Faculty Bibliography

PURPOSE: To assess change in intraocular pressure (IOP) in patients with neovascular age-related macular degeneration (NVAMD) receiving intravitreal aflibercept injection (IAI) or ranibizumab in VEGF Trap-Eye: Investigation of Efficacy and Safety in Wet AMD (VIEW) 1 and 2 studies. DESIGN: Analyses from 2 randomized, active-controlled, phase III trials. PARTICIPANTS: A total of 2457 patients with NVAMD. METHODS: Patients received IAI 2 mg every (q) 4 weeks (2q4), 0.5 mg q4 weeks (0.5q4), 2 mg q8 weeks (after 3 monthly doses; 2q8), or ranibizumab 0.5 mg q4 weeks (Rq4) for 52 weeks. At week 52, patients were switched to a variable regimen requiring at least quarterly dosing and allowing interim injections based on anatomic and visual assessment. MAIN OUTCOME MEASURES: Pre-injection IOP was analyzed in study and uninjected fellow eyes from baseline to week 96. Prespecified end points included mean change in IOP from baseline and prevalence of a >21 mmHg and >10 mmHg increase in IOP from baseline. Cumulative incidence of sustained (at 2 consecutive visits) IOP >21 mmHg, a single event of IOP >25 mmHg, and sustained IOP increase from baseline (>/=5 mmHg) was also evaluated. RESULTS: Mean IOP change from baseline over 96 weeks in all IAI groups was consistently lower than in the Rq4 group, and this finding was replicated in both trials. In an analysis integrating both studies, the proportion of study eyes with IOP >21 mmHg at week 96 was 20.2%, 14.2%, 12.1%, and 12.5% in Rq4, 2q4, 2q8, and 0.5q4, respectively. Reduction in risk, relative to Rq4, of having sustained IOP >21 mmHg over 96 weeks was 62% (95% confidence interval [CI], 36%-78%), 50% (95% CI, 19%-70%), and 69% (95% CI, 45%-84%) for 2q4, 2q8, and 0.5q4, respectively. Risk reduction in the IAI groups for a sustained IOP increase >/=5 mmHg was 31% (95% CI, 8%-48%), 38% (95% CI, 17%-54%), and 47% (95% CI, 27%-61%), respectively. In uninjected fellow eyes, only sustained IOP >21 mmHg events were higher in the Rq4 group compared with all IAI groups. CONCLUSIONS: Incidence of elevated IOP in eyes with NVAMD was lower in all IAI groups than in the ranibizumab group.

PURPOSE:: To compare the effect of 30-gauge versus 32-gauge needle size on postinjection reflux and immediate postinjection intraocular pressure (IOPimmed_post) spikes in eyes injected with anti-vascular endothelial growth factor agents. METHODS:: This was a prospective interventional case series of 65 eyes of 54 consecutive patients in a clinical practice setting who received intravitreal anti-vascular endothelial growth factor therapy. All eyes had preinjection IOP, IOPimmed_post, postinjection reflux, and axial lengths recorded. RESULTS:: There was a higher incidence of postinjection reflux in eyes injected with 30-gauge (53%) compared with those injected with 32-gauge (13%, P = 0.0007). Among 34 eyes injected with 30-gauge, 16 eyes without appreciable postinjection reflux had mean IOPimmed_post of 44.3 +/- 7.48 mmHg and mean IOPimmed_post elevation of 29.6 +/- 2.10 mmHg, which was significantly higher than the 18 eyes with reflux (mean IOPimmed_post of 18.8 +/- 7.15 mmHg and mean IOPimmed_post elevation of 4.5 +/- 1.74 mmHg, P < 0.0001). Among 31 eyes injected with 32-gauge, 27 eyes without appreciable postinjection reflux had mean IOPimmed_post of 44.4 +/- 10.82 mmHg and mean IOPimmed_post elevation of 29.5 +/- 1.99 mmHg, which was significantly higher than the 4 eyes with reflux (mean IOPimmed_post of 21.3 +/- 8.54 mmHg and mean IOPimmed_post elevation of 9.5 +/- 4.05 mmHg, P < 0.001). The differences in reflux and IOP between the two groups were unrelated to axial lengths (P = 0.451). CONCLUSION:: Eyes receiving injections with 32-gauge needles had a lower incidence of postinjection reflux and higher mean IOP immediately after injection.

