Part 4 • Infectious Uveitic Conditions

Chapter 15 Ocular Histoplasmosis

disorders, including ocular histoplasmosis. In these studies, untreated eyes with extrafoveal choroidal neovascularization due to ocular histoplasmosis had a 3.6 times greater risk of losing six or more lines of visual acuity than did laser-treated eyes. However, recurrent neovascularization was noted in 26% of the treated eyes. In a multicenter, randomized controlled clinical trial the Canadian Ophthalmology Study Group57 found that krypton red laser photocoagulation was no better for well-defined extrafoveal nets than was argon green laser photocoagulation.

A study was reported in which laser therapy treated subfoveal neovascular nets.58 Only 25 patients were enrolled, and the follow-up period was fairly short. The observers could not conclude whether the approach was useful or not, but a marked decrease in vision did not appear to occur in the group treated with laser photocoagulation, nor was there a striking increase. One interesting aspect of this report was the difficulty of recruiting patients; the authors hypothesized that most patients’ nets begin outside the fovea and therefore are treated before reaching the more advanced stage. Recurrence of subretinal neovascular nets is problematic. Green59 reported a clinicopathologic study of treated choroidal neovascular membranes and noted that recurrences of choroidal neovascularization, some contiguous and some not contiguous to treated areas, occurred in nine of 12 lesions in the 10 eyes he studied. It is interesting to note that the scar induced by laser photocoagulation resembled that of the naturally occurring scar, portions of which consisted of hyperplastic retinal pigment epithelium.

Photodynamic therapy can be considered as a therapeutic approach for macular subretinal neovascular lesions associated with this disease.60 Saperstein and colleagues61 reported the results of a small (26-patient) open-label, three-center noncomparative case series using photodynamic therapy in the treatment of subfoveal neovascular lesions related to ocular histoplasmosis. By month 12 patients averaged 2.9 treatments, and there was a median improvement of seven letters from baseline for 14 patients, whereas four patients lost eight or more letters and two lost 15 or more. No serious systemic side effects or ocular adverse events were reported. More recently, Leslie and coworkers62 retrospectively reviewed the cases of six patients with predominantly classic CNVs secondary to inflammatory disease and whose CNV apparently did not regress with immunosuppressive therapy. According to the report two of the six patients had ocular histoplasmosis. With a median follow-up of 10 months, an improvement in vision (median improvement 18 letters) occurred in all cases. Thus the authors felt that PDT was a useful consideration in such patients. Lim and colleagues63 came to a different conclusion in their report, stating that PDT may stabilize but not improve the visual acuity of eyes with CNV secondary to inflammatory disease. Our experience, albeit based on few patients, has not been as positive, but certainly the literature seems to present a more nuanced picture.

Subretinal surgery

The removal of choroidal neovascular nets by means of subretinal surgery techniques has especially provocative

implications. Although subretinal surgery reports appeared in the 1980s,64,65 this type of surgery did not really develop until the 1990s, with the advent of new instruments and indications. Choroidal neovascularization due to ocular histoplasmosis has been one disease in which this approach has been explored in some depth. An initial paper by Thomas and Kaplan66 reported on two patients with subfoveal neovascularization due to the ocular histoplasmosis syndrome whose visual acuities were 20/400. After surgery the visual acuity returned to 20/20 in one patient and to 20/40 in the other, with a short follow-up time. Subsequent reports have put the technique in perspective, albeit not definitively. Berger and Kaplan67 reported that eight of 15 patients with subfoveal choroidal neovascularization due to ocular histoplasmosis had an improvement of two lines or better after subretinal surgery and removal of the membrane. They noted an improvement in vision even after 6 months of reduced vision. Recurrent neovascularization occurred in two of the 15 eyes. Thomas and coworkers68 performed two types of procedure on patients with histoplasmosis who had subfoveal nets. After performing a vitrectomy, the authors either disconnected the choroidal circulation or extracted the net through their retinotomy site. Of 16 eyes that had membranes removed, six improved by at least two Snellen lines, whereas none of the eyes of four patients in which the membranes’ choroidal circulation was disconnected showed such improvement. A large study of 117 patients with ocular histoplasmosis and subretinal neovascularization provided some insight into the long-term effects of subretinal surgery.69,70 In a median 13-month follow-up, recurrence of disease was noted in 51 eyes (44%), the median time to recurrence being 3 months. Recurrences were extrafoveal (16%), juxtafoveal (18%), and subfoveal (66%). In this group of eyes with recurrent disease, 16 were treated with laser, 17 had repeat surgery, and 18 were observed. Visual outcome was better in the eyes treated with laser. During this median 13-month follow-up approximately 35% of eyes saw 20/40 or better, and 40% had improvement of three lines or better than before surgery. For those patients followed for at least 1 year, vision appeared to be stable or improved compared to the 3-month postoperative visual acuity measurements. Recently, Almony and colleagues71 reported a retrospective review of patients with extensive peripapillary choroidal neovascularization, a different type of lesion than discussed before. They found that this approach yielded positive results with stabilization or improvement of visual acuity.

