Ocular Histoplasmosis

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Choroidal Vascular/Bruch’s Membrane Disease

Ocular Histoplasmosis Justis P. Ehlers, Barbara S. Hawkins, Andrew P. Schachat

HISTORICAL PERSPECTIVE In 1942 Reid provided the first description of histoplasmosisassociated ophthalmic abnormalities from a patient with acute disseminated histoplasmosis.1 Following Reid’s description, additional reports surfaced of atrophic chorioretinal lesions associated with positive histoplasmin skin testing.2–4 In 1959 Woods and Wahlen4 published a series of 62 patients with granulomatous uveitis. Nineteen of these patients “showed a peculiar and consistent pattern of ocular lesions” that included both discrete atrophic, sparsely pigmented or unpigmented, peripheral lesions (frequently referred to as “histo spots”) and later cystic lesions in the macula. Skin testing for histoplasmin was positive in all of these 19 patients. Woods and Wahlen concluded that previous benign systemic histoplasmosis was responsible for the ocular findings in these 19 patients.4 A few years later Schlaegel and Kenney5 demonstrated that atrophic lesions around the optic nerve were also part of the clinical spectrum of ocular histoplasmosis syndrome (OHS), often called ocular histoplasmosis or presumed ocular histoplasmosis syndrome (POHS).

CLINICAL FEATURES OF OCULAR HISTOPLASMOSIS

• Discrete, focal, atrophic (i.e., punched-out) choroidal scars in the macula or the periphery, smaller in size than the optic disc (histo spots) (Fig. 70.1). • Peripapillary chorioretinal scarring (i.e., peripapillary atrophy) (Fig. 70.2). • CNV or associated sequelae (hemorrhagic retinal detachment, fibrovascular disciform scar) (Figs 70.3–70.5). Most often both eyes have typical lesions, although the appearance may not be symmetric at initial presentation. The early granulomatous stage of ocular histoplasmosis, as described by Woods and Whalen, is rarely seen clinically.4,6 The initial focal scars are probably too small to be seen with the ophthalmoscope. Gass6 has postulated that lymphocytic infiltration of the surrounding tissue produces enlargement of the lesion over a period of years and thus allows it to become clinically detectable.

Differential diagnosis

The symptoms associated with ocular histoplasmosis are wideranging and are dependent on the pathology present. Atrophic lesions are typically asymptomatic. The presence of choroidal neovascularization (CNV) often results in variable vision loss and metamorphosia.

A

A clinical diagnosis of ocular histoplasmosis is based on the presence of at least two of the following fundus lesions in one or both eyes in the absence of ocular inflammation:6,7

B

The differential diagnosis of ocular histoplasmosis includes a wide spectrum of disorders: • Multifocal choroiditis with panuveitis. Characterized by multiple chorioretinal scars with similar findings to ocular histoplasmosis. Significant anterior and/or posterior

C

Fig. 70.1 Chorioretinal scars (i.e., “histo spots”) characteristic of ocular histoplasmosis. (A) Peripheral histo spots. (B) Macular histo spots. Larger lesion with pigment proliferation may represent spontaneously regressed choroidal neovascularization (CNV). (C) Histo spots and peripapillary scarring. The peripapillary lesion superotemporal and within the peripapillary scarring probably represents spontaneously regressed CNV.

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Fig. 70.2 Two examples of peripapillary scarring.

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inflammation present in the active phase, and there may have associated CNV. One study examined distinguishing features of multifocal choroiditis compared to ocular histoplasmosis.8 Findings that were more characteristic of multifocal choroiditis included progressive growth of lesions, bridging scars, progressive proliferation of pigment, myopic disc changes, clustering of lesions (e.g., macula, equator), disc swelling, subretinal fibrosis, and narrowed/ sheathed vessels.8 These features may be particularly important in distinguishing quiescent multifocal choroiditis from ocular histoplasmosis (see Chapter 76, White spot syndromes and related diseases).

