Denise Cunningham

Treatment of Geographic Atrophy by the Topical Administration of OT-551: Results of a Phase II Clinical Trial

PURPOSE To investigate the safety and preliminary efficacy of OT-551, a disubstituted hydroxylamine with antioxidant properties, for the treatment of geographic atrophy (GA), the advanced atrophic form of age-related macular degeneration (AMD). METHODS The study was a single-center, open-label phase II trial, enrolling 10 participants with bilateral GA. Topical 0.45% OT-551 was administered in one randomly assigned eye three times daily for 2 years. Safety measures were assessed by complete ophthalmic examination, fundus photography, and review of symptoms. The primary efficacy outcome measure was the change in best corrected visual acuity at 24 months. Secondary efficacy measures included changes in area of GA, contrast sensitivity, microperimetry measurements, and total drusen area from baseline. RESULTS Study drug was well tolerated and was associated with few adverse events. The mean change in BCVA at 2 years was +0.2 ± 13.3 letters in the study eyes and -11.3 ± 7.6 letters in fellow eyes (P = 0.0259). However, no statistically significant differences were found between the study and fellow eyes for all other secondary outcome measures. CONCLUSIONS OT-551 was well tolerated by study participants and was not associated with any serious adverse effects. Efficacy measurements in this small study indicate a possible effect in maintaining visual acuity. However, the absence of significant effects on other outcomes measures in this study suggests that OT-551, in the current concentration and mode of delivery, may have limited or no benefit as a treatment for GA (ClinicalTrials.gov number, NCT00306488).

Fundus Autofluorescence in Type 2 Idiopathic Macular Telangiectasia: Correlation with Optical Coherence Tomography and Microperimetry

PURPOSE To use multiple imaging methods to investigate patients with type 2 idiopathic macular telangiectasia (IMT) at different disease severity stages so as to characterize and categorize disease progression through the full spectrum of disease phenotypes. DESIGN Observational case series. METHODS Twelve patients with type 2 IMT (22 eyes) examined with fundus photography, angiography, optical coherence tomography imaging, fundus autofluorescence (FAF), and microperimetry testing in an institutional setting. RESULTS Eyes examined by multiple imaging methods were classified into 5 proposed categories (0 through 4): category 0 (fellow) eyes had normal results on all imaging methods. Category 1 eyes had increased foveal autofluorescence on FAF imaging as the only imaging abnormality. Category 2 eyes had increased foveal autofluorescence together with funduscopic and angiographic features typical of type 2 IMT. Category 3 eyes had additional evidence of foveal atrophy on optical coherence tomography, and category 4 eyes had all the above features plus clinically evident pigment clumping. FAF signal increased in intensity in the foveal region from category 0 through category 3, whereas category 4 eyes demonstrated a mixed pattern of increased and decreased FAF signal. CONCLUSIONS The findings here outline a sequence of progressive changes seen with multiple imaging methods in advancing stages of disease. Increase in foveal autofluorescence is an early anatomic change in type 2 IMT that may precede typical clinical and angiographic changes. Loss of macular pigment density in the fovea and a changing composition of fluorophores in the retinal pigment epithelium may underlie these changes on FAF in the fundus.

Centrifugal Expansion of Fundus Autofluorescence Patterns in Stargardt Disease Over Time

OBJECTIVE To study the longitudinal changes in autofluorescence in Stargardt disease to reveal aspects of disease progression not previously evident. Changes in autofluorescence reflect changing fluorophore compositions of lipofuscin and melanin in retinal pigment epithelial cells, which has been hypothesized to contribute to Stargardt disease pathogenesis. METHODS We examined the temporospatial patterns of fundus autofluorescence with excitation at both 488 nm (standard fundus autofluorescence) and 795 nm (near-infrared autofluorescence) in a longitudinal case series involving 8 eyes of 4 patients (range of follow-up, 11-57 months; mean, 39 months). Image processing was performed to analyze spatial and temporal cross-modality associations. RESULTS Longitudinal fundus autofluorescence imaging of fleck lesions revealed hyperautofluorescent lesions that extended in a centrifugal direction from the fovea with time. Patterns of spread were nonrandom and followed a radial path that left behind a trail of diminishing autofluorescence. Longitudinal near-infrared autofluorescence imaging also demonstrated centrifugal lesion spread but with fewer hyperautofluorescent lesions, suggestive of more transient hyperautofluorescence and more rapid decay at longer wavelengths. Fundus autofluorescence and near-infrared autofluorescence abnormalities were spatially correlated with each other, and together they reflect systematic progressions in fleck distribution and fluorophore composition occurring during the natural history of the disease. CONCLUSIONS Stargardt disease fleck lesions do not evolve randomly in location but instead follow consistent patterns of radial expansion and a systematic decay of autofluorescence that reflect changing lipofuscin and melanin compositions in retinal pigment epithelial cells. These progressive foveal-to-peripheral changes are helpful in elucidating molecular and cellular mechanisms underlying Stargardt disease and may constitute potential outcome measures in clinical trials.

