Grand Rounds Solly Elmann, MD SUNY Downstate Medical Center Department of Ophthalmology April 18, 2013
Case Presenta*on An 84 year-‐old white male presents to the clinic for the first *me, for rou*ne examina*on, complaining only of mildly blurry vision in the right eye over the past few years, including worsened night vision. Denies any other complaints, including pain, irrita*on, floaters, flashes, curtains, or any other symptoms. Pa*ent Care
History PMH: Diabetes Mellitus II, HTN, Hypercholesterolemia. All well controlled. POH: LP OS secondary to trauma over 40 years ago; Ocular Hypertension OD “for many years;” s/p CE/PCIOL OD GTs: Betop*c 2/2 All: nkda SH/FH: nega*ve Pa*ent Care
Examina*on BCVA: 20/30 phni, LP SLE: LLA: CollareTes ou; EOMS full ou ectropion os CS: w/q ou CVF: [cf od K: cl ou P: 6-‐4 mm od; +APD os AC: d/q ou Tapp: 10/12 I/P: rr ou, no nvi L: PCIOL, cl and
centered od; dense white cataract os Pa*ent Care
DFE
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Differen*al?
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Differen*al Diagnosis: • • • • • • •
Presumed Ocular Histoplasmosis Syndrome Mul*focal choroidi*s Prior choroidal rupture (prior history of trauma) Idiopathic Choroidal Neovasculariza*on Age-‐Related Macular Degenera*on Myopic degenera*on (this pa*ent is not myopic) Mul*ple Evanescent White Dot Syndrome
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Next step?
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Presumed Ocular Histoplasmosis Syndrome • A dis*nct clinical en*ty defined by specific signs: – Atrophic choriore*nal scarring – Peripapillary scarring – Maculopathy – Absence of vitri*s
• “Presumed” secondary to exposure to Histoplasma capsulatum. – Rarely isolated or cultured from these eyes. Pa*ent Care, Prac*ce-‐Based Learning and Improvement
Histoplasma capsulatum
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The “Histo Belt” • 60% of residents of the Ohio and Mississippi river valleys have posi*ve histoplasmin skin tes*ng • Comstock: Triangle connec*ng Eastern Nebraska, Central Ohio, Southwestern Mississippi
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Spores are inhaled, with an influenza-‐like prodrome. In few pa*ents, a chronic cavitary pulmonary disease occurs. In immunocompromised pa*ents, this may lead to disseminated granulomatous disease. Medical Knowledge
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A Complicated History 1942: Reid: Atrophic choriore*nal lesions found in a pa*ent with acute disseminated histoplasmosis 1959: Woods and Wahlen:
– “peculiar and consistent paTern of ocular les*ons” in 19 pa*ents – Posi*ve histoplasmin skin tes*ng – Atrophic pigmented or unpigmented peripheral lesions (“histo spots”),and late cys*c lesions in the macula. – Theory: prior disseminated histoplasmosis led to these chronic changes
1966: Schlaegel and Kenney:
– Op*c nerve head lesions included in the spectrum of POHS
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Diagnosis No ocular inflamma*on, plus two of the following: 1. “Histo spots” 2. Peripapillary atrophy 3. CNV or CNV-‐related sequelae
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Histo Spots Discrete, focal, atrophic, punched-‐out choroidal scars in the macula or periphery, smaller in size than the op*c disc.
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Peripapillary Atrophy
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CNV or Associated Sequelae CNV Associated sequelae: Hemorrhagic re*nal detachment, fibrovascular disciform scar
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One day post treatment
Two years post treatment
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Other Pearls • Usually bilateral • O[en asymmetric • Seeing the ini*al granulomatous disease is rare
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So… is this Histoplasmosis? Although it is well-‐established that POHS and Histoplasma capsulatum are associated, causality has not been completely established.
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1964
Almost all pa*ents with POHS in the USA have history of living in an endemic area. Posi*ve histoplasmin skin tes*ng occurs more frequently in pa*ents with ocular histoplasmosis compared with controls.