PURPOSE:: To report three cases of late recurrence of myopic foveoschisis (MF) after initial successful repair with pars plana vitrectomy and membrane peeling to assess the importance of internal limiting membrane peeling. METHODS:: A retrospective noncomparative case series was performed of patients who underwent a primary pars plana vitrectomy by a single surgeon with successful resolution of MF, but eventually underwent repeat pars plana vitrectomy for recurrent MF. Best-corrected visual acuity, fundus photography, and optical coherence tomography were obtained at each examination. RESULTS:: Three eyes of three patients underwent pars plana vitrectomy for recurrent MF. Myopic foveoschisis recurrence occurred 6, 3.5, and 12 years after the primary vitrectomy, respectively. Repeat vitrectomy with staining and additional peeling of the internal limiting membrane resulted in good anatomical outcome and stabilization of visual acuity in all cases. CONCLUSION:: Late recurrence of MF after successful primary vitrectomy is described. Fibrocellular proliferation on residual cortical vitreous or incomplete internal limiting membrane peeling during the initial vitrectomy may underlie recurrence.

Defects in Membrane Frizzled-related Protein (MFRP) cause autosomal recessive retinitis pigmentosa (RP). MFRP codes for a retinal pigment epithelium (RPE)-specific membrane receptor of unknown function. In patient-specific induced pluripotent stem (iPS)-derived RPE cells, precise levels of MFRP, and its dicistronic partner CTRP5, are critical to the regulation of actin organization. Overexpression of CTRP5 in naive human RPE cells phenocopied behavior of MFRP-deficient patient RPE (iPS-RPE) cells. AAV8 (Y733F) vector expressing human MFRP rescued the actin disorganization phenotype and restored apical microvilli in patient-specific iPS-RPE cell lines. As a result, AAV-treated MFRP mutant iPS-RPE recovered pigmentation and transepithelial resistance. The efficacy of AAV-mediated gene therapy was also evaluated in Mfrprd6/Mfrprd6 mice-an established preclinical model of RP-and long-term improvement in visual function was observed in AAV-Mfrp treated mice. This report is the first to indicate the successful use of human iPS-RPE cells as a recipient for gene therapy. The observed favorable response to gene therapy in both patient-specific cell lines and the Mfrprd6/Mfrprd6 preclinical model suggests that this form of degeneration caused by MFRP mutations is a potential target for interventional trials.Molecular Therapy (2014); doi:10.1038/mt.2014.100.

PURPOSE:: To describe the spectral domain optical coherence tomography findings in eyes with chronic fibrovascular pigment epithelial detachment (PED) receiving intravitreal anti-vascular endothelial growth factor (anti-VEGF) therapy. METHODS:: Retrospective observational case series of patients with chronic fibrovascular PEDs receiving serial intravitreal anti-VEGF therapy. Corresponding spectral domain optical coherence tomography scans of chronic PEDs were studied in detail over multiple visits. The internal structure within the sub-PED compartment was analyzed, characteristic features were identified, and then correlated with visual outcome. RESULTS:: Thirty-eight eyes of 34 patients with fibrovascular PEDs were included. Mean and median Snellen visual acuity was 20/50 (range, 20/20-20/400). Eyes received a mean of 28.2 intravitreal anti-VEGF injections (median, 23.0; range, 3-70) administered over a mean of 36.9 months (median, 37.5; range, 6-84). A fusiform, or spindle-shaped, complex of highly organized layered hyperreflective bands was noted within each PED. Nineteen eyes demonstrated heterogenous, dilated, irregular neovascular tissue adherent to the undersurface of the retinal pigment epithelium. Additionally, 25 eyes demonstrated a hyporeflective cavity separating the choroidal neovascularization complex from the underlying choroid. CONCLUSION:: Chronic fibrovascular PEDs receiving serial anti-VEGF therapy demonstrate a characteristic fusiform complex of highly organized, layered, hyperreflective bands, termed a "multilayered PED," which is often seen in conjunction with neovascular tissue adherent to the undersurface of the retinal pigment epithelium monolayer. On the basis of previous histopathologic correlations, these bands may represent a fibrous tissue complex with contractile properties. An associated hyporeflective space, termed a "pre-choroidal cleft," separates the fusiform complex from the underlying choroid and may be due to contraction, the exudation of fluid, or both. Many of these eyes maintain good visual acuity, presumably because the neovascular and cicatricial process is suppressed within the sub-retinal pigment epithelium space by chronic anti-VEGF therapy, thus permitting the viability of the photoreceptor population through preservation of the retinal pigment epithelium.