Bilateral posterior uveitis associated with Zika virus infection

A 26-year-old healthy white man returned to Washington, DC, from visiting Puerto Rico, in June, 2016. The day after his return he developed chills, myalgia, arthralgia, and a centrifugal skin rash, and was given a diagnosis of Zika virus infection by his physician, confi rmed by realtime PCR (RT-PCR) assay (US Centers for Disease Control and Prevention [CDC]) on a serum specimen taken on the fi fth day of illness. RT-PCR assays for Dengue and Chikungunya viruses were negative. A week after his return, he developed 1 week of redness of both eyes without discharge, which resolved without treatment, but was followed a week later by fl ashes of light (photopsias) in the left eye. Ophthalmic examination showed visual acuities of 20/20 and normal anterior segment in both eyes, but 0·5+ cells in the vitreous (graded on a scale of 0 to 4+) on dilated fundus examination and scattered faint mid-peripheral yellowwhite lesions in the left eye only. The patient was started on loteprednol etabonate 0·5% ophthalmic suspension three times daily to the left eye and referred to our uveitis service, about 1 week after onset of his ocular symptoms and 1 month after his return. He reported some improvement but remained mildly symptomatic with photopsias. His visual acuities were stable at 20/20 and the anterior segment was normal bilaterally. The mild vitreous infl ammation in the left eye had completely resolved. Fundus examination of the right eye remained normal, but the left eye had nasal pigmented outer retinal and choroidal lesions (fi gure). Involvement of the retinal pigment epithelium was confi rmed by fundus autofl uorescence, which showed hyperautofl uorescence (appendix). Optical coherence tomography (OCT) imaging showed hyper-refl ective nodular elevations in the outer retina at the site of these pigmented lesions (fi gure, appendix, video). Indocyanine green dye (ICG) angiography (used to visualise the choroidal circulation) showed foci of hyperfl uorescence in a circumscribed pattern, consistent with active choroidal lesions (appendix) in both eyes, although fundocopy and OCT showed no changes corresponding with these areas. We did an anterior chamber paracentesis and both aqueous humor and conjunctival swabs tested negative for Zika virus on RT-PCR testing (CDC). The patient’s serum also tested negative for rapid plasma reagin, anti-Epstein Barr Virus IgM antibodies, and antibodies against HIV 1/2, Borrelia burgdorferi, Cytomegalovirus, and Mycobacterium tuberculosis. In view of the resolution of anterior vitreous infl ammation and the peripheral location of the left chorioretinal lesions on fundoscopy, we decided to stop the topical steroids. At follow-up examination 4 weeks later, his visual acuities remained unchanged. The nasal chorioretinal lesions in the left eye appeared less prominent and showed less hyperautofl uorescence, suggesting they were resolving, and repeat OCT showed improved outer retinal changes (appendix). The patient is scheduled for routine followup care. We believe this is the fi rst reported case of bilateral posterior uveitis and acquired chorioretinal lesions associated with Zika virus disease. The presence of chorioretinal lesions in the left eye and several foci of leakage on ICG angiography bilaterally are suggestive of lesions at diff erent stages of activity. We do not yet understand the cause of these chorioretinal lesions. Many reports have described congenital chorioretinal lesions after maternal infection with Zika virus, but few have described ocular complications in adults. Furtado and colleagues described bilateral low-grade anterior uveitis in a Brazilian man who developed ocular symptoms 8 days after the onset of systemic symptoms, which resolved with topical glucocorticoid therapy; the aqueous sample from his right eye tested positive for Zika virus on RT-PCR, but repeat testing from the left eye was negative. The negative aqueous sample from our patient could mean that anterior uveitis did not occur in this case or that the virus might no longer be detectable 1 month after the onset of symptoms. A case of unilateral acute maculopathy in a 64-year-old white man with positive Zika virus serology has also been reported. He developed Bilateral posterior uveitis associated with Zika virus infection

