold (hyphae) form
– Mold (hyphae) form occurs and lives in natural soil habitat/environment
• Mass of hyphae = mycelium
– Yeast form occurs in human tissues
25deg C Reversible 37deg C
Facts on Histoplasma Capsulatum• Dimorphic fungus - either yeast or mold (hyphae) form
– Mold (hyphae) form occurs and lives in natural soil habitat/environment
• Mass of hyphae = mycelium
Mold (hyphae) form occurs and lives in:
• Soil habitat well fertilized by fecal matter of domestic birds (ex: chickens, pigeons) or bats
• Found in temperate and tropical regions worldwide
• Endemic to certain areas
– River valleys around the world, including North America, Asia and Africa
– North America: Ohio-Mississippi River valley
• Considered endemic in 31 of the 48 contiguous US states
– ~200,000-500,000 new infections occur annually in endemic areas
• 70% of people living in endemic areas are (+) to histoplasmin skin antigen
– 4.4% have POHS
• 80-100% (nearly universal) people with POHS in endemic areas test (+) histoplasmintest
– Rare in Europe except for a localized region in Italy
• At room temperature in the laboratory
Facts on Histoplasma Capsulatum
• Dimorphic fungus - either yeast or mold (hyphae) form
– Yeast form occurs in human tissues
Systemic Infection:
• Inhalation of spores Enters pulmonary system spleen, liver and elsewhere including uveal tract (eyes)
• Self-limiting hematogenous spread
• Acute systemic dissemination is self-limited and can:
– Be asymptomatic
– Resemble a viral illness (flu-like disease)
– Experience fatigue and fever lasting from a few days to two weeks
– Also experience respiratory symptoms in an immunocompetent host
• Affect individuals can report: h/o growing up on a farm or exploring caves
• Someone infected with Histoplasmosis is not contagious to others
• Course of disease depends on number of inhaled spores and immune status of host
• Systemically, life threatening complications are usually associated with an immunocompromised state
Facts on Histoplasma Capsulatum
Ocular Infection:
• Ocular infection via hematogenous spread to the choroid
• Mechanism:
• All lesions possess potential to provoke subretinal cytokine formation for CNV
Fungus enters host’s respiratory system via
inhalation
Lies dormant for a period of time
Activation!Migrates to eye and
grows within choriocapillaris
Hematogenous spread of Histoplasma capsulatumto the choroid causes an inflammatory reaction
Break in Bruch’s membrane
Chorioretinal damage Chorioretinal scars –
sometimes fibrvasculartissue invades
Infiltrates between the RPE and Bruch’s
membraneCNV risk
If chorioretinal scar in the macular or
peripapillary regionCNV risk (VISION LOSS)
WHY “PRESUMED”?Presumed Ocular Histoplasmosis Syndrome (POHS)
POHS: Why “presumed”?• Historically, the link between POHS and Histoplasma capsulatum has been based largely on
epidemiological evidence
– Areas with highest prevalence of H. capsulatum show the highest incidence of POHS
– POHS outside endemic areas typically develop in individuals who have moved from endemic areas
• Histoplasmin skin test:
– POHS linked to (+) histoplasmin skin test
– Up to 70% of the population living in endemic areas has been exposed to the fungus and react positively to the histoplasmin skin antigen test
– Positive histoplasmin skin test has been + correlated with POHS in 59% of an endemic population; 80-100% histoplasmin skin reactivity in POHS patients
*****Confusion*****
• However: POHS is described in areas where histoplasmosis is absent
– Example: parts of Western Europe
– Pathogenetic role of Histoplasma capsulatum highly unlikely
• POHS shows up where H. capsulatum does not exist and individuals without serologic evidence of H. capsulatum infection and negative skin tests
Why “presumed”?