PURPOSE: To assess an association of axial length (AL) or postinjection reflux with transient or sustained intraocular pressure (IOP) elevation in patients with neovascular age-related macular degeneration receiving anti-vascular endothelial growth factor injections. METHODS: One hundred and forty-seven eyes from 74 consecutive patients with neovascular age-related macular degeneration who presented to a single physician over a 2-month period had ALs measured by IOLMaster. Twenty-one patients had preinjection and immediate postinjection IOP measured and immediate reflux assessed. RESULTS: Overall, 9.5% of eyes had been identified with sustained IOP elevation in our previous study. Axial length did not significantly differ between eyes that had (AL, 23.96 +/- 0.66 mm; n = 14) and had not experienced sustained IOP elevation (AL, 23.44 +/- 1.24 mm; n = 133; P = 0.12, t-test). By linear regression analysis, the relationship between experiencing sustained IOP elevation and AL was not statistically significant (R = 0.0165; P = 0.121). The relationship between AL and immediate postinjection IOP elevation was also not statistically significant (R = 0.0001; P = 0.97). Immediate postinjection IOP increase did differ between eyes without reflux (30.2 +/- 9.3 mmHg; n = 12) and those with reflux (1.1 +/- 7.2; n = 9; P < 0.001). CONCLUSION: Axial length does not seem to be a predictor of transient or sustained IOP elevation. Repeated trabecular meshwork trauma related to the absence or presence of reflux and immediate postinjection IOP elevation may be a contributing factor.

PURPOSE: To report nine cases of pachychoroid pigment epitheliopathy. METHODS: An observational case series of nine patients who underwent comprehensive ophthalmic examination, fundus photography, fundus autofluorescence, spectral-domain optical coherence tomography, and enhanced depth imaging optical coherence tomography. RESULTS: Eighteen eyes of 9 patients, aged 27 years to 89 years, were diagnosed with pachychoroid pigment epitheliopathy based on the characteristic funduscopic appearance of reduced fundus tessellation with overlying retinal pigment epithelial changes in one or both eyes, fundus autofluorescence abnormalities, and increased subfoveal choroidal thickness confirmed by enhanced depth imaging optical coherence tomography (mean, 460.2 mum). The five older patients had been previously diagnosed with age-related macular degeneration, while the four younger subjects were referred for possible inflammatory chorioretinitis, pattern dystrophy, or nonspecific drusen. No subjects had a history of or subsequently developed subretinal fluid. CONCLUSION: Pachychoroid pigment epitheliopathy falls within a spectrum of diseases associated with choroidal thickening that includes central serous chorioretinopathy and polypoidal choroidal vasculopathy, and it should be suspected in eyes with a characteristic fundus appearance related to choroidal thickening and associated retinal pigment epithelial abnormalities but no history of subretinal fluid. Enhanced depth imaging optical coherence tomography confirming an abnormally thick choroid and characteristic retinal pigment epithelial changes on fundus autofluorescence support the diagnosis. Because these patients are frequently misdiagnosed, the recognition of pachychoroid pigment epitheliopathy may avoid unnecessary diagnostic testing and interventions.

BACKGROUND: Acute zonal occult outer retinopathy (AZOOR) was described by Gass in 1992 as an independent posterior uveitis characterized by photopsias and rapid visual field zonal loss, with 70% of cases stabilizing within 6 months, although there is a paucity of long-term documentation of AZOOR cases. METHODS: The authors reported the case of a 55-year-old woman diagnosed with AZOOR and followed for 13 years. RESULTS: Best-corrected visual acuity at baseline was 20/60 in her right eye and 20/25 in her left eye, with an annular peripapillary area of irregular retinal thickening and temporal visual field loss in both eyes. Over her 13-year follow-up, best-corrected visual acuity dropped to 20/60 in both eyes and visual field loss because of chorioretinal atrophy progressed significantly. Antiviral and immunomodulatory drugs did not halt this progression. CONCLUSION: The prognosis of cases with AZOOR should be cautiously considered. The authors showed that in the long