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MANAGEMENT OF NEOVASCULAR OCULAR HISTOPLASMOSIS

Past and Present

Blinder, Kevin J., MD

doi: 10.1097/IAE.0000000000002352
Review
Free
SDC

Purpose: To review the wide variety of treatment modalities available for choroidal neovascularization secondary to the presumed ocular histoplasmosis syndrome.

Methods: A literature search was performed to review the multitude of studies conducted to investigate the efficacy and safety of treatment modalities available for choroidal neovascularization secondary to the presumed ocular histoplasmosis syndrome.

Results: Each treatment modality is reviewed, with the studies summarized and presented to support or refute the method of treatment. Two case reports are presented to demonstrate the treatment regimens.

Conclusion: This is a comprehensive review of the treatment modalities available to address choroidal neovascularization secondary to the presumed ocular histoplasmosis syndrome. Investigators will continue to strive toward higher efficacy and safety with future innovations in the field.

This is a review of treatment modalities available for choroidal neovascularization secondary to the presumed ocular histoplasmosis syndrome. Two cases are presented initially. This is followed by a historical view of antiquated treatment options, ending with contemporary treatment recommendations with the various studies presented and reviewed.

The Retina Institute, St. Louis, Missouri; and Ophthalmology and Visual Sciences, Washington University, St. Louis, Missouri.

Reprint requests: Kevin J. Blinder, MD, The Retina Institute, 1600 S Brentwood Boulevard, Suite 800, St. Louis, MO 63144; e-mail: KJBlinder@gmail.com

K. J. Blinder is a consultant for Regeneron, Bausch & Lomb, Allergan, and Dorc.

The author declares no significant competing financial, professional, or personal interests that might have influenced the performance or presentation of the work described in this manuscript.

The ocular histoplasmosis syndrome (OHS) is also referred to as the presumed OHS (POHS), due to persistent controversy concerning the etiology of the syndrome.1–3 In the Mississippi-Ohio River Valley, where exposure is common and the disease is endemic, physicians accumulate a vast amount of experience with the syndrome.4 Choroidal neovascularization (CNV) can be a visually devastating complication of POHS, occurring in a minority of people afflicted with the syndrome. Treatment modalities over the years have ranged from laser photocoagulation, to surgical intervention, oral medications, and intravitreal therapy, with varying results. In this review, we will present two case reports demonstrating past and present treatment modalities. We will then discuss historical as well as contemporary treatment of neovascular POHS.

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Case 1

A 32-year-old mother of four with a set of triplets originally presented 18 years ago with vision 20/200 in the right eye and 20/20 in the left eye. The patient was diagnosed with subfoveal CNV in the right eye secondary to POHS. The patient was explained the risks, benefits, and potential complications of surgical intervention. After a thorough discussion, patient decided on CNV excision to the right eye. This was performed without complication. Postoperatively at 2 months, the patient deteriorated to vision 20/300 in the right eye with a recurrent CNV in the right eye. We again discussed with the patient the risks, benefits, and potential complications of the treatment options available. We discussed the possibility of photodynamic therapy (PDT) off label. The patient decided to proceed with repeat surgery. This was performed again without complication. Postoperatively, the patient improved to 20/30 in the right eye and remained stable in that eye for many years. Five years later, she presented with decreased vision in the left eye. A juxtafoveal CNV was diagnosed and she underwent PDT to the left eye times two. We last saw this patient a few weeks ago. Vision was 20/60 in the right eye and 20/20 − 1 in the left eye (Figures 1 and 2). The vision had deteriorated slightly in the right due to atrophic creep of the chorioretinal surgical scar.

Fig. 1

Fig. 1

Fig. 2

Fig. 2

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Case 2

A 69-year-old retired ophthalmic photographer presented 8 years ago complaining of distortion with decreased vision in the left eye. Vision was 20/20 − 1 in the right eye and 20/80 − 1 in the left eye (Figures 3–5). Patient was diagnosed with subfoveal CNV in the left eye secondary to POHS. After a thorough discussion of the risks, benefits, and potential complications, patient underwent bevacizumab injection to the left eye without complication. He did well for almost three years, and then had a decrease in vision to 20/80 + 2 in the left eye with a recurrence of his CNV. He was enrolled in an investigational protocol with aflibercept injections to the left eye. He underwent monthly injections for 1 year and improved back to 20/20 − 2. He has required 4 bevacizumab injections over the past 4 years to treat infrequent recurrences and maintain a vision of 20/30.

