Dr Pradeep Venkatesh
Amol D Kulkarni and Suresh R Chandra
Introduction Histoplasmosis is a systemic disease caused by Histoplasma capsulatum. 1 Introduction Histoplasmosis is a systemic disease caused by Histoplasma capsulatum. 1It produces intracellular granulomatous inflammation of many organs including eyes, lungs, liver, spleen etc. ofpunched-out atrophic choroidal scars in the macula or periphery, peripapillary atrophy and choroidalneovascular membrane (CNVM). 2 Etiology- Histoplasmacapsulatum , a dimorphic fungus, is presumed to play a causative role in the development of OHS. 1 There are few reports of pathologic and molecular evidence supporting a direct role for H. capsulatum in the development of chorioretinal scars , however, no serologic confirmation of histoplasmosis infection has been reported. 3,4 A hematogenous dissemination of the fungus results in choroidal invasion and subsequent scarring. Additionally, disseminated histoplasmosispresents with intraretinal infiltrates composed of histoplasma yeast cells easily demonstrable on histology. Extensive study of the affected individuals in Europe and the United States has revealed presence of human leukocyte antigen -DR15 . 5 This HLA association suggests immune reaction is likely to play a major role during the development of scarring and CNVM. H. capsulatummayinduce d localized autoimmune reaction in the retina. However, an infection with this fungus is not an absolute requirement for development of clinical OHS. Because of this lack of association, there has been a suggestion to rename this clinical syndrome as ‘multifocal choroidopathy’. Epidemiology OHS is most common in the Ohio and Mississippi River valleys of the United States, which are endemic for H. capsulatum. 6 Up to 70% of the population living in the endemic areas react positively to the histoplasmin skin testing and 1.5% exhibits the typical fundus findings. 7Itcan be a blinding disease in its more severe manifestations. There is no gender predilection, although some reports show a higher prevalence in women. Pathobiology OHS belongs to the spectrum of autoimmune diseases triggered by an infectious organism, with H. capsulatum being one of several candidate pathogens. It is characterized by a chronic reaction to the immunogenic residua of the H. capsulatum, which acts as a nidus for inflammation. Light microscopy reveals mixed inflammatory cells in the choroidal lesions with loss of overlying retinal pigment epithelium. There are adhesions between the outer retina and choroidal lesions. The genesis of CNVM in OHS is thought to be caused by disruption of Bruch ‘s membrane at the site of atrophic scar. Systemic Features Mycilia of Histoplasmosisareinhaled and they transform to yeast form shortly and infect lungs.They can produce caseation and enlargement of hilar nodes which produce typicalshadows on X-ray. About 90% of cases are benign and do not produce symptoms. In disseminated histoplasmosis are characterized by pyrexia, vomiting and enlargement of liver, spleen , and lymph glands. Involvement of skin, mouth, gastrointestinal tract and heart may also occur. Ocular Features The clinical findings in OHS include peripapillary atrophy, multiple punched out white atrophic choroidal scars (histo spots) , and a macular CNVM, accompanied by the complete absence of a cellular reaction in the anterior chamber or vitreous cavity (Fig. 1 A). 6 The histo spots are considered to be the earliest stage of the disease , and are usually asymptomatic (Fig. 1 B). CNVM will develop in fewer than 5% of individuals with histo spots. Clinical presentation of CNVM involves acute or insidious onset painless progressive blurring of central vision and metamorphopsia. Fundus examination typically shows a yellow-green subretinal discoloration with accumulation of subretinal fluid. In advanced cases there is subretinal fibrosis leading to disciform scar formation and is associated with severe central visual loss. 9The exact time frame between the initial choroidal scarring and CNV development is difficult to determine given that histo spots are asymptomatic. New histo spots may develop in more than 20% of individuals while they are under observation , however, only 3.8% progress to CNV. The precipitating factors promoting such progression are not known. Some studies implicate emotional stress and tension headaches as associated event. Diagnosis OHS is a clinical diagnosis and relies on observation of characteristic fundus lesions in one or both eyes. Intravenous fluorescein angiography (FA) and optical coherence tomography (OCT) can assist in the evaluation of CNVM (Figs 2 and 3). FA assists in identifying areas of CNVM and planning photodynamic therapy. OCT is a useful tool for the detection and monitoring of treatment response. 10 Treatment The optimumtreatment of subfoveal and juxtafovealCNVM is main focus in OHS. Histo spots are asymptomatic in most cases and require no treatment until a progression of the disease is detected. 9-11 Corticosteroids Regimens of systemic corticosteroid therapy were widely used in early studies of ocular histoplasmosis. 12Few clinical studies have evaluated the role of subtenon ’s and intraocular triamcinolone. The intravitreal steroids demonstrated favorable visual outcomes however are associated with cataract formation or progression and increased intraocular pressure. 13 Laser photocoagulation Laser Photocoagulation effectively inhibits the progression of OHS-related CNV. In randomized trials, the Macular Photocoagulation Study demonstrated that argon and kryptonlaser photocoagulation is effective in treating well-defined, classic extrafoveal, juxtafoveal , and peripapillary CNV lesions secondary to OHS. 14, 15Only 12% of treated individuals experienced significant disease progression , compared with 42% of the control patients.