Comparison of Wide-Field Fluorescein Angiography and 9-Field Montage Angiography in Uveitis

PURPOSE To compare qualitatively and quantitatively Optos fundus camera fluorescein angiographic images of retinal vascular leakage with 9-field montage Topcon fluorescein angiography (FA) images in patients with uveitis. We hypothesized that Optos images reveal more leakage in patients with uveitis. DESIGN Retrospective, observational case series. METHODS Images of all patients with uveitis imaged with same-sitting Optos FA and 9-field montage FA during a 9-month period at a single institution (52 eyes of 31 patients) were graded for the total area of retinal vascular leakage. The main outcome measure was area of fluorescein leakage. RESULTS The area of apparent FA leakage was greater in Optos images than in 9-field montage images (median 22.5 mm(2) vs 4.8 mm(2), P < 0.0001). Of the 49 (45%) eyes with gradable photos, 22 had at least 25% more leakage in the Optos image than in the montage image; 2 (4.1%) had at least 25% less leakage in Optos; and 25 (51%) were similar in the 2 modalities. There were 2 eyes that had no apparent retinal vascular leakage in 9-field montage but were found to have apparent leakage in Optos images. Of the 49 eyes, 23 had posterior pole leakage, and of these, 17 (73.9%) showed more posterior pole leakage in the Optos image. A single 200-degree Optos FA image captured a mean 1.50× the area captured by montage photography. CONCLUSIONS More retinal vascular pathology, in both the periphery and the posterior pole, is seen with Optos FA in patients with uveitis when compared with 9-field montage. The clinical implications of Optos FA findings have yet to be determined.

Treatment of Geographic Atrophy With Subconjunctival Sirolimus: Results of a Phase I/II Clinical Trial

PURPOSE To investigate the safety and effects of subconjunctival sirolimus, an mTOR inhibitor and immunosuppressive agent, for the treatment of geographic atrophy (GA). METHODS The study was a single-center, open-label phase II trial, enrolling 11 participants with bilateral GA; eight participants completed 24 months of follow-up. Sirolimus (440 μg) was administered every 3 months as a subconjunctival injection in only one randomly assigned eye in each participant for 24 months. Fellow eyes served as untreated controls. The primary efficacy outcome measure was the change in the total GA area at 24 months. Secondary outcomes included changes in visual acuity, macular sensitivity, central retinal thickness, and total drusen area. RESULTS The study drug was well tolerated with few symptoms and related adverse events. Study treatment in study eyes was not associated with structural or functional benefits relative to the control fellow eyes. At month 24, mean GA area increased by 54.5% and 39.7% in study and fellow eyes, respectively (P = 0.41), whereas mean visual acuity decreased by 21.0 letters and 3.0 letters in study and fellow eyes, respectively (P = 0.03). Substantial differences in mean changes in drusen area, central retinal thickness, and macular sensitivity were not detected for all analysis time points up to 24 months. CONCLUSIONS Repeated subconjunctival sirolimus was well-tolerated in patients with GA, although no positive anatomic or functional effects were identified. Subconjunctival sirolimus may not be beneficial in the prevention of GA progression, and may potentially be associated with effects detrimental to visual acuity. (ClinicalTrials.gov number, NCT00766649.).

Drusen regression is associated with local changes in fundus autofluorescence in intermediate age-related macular degeneration.