Fig. 3

Fig. 3

Fig. 4

Fig. 4

Fig. 5

Fig. 5

For many years, laser photocoagulation was the only scientifically proven treatment option available for CNV secondary to POHS. Anecdotal evidence early on suggested that xenon arc photocoagulation,5 argon laser,6 and krypton7 laser were effective in the treatment of CNV secondary to POHS. The first multicenter randomized controlled clinical trial proving the efficacy of laser photocoagulation in the treatment of neovascular maculopathy secondary to POHS was published in 1983 by the Macular Photocoagulation Study Group.8 Eligible patients with extrafoveal choroidal neovascular nets (200–2,500 μm from the center of the foveal avascular zone) were assigned to laser (n = 124) versus observation (n = 121). Recruitment was terminated when it was evident that untreated eyes were experiencing severe visual acuity loss at a much higher incidence than the treated eyes. At a median follow-up of 18 months, 34.2% of untreated eyes lost six or more lines of vision compared with 9.4% of treated eyes. Further follow-up at 39 and 510 years revealed maintenance of the treatment effect. At 5 years, untreated eyes had a 3.6-fold risk of visual loss with a mean of 4.4 lines lost, versus only 0.9 lines lost by laser-treated eyes. Recurrent neovascularization occurred in 26% of treated eyes by 5 years.

For patients with juxtafoveal CNV (1–199 μm from the center of the foveal avascular zone, or CNV 200 μm or further with blood and pigment extending to within 200 μm) secondary to POHS, krypton laser was found to be more effective than observation.11 The MPS again looked at the different categories of CNV and devised krypton laser study protocols for age-related macular degeneration (AMD), POHS, and idiopathic. The POHS group had the most robust response of the three. Patients were randomized to treatment (n = 143) versus observation (n = 145). Recruitment was once more halted due to the obvious treatment benefit seen. At 1 year, 24.8% of untreated eyes lost 6 or more lines of vision, compared with 6.6% of treated eyes. At 3 years, numbers were 24.6% and 4.6%, respectively. At 5 years, untreated eyes had an adjusted risk ratio of 4.26 for a 6-line decrease in vision compared with treated eyes.12 Yet, there was certainly difficulty in determining the extent of the lesion and how close to treat on the foveal side.13

Laser for subfoveal lesions has been a much more difficult thing to discuss with patients and apply clinically. The MPS in 1991 published their trial in patients with AMD, demonstrating an immediate decrease in vision in treated eyes.14 Yet, by 24 months, the treated group experienced less severe visual loss than the observation group. In 1988, Fine et al began recruiting for a subfoveal POHS laser trial.15 Three years later, they only had 25 patients enrolled. They could not demonstrate a beneficial effect of laser in this small series, and recruitment was discontinued.

The MPS also evaluated patients with peripapillary lesions, or large lesions nasal to the fovea.16 A total of 113 eyes were identified with these lesions. The recommendation was to treat lesions if you could spare at least 1.5 consecutive clock hours of the retina adjacent to the temporal half of the disk. At 3 years, 11% of treated eyes and 41% of untreated eyes had lost 5 or more lines of vision.

In 1991, Thomas et al published their landmark article sparking the decade of submacular surgery with surgical excision of choroidal neovascular nets.17 They presented 2 patients with subfoveal CNV secondary to POHS with initial visual acuity of 20/400. Postoperatively, 1 patient improved to 20/40 at 3 months, and the other patient improved to 20/20 at 7 months. Neither patient showed signs of persistence or recurrence of the CNV. Thomas et al18 reported on a subsequent series of patients with AMD and POHS undergoing surgical excision. There were 16 patients with POHS with a limited postoperative follow-up of an average of 4.8 months. Six patients experienced visual improvement, one declined, and nine remained unchanged. Six patients experienced persistent or recurrent CNV postoperatively. In a subsequent series, Thomas et al19 reported on 67 eyes with POHS with a mean follow-up of 10.5 months. Visual acuity was stable or improved in 83% of eyes with a recurrence rate of 37%. There were subsequent reports of the variable success of the surgical excision of CNV in neovascular POHS.20–23 To determine the efficacy of this unique surgical procedure, The Submacular Surgery Trials Pilot Study was initiated in November 1993.24 After this initial pilot study, the recommendation of the Data and Safety Monitoring Committee was to proceed with 3 different arms of the study, with Group H representing the idiopathic and POHS group that were randomized to observation (113 eyes) versus surgical excision (112 eyes).25 With a median baseline visual acuity of 20/100, the median visual acuity at 24 months was 20/250 in the observation group, and 20/160 in the surgical group. Recurrent CNV in the surgical group was 58% at 24 months. They concluded there was minimal to no benefit to surgery unless the baseline visual acuity was 20/100 or worse. Initially, one SST analysis suggested that vision-targeted quality of life improved after submacular surgery more than after observation.26 Yet, in a subsequent report, these data were negated, showing no difference between the 2 groups unless the baseline vision was 20/125 or worse.27 With the knowledge of high recurrence rates postoperatively, and the advent of newer treatment modalities, submacular surgery has become a part of history; to be discussed, but not practiced.