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1967
Following histoplasmin skin tes*ng, histo lesions have been shown to ac*vate
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However… • A clinical syndrome nearly iden*cal to POHS is found in the UK and Europe, in pa*ents that have never visited an endemic area, without posi*ve histoplasmin skin tes*ng. • H. Capsulatum has never been iden*fied in the UK. • Amphotericin B has been shown not to be effec*ve in trea*ng POHS. Medical Knowledge
Gene*c Suscep*bility? • HLA–B7 and HLA–DRw2 have been isolated in higher quan*ty in disciform lesions and histo spots. • There may be a component of gene*c suscep*bility either: – To histoplasmosis primary infec*on – To ocular histoplasmosis
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Pathogenesis
(the most widely accepted theory) 1. Acute disseminated infec*on 2. Focal infec*on of the choroid 3a. Inflammatory and infec*ous process disrupts Bruch’s Membrane and causes atrophic scarring 3b. Infec*on spreads to the RPE and choriocapillarisà subre*nal hemorrhage/exudate with a fibrovascular scar 4. CNV Medical Knowledge
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Choroidal Neovasculariza*on Mul*ple factors and theories: • Disrup*on of Bruch’s Membrane: – access to subre*nal space
• • • • •
HLA typing: gene*c predisposi*on? Larger fungus inoculum Reinfec*on Hypersensi*vity Higher proangiogenic factors, e.g. VEGF Medical Knowledge
Natural History • Asymptoma*c ini*ally – Rarely, atrophic scars may cause some visual disturbances
• O[en, presenta*on of pa*ent is only when vision loss occurs secondary to hemorrhage and exuda*on, decades a[er ini*al infec*on and scarring – Middle aged individuals are most commonly affected
• Spontaneous recovery has been reported in the Macular Photocoagula*on Study. Medical Knowledge
Impairment • In Tennessee: POHS responsible for 2.8% of blindness in individuals applying for governmental support. • In Maryland: No difference in visual impairment in individuals with and without histo spots. • Submacular Surgery Trials Research Group: Bilateral CNV secondary to POHS had similar impairment to pa*ents with AMD Medical Knowledge
Treatment What doesn’t work: • Avoidance of valsalva • Hyposensi*za*on/Desensi*za*on to Histoplasmin • Immunosuppressants • Photocoagula*on (on inac*ve lesions) • Amphotericin B • Nothing has been shown to work on inac*ve lesions. – Most spontaneously involute.
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Photocoagula*on • Macular Photocoagula*on Study (MPS)
– Two randomized control trials; argon laser vs observa*on; 262 pa*ents – At least 200 μm from the FAZ – Enrollment was halted a[er it was clear than argon laser photocoagula*on was superior to observa*on:
• Extrafoveal CNV at 5 years: 44% in observed eyes vs. 9% in treated eyes • Juxtafoveal CNV at 5 years: 28% in observed eyes vs. 12% in treated eyes
– Major complica*on: permanent scotoma secondary to laser photocoagula*on • Not to be used on foveal lesions.
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Photocoagula*on • Macular Photocoagula*on Study (MPS) – A second study was tried again in 1981, this *me allowing pa*ents with visual acuity up to 20/400 with juxtafoveal lesions – This study was also halted a[er it was clear than photocoagula*on offers significant benefit. • 6-‐or more line loss: 11% in treated, 30% in controls • No contraindica*on to treatment of lesions in papillomacular bundle.
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Photodynamic Therapy • Verteporfin for Ocular Histoplasmosis Trial: • 45% of pa*ents had improved vision • 9% with severe vision loss at two years • Mean number of treatments: 2.9 in first year; 1 in second
• Now approved by the FDA for subfoveal CNV due to POHS.