The role of submacular surgery for the removal of CNV lesions was evaluated in a multicent er randomized clinical trial. 16The study data indicate that surgery may be beneficial to patients with visual acuity worse than 20/100 , and subfoveal CNV.
Verteporfin in Ocular Histoplasmosis study enrolled 26 patients prospectively with subfoveal CNV and demonstrated an improvement of visual acuity from baseline as well as an absence of serious adverse events at 2 years. 17
Anti-vascular endothelial growth factor
Several intravitrealanti- VEGF treatments are currently being pursued for the treatment of OHS-related CNV. Few retrospective studies have evaluated the role of intravitreal anti-VEGF therapy for CNV associated with OHS. One such study by Ehrlich et al. found that at least 50% of eyes with subfoveal or juxtafoveal CNV experienced
>=3 lines of vision gain and 91.5 % to 100% of patients improved or had stable visual acuity (at 3- to 12-month follow-up) after intravitrealbevacizumab therapy. 18Similary, the results concerning the therapeutic efficacy of ranibizumab are promising. Both treat-and-extend and pro renata treatment strategies were effective. A study by Nielsen et al. demonstrated that many eyesrequire long-term anti-VEGF therapy to suppress choroidalneovascular activity in OHS. 19 Suggested reading Smith RE, Ganley JP. An epidemiologic study of presumed ocular histoplasmosis. Trans Am Acad Ophthalmol Otolaryngol 1971; 75:994 -1005. Gass JDM, Wilkinson CP. Follow-up study of presumed ocular histoplasmosis. Trans Am Acad Ophthalmol Otolaryngol 1972; 76:672 – 94. Hawkins BS, Alexander J, Schachat AP. Ocular histoplasmosis. In: Ryan, SJ, Sch ah chat, AP, editors. Retina . St. Louis , MO: Mosby; 2001 . Oliver A, Ciulla TA, Comer GM. New and classic insights into presumed ocular histoplasmosis syndrome and its treatment. Curr Opin Ophthalmol. 2005 Jun;16(3):160 – 5. Prasad AG, Van Gelder RN. Presumed ocular histoplasmosis syndrome. Curr Opin Ophthalmol. 2005 Dec;16(6):364 – 8. Macular Photocoagulation Study Group. Argon laser photocoagulation for ocular histoplasmosis: results of a randomized trial. Arch Ophthalmol 1983; 101:1347 – 57. Macular Photocoagulation Study Group. Krypton laser photocoagulation for neovascular lesions of ocular histoplasmosis: results of a randomized clinical trial. Arch Ophthalmol 1987; 105:1499 -1507. Rosenfeld PJ, Saperstein DA, Bressler NM, et al. Photodynamic therapy with verteporfin in ocular histoplasmosis: uncontrolled, open-label 2-year study. Ophthalmology 2004; 111:1725 – 33. Nielsen JS, Fick TA, Saggau DD, Barnes CH. Intravitreal anti-vascular endothelial growth factor therapy for choroidal neovascularization secondary to ocular histoplasmosis syndrome. Retina. 2012 Mar;32(3):468 – 72. Fig. 1 Fundus photo s of patient with OHS showing peri-papillary atrophy and CNV with subretinal h emorrhage in the right eye (A) and macular histo spot in the left eye (B).