There was certainly enough information to support a randomized trial to evaluate the use of surgery for foveal or perifoveal choroidal neovascular lesions secondary to ocular histoplasmosis, or those that appear to be idiopathic. The results of this study were published in a series of papers and are important reading for those interested in the subject. The Submacular Surgery Trials (SST) Research Group randomized 225 patients to either observation (113) or subretinal surgery (112): 46% of the observation arm and 55% of those in the surgery arm had a successful outcome.72 Five in the surgery arm had rhegmatogenous detachments. The conclusion overall was that there was no or a smaller benefit to surgery than the trial was designed to detect. One subgroup that may benefit more from surgery was a group with a visual acuity of 20/100 or worse and had other criteria

mentioned in the report. To be fair, another report73 of this study measured vision-targeted quality of life measures in these patients, and the surgical arm did show a larger

References

References

improvement in the measure of this parameter than did the observation arm. The authors called it a ‘possible small overall benefit.’

1.Asbury T. The status of presumed ocular histoplasmosis: including a report of a survey. Trans Am Ophthalmol Soc 1966; 64: 371–400.

2.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: 419–434.

3.Woods AC, Wahlen HE. The probable role of benign histoplasmosis in the etiology of granulomatous uveitis. Am J Ophthalmol 1960; 49: 205– 220.

4.Schlaegel TFJ. Ocular histoplasmosis. 1977, New York: Grune & Stratton.

5.Saraux H, Pelosse B, Guigui A. Multifocal inner choroiditis: pseudohistoplasmosis – the European form of the presumed American histoplasmosis. J Fr Ophtalmol 1986;

9:645–651.

6.Braunstein RA, Rosen DA, Bird AC. Ocular histoplasmosis syndrome in the United Kingdom. Br J Ophthalmol 1974; 58: 893–898.

7.Davidorff FH, Anderson JD. Ocular lesions in the Earth Day 1970 histoplasmosis epidemic. Int Ophthalmol Clin 1975; 15: 51–60.

8.Smith RE, Ganley JP. An epidemiologic study of presumed ocular histoplasmosis. Trans Am Acad Ophthalmol Otolaryngol 1971; 1971: 994–1005.

9.Gass JDM, Wilkinson CP. Follow-up study of presumed ocular histoplasmosis. Trans Am Acad Ophthalmol Otolaryngol 1972; 76: 672–694.

10.Smith RE, Ganley JP, Knox DL. Presumed ocular histoplasmosis. II. Patterns of peripheral scarring in persons with nonmacular disease. Arch Ophthalmol 1972; 87: 251– 257.

11.Walma D, Schlaegel TFJ. Presumed ocular histoplasmosis. Am J Ophthalmol 1964; 57: 107–110.

12.Kranias G. Vitreous hemorrhage secondary to presumed ocular histoplasmosis syndrome. Ann Ophthalmol 1985; 17: 295–298.

13.Rivers MB, Pulido JS, Folk JC. Illdefined choroidal neovascularization within ocular histoplasmosis scars. Retina 1992; 12: 90–95.