More investigation…• Pathology evaluation via Light Microscopy
– Light microscopy evaluation of typical chorioretinal lesions shows:
• (-) fungal elements
• (+) mixed population of inflammatory cells
• (+) loss of RPE and adhesion between the outer retina and choroidal lesion
• HLA haplotypes DRw2 and B7:
– POHS is also linked to HLA haplotypes DRw2 and B7:
• Autoimmune inflammatory reaction triggered by certain organisms
• (-) vitritis in diagnostic criteria for POHS supports an inflammatory vs active infectious etiology
• Patients with peripapillary and macular hemorrhages have a significantly higher prevalence for the HLA-B7 antigen
Unsure if disease is caused by infectious, auto-immune, genetic or even multifactorial
• That’s why we use the term “PRESUMED”
Evidence against H. Capsulatum1. Histoplasmin skin test and serum antibody test inconsistencies
2. POHS found in non-endemic areas
3. Attempts to isolate H. capsulatum have been unsuccessful
Supportive cases:
Walkersville, Maryland
• Identified overall only 4.4% who tested positive had clinical POHS
•Majority of people who presented with POHS does not show a history of being infected with H. capsulatum
Brazil
•8 immunocompetent patients between ages 20-44 all presented with POHS like syndrome and all negative for H. capsulatum serum antibody, also negative for toxoplasmosis, syphilis and tuberculosis
Netherlands
•One study found all patients with POHS had negative histoplasmin skin antigen test
•Case series of 23 patients with POHS showed all patients tested negative to antibodies that are endemic to northern Europe, the authors suggested renaming POHS to “multifocal choriodopathy”
Evidence against H. Capsulatum
Supportive cases (continued):
Recent advances in subretinalsurgery has not led to any report
of direct histopathological evidence of Histoplasma
capsulatum
Experimental animal models in primates for POHS found similar
histoplasmosis choroiditis but not able to reproduce same clinical
picture, especially subretinalneovascularization
Hernandez et al proposed using a PCR assay (Hcp100-PCR) for
detection of DNA of the microorganism from a peripheral blood sample as opposed to an antibody test – found negative
serological testing
Systemic histoplasmosis infection (subclinical disease) and POHS is
not clear
Should be seen more often in AIDS (like toxoplasmosis)
Evidence for H. Capsulatum
More than just epidemiological evidence:• Schoelz et la and Spencer et al identified blastoconidia and H.
capsulatum within the endothelial cells of choroid in an enucleated eye of a patient with bilateral POHS and seropositivity to H. capsulatum
• Wong et al infected rabbits and Smith et al infected monkeys with H. capsulatum spores which led to an acute multifocal choroiditis
Evidence for H. Capsulatum
Proposed mechanism suggested by Gass and Wilkinson:
• Histopathological exam of lesions show no H. capsulatum with varying degrees of associated lymphocytic choroiditis
• Similar findings have been demonstrated after intracarotid injection of H. Capsulatum in primates
Infection to choroid
Visually insignificant and asymptomatic
focal choroidal granulomas develop
with subsequent destruction of
organism
Resolving granulomas evolve to small focal atrophic choroidal
and RPE scars
Pathologic evidence
• Spencer et. al did detect H. capsulatum DNA in the enucleated eye of a patient with bilateral POHS and positive histoplasmin skin testing
– Using laser capture microdissection and polymerase chain reaction, detected H. capsulatum DNA from macular and midperipheral choroidal lesions but did not detect H. capsulatum DNA from uninvolved choroid
– Suspect that POHS is a chronic immune reaction to residual fragments of the organism
• This immune reaction causes inflammation which results in the chorioretinal scarring observed
– Light microscopy did not reveal any fungal components, but it did demonstrate the typical characteristics of the choroidal lesions
• A detection of a population of mixed inflammatory cells in the choroidal infiltrates, loss of retinal pigment epithelium, delineation of lesions with normal surrounding choroids, and adhesions between outer retina and choroidal lesions
– In addition, HLA subtypes (DRw2 and B7) have been found to be associated with POHS
– This may suggest that POHS belongs to the spectrum of autoimmune diseases triggered by an infectious organism, and perhaps H. capsulatum is one of several candidate pathogens.