It was interesting that during the surgical era of CNV excision, we seemed to learn more about the pathophysiology of the neovascular component of POHS and AMD. Surgical removal of the neovascular complex most commonly would produce an atrophic scar due to the concurrent removal of the retinal pigment epithelium (RPE)/Bruch membrane and choriocapillaris.28 This was usually the rule with CNV excision in AMD due to the fibrovascular membrane found histologically within Bruch membrane, beneath the RPE, and beneath the neurosensory retina. However, in POHS and other non-AMD entities, there was usually a solitary ingrowth site through a focal break in Bruch membrane. The neovascular complex could then grow anterior to the RPE cell layer, posterior, or on both sides. The anterior growth pattern (classified as Type 2) responded better to surgical excision, with minimal disruption to the RPE/Bruch membrane and choriocapillaris.29,30 Clinically, one could see clues of the anterior location of the CNV with the appearance of well-defined borders, a thin layer of blood between the membrane and the RPE, pigmented edges, and absence of elevation of the RPE beyond the CNV edges on fluorescein angiogram.31 Fluorescein angiography and indocyanine green angiography played an important role in differentiating the type of CNV present in patients preoperatively. Indocyanine green supplemented fluorescein angiography in patients with sub-RPE or occult lesions.32 The more commonly used optical coherence tomography (OCT), and now even newer OCT angiography, had great potential in differentiating lesion morphology and correlating the histopathology into useful clinical data.33

With the introduction of PDT with verteporfin for AMD, investigators began applying PDT to non-AMD entities.34 The Verteporfin in Ocular Histoplasmosis study group was formed to evaluate the safety and efficacy of PDT in the treatment of subfoveal CNV secondary to POHS.35 This was an open-label, multicenter series of 26 patients that received standard PDT therapy. From the 25 patients who completed the study at 12 months, average number of treatments was 2.9, average letters gained was 7, with 56% gaining 7 or more letters, 16% losing 8 or more letters, and 8% losing 15 or more letters. At the 2-year follow-up, 22 eyes remained, with an average letters gained of 6 and an average of one treatment during the 2nd year.36 There was absence of leakage on fluorescein angiography in 85% of the classic CNVs, and 100% of the occult CNVs. Busquets et al37 performed a retrospective analysis of 38 patients who underwent PDT for neovascular POHS. Over a mean follow-up of 28 weeks, patients developed a mean visual improvement of 0.88 lines. Patients were 2.07 times more likely to have stable or improved vision than the natural history. Of note, 38% of patients in Busquets' series had a history of submacular surgery before PDT. Other studies have shown similar results of PDT with verteporfin and POHS.38–42 Shah et al43 reported their retrospective series of 23 patients treated with PDT for juxtafoveal CNV secondary to POHS. Over a mean follow-up of 9.5 months, 75% of patients demonstrated stable or improved vision after treatment. Sixteen percent had submacular surgery for nonresponsive CNV after PDT treatment. Rosenblatt et al44 described a new, unique treatment of peripapillary CNV with PDT. Their series included 7 patients, 2 with POHS. The final vision range improved over the baseline vision range. Only one patient of seven did not have total resolution of the submacular fluid, hemorrhage, or exudate.