C

Fig. 70.3 (A) Choroidal neovascularization (CNV) secondary to ocular histoplasmosis with subretinal fluid in the macula. (B) Early frame of fluorescein angiogram shows extrafoveal CNV. (C) Late frame of fluorescein angiogram shows increased leakage of fluorescein dye. (D) Color photograph taken 1 day after laser photocoagulation shows whitening of retina from treatment. (E) Treatment scar 2 years after laser photocoagulation; no evidence of recurrent CNV.

• Myopic degeneration. Peripapillary atrophy and CNV may be seen in patients with myopic degeneration. Small white focal areas of chorioretinal atrophy along with linear atrophic areas (e.g., lacquer cracks) may also be present in the posterior pole (see Chapter 68, Myopic macular degeneration). • Multiple evanescent white-dot syndrome (MEWDS). White lesions of the retinal pigment epithelium (RPE)/outer retina may be present with associated granularity of the fovea. Often the vision is transiently decreased with an associated enlarged blind spot. Mild inflammation may be present. Scarring and permanent chorioretinal lesions are not usually

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Fig. 70.4 (A) Choroidal neovascularization (CNV) secondary to ocular histoplasmosis with subretinal fluid in the macula. (B) Extrafoveal CNV is visible on this early frame of a fluorescein angiogram. (C) Late frame of fluorescein angiogram shows increased leakage of fluorescein dye from the CNV. (D) Color photograph taken 1 day after laser photocoagulation shows whitening of retina from treatment. (E) Atrophic treatment scar 2.5 years after laser photocoagulation; no evidence of recurrent CNV.

C

Fig. 70.5 The Macular Photocoagulation Study Group demonstrated that laser treatment of eligible choroidal neovascular lesions was better than no treatment with respect to delaying or preventing loss of visual acuity. However, some CNV regresses spontaneously. These two patients did not have laser treatment of their choroidal neovascularization (CNV), which involuted spontaneously. (A) Juxtafoveal CNV in first patient. (B) Disciform scar 4 years later. (C) This patient had extrafoveal CNV with a rim of hemorrhage visible on the photograph. (D) CNV, hemorrhage, and fluid are all visible on this early frame of a fluorescein angiogram. (E) A small scar with pigment proliferation is visible 4 years later. Visual acuity returned to 20/20 3 months after enrollment and remained at 20/20 throughout the 5-year follow-up period.

RELATIONSHIP OF OCULAR DISEASE TO SYSTEMIC INFECTION Systemic infection with Histoplasma capsulatum via the respiratory tract is thought to be the initial event prior to the development of ocular histoplasmosis. Although a definitive causal relationship between H. capsulatum and the ocular disorder has not been demonstrated to satisfy Koch’s postulates completely,9,10 continuing experimental work with primates,11,12 may eventually satisfy this requirement. Several observations support a causal relationship between H. capsulatum and the ocular histoplasmosis syndrome: • Almost all patients diagnosed as having ocular histoplasmosis in the USA have lived some or all of their lives in an endemic area.13,14 • Positive histoplasmin skin testing occurs more frequently in patients with ocular histoplasmosis compared with controls.14–16 • Activation of lesions of ocular histoplasmosis has been reported following histoplasmin skin testing.2–4,16–18 • DNA from H. capsulatum has been isolated from an enucleated eye previously diagnosed with ocular histoplasmosis.19 Other observations can be used to question the causal relationship between H. capsulatum and the ocular syndrome. In the UK and Europe, a clinical syndrome nearly identical to ocular

Clinical features of systemic infection Goodwin27 classified systemic infection based on the immune status of the host and exposure type. The usual histoplasmosis infection is a relatively mild illness with flu-like respiratory symptoms. Most patients do not seek medical care. Studies in Tennessee have demonstrated that almost 90% of children of 13 years of age had positive reactions to histoplasmin skin tests.28 A great deal of variation has been observed in the distribution of positive reactors by neighborhood of residence.29,30 Rarely, more severe, even fatal cases of disseminated infection may occur, but these are usually associated with immune system deficiencies, such as acquired immunodeficency syndrome (AIDS). Occasionally, epidemics of systemic disease outbreak may occur which are often associated with high levels of environmental exposure (e.g., excavations, construction projects in old buildings, work in chicken or other fowl habitats, or exposure in bat-inhabited caves).31–46