Final thought…
• “Presumed” it is…
• We are still unsure
• Needs more research
Differential Diagnosis
• High myopia
– Atrophic spots in posterior pole• Whiter than these
chorioretinal scars
• Not seen beyond posterior pole
– Myopic crescent (temporal)• Rim of pigment on outer
edge separating crescent from the retina
PPA: myopia vs. histoplasmosis
Myopia Histoplasmosis
Differential Diagnosis
• Ocular Toxoplasmosis– Toxoplasma gondii: intracellular parasite
• Spread through cat feces– Active Toxo:
• Retinitis & vitritis "Headlight in Fog“• AC reaction: fine KP• Patches of necrotizing retinitis
• Often adjacent to pre-existing scar
• CME, Optic Neuritis, Vasculitis, scleritis, papillitis, BRVO in areas of retinitis
– Inactive Toxo: • Large oval or round FOCAL pigmented
retinochoroidal atrophic scar• Macular scars: large, heavily pigmented
margins, white centrally• Severe VA reduction (20/200 to
20/400 or worse)
Differential Diagnosis
POHS Ocular Toxoplasmosis
Infecting organism: H. capsulatum Infecting organism: T. gondii
Infection route: endemic areas (i.e. Ohio and
Mississippi river valleys)
Infection route: cat feces
Clinical features:
Asympatomatic
Punched-out chorioretinal lesions
Peripapillary atrophy around optic nerve
No active anterior uveitis or vitritis
Choroidal neovascularization
Clinical features:
Symptoms:
o Decreased VA, pain, photophobia,
floaters
Focal necrotizing retinochoroiditis
Anterior uveitis
Vitritis
Optic neuritis or papillitis
Punched-out retinochoroidal scars
Most common cause of posterior uveitis
Differential Diagnosis
• Age-related macular degeneration
– Similar macular changes
– Macular drusen
– Age: >50yrs old
– No chorioretinal scars or scarring/atrophy around disc
Differential Diagnosis
Choroidopathies: • Ex: Multifocal choroiditis with panuveitis, Birdshot chorioretinopathy, diffuse unilateral
subacute neuroretinitis and other multifocal choroiditis syndromes
– Can be distinguished by accompanying intraocular inflammation
– Anterior or vitreous inflammatory cells
– young women
– Multiple, circular, pale, subretinal inflammatory lesions causing visual loss
– Chronic, recurrent, lasting months to years with new lesions developing in either eye without regard to location of previous lesions
– 50% of pts have vision worse than 20/200 in the affected eye
• Other causes of granulomatous disease: tuberculosis, cryptococcosis, sarcoidosis, coccidioidomycosis
– All should be associated with intraocular inflammation
• Resolved punctate inner choroidopathy most closely resembles POHS but typically develops smaller choroidal scars that are confined to posterior pole
– Acute disease is accompanied by vitritis
Differential Diagnosis • Multiple evanescent white dot syndrome
(MEWDS):
– Multiple, creamy white lesions (outer retina/RPE)
– Few vitreous cells
– Occasional sheathing of vessels
– Enlarged blind spot
– Vision typically returns to normal within weeks without treatment
Optional Testing
Histoplasmin skin test• h/o being exposed to Histoplasma capsulatum• Allergen injected below skin surface, injection site checked 24-48 hours later for signs of
reaction• Histoplasmin skin testing is not performed any more in patients with POHS
– Controversial – might increase risk of reactivation in inactive ocular lesions• Studies after 1967 have no direct or indirect evidence of the presumed infectious agent• Based on Netherlands cohort study, (+) histoplasmin antigen skin test ≠ POHS and vice versa • Classic Triad of POHS – no need for skin test
FA: • Histo spots: late staining and window defect (hypofluorescence)• Can show early CNV: late leakage• Helps to define the clinical picture:
– To detect subclinical scars requiring close follow up – To elucidate presence and extent of neovascularization
HLA-B7 testing: • Consider testing for serum antigen and antibodies using the HLA-B7
Management
POHS ≠ infectious process– Antifungal therapy is not beneficial for cases of purely ocular
histoplasmosis • Ineffective – abandoned 40 years ago
• Cases that exhibit chronic or disseminated disease and severe, acute infection, these agents may be indicated – Amphotericin B is the agent of choice in severe cases
• Must monitor for nephrotoxicity and hypokalemia • Responds quickly with initial treatment, then can switch to
itraconazole to finish course of therapy– Itraconazole is effective in moderate cases and is well tolerate even
with long term use • Hepatotoxicity, most severe adverse effect of itraconazole is
uncommon and usually transient– Posaconazole (a triazole antifungal agent), shown to be effective
against range of fungi with invasive fungal infections who were refractory to or intolerant of other antifungal therapies
Management
So therefore…• If patient shows clinical signs of POHS, your goal is to monitor for CNV!