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An*-‐VEGF
• Phase-‐I randomized 12-‐month trial inves*ga*ng ranibizumab for CNV for non-‐AMD pa*ents; 30 pa*ents • 9 pa*ents with POHS • Monthly Ranibizumab vs 3-‐monthly injec*ons followed by prn dosing at monthly visits • 7.4 lines of improvement seen in monthly, 5.0 lines in prn group • No significant differences between the groups at any *me point • No complica*ons seen Medical Knowledge
An*-‐VEGF
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Other op*ons • Combina*on treatment: – PDT plus An*-‐VEGF
• Triamcinolone: – not as effec*ve, high complica*on rate, high failure rate
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Submacular Surgery • Prior to PDT and an*-‐VEGF therapy • Recurrence rate of CNV higher for submacular surgery than for photocoagula*on • Submacular Surgery Trials Group: – 225 pa*ents with non-‐AMD CNV, 192 with POHS – Vision improved or stable in 20% more pa*ents with surgery – Not sta*s*cally significant: all of benefit in pa*ents with 20/100 or worse baseline VA. – Quality of life scores improved with surgery Medical Knowledge
Macular Transloca*on • Limited evidence in the literature • Three cases of POHS treated with 360 degree MTL. • 2/3 with improved VA, 2/3 with recurrent CNV, 2/3 with chronic CME
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Medical Knowledge
Mainstays of treatment • Extrafoveal CNV: laser photocoagula*on • Subfoveal and Juxtafoveal CNV: an*-‐VEGF, PDT • Select situa*ons: surgery • Inac*ve POHS: Observa*on
Pa*ent Care, Prac*ce-‐Based Learning and Improvement
Our Pa*ent • Has received his first Avas*n injec*on with improvement in vision a[er one month of one line (20/40-‐ to 20/30) • Has been offered a second injec*on one month a[er the first. • Is very happy with improvement in vision.
Pa*ent Care, Prac*ce-‐Based Learning and Improvement
Reflec*ve Prac*ce This case taught me the value of a good differen*al diagnosis for choroidal lesions and CNV, and understanding of the criteria of diagnosis involved with POHS. I also learned the value of history taking and focusing on risk factors involved in a diagnosis. I worked together with the aTending, senior residents ocular photographer, and the pa*ent to agree on proper management and interven*on modali*es. The pa*ent and I created good rapport and were able to agree on a plan together. Pa*ent Care, Prac*ce-‐Based Learning and Improvement
References • • • • • • • • • • • • •
Stephen J. Ryan et al., Re1na, 3rd ed. (C.V. Mosby, 2001) Reid JD, Scherer JH, Herbut PA, et al. Systemic histoplasmosis diagnosed before death and produced experimentally in guinea pigs. J Lab Clin Med 1942;27:419–34. Schlaegel TF. Granulomatous uvei*s: an e*ologic survey of 100 cases. Trans Am Acad Ophthalmol Otolaryngol 1958;62:813–25. Woods AC, Wahlen HE. The probable role of benign histoplasmosis in the e*ology of granulomatous uvei*s. Trans Am Ophthalmol Soc 1959;57:318–43. Schlaegel TF, Kenney D. Changes around the op*c nerve head in presumed ocular histoplasmosis. Am J Ophthalmol 1966;62:454–8. Schlaegel TF. Ocular histoplasmosis. New York: Grune & StraTon; 1977. Spencer WH, Chan C-‐C, Shen DF, et al. Detec*on of Histoplasma capsulatum DNA in lesions of chronic ocular histoplasmosis syndrome. Arch Ophthalmol 2003;121:1551–5. Braunstein RA, Rosen DA, Bird AC. Ocular histoplasmosis syndrome in the United Kingdom. Br J Ophthalmol 1974;58:893–8. Submacular Surgery Trials Research Group. Health-‐ and vision-‐related quality of life among pa*ents with ocular histoplasmosis or idiopathic choroidal neovasculariza*on at *me of enrollment in a randomized trial of submacular surgery. SST report no. 5. Arch Ophthalmol 2005;123:78–88. Macular Photocoagula*on Study Group. Argon laser photocoagula*on for neovascular maculopathy: five-‐year results from randomized clinical trials. Arch Ophthalmol 1991;109:1109–14. Macular Photocoagula*on Study Group. Laser photocoagula*on for neovascular lesions nasal to the fovea: results from clinical trials for lesions secondary to ocular histoplasmosis and idiopathic causes. Arch Ophthalmol 1995;113:56–61 Comstock GW, Vicens CN, Goodman NL, et al. Differences in the distribu*on of sensi*vity to histoplasmin and isola*ons of Histoplasma capsulatum. Am J Epidemiol 1968;88:195–209. Heier JS, Brown D, Ciulla T, et al. Ranibizumab for choroidal neovasculariza*on secondary to causes other than age-‐related macular degenera*on: a phase I clinical trial. Ophthalmology 2011;118:111–8.
Thank You • • • • •
Dr Shrier Dr Rubaltelli Christopher Minning Michael DaGlo Our PaIent and neighbor