EPIDEMIOLOGY OF OCULAR HISTOPLASMOSIS Geographic distribution of H. capsulatum in the USA The Ohio and Mississippi river valleys make up the largest part of the “histo belt,” where 60% or more of lifelong residents have positive histoplasmin skin testing.47 Comstock described the major endemic histoplasmosis area as a triangle with its apices in Eastern Nebraska, Central Ohio, and Southwestern Mississippi.29

Prevalence and incidence The prevalence of asymptomatic ocular histoplasmosis in endemic areas (e.g., Ohio, Maryland) within the USA ranges from 1.6 to 5.3%.14,15,48 The disciform lesion prevalence rates in the same areas were 0.0 to 0.1% of the endemic populations.14,15,48 In those eyes that had atrophic spots, the prevalence of disciform lesions was 4.5%.48 The incidence rate of neovascular disciform lesions and atrophic lesions is largely unknown. The development of initial neovascular disciform lesions has been reported at around 2 per 100 000 population per year.49 Studies examining the incidence rate of neovascular lesions in fellow eyes have shown a rate of 0.0 to 12% per year.50–54

Age The median age of patients with vision-threatening disciform lesions has typically been reported to be in the fourth and fifth decade, with an age range of 10 to 81 years old.13,17,49,55–58 The median age of persons who have atrophic scars has been reported to be in the fourth, fifth, and sixth decades of life by various investigators.15,59 These reports are of the age at detection, however, and not necessarily the age of development of the

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histoplasmosis may occur.20–24 These patients have never lived in or visited an endemic area, however, and only a small proportion of Europeans are positive reactors to histoplasmin skin testing.20–25 Additionally, H. capsulatum has not been identified in the UK.25 Certainly, the possibility exists that an alternate organism may result in a similar ocular syndrome in these areas.22 Systemic antifungal treatment with amphotericin B has not been shown to be effective for the treatment of the ocular disorder.26.

Ocular Histoplasmosis

observed (see Chapter 76, White spot syndromes and related diseases). • Idiopathic CNV. A diagnosis of exclusion. Particularly in younger individuals, idiopathic CNV is seen in the absence of other signs of ocular histoplasmosis, age-related macular degeneration (AMD), angioid streaks, and other CNVrelated conditions. • Choroidal rupture with CNV. A history of trauma is usually present. A partially circumferential concentric chorioretinal macular scar is typically present and is associated with the CNV. Peripapillary atrophy and associated peripheral chorioretinal atrophy is not present (see Chapter 91, Traumatic chorioretinopathies). • Punctate inner choroidopathy. Minimal to mild inflammation may be present. Atrophic scars may be associated with CNV. Spots are usually smaller than those seen with ocular histoplasmosis. Predominantly seen in women. Peripapillary atrophy is usually not present. Acute symptoms (e.g., photopsias) are usually associated with the initial diagnosis of the white lesions and may correlate with location of lesions (see Chapter 76, White spot syndromes and related diseases). • Neovascular AMD. Typically in older patients (i.e., >50 years). Drusen present. Areas of focal atrophy may be present in the macula but the atrophy is not usually seen in the periphery. Peripapillary atrophy is often not present (see Chapter 66, Neovascular (exudative or “wet”) age-related macular degeneration). • Sarcoidosis. Scattered active inflammatory choroidal lesions may be present. Usually accompanied by anterior/posterior inflammation. CNV and peripapillary atrophy not typically present. Elevated angiotensin-converting enzyme may be seen. Often associated with hilar adenopathy on chest X-ray or CT scan of the chest (see Chapter 78, Sarcoidosis).

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atrophic lesion. It is likely that these lesions develop earlier in life and are only coincidentally discovered during ophthalmic examinations for causes of visual symptoms that may or may not be related to ocular histoplasmosis.

