Reactivation of Inflammatory Lesions in Ocular Histoplasmosis

CLINICAL SCIENCES Reactivation of Inflammatory Lesions in Ocular Histoplasmosis

David Callanan, MD; Gary E. Fish, MD, JD; Rajiv Anand, MD

Background: Active inflammation has not been tradi- Results: Twelve patients were seen with active inflam- tionally associated with the ocular histoplasmosis syn- matory lesions. Eleven had resolution of the loci with less- drome. ening of symptoms and improvement in acuity and angiographic findings. A typical subretinal neovascular Objective: To investigate the occurrence of presumed membrane developed in 1 patient 8 months after the on- inflammatory chorioretinal lesions in patients with the set of symptoms. ocular histoplasmosis syndrome. Conclusions: Inflammatory chorioretinal lesions can re- Methods: Patients seen with acute symptoms and a clini- activate in the ocular histoplasmosis syndrome. In most cal picture of ocular histoplasmosis were observed pro- of these patients, neovascularization did not develop and spectively between August 13, 1993, and December 2, 1997. visual acuity was preserved. Symptoms, visual acuity, and fluorescein sodium angiography were used to document changes in inflammatory loci. Arch Ophthalmol. 1998;116:470-474

HE OCULAR histoplasmosis (range, 16-74 years). Of the 12 patients, syndrome (OHS) has typi- 7 were women. The patients had a docu- cally included atrophic cho- mented diagnosis of OHS for a mean of rioretinal lesions, peripapil- 10.9 years (range, 1.1-28.7 years). The lary scarring, and the mean follow-up of the study was 2.1 years absenceT of vitreal inflammation.1-4 Choroi- (range, 0.9-3.7 years). dal neovascularization is the common cause The mean acuity on presentation was of loss of vision in involved eyes and is es- 20/100 (range, 20/20-20/400) in the af- timated to occur in up to 5% of affected fected eye. The mean final acuity in the af- eyes.3,5 Gass and Wilkinson4 have re- fected eye was 20/60 (range, 20/20-20/ ported that patients observed for an ex- 400). Seven patients had more than 2 lines tended period can demonstrate enlarge- of improvement in their acuity, and 4 pa- ment of previous scars and even the tients maintained good acuity in the af- development of new ones. Palvolgyi et al6 fected eye with resolution of their symp- have shown in a primate model of OHS that toms. Only 1 patient (patient 5) lost inflammatory lesions can reactivate. The significant acuity during the study. This Macular Photocoagulation Study Group7 re- patient initially improved, but 5 months cently reported the results of a 5-year fol- later his symptoms recurred and a lesion low-up of fellow eyes in patients with OHS. developed into a typical subfoveal neo- In a retrospective review of photographs be- vascular membrane during a 3-month pe- fore the development of choroidal neovas- riod. cularization, “atypical” histoplasmosis le- The mean acuity in the fellow eye was sions were noted. It is unclear what these 20/170. Each of the decreased acuities in atypical spots represent. This report pro- the fellow eye was from previous choroi- vides an extended follow-up of patients with dal neovasculariation. OHS who had an acute reactivation of pre- Of the 12 patients, 6 had myopia. sumed inflammatory loci. Eight of the patients had only 1 episode during the follow-up. Three patients had RESULTS 2 separate episodes during the follow-up, and 1 patient had 3 separate episodes. From the Texas Retina The Table shows the characteristics of the Of the 12 patients, 7 had a history of Associates, Arlington. patients. The mean age was 50.1 years onychomycosis or recurrent vaginal yeast