14.Ryan SJJ. De novo subretinal neovascularization in the histoplasmosis syndrome. Arch Ophthalmol 1976; 94: 321–327.

15.Schlaegel TFJ. The concept of invisible choroiditis in the ocular histoplasmosis syndrome. Int Ophthalmol Clin 1983;

23:55–63.

16.Weinberger AWA, Kube T, Wolf S. Dark spots in late-phase indocyanine green

angiographic studies in a patient with presumed histoplasmosis syndrome. Graefe’s Arch Clin Exp Ophthalmol 1999; 237: 524–526.

17.Jost BF, Olk RJ, Burgess DB. Factors related to spontaneous visual recovery in the ocular histoplasmosis syndrome. Retina 1987; 7: 1–8.

18.Kleiner RC, Ratner CM, Enger C, et al. Subfoveal neovascularization in the ocular histoplasmosis syndrome: a natural history study. Retina 1988; 8: 225–227.

19.Campochiaro PA, Morgan KM, Conway BP, et al. Spontaneous involution of subfoveal neovascularization. Am J Ophthalmol 1990; 109: 668–675.

20.Perry JD, Girkin CA, Miller NR, et al. Disseminated histoplasmosis causing reversible gaze palsy and optic neuropathy. J Neuro-Ophthalmol 1999; 19: 140–143.

21.Parnell JR, Jampol LM, Yannuzzi LA,

et al. Differentiation between presumed ocular histoplasmosis syndrome and multifocal choroiditis with panuveitis based on morphology of photographed fundus lesions and fluorescein angiography. Arch Ophthalmol 2001; 119: 208–212.

22.Nozik RA, Dorsch W. A new chorioretinopathy associated with anterior uveitis. Am J Ophthalmol 1973; 76: 758–762.

23.Deutsch TA. Tessler HH. Inflammatory pseudohistoplasmosis. Ann Ophthalmol 1985; 17: 461–465.

24.Suttorp-Schulten MSA. The etiology of the presumed ocular histoplasmosis syndrome. Ocul Immunol Inflamm 1997; 5: 71–72.

25.Watzke RC, Klein ML, Weiner MH. Histoplasmosis-like choroiditis in a nonendemic area. The Northwest United States. Retina 1998; 18: 204–212.

26.Suttorp-Schulten MSA, Bollemeijer JG, Bos PJ, et al. Presumed ocular histoplasmosis in the Netherlands – an area without histoplasmosis. Br J Ophthalmol 1997; 81: 7–11.

27.Sinha R, Raju S, Garg SP, et al. Presumed ocular histoplasmosis syndrome in India. Ocul Immunol Inflamm 2007; 15(4): 315–317.

28.Amaro MH, Muccioli C, Abreu MT. Ocular histoplasmosis-like syndrome: a report from a nonendemic area. Arq Bras Oftalmol 2007; 70(4): 577–580.

29.Scholz R, Green WR, Kutys R, et al.

Histoplasma capsulatum in the eye. Ophthalmology 1984; 91: 1100– 1104.

30.Goldstein BG, Buettner H. Histoplasmic endophthalmitis: a clinicopathologic correlation. Arch Ophthalmol 1983; 101: 774–777.

31.Specht CS, Mitchell KT, Bauman AE, et al. Ocular histoplasmosis with retinitis in a patient with acquired immune deficiency syndrome. Ophthalmology 1991; 98: 1356– 1359.

32.Pulido JS, Folberg R, Carter KD, et al.

Histoplasma capsulatum endophthalmitis after cataract extraction. Ophthalmology 1990; 97: 217–220.

33.Khalil MK. Histopathology of presumed ocular histoplasmosis. Am J Ophthalmol 1982; 94: 369–376.

34.Ryan SJJ. Histopathological correlates of presumed ocular histoplasmosis. Int Ophthalmol Clin 1975; 15: 125–137.

35.Maumenee AE. Clinical entities in ‘uveitis’: an approach to the study of intraocular inflammation. Am J Ophthalmol 1970; 69: 1–27.