There is no gender predilection for ocular histoplasmosis. The vast majority of disciform lesions occur in Caucasians with only around a dozen cases reported among African Americans.60 Interestingly, histo spots and positive skin tests have been reported in some studies to have similar prevalence among Caucasians and African Americans.15,61 Other studies have found a much higher prevalence in Caucasians (i.e., nearly 100% of all cases) as compared to Hispanics or African Americans.14,16,48,55

Histocompatibility antigens and genetic predisposition In disciform lesions, both human leukocyte antigen (HLA)-B7 and HLA-DRw2 have been reported to be two to four times more common among cases than controls.62–64 For histo spots, HLADRw2 was twice as common among cases as among controls, but less difference was seen between the groups in regards to HLA-B7.64,65 These findings suggest an underlying genetic susceptibility or predisposition for development of ocular histoplasmosis. It is unclear whether this genetic predisposition specifically reflects the susceptibility to ocular histoplasmosis or to infection by H. capsulatum. Although these associations exist, routine testing for HLA typing in connection with ocular histoplasmosis is not typically performed owing to the lack of significant positive and negative predictive values.

PATHOGENESIS Numerous theories regarding the pathogenesis of ocular histoplasmosis have been proposed. The most widely accepted theory involves focal infection of the choroid at the time of systemic infection. The focal inflammatory/infectious process results in an atrophic scar that disrupts Bruch’s membrane. Alternatively, the infection may involve the retinal pigment epithelium and choriocapillaris and may progress rapidly to subretinal hemorrhage, exudation, and a fibrovascular disciform scar (Fig. 70.6). CNV formation may be promoted by multiple factors at the site of the atrophic scar. Disruption of Bruch’s membrane provides access to the subretinal space for neovascularization.66 The fragile vessels are prone to hemorrhage and exudation, often ultimately resulting in disorganization of the RPE and neurosensory retina and, ultimately, a fibrovascular scar. The initiator for CNV development is unknown. The results from HLA typing suggest a possible genetic predisposition for progression from atrophic scars to disciform lesions in ocular histoplasmosis.62–65 Other hypotheses have attributed these phenomena to a larger initial inoculum of the fungus,11,67 reinfection,4,68 hypersensitivity,4,14 and the presence of other factors that compromise the vascular system14,69,70 or the immune system.71 CNV development has also been associated with proangiogenic factors such as vascular endothelial growth factor.72 Studying ocular histoplasmosis with animal models has been difficult. Histoplasmosis is known to occur in many species of animals.73–77 However, efforts to develop an animal model for ocular histoplasmosis have been hampered by two major factors: (1) nonprimates do not have a macula with its special anatomic,

physiologic, and neurologic characteristics; and (2) decades are believed to elapse between initial infection with H. capsulatum and the development of characteristic macular lesions. The most promising animal models are primates, in which systemic infection and ocular lesions have been produced.11,12

NATURAL HISTORY OF OCULAR HISTOPLASMOSIS AND PUBLIC HEALTH IMPLICATIONS Histo spots outside the macular area are typically asymptomatic, although visual symptoms occasionally have been reported that correlate with the location of the atrophic scars.78 Active CNV may result in sudden decrease in vision secondary to hemorrhage or exudation. The vision loss in this disease often occurs in middle-aged individuals who are in the most active and productive stage of their life.13,17,49,55–58 Spontaneous recovery of central vision has been reported in the Macular Photocoagulation Study (MPS)51,56 and by other investigators.79–81 Two studies have addressed the public health importance of ocular histoplasmosis as a cause of visual impairment. One study in Tennessee found that ocular histoplasmosis was responsible for 2.8% of visual impairment among applicants for aid for the blind.49 In Maryland a study comparing the 15-year incidence of visual impairment in those persons with histo spots to those persons without histo spots found that there was no difference in the rates of visual impairment.50 The Submacular Surgery Trials Research Group found that individuals with unilateral and bilateral CNV cases had significant deficits in visual function, similar to patients with neovascular age-related macular degeneration (AMD).82 Not surprisingly, the study showed that patients with bilateral CNV had significantly worse functional impairment of all groups, but those with unilateral involvement also had significant functional deficits.82