Another treatment modality early on consisted of systemic or periocular corticosteroids in an attempt to stabilize the vision.45,46 This seemed like a logical choice considering a probable inflammatory component to the pathogenesis of POHS.47 Olk et al48 reported on the visual prognosis of 148 eyes in patients with subfoveal or juxtafoveal CNV secondary to POHS. In the review of these patients, 25 had at some point been treated with some type of steroid therapy—either systemic or periocular. There was no significant difference in visual outcome between those who received steroids and those who did not. Mann et al49 reported a case of neovascular POHS with histopathologic confirmation of granulomatous inflammation on an excised CNV specimen. The patient had not responded to systemic corticosteroid therapy, thus necessitating an alternative treatment modality. Martidis et al50 reported a series of 18 patients with subfoveal CNV secondary to POHS treated with corticosteroid therapy. Eight patients received a single sub-Tenon's triamcinolone injection, and 10 patients received oral prednisone for a duration of 4 to 6 weeks. The oral prednisone group experienced a 2-line gain at 2 weeks, which decreased to a half-line loss at 3 months. The sub-Tenon's triamcinolone group did not experience any gains, with a similar half-line loss at 3 months. The oral prednisone group experienced the normal steroid-related side effects of anxiety, increased appetite, and weight gain, with no significant ocular adverse effects noted in either group. Rechtman et al51 evaluated the effect of intravitreal triamcinolone acetonide injections for neovascular POHS. In their retrospective analysis, they reported 10 patients in total, evenly divided between subfoveal and juxtafoveal CNV. Over a mean follow-up of 17 months, visual acuity and greatest linear dimension on OCT remained stable. The safety profile was good, with transient intraocular pressure elevation and mild cataract formation. Investigators subsequently attempted a longer-acting fluocinolone implant to treat patients with neovascular POHS.52 Patients were enrolled in a compassionate use protocol with the following diagnoses: POHS (n = 7), myopic degeneration (n = 4), angioid streaks (n = 2), and punctate inner choroidopathy (n = 1). Patients were treated with either 2-mg (n = 8) or 6-mg (n = 6) implants of fluocinolone acetonide sutured into the pars plana location. Over an average follow-up of 33 months, all patients developed elevated intraocular pressure and cataracts, 4 developed nonischemic central retinal vein occlusions, and 8 eyes required removal of the implant due to complications. Visually, the patients did well, improving from a median baseline of 20/64 to a median final vision of 20/40. In this series, the benefits did not seem to justify the high rate of complications. Other possibilities could be long-acting corticosteroid injections with easier insertion and better safety profiles.

With the advent of the anti–vascular endothelial growth factor (anti-VEGF) agents in the treatment of neovascular AMD, it seemed logical to attempt treatment of CNV secondary to POHS with these agents. Adán et al53 was the first to publish a report of the use of bevacizumab in the treatment of a 23-year-old woman with POHS. The patient presented with a visual acuity of 20/200 and fluorescein angiography confirmed a juxtafoveal CNV. An intravitreal bevacizumab injection was performed. Twelve months after injection the CNV remained inactive with a visual acuity of 20/30. Schadlu et al54 reported their retrospective analysis of 28 patients who underwent bevacizumab injections for the treatment of CNV secondary to POHS. In their series, the average pretreatment visual acuity was 20/88, with the average posttreatment visual acuity of 20/54. The mean follow-up was 22.4 weeks. Sixteen of 28 (57%) patients had previously failed PDT. Of these PDT failures, 12 (75%) stabilized after bevacizumab. Of the PDT-naive patients, 100% (12 patients) stabilized or improved after bevacizumab. Five patients in their series underwent combination therapy with PDT, with significant visual improvement. No safety issues were noted in their series. Ehrlich et al55 reported similar results in their 24-eye treatment-naive series. At 12-month follow-up, visual acuity improved from 20/150 to 20/45. The average number of injections was 6.8. 58.3% (14) had a final visual acuity of 20/40 or better, compared with 20.8% (5) preinjection. Again, a very good safety profile was demonstrated in their series.