PURPOSE To investigate the association of spontaneous drusen regression in intermediate age-related macular degeneration (AMD) with changes on fundus photography and fundus autofluorescence (FAF) imaging. DESIGN Prospective observational case series. METHODS Fundus images from 58 eyes (in 58 patients) with intermediate AMD and large drusen were assessed over 2 years for areas of drusen regression that exceeded the area of circle C1 (diameter 125 μm; Age-Related Eye Disease Study grading protocol). Manual segmentation and computer-based image analysis were used to detect and delineate areas of drusen regression. Delineated regions were graded as to their appearance on fundus photographs and FAF images, and changes in FAF signal were graded manually and quantitated using automated image analysis. RESULTS Drusen regression was detected in approximately half of study eyes using manual (48%) and computer-assisted (50%) techniques. At year-2, the clinical appearance of areas of drusen regression on fundus photography was mostly unremarkable, with a majority of eyes (71%) demonstrating no detectable clinical abnormalities, and the remainder (29%) showing minor pigmentary changes. However, drusen regression areas were associated with local changes in FAF that were significantly more prominent than changes on fundus photography. A majority of eyes (64%-66%) demonstrated a predominant decrease in overall FAF signal, while 14%-21% of eyes demonstrated a predominant increase in overall FAF signal. CONCLUSIONS FAF imaging demonstrated that drusen regression in intermediate AMD was often accompanied by changes in local autofluorescence signal. Drusen regression may be associated with concurrent structural and physiologic changes in the outer retina.

Intravitreal Sirolimus for the Treatment of Geographic Atrophy: Results of a Phase I/II Clinical Trial

PURPOSE To investigate the safety and effects of intravitreal sirolimus for the potential treatment of geographic atrophy (GA). METHODS The study was a single-center, open-label, phase I/II trial enrolling six participants with bilateral GA treated with intravitreal sirolimus in only one randomly assigned eye, with the fellow eye as control. The primary efficacy outcome measure was the change in total GA area from baseline on color fundus photography (CFP); secondary outcomes included changes in GA area on fundus autofluorescence (FAF), visual acuity, central retinal thickness (CRT), and macular sensitivity from baseline. RESULTS Although no systemic adverse events were attributed to treatment, two of six participants had ocular adverse events that were possibly associated. The treated eye of one participant developed abnormal paralesional changes on FAF that were associated with accelerated retinal thinning. This accelerated retinal thinning was also seen in the treated eye of a second participant. Because of concern that these events were associated with treatment, treatment was suspended. Comparisons of treated and fellow eyes for change in visual acuity, change in GA area, and change in CRT showed no evidence of treatment benefit and generally favored the untreated fellow eye. CONCLUSIONS While paralesional FAF changes and rapid retinal thinning observed are potentially part of the natural course of GA, they may possibly be related to treatment. No general evidence of anatomical or functional benefit was detected in treated eyes. Further data on intravitreal sirolimus for GA treatment will be available from a larger phase II trial. (ClinicalTrials.gov number, NCT01445548.).

High-Resolution Autofluorescence Imaging for Mapping Molecular Processes within the Human Retina

Age related macular degeneration (AMD) is a common eye disease that often leads to vision loss. High levels of increased accumulation of fluorescent photoproducts appear to induce local retinal pigment epithelium (RPE) dysfunction associated with AMD. Low macular pigment level has also been identified as a risk factor for AMD.

Rapid vision loss associated with fludarabine administration.

Purpose: The purpose of this study was to report the clinical and pathologic findings of three cases of rapid vision loss associated with fludarabine toxicity. Methods: A retrospective, single-center case series was conducted. Autopsies of the eyes from three cases were performed. Results: A 23-year-old man (Case 1) with systemic lupus erythematosus developed rapid and severe vision loss, generalized neurologic decline, and eventual death after administration of fludarabine before stem cell transplantation. A 48-year-old woman (Case 2) and a 60-year-old man (Case 3), both with metastatic melanoma, had similar courses after receiving fludarabine as part of a preparatory regimen before adoptive cell therapy. Fundus examination showed punctuate yellow flecks in the macula after visual decline in two cases. In all three cases, serum antiretinal antibodies were negative before and after treatment; electrophysiological testing showed markedly decreased B-waves; and pathologic analysis showed loss of retinal bipolar and ganglion cells, gliosis within the retina and optic nerve, and optic nerve atrophy. Conclusion: Fludarabine toxicity can result in severe vision loss attributable to damage to retinal bipolar and ganglion cells. Although effective treatments are not known, care should be taken to consider fludarabine toxicity in patients who present with vision loss ∼1 month after treatment.