TREATMENT Numerous approaches for ocular histoplasmosis management have been suggested, including avoidance of stress, avoidance of aspirin, avoidance of the Valsalva maneuver, hyposensiti­ zation to histoplasmin, use of immunosuppressive agents, and photocoagulation.9 Histoplasmin desensitization,83 amphotericin B,17,26 and other prophylactic interventions84,85 have been tried by many investigators and discarded. No treatment is known to prevent inactive lesions from giving rise to exudative or hemorrhagic neovascular complexes that typically end in disciform macular scars. Systemic corticosteroids also have been suggested, particularly in cases of “active” histo spots and subfoveal CNV.6 in the era of anti-vascular endothelial growth factor (VEGF) and photodynamic therapy (PDT), however, the use of systemic corticosteroids even in subfoveal cases is now mainly of historic interest. Whether there is a role to manage active histo spots is unclear since many or perhaps most spontaneously involute.

Laser photocoagulation Initiated in 1979, the Macular Photocoagulation Study (MPS) Group demonstrated the effectiveness of laser treatment in comparison to no treatment two randomized clinical trials for patients with well-defined extrafoveal or juxtafoveal CNV.56,57,86,87 The first trial enrolled 262 patients with well-demarcated extrafoveal CNV.57,86 The posterior border of these lesions could not

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Focal choroiditis–predisciform stage

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Involvement of RPE and choriocapillaris

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Ocular Histoplasmosis

Hemodynamic or allergic factors

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Serous disciform retinal detachment

Hemorrhagic disciform retinal detachment

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Focal atrophic chorioretinal scar

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Serous retinal detachment and choroidal neovascularization

Hemorrhagic dsciform retinal detachmenti

Fibrovascular disciform scar

Fig. 70.6 Hypothesized mechanism of the pathogenesis of disciform lesions of ocular histoplasmosis. Focal choroiditis (A) damages the choriocapillaris, retinal pigment epithelium (RPE), and Bruch’s membrane and produces an exudative detachment of the retina (B) or hemorrhage into the subretinal space (C). Any of these three stages may resolve, leaving either a focal area of atrophy of the retinal pigment epithelium, Bruch’s membrane, and choroid (D) or, in the case of subretinal hemorrhage, a disciform scar (G). Either in the absence of further inflammation or under the influence of recurrent episodes of inflammation, the choroidal blood vessels surrounding an atrophic chorioretinal scar (D) may decompensate and cause serous exudation, choroidal neovascularization, and transient serous detachment of the retina (E). This process in turn may result in a hemorrhagic detachment of the retina (F) that resolves as a disciform scar (G). (Reproduced with permission from Gass JDM. Stereoscopic atlas of macular diseases, vol. 1: Diagnosis and treatment. St Louis: Mosby; 1987. p 6.)

be closer than 200 µm from the center of the foveal avascular zone; initial best-corrected visual acuity of the affected eye was 20/100 or better. Eligible eyes were randomly assigned to argon laser treatment or to no treatment. The eyes were re-examined twice each year, at which time best-corrected VA was measured and color photographs were taken. Fluorescein angiograms

were taken at time of study entry, 6 and 12 months after enrollment, and annually thereafter. In 1983, the MPS Data and Safety Monitoring Committee halted enrollment after concluding that argon laser photocoagulation was beneficial in preventing or delaying large loss of visual acuity compared to observation without treatment. From