There are, of course, other anti-VEGF agents available to patients with neovascular POHS; yet, there is a sparsity of data, with no agents Food and Drug Administration–approved for this indication. Heier et al56 was the first to report the use of ranibizumab in patients with POHS in a Phase 1 randomized clinical trial comparing monthly with pro re nata dosing after a loading dose of 3 monthly injections. The patient population consisted of patients with the diagnosis of CNV secondary to causes other than AMD. Nine of 30 patients had the diagnosis of POHS. The overall results, although not divided into separate diagnoses, revealed that both treatment strategies were effective. The monthly group had 66.7% of patients gaining 15 or more letters of vision, versus 57.1% in the pro re nata group at 12-month follow-up. Hu et al57 reported on the efficacy of bevacizumab and ranibizumab treatment in eight eyes of seven patients in a retrospective review. Over an average of 121.4 weeks, the mean vision had improved from 20/60 to 20/47, with an average of 2.6 injections per year. In a similar study, Nielsen et al58 reported their retrospective analysis of 54 eyes treated with bevacizumab only (40 eyes), ranibizumab only (1 eye), or a combination of the 2 (13 eyes). Over an average of 26.8 months, vision improved from 20/53 to 20/26, with only 3 eyes losing a single line of vision. Ramaiya et al reported an open-label, Phase II randomized clinical trial comparing ranibizumab with PDT.53,59 Nine patients were randomized in a 2:1 fashion to ranibizumab versus PDT. At 1-year follow-up, both groups experienced a marked improvement in vision, with a 19.6-letter gain in the ranibizumab group, and a 21-letter gain in the PDT group. All patients in the PDT group required ranibizumab rescue therapy at some point in the study.

There is even less data in the literature addressing aflibercept in the treatment of neovascular POHS. One would think there might be greater efficacy with aflibercept, considering the results of the Diabetic Retinopathy Clinical Research network Protocol T trial in the comparison of the three anti-VEGF agents in the treatment of diabetic macular edema.60 Walia et al61 was the first to report the use of aflibercept and POHS. They evaluated aflibercept prospectively in a 5-patient series, with an initial 3 monthly loading dose, and an injection every 2 months for 1 year. At the final visit, there was a mean vision gain of 12.4 letters, with 100% of patients stable or improved. Eighty percent of patients had complete resolution of any fluid on spectral domain OCT. Toussaint et al62 evaluated aflibercept in a prospective, randomized Phase I/II trial comparing aflibercept every 2 months (sustained group) after an initial 3 monthly loading dose, with pro re nata aflibercept (PRN group) after an initial dose. At 1 year, the sustained group had a mean gain of 12 letters, with a final mean vision of 20/21. The PRN group started with worse baseline vision and had a mean gain of 19.2 letters with a final mean vision of 20/26. Overall, both groups had equivalent results, with the PRN group requiring fewer injections.

It has been suggested that combination therapy can combine the strengths of the different treatment modalities while minimizing the number of treatments necessary.63 Although this has been investigated in AMD, in the realm of POHS, not much has been sought.64,65 Han et al66 evaluated the efficacy of PDT every 12 weeks combined with either ranibizumab every 4 weeks or bevacizumab every 6 weeks. Ten patients were evaluated with juxtafoveal or extrafoveal CNV—5 with AMD and 5 with either myopia or POHS. Baseline mean vision was 20/44. With a follow-up of 17.5 months, the final mean vision was 20/28. The non-AMD eyes did not necessitate as many treatments as the AMD eyes. We have already reviewed the article by Schadlu et al discussing the utility of bevacizumab in neovascular POHS.54 Within their series, they had 5 patients who underwent combination therapy with PDT. These patients seemed to do slightly better visually than the monotherapy patients. Cionni et al67 reported their retrospective analysis of 150 eyes that underwent monotherapy bevacizumab (117) versus combination therapy with PDT (34). There was no significant difference visually between the 2 groups, with an average pretreatment vision of 20/86 and an average posttreatment vision at 24 months of 20/55. The PDT subfoveal combination group, however, did require less intravitreal injections.

There are a multitude of treatment modalities to address the problem of neovascular ocular histoplasmosis. We began with laser photocoagulation, which seemed like a viable option in its day. Next, we reviewed the advent of submacular surgery and showed that even at the time, the results were questionable. Then came PDT, and this modality seemed to be a stabilizing therapy, that probably did better in combination with the anti-VEGF agents. We discussed the utility of steroid therapy, with average results, and a borderline safety profile. The present-day treatment of choice consists of the anti-VEGF agents. There is sufficient data to support application for Food and Drug Administration approval of all of the anti-VEGF agents for the treatment of neovascular POHS—yet, the motivation for this seems to be lacking. Investigators will continue to strive toward higher efficacy and safety with future innovations in the field.

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Keywords:

aflibercept; bevacizumab; choroidal neovascularization; corticosteroids; laser photocoagulation; photodynamic therapy; presumed ocular histoplasmosis syndrome; ranibizumab; submacular surgery; verteporfin

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