**Early detection of CNV via Amsler grid and routine DFE
• If patient is asymptomatic and without CNV
– Educate patient about findings and its origin• Amsler grid• Smoking cessation (3x’s more likely to develop CNV)
To monitor for CNV: • Follow up Care
– F/U q6 months (+) macular changes – F/U q1 year (-) macular changes
• Key to successful treatment is early detection of maculopathy and prevention of macular or paramacular CNV
• Complications with: – POHS: CNV scarring
Management: Stats on CNV
• Predictions (Gass and Wilkinson)– POHS in one eye only other eye has 1% risk of CNV– (+) Peripapillary atrophy have a 4% risk of CNV– (+) Histo spots in the macula have a 25% risk of CNV– Early CNV detection can maintain VA ~20/25 after 2 years of treatment
with anti-VEGF
• Overall: 5% of all patients with peripheral lesions will develop symptomatic macular CNVM
• <5% develop CNV arising from areas of chorioretinal scarring
– By the time patients get eye examined, they would have developed foveal-compromising CNV and complained of painless progressive blurring of central vision and metamorphopsia which can be acute or gradual
Studies for Treatment of CNV
If patient has CNV or develops CNV, patient needs immediate treatment!
• The Macular Photocoagulation Study (MPS)
• Verteporfin for Ocular Histoplasmosis Study
• Submacular Surgery
• Anti-VEGF: therapy studies for AMD
• Intravitreal corticosteroid therapy
Studies for Treatment of CNV
• The Macular Photocoagulation Study (MPS):
– Laser photocoagulation - destructive, causes absolute scotoma where laser is applied
– Evaluated laser photocoagulation for extrafoveal, juxtafoveal, and peripapillary CNV
– Found decreased risk of severe vision loss from:
• 44% to 9% at 5 years follow up for extrafoveal CNV
• 28% to 12% for juxtafoveal CNV
– Complication: permanent scotoma
• Limited use with subfoveal CNV
– Unless lesion is classic (borders are well-defined) there is substantial incidence of regrowth
Studies for Treatment of CNV• Verteporfin/PDT for Ocular Histoplasmosis Study:
– PDT with verteporfin is a 2 step procedure involving intravenous infusion of the photosensitive verteporfin and then activiation by a specific wavelength of laser energy resulting in a partial occlusion of treated vessels
– Major benefit to this method is its ability to selectively damage CNV without harming the overlying retina
– Useful for subfoveal and juxtafoveal CNVM
– Evaluated photodynamic therapy (PDT) for subfoveal CNV
– Findings:
• 45% of patients had improved vision
• 9% suffered severe vision loss after 2 years of follow up
– Demonstrated stabilization of CNV and overall visual benefit
Studies for Treatment of CNV
• Submacular Surgery:
– Benefit of submacular surgery for treatment of subfoveal CNV
– Found no benefit, small benefit for patients with preoperative BCVA less than 20/100
– Recurrence of CNVM and leakage in 58% of surgical eyes at 24 months
– Highly advanced procedure with significant complicantions: macular striae, retinal tears/detachments and cataract
Studies for Treatment of CNV• Anti-VEGF: therapy studies for AMD
– The emergence of intravitreal anti-VEGF therapy has truly revolutionized the treatment of CNV
– Schadlu et al. reported that 85% of 28 eyes had stabilized or improvement in vision with intravitreal bevacizumab therapy with approximately 43% eyes gaining three or more lines of vision.