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©1998 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/01/2021 PATIENTS AND METHODS with a Hruby lens or 90-diopter lens. Each of the patients demonstrated at least 1 active lesion that showed progressive leakage with irregular borders on All patients with OHS who were seen with new symp- angiography. The lesions did not resemble typical well- toms between August 13, 1993, and November 25, 1995, defined neovascular membranes; they lacked a branch- and who did not have typical neovascular membranes ing network of vessels, early choroidal fluorescence, were included in the study. Twelve patients with a mini- subretinal hemorrhage, or increased pigmentation. The mum follow-up of 6 months are included in this report. optic nerve did not show any signs of active inflamma- In each case, the patients had acute symptoms of tion such as leakage or staining. Routine visual field test- decreased vision or metamorphopsia. A detailed clinical ing was not done. Indocyanine green angiography and history was obtained, visual acuity was measured, and electrophysiologic testing were also not done on a rou- an examination of dilated eyes was performed. None of tine basis. the patients reported peripheral photopsias that could be The follow-up consisted of monitoring visual acuity, associated with other inflammatory diseases. The symptoms, clinical appearance, and fluorescein sodium an- patients’ best Snellen acuity with either their current giography as indicated. refraction or pinhole acuity was recorded on each visit. Of the 12 patients, 6 had been placed on a regimen of An afferent pupillary defect was not noted in any of the oral corticosteroids before being seen by us. The dosage was patients. In all patients there were typical punched-out rapidly tapered in all cases. All 12 patients received a course atrophic chorioretinal lesions as well as peripapillary of oral itraconazole, an antifungal medication. chorioretinal atrophy. In addition, none of the patients Informed consent was obtained from all patients in the had vitreous cells as determined by slitlamp examination study.

Characteristics of Patients With the Ocular Histoplasmosis Syndrome (OHS)

Visual Acuity ‡

Patient/Sex/ Duration of Acute Phase Involved Fellow Episodes, Age, y Disease, y* Follow-up, y† Initial Final Eye Eye Myopia§ Steroid§ No.ሻ Systemic Fungus¶ 1/F/50 10.2 1.4 25 20 OS 25 N Y 1 None 2/F/54 5.9 3.7 30 20 OD 20 Y Y 2 Toenail 3/M/56 9.0 2.7 20 20 OS 200 Y Y 3 Toenail 4/M/49 3.1 3.1 70 25 OS 60 N Y 1 None 5/M/61 11.3 1.2 60 400 OD 20 N N 2 Toenail 6/M/48 16.1 0.9 200 60 OS 300 Y N 1 Athlete’s foot 7/F/45 2.7 2.1 80 25 OD 400 N Y 2 None 8/F/74 18.7 3.0 80 25 OD 200 Y Y 1 Athlete’s foot 9/F/16 1.1 1.2 200 20 OD 20 N N 1 None 10/F/40 2.9 2.1 400 60 OD 100 Y N 1 Recurrent vaginal 11/F/52 28.7 1.8 20 20 OD 400 Y N 1 Fingernail, vaginal 12/M/58 20.9 2.0 25 20 OD 300 N N 1 None Mean 50.1 10.9 2.1 100.8 59.6 . . . 170.4 ......

*Duration of documented history of OHS. †Length of follow-up for current active phase. ‡Snellen acuity (best of current refraction or pinhole). §N indicates no; Y, yes. For steroid, patient received steroids for treatment (Y) or did not (N). ࿣Number of separate symptomatic episodes during follow-up. ¶History of external fungal infection.

infections. Because of this, they were treated with itra- 3 atrophic lesions temporal to the fovea. The patient un- conazole. Of these 7 patients, 3 were treated with oral derwent laser photocoagulation in his right eye in April prednisone at the beginning of their course before being 1989 for a typical choroidal neovascular membrane. He seen by us; the steroid dosage was rapidly tapered. The was seen in July 1994 with a “spot” in his left eye for 3 remaining 5 patients without a history of systemic fun- weeks. Acuity was 20/70 OD and 20/25 OS. He had an gal infection were also treated with itraconazole be- atrophic scar in the right eye (Figure 1, B). One of the cause they did not show a prompt response to steroid ad- spots next to the fovea in his left eye was significantly ministration or had previously lost vision in the fellow larger (Figure 1, C) and had lost its sharp borders. The eye despite corticosteroid treatment. angiogram demonstrated active leakage at this site (Fig- Six patients had documented evidence that the ac- ure 1, D and E). Oral prednisone at a dosage of 40 mg/d tive inflammatory lesion had been present previously as was started and then tapered over 1 week. A regimen of an inactive scar. Figure 1 shows the course of patient 3 oral itraconazole was also started, which was continued and highlights the characteristics of these patients. A pho- for 2 months at a dosage of 100 mg twice a day. He noted tograph of the left eye in May 1988 (Figure 1, A) shows gradual improvement during the next month. The pa-

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C D

E F

G H

Figure 1. Patient 3. A, The left eye in May 1988 shows 3 atrophic lesions just temporal to the fovea. B, The right eye in July 1994 shows an atrophic laser treatment scar. C, The left eye in July 1994 shows enlargement of an inferior lesion (arrow). Early (D) and late (E) phases of angiography show the inferior lesion as a hyperfluorescent spot with leakage. F, In October 1994 there was resolution of the lesion in the left eye (arrow). Early (G) and late (H) angiography shows staining of the inactive scar without any leakage.