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18 months through 5 years, a 6 or more line loss of VA was experienced in 10% of treated eyes compared to 40% of untreated controls. Median VA at baseline was 20/25 and after five years dropped to 20/40 in the treated group compared to 20/80 in controls.86 In the laser-treated group, 26% of eyes had persistence of CNV or recurrence of CNV at the scar edge, and 7% developed a new CNV not contiguous with the laser scar.86 In 1981 a second trial was initiated by the MPS Group for patients with juxtafoveal CNV.87 In this trial, best-corrected VA at entry was permitted to be as poor as 20/400 in the study eye. A total of 289 eyes were randomized between krypton laser treatment and no treatment. Five years after the trial began, the MPS Data and Safety Monitoring Committee again halted enrollment after concluding that eyes treated with krypton laser were less likely to lose visual acuity than untreated eyes. A 6- or more line loss was seen in 11% of the treated eyes compared to about 30% of the controls.87 Approximately one-third of treated patients had persistent or recurrent CNV contiguous with the zone of laser treatment; and new, noncontiguous areas of CNV developed in 2% of treated eyes.87 A subgroup analysis by the MPS group of CNV located between the fovea and optic nerve showed that there was no contraindication to treatment of these lesions in the papillomacular bundle with laser.88 A subset of the MPS Group piloted laser photocoagulation for subfoveal CNV secondary to ocular histoplasmosis but observed no short-term benefit compared to observation.89 In view of the very good results with extrafoveal CNV and even juxtafoveal CNV from the MPS studies, laser photocoagulation therapy should be seriously considered for these lesions. Additionally, when compared to anti-VEGF therapy, laser photocoagulation is not as expensive and avoids many of the ocular and possible systemic risks of intravitreal injections with antiVEGF agents. If subfoveal recurrence or primary subfoveal disease develops, photodynamic therapy or anti-VEGF treatment should be considered (see below).

Photodynamic therapy The treatment of subfoveal CNV secondary to ocular histoplasmosis with photodynamic therapy (PDT) was first suggested in 2002.90 Since that small study, numerous studies have been published examining the use of PDT for ocular histoplasmosis. In fact, PDT is now approved by the United States Food and Drug Administration (FDA) for the treatment of subfoveal CNV secondary to ocular histoplasmosis. Most of the studies performed for PDT with ocular histoplasmosis have been retrospective case series. In a 2003 retrospective

A

review of 38 eyes with juxtafoveal CNV treated with PDT, treated eyes were more than twice as likely to have visual improvement or stabilization compared to the natural history group in the corresponding MPS clinical trial. Visual acuity improved or stabilized in 69% of eyes, with 44% of eyes improving at least 2 lines. Nearly 40% of eyes had undergone submacular surgery prior to PDT.91 In 2004 a retrospective review of 11 eyes, of which 5 had juxtafoveal CNV and 6 had subfoveal CNV, documented similar findings. Eighty percent of eyes showed vision stabilization or improvement in the juxtafoveal group. Sixty percent of eyes with juxtafoveal lesions achieved a final visual acuity of 20/40 or better. Eyes with subfoveal lesions had similar results with 83% of eyes having stabilization or improvement in vision. Fifty percent of eyes with subfoveal CNV also had a final visual acuity of 20/40 or better.92 In 2005 a retrospective review of 23 eyes with juxtafoveal CNV associated with ocular histoplasmosis found that approximately 82% of eyes had visual stabilization (less than 2 line loss) or improvement. Thirty percent of eyes gained more than 2 lines of vision. Approximately, 60% of patients required only a single PDT session. Following PDT, submacular surgery was performed in 16% of patients due to CNV progression.93 In 2006 a retrospective review of young patients undergoing PDT for CNV secondary to etiologies other than AMD included 6 patients with ocular histoplasmosis with subfoveal CNV. The mean pretreatment acuity in these eyes was 20/50 and the mean final visual acuity was 20/50. Three of these eyes (50%) required at least one retreatment session with PDT. One of 6 patients improved by more than 1 line of VA. Four eyes (67%) maintained their visual acuity (i.e., less than 2 lines lost or gained), and one eye gained more than 2 lines of VA and one eye lost 2 lines.94 An uncontrolled prospective trial evaluating PDT for subfoveal CNV secondary to POHS included 26 eyes. Examination of 22 eyes 2 years following initial treatment revealed that 45% of eyes had gained 1.5 lines or more. Eighteen percent of eyes lost 1.5 lines or more, including 9% of eyes that lost 3 or more lines of VA. The mean number of treatments was 2.9 during the first year and 1 during the second year. After 2 years, only 15% of eyes had persistent angiographic leakage.95