– In a retrospective review, Nielsen et al. found a benefit using bevacizumab and ranibizumab in CNV as a result of POHS.
• In 94% eyes had improved (81%) or stabilized (13%) visual acuity [36].
– A larger retrospective study found that average VA improved from 20/53 to 20/26 in 54 eyes treated over a 26 months period
– The average injections were 4.5/year
– Anti-VEGF therapy is now first line for treatment of CNV secondary to POHS
PDT vs Anti-VEGF therapy
• Although there are many studies supporting anti-VEGF therapy in POHS-related CNV, no strong conclusions can be made to demonstrate its superiority over PDT
• In a recent study comparing ranibizumab vs PDT:
– There was a marked improvement in visual acuity over a 1-year period with a 19.6-letter gain in the ranibizumab group and a 21-letter gain in the PDT group
– However, all patients in the PDT group required rescue bevacizumab therapy
• After this study, it was concluded that ranibizumab either alone or in combination with PDT was a reasonable option for management of CNV from POHS
Studies for Treatment of CNV
• Intravitreal corticosteroid therapy – Some effectiveness has been reported for recalcitrant cases of POHS-related CNVM
– A retrospective study of 10 patients, 5 with subfoveal and 5 with juxtafoveal lesions, revealed good outcomes of visual improvement and stability at a mean of 17 months of follow-up
– A retrospective review of 10 patients treated with IV triamcinolone for CNVM associated with POHS showed 80% improvement or stabilization of the lesion but no mean improvement in visual acuity
• Visual outcomes were: 30% of patients gained greater than or equal to five letters, 50% remained stable, whereas 20% lost 5–14 letters
– Most patients (70%) required only one injection, whereas 10% and 20% underwent two injections and three injections, respectively
– These results are comparable with PDT, although further follow-up is necessary
– PDT combined with intravitreal steroid treatment may possibly prove to be beneficial for CNVM caused by POHS.
Treatment CNV
Anti-VEGF
(First line therapy)
Good response Poor response
Laser Photocoagulation
(Extrafoveal/Juxtafoveal CNV)
Combo:
Anti-VEGF + PDT
Anti-VEGF
IV corticosteroid therapy
(IV steroid + PDT?)
Prognosis
• Location of CNV is associated with prognostic visual outcome
– Extrafoveal location – 44% 5 year risk of severe vision loss if not treated
– Subfoveal location – 75% risk of decline in vision to 20/200 or worse in 2-3 years if not treated
CNV Risks
• Avoidance of aspirin, stress or Valsalva maneuver
• Smoking cessation:
– Smoking promotes inflammation increased risk of CNV by increased scarring and further damage to Bruch’s membrane
– Smoking shown to be a strong risk factor with odds being almost three times higher than that of nonsmokers
• Age – CNV more likely with increased age– Average age of onset of CNVM is early 40s but cases have been
reported in teenagers and elderly• LASIK surgery
– May trigger CNV• Immunocompromised:
– HIV patients has potential to create ideal conditions for reactivation of CNV
In Summary
• Know the Classic Triad of POHS– Histo spots
– Macular CNV
– PPA/scarring
• “Presumed” Ocular Histoplasmosis Syndrome
– Unclear etiology: infection vs. inflammation
• Management:
– No CNV monitor for CNV
– CNV Refer for treatment
Thank you
Amiee Ho, O.D.
Assistant Professor
Pacific University College of Optometry
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