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C D

E F

Figure 2. Patient 5. A, The right eye in July 1985 shows no lesion in the macula, and this is confirmed on the angiogram (B). Both eyes (C and D) in August 1995 show a new white-yellow lesion in the fovea of the right eye and atrophic scar in the left. Early (E) and late (F) phases of angiography show a poorly defined hyperfluorescent lesion with leakage in the right eye.

tient later reported that a chronic fungal infection of the treated with laser. He was seen in August 1995 with new toenails had cleared while he was taking the itracona- symptoms in his right eye. Acuity was 20/60 OD. He also zole. Figure 1, F through H, shows the color and angio- reported a chronic fungal infection of the toenails. There graphic appearance 3 months after onset. There is no was a new lesion present in the right eye and an atrophic longer any evidence of active inflammation. Acuity was scar in the left eye (Figure 2, C-F). The new lesion in the 20/80 OD and 20/20 OS. right eye was poorly defined and did not resemble a typi- Five patients had no previous photographs to deter- cal neovascular membrane. A regimen of itraconazole, 100 mine whether the active spot had been present previ- mg twice a day, was started. During the next month, the ously. One patient (patient 5) had photographic and an- patient had improvement of his vision to 20/30. The dos- giographic evidence that the inflammatory lesion was new. age of itraconazole was decreased to 100 mg/d. In Decem- Figure 2, A and B, shows the patient’s right eye in July ber 1995 the patient thought his vision was stable, and his 1985. There is no macular lesion visible on the photo- acuity measured 20/25+2. The itraconazole was stopped. graph or angiogram. At that time, he had an extrafoveal neo- Three months later, a classic subfoveal neovascular vascular membrane in his left eye that was successfully membrane developed in the right eye. Acuity decreased to