Anti-VEGF therapy Over the last several years, the use of anti-VEGF agents has transformed the landscape in the treatment of CNV-related disease, particularly neovascular AMD. Case reports and case series suggest that anti-VEGF agents may also be effective in the treatment of CNV secondary to ocular histoplasmosis (Fig. 70.7). In 2007 the first case report was published documenting a

B

Fig. 70.7 Optical coherence tomography images of subfoveal choroidal neovascularization (CNV). CNV is visible in the subfoveal area with overlying subretinal fluid (A). Following intravitreal bevacizumab therapy, the subretinal fluid is significantly improved although the CNV remains (B).

Combination therapy Similar to AMD, combination therapy is also being considered for the treatment of CNV secondary to ocular histoplasmosis. Combination therapy may reduce the need for ongoing intravitreal injections. PDT or laser photocoagulation may provide a more enduring effect, compared to anti-VEGF therapy alone. Adding anti-VEGF therapy may reduce the required spot size needed for either laser modality. In 2010, a small retrospective case series examining combination anti-VEGF agents with PDT

Intravitreal triamcinolone Given the possible underlying inflammatory pathogenic mechanisms of ocular histoplasmosis, the use of intravitreal steroids may be of use in the treatment of CNV secondary to ocular histoplasmosis. A retrospective case series examined the use of intravitreal triamcinolone in 10 eyes with CNV secondary to ocular histoplasmosis (5 subfoveal and 5 juxtafoveal) was conducted with a median follow-up of 17 months. Visual acuity improved or stabilized in 80% of eyes, including 30% that gained 1 line or more. Twenty percent of eyes lost 1–3 lines of visual acuity, and no eyes lost more than 3 lines of vision. Cataract progression and increased intraocular pressure were concerning ocular side effects.101

Submacular surgery and macular translocation Prior to PDT and anti-VEGF therapy, submacular surgery for CNV secondary to ocular histoplasmosis was an important treatment alternative for many patients with significant vision loss.102–104 As with many treatment modalities for CNV, recurrence of CNV is a major issue. In fact, the recurrence rate after submacular surgery is higher than recurrence following laser photocoagulation.105 In 1997 the National Eye Institute and the National Institutes of Health initiated the Submacular Surgery Trials group H trial in order to compare functional outcomes and quality of life between patients assigned to surgery versus those assigned to observation (Fig. 70.8). The trial included 225 patients non-AMD with subfoveal CNV and visual acuity of 20/50 to 20/800. Of the 225 patients, 192 patients had ocular histoplasmosis. At 2 years, vision had improved or remained stable in 20% more patients treated with surgery than with observation.106 This outcome difference was not statistically significant. Subgroup analyses revealed that nearly all of the benefit seen with surgery was in those eyes with 20/100 or worse baseline visual acuity. In this subset of 92 eyes, 76% of surgery eyes remained stable or improved compared to 50% of eyes that were observed. Additionally, quality-of-life scores improved more with surgery.107 Macular translocation has also been utilized for the treatment of patients with bilateral vision loss associated with ocular histoplasmosis.108 One report described three cases of ocular histoplasmosis treated with 360-degree macular translocation. Two of the 3 eyes showed improvement in visual acuity. Two of the 3 cases developed recurrent CNV, and 2 of the 3 cases developed chronic cystoid macular edema.108 Limited macular translocation for ocular histoplasmosis has also been reported, but the specific visual acuity results were not separated from the larger study which included predominantly AMD cases so that conclusions

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included three eyes with CNV secondary to ocular histoplasmosis. Treatment consisted of PDT and intravitreal bevacizumab initiated concurrently with retreatment with PDT every 10–12 weeks and with bevacizumab every 4–6 weeks. Retreatment was based on persistent edema or subretinal fluid. Three of 3 (100%) eyes improved 2 lines or more at final follow-up.100 As outlined in the previous section, a retrospective case series utilizing bevacizumab for CNV secondary to ocular histoplasmosis included 5 eyes that were treated with concurrent PDT therapy. Subgroup analysis of these five patients revealed that all five eyes experienced stabilization or improvement in visual acuity with a mean gain of 2.4 lines.98