36.Gwin RM, Makley TA Jr, Wyman M, et al. Multifocal ocular histoplasmosis in a dog an cat. J Am Vet Med Assoc 1980; 176: 638–642.

37.Smith RE, Dunn S, Jester JV. Natural history of experimental histoplasmic choroiditis in the primate. Invest Ophthalmol Vis Sci 1984; 25: 810–819.

38.Jester JV, Smith RE. Subretinal neovascularization after experimental ocular histoplasmosis in a subhuman primate. Am J Ophthalmol 1985; 100: 252–258.

39.Anderson A, Clifford W, Palvolgyi I, et al. Immunopathology of chronic experimental histoplasmic choroiditis in the primate. Invest Ophthalmol Vis Sci 1992; 33: 1637–1641.

40.Check IJ, Diddie KR, Jay WM, et al. Lymphocyte stimulation by yeast phase

Histoplasma capsulatum in presumed ocular histoplasmosis syndrome. Am J Ophthalmol 1979; 87: 311–316.

41.Brahmi Z, Wheat J, Rubin RH, et al. Humoral and cellular immune response in ocular histoplasmosis. Ann Ophthalmol 1985; 17: 440–444.

42.Godfrey WA, Sabates R, Cross DE. Association of presumed ocular histoplasmosis with HLA-B7. Am J Ophthalmol 1978; 85: 854–858.

43.Braley RE, Meredith TA, Aaberg TM, et al. The prevalence of HLA-B7 in presumed ocular histoplasmosis. Am J Ophthalmol 1978; 85: 859–861.

44.Spaide RF, Skerry JE, Yannuzzi LA, et al. Lack of HLA-DR2 specificity in

multifocal choroiditis and panuveitis. Br J Ophthalmol 1990; 74: 536–537.

45.Ongkosuwito JV, Tilanus MG, Van der Lelij A, et al. Amino acid residue 67 (isoleucine) of HLA-DRB is associated with POHS. Invest Ophthalmol Vis Sci 2002; 43: 1725–1729.

46.Ongkosuwito JV, Kortbeek LM, Van der Lelij A, et al. Aetiological study of the

217

66.Thomas MA, Kaplan HJ. Surgical removal of subfoveal neovascularization in the presumed ocular histoplasmosis syndrome. Am J Ophthalmol 1991; 111: 1–7.

67.Berger AS, Kaplan HJ. Clinical experience with the surgical removal of subfoveal neovascular membranes: short term postoperative results. Ophthalmology 1992; 99: 969–975.

68.Thomas MA, Grand MG, Williams DF, et al. Surgical management of subfoveal choroidal neovascularization. Ophthalmology 1992; 99: 952–968.

69.Melberg NS, Thomas MA, Dickinson JD, et al. Managing recurrent neovascularization after subfoveal surgery in presumed ocular histoplasmosis syndrome. Ophthalmology 1996; 103: 1064–1069.

70.Holekamp NM, Thomas MA, Dickinson JD, et al. Surgical removal of subfoveal choroidal neovascularization in presumed ocular histoplasmosis. Ophthalmology 1997; 104: 22–26.

71.Almony A, Thomas MA, Atebara NH, et al. Long-term follow-up of surgical removal of extensive peripapillary choroidal neovascularization in presumed ocular histoplasmosis syndrome. Ophthalmology 2008; 115(3): 540–545 e5.

72.Hawkins, BS, Bressler NM, Bressler SB, et al. Surgical removal vs observation for subfoveal choroidal neovascularization, either associated with the ocular histoplasmosis syndrome or idiopathic: I. Ophthalmic findings from a randomized clinical trial: Submacular Surgery Trials (SST) Group H Trial: SST Report No. 9. Arch Ophthalmol 2004; 122(11): 1597–1611.

73.Hawkins BS, Miskala PH, Bass EB, et al. Surgical removal vs observation for subfoveal choroidal neovascularization, either associated with the ocular histoplasmosis

syndrome or idiopathic: II. Quality-of- life findings from a randomized clinical trial: SST Group H Trial: SST Report No. 10. Arch Ophthalmol 2004; 122(11): 1616–1628.