Ocular Histoplasmosis

Robert B. Nussenblatt

Key concepts

•Amphotericin therapy does not help.

•Lesions have a high possibility of chorioretinal neovascularization.

•Laser therapy has been used to treat   neovascularizations, as well as anti-VEGF therapies.

•Subretinal surgical removal of neovascular lesions is of minimal value.

Ocular histoplasmosis is the only syndrome in the spectrum of ocular inflammation in which ‘presumed’ has appeared in its name. Epidemiologic evidence supports the concept that an invading organism is the cause of this ocular disease. However, accruing evidence supports the notion that there is a complex interaction between the exogenous pathogen and the immune response. Also, the recent advances in submacular surgery have provided sufferers with this entity with a possible yet-to-be-fully-proven, alternative therapeutic approach to consider besides medical and laser therapy or simply observation.

Systemic findings

Histoplasma capsulatum, a fungus found worldwide in valleys with rivers, is endemic to the midwestern United States. Found in the soil, it is readily inhaled and phagocytosed. Although histoplasmosis may start in the lungs, it can spread to the liver and spleen, leaving small calcified lesions that can be seen on X-ray examination. The disease can take three major forms: a nonfatal acute pneumonitis with fever; an acute progressive form that can be fatal in 1–2 months; and a chronic form similar to tuberculosis.1 These disease presentations rarely have ocular manifestations. The ocular histoplasmosis syndrome is rather a distinct entity found almost exclusively in the United States, and it usually occurs in symptom-free persons living in endemic regions. However, a similar clinical entity has been seen in nonendemic regions both in and outside the United States.

Ocular appearance

Probably Reid and coworkers2 described the first ocular case that we now recognize as the ocular histoplasmosis syndrome, but Woods and Wahlen3 were the first to describe

the ocular syndrome in full detail. They believed that H. capsulatum might be the cause for both the typical atrophic spots in the retinal periphery and the disciform changes in the macula. Although the disorder is found most commonly in the midwestern United States, particularly in the Ohio– Mississippi River valleys, it also appears in the Middle Atlantic states such as Maryland. In these areas, skin tests for histoplasmosis show positive results in a high percentage of the population, indicating systemic sensitization by the immune system. The ocular histoplasmosis syndrome is a rare disease in other parts of the world, even in areas endemic for histoplasmosis.4 From outside the United States there are reports of patients with symptoms that meet the criteria for the diagnosis; however, test results are negative for evidence of histoplasmosis infection and sensitization.5, 6

Studies in the United States have suggested that typical findings of ocular histoplasmosis will be found in 1.6%1 to 12.9%7 of the population in an endemic area. Further, Smith and Ganley8 determined from the Walkersville, Maryland, study that maculopathy due to ocular histoplasmosis will develop in 1 of 1000 adults in an endemic area. The disease appears most commonly in the third to fourth decades of life, with men more likely to have involvement of both maculae.4 It appears that the disease is considerably less common in African-Americans9 (Box 15-1). H. capsulatum causes four major clinical manifestations of the ocular disease: ‘histo’ spots, maculopathy, peripapillary pigment changes, and clear vitreous.

‘Histo’ spots

A disseminated choroiditis produces the typical histo spots. Numbering on average four to eight per eye, these choroidal scars are circular, depigmented, and atrophic; they have a disc diameter of 0.2–0.7 and may have a pigment clump centrally10 (Fig. 15-1). The peripheral lesions are not thought to be significant in terms of prognosis for the maintenance of good visual acuity. In a small number of patients these lesions occur in the equatorial ocular region as streaks running parallel to the ora serrata. They can become larger or smaller, and they may disappear.

Maculopathy

Maculopathy results in a macular lesion that is sightthreatening, causing a sudden, abrupt change in vision. During the initial stage the choroid may take on a groundglass appearance and push the retina upward. In the macula a retinal pigment epithelial detachment can occur, and in 7% of patients a central serous choroidopathy is seen.11 In a

Box 15-1  Characteristics of ocular histoplasmosis

Syndrome

Resident of histoplasmosis belt of the US

White, 20–50 years of age

Multiple choroidal spots (‘histo’ spots)

Peripapillary changes

Disciform scar

No vitreous inflammatory disease

HLA-B7 positivity (macular disease)

large number of patients (63%) the lesion is hemorrhagic,11 and in rare instances causes vitreous hemorrhage.12 Intervals between macular attacks may vary from 1 month to years, leading to a disciform scar (Fig. 15-2). Schlaegel4 informed his patients that if there were histo scars in the macula, then there was a 1 in 4 chance of recurrence in the macula over the ensuing 3 years. However, if no scars are noted, then the chances for ocular problems are about 1 in 50. About 60% of the time this process leads to severe visual impairment, and only 10–15% of patients will maintain 20/20 vision in the affected eye after a 2-year period. The development of a disciform lesion in the second eye depends on whether there are old atrophic histo scars in the macular region, because new lesions appear to arise at the edges of old ones.9 At times these membranes can be difficult to diagnose because of the absence of hemorrhage or pigmentation.13 Rarely, subretinal neovascularization leading to a disciform scar can appear in the absence of previous pigmentary changes, usually denoting a nidus of activity,14 which supports the concept

that there are invisible foci of choroidal inflammation in this disorder.15 Indocyanine green angiography has shown areas of hypofluorescence in areas that can be mapped to points where patients were reporting visual disturbances.16

A point of great interest is the natural history of disciform lesions due to ocular histoplasmosis, particularly in light of new surgical techniques (see later discussion). In ocular histoplasmosis a spontaneous improvement of visual acuity is possible in patients with disciform changes due to this disorder. Jost and coworkers17 found that 10 of 700 patients with ocular histoplasmosis had a spontaneous improvement. In a report by Kleiner and colleagues,18 the visual outcome of 74 eyes having ocular histoplasmosis and active subretinal neovascular membranes was studied. Over a fol- low-up period that ranged from 12 to 109 months (median, 36.5 months) the authors found that 14% of eyes retained a visual acuity of 20/40 or better.

Some of the factors associated with the retention of good vision were the patient’s age (<30 years), the small size of the membrane, and an absence of visual loss due to ocular histoplasmosis in the other eye. Campochiaro and colleagues19 reported on five patients who maintained or spontaneously regained good visual acuity in the presence of a subfoveal neovascular membrane. They believed that a typical pattern emerged for all of these patients when the sequential photographs and angiograms were studied. A pigmented ring forms around the membrane, and the membrane begins to change character on the angiogram, going from one that leaks fluorescein to one that stains but does not leak. With time, there is resorption of subretinal fluid, with limitation of the hemorrhage and fibrosis (Fig. 15-3).

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