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©1998 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/01/2021 20/60. He underwent successful subretinal surgery in April all, of our patients had a chronic fungal infection of the foot 1996 but had a recurrence 3 months after that. Acuity is or a history of recurrent vaginal yeast infections. We could currently 20/400. speculate that these patients have some immunologic or genetic inability to eradicate fungal infections. We could COMMENT also speculate that the peripheral fungal infection may some- how trigger an immune response leading to the reactiva- Gass and Wilkinson4 previously reported the results of tion of ocular inflammation. This was the rationale in ini- follow-up of 81 patients with OHS. Only 1 of these pa- tially treating these patients with itraconazole. tients had a new histoplasmosis lesion develop during a One of the more important questions raised by this 7-year follow-up. During this time, 11 patients had en- report is whether it is possible to prevent neovascular- largement of an existing lesion, as determined by a com- ization and its subsequent effect on vision. It is not pos- parison of color photographs. Patient 5 in this report had sible from this small group of patients to determine the angiographic evidence of the development of a new his- efficacy of intervention. Neovascularization developed in toplasmosis lesion. Rivers et al8 described 2 patients with only 1 of 12 patients during an extended period. It can- OHS who were seen with metamorphopsia. Both pa- not be said whether these presumed inflammatory le- tients had poorly defined neovascularization, but typi- sions would have resolved spontaneously. The previous cal choroidal neovascularization developed within a short course of the fellow eye in our patients suggests that these period. The authors concluded that ill-defined lesions seen patients are at considerable risk of vision loss. Only a large on fluorescein angiograms probably represented early neo- randomized study of patients with OHS will determine vascularization. Recently the Macular Photocoagula- the efficacy of any treatment. The purpose of this study tion Study Group released a 5-year follow-up report7 on was to document that active inflammation occurs in OHS. the development of neovascularization in the fellow eye We can speculate that there is a potential to prevent neo- of patients with OHS. The group presented evidence that vascularization in some patients with OHS, if we can de- neovascularization occurred in association with atypi- termine a treatment that is effective for inflammation and cal histoplasmosis lesions in the macula of the fellow eye. the patients are seen early in the disease. Patients with How these atypical spots evolve or how frequent they are known OHS should be encouraged to use an Amsler grid is still not well understood. Each of these previous re- regularly. This may allow earlier detection of an active ports has suggested that there is an evolution of the dis- process. It is hoped that further study will allow us to ease in some patients with OHS. determine the correct therapeutic intervention. Smith and colleagues6,9,10 have contributed substan- tially to our understanding of OHS with an experimen- Accepted for publication December 30, 1997. 10 tal primate model. Smith et al initially demonstrated that Presented in part at the McGill Symposium on Uve- typical lesions of OHS could be produced in monkeys fol- itis, Montreal, Quebec, May 12, 1995, and the American Uve- lowing the intravenous administration of live Histo- itis Society, Atlanta, Ga, October 30, 1995. 6 plasma capsulatum. Palvolgyi et al subsequently re- Ronald E. Smith, MD, provided helpful review and com- ported that inflammatory reactivation occurred in ocular ments. histoplasmosis lesions when these same monkeys were Reprints: David Callanan, MD, Texas Retina Associ- administered antigen only. This report was the stimulus ates, 1001 N Waldrop Dr, Room 605, Arlington, TX 76012 for our investigation. (e-mail: [email protected]). Many ophthalmologists think of OHS as a static con- dition in which neovascularization develops at the site of previous scars. The course of our patients indicates REFERENCES that inflammation does indeed recur in humans with OHS. This can result in enlargement of an existing lesion and 1. Krause AC, Hopkins WG. Ocular manifestation of histoplasmosis. Am J Ophthal- mol. 1951;34:564-566. the formation of a new lesion. If the active lesions in our 2. Woods AC, Wahlen HE. The probable role of benign histoplasmosis in the etiol- patients represented early neovascularization, then there ogy of granulomatous uveitis. Am J Ophthalmol. 1960;49:205-220. was an unusually rapid regression of these neovascular 3. Smith RE, Ganley JP. An epidemiologic study of presumed ocular histoplasmosis. Trans Am Acad Ophthalmol Otolaryngol. 1971;75:994-1005. membranes. They did not appear to be typical neovas- 4. Gass JDM, Wilkinson CP. Follow-up study of presumed ocular histoplasmosis. cular lesions for other reasons as well. They lacked a sharp Trans Am Acad Ophthalmol Otolaryngol. 1972;76:672-694. 5. Lewis ML, Van Newkirk MR, Gass JDM. Follow-up study of presumed ocular his- border in the early phase of angiography and did not have toplasmosis syndrome. Ophthalmology. 1980;87:390-398. a fine mesh or branching structure. In addition, they did 6. Palvolgyi I, Anderson A, Rife L, Taylor C, Smith RE. Immunopathology of reac- not follow a typical course for neovascular membranes. tivation of experimental ocular histoplasmosis. Exp Eye Res. 1993;57:169-175. 7. Macular Photocoagulation Study Group. Five-year follow-up of fellow eyes of in- They quickly became quiescent without laser treat- dividuals with ocular histoplasmosis and unilateral extrafoveal or juxtafoveal cho- ment. They also did not have a permanent deleterious roidal neovascularization. Arch Ophthalmol. 1996;114:677-688. effect on vision that would be typical of untreated neo- 8. Rivers MB, Pulido JS, Folk JC. Ill-defined choroidal neovascularization within ocular histoplasmosis scars. Retina. 1992;12:90-95. vascular membranes. 9. Anderson A, Clifford W, Palvolgyi I, Rife L, Taylor C, Smith RE. Immunopathol- Perhaps these patients represent only a subset of pa- ogy of chronic experimental histoplasmic choroiditis in the primate. Invest Oph- 11,12 thalmol Vis Sci. 1992;33:1637-1641. tients with OHS. Previous studies have shown a ge- 10. Smith RE, Macy JI, Parrett C, Irvine J. Variations in acute multifocal histoplasmic netic association in patients with OHS. Both HLA-DRw2 choroiditis in the primate. Invest Ophthalmol Visual Sci. 1978;17:1005-1018. and HLA-B7 have been found in a high percentage of pa- 11. Meredith TA, Smith RE, Duquesnoy RJ. Association of HLA-DRw2 antigen with 11 presumed ocular histoplasmosis. Am J Ophthalmol. 1980;89:70-76. tients with OHS. In addition, HLA-B7 appeared to be re- 12. Braley RE, Meredith TA, Aaberg TM, Koethe SM, Witkowski JA. The prevalence of lated to the presence of disciform scars.12 Several, but not HLA-B7 in presumed ocular histoplasmosis. Am J Ophthalmol. 1978;85:859-861.

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