Ocular Histoplasmosis

23-year-old female with sudden vision loss to 20/200 with subfoveal CNV. After a single intravitreal injection of bevacizumab, the visual acuity improved to 20/30 by 6 months follow-up.96 Of course, the control arms of the MPS studies discussed above show that spontaneous involution can occur, but following this case report, retrospective consecutive case series were published examining the use of the intravitreal bevacizumab for the treatment of CNV in ocular histoplasmosis. One study examined intravitreal bevacizumab in 24 treatment-naïve eyes. The mean age was 43 years and the average number of injections was 6.8 per year. After 3 months, visual acuity improved from a mean baseline visual acuity of 20/114 to 20/55 (i.e., approximately 3-lines). Fifty-eight percent of eyes had 20/40 or better vision at final follow-up compared to 21% at baseline. Nine patients had 12 month follow-up and improved from a mean baseline visual acuity of 20/150 to 20/45 (i.e., approximately 6 lines). No significant complications were reported.97 A second study examined the use of bevacizumab in 28 eyes with CNV secondary to histoplasmosis. All patients included had active CNV with subfoveal fluid and either juxtafoveal or subfoveal CNV. Previous or concurrent PDT was allowed in this study. Seven patients were treatment naïve, 16 were PDT failures, and 5 patients were treated with combination PDT/ bevacizumab therapy. The mean age was 46 years and mean follow-up was 5 months. Overall, the mean initial visual acuity was 20/88 and the mean final visual acuity was 20/54. Stability of visual acuity (<1.5 line loss) was seen in 93% of patients. Additionally, 43% of eyes experienced a 3 or more line gain. Both of the studies examining bevacizumab were retrospective with significant methodologic shortcomings and the results should be interpreted with caution.98 A phase I randomized 12-month clinical trial evaluated ranibizumab for the treatment of CNV secondary to conditions other than AMD has been conducted. This study randomized eyes to monthly ranibizumab or 3-monthly injections followed by an as needed (prn) dosing schedule at monthly visits. Nine eyes (of 30) with ocular histoplasmosis were included in this trial, 4 in the monthly arm and 5 in the prn arm. Prior treatment with other therapeutic modalities was allowed. Subgroup analysis was not performed for each diagnosis included. As a group, mean lines of change from baseline was +7.4 in the monthly injection arm and +5.0 in the prn group. A 3-line or more gain in visual acuity was seen in 66.7% of the monthly arm patients and in 57% in the prn arm. There were no statistically significant differences between the groups at any time point. No serious ocular or systemic adverse events were observed but larger sample sizes are needed to detect infrequent severe adverse events.99 Further research is needed to define better the role of antiVEGF therapy in the management of CNV secondary to ocular histoplasmosis. Early research suggests that it may have an important role in the management of this condition.

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Fig. 70.8 Eye with subfoveal choroidal neovascularization (CNV) treated with submacular surgery in the Submacular Surgery Trials (group H trial). Color photograph (A) and early frame of fluorescein angiogram (B) shows subfoveal CNV in an eye with characteristic lesions of ocular histoplasmosis. Color photograph (C) and early frame of fluorescein angiogram (D) taken 6 months after submacular surgery show a well-demarcated postoperative disturbed area of the retinal pigment epithelium.

cannot be drawn regarding the effectiveness of limited translocation for ocular histoplasmosis.109 Although surgical intervention remains a viable option in select situations, anti-VEGF therapy and PDT are now the mainstays of treatment for subfoveal and juxtafoveal CNV secondary to ocular histoplasmosis and laser photocoagulation is the typical treatment advised for extrafoveal CNV.

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Ocular Histoplasmosis

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Medical Retina

Choroidal Vascular/Bruch’s Membrane Disease

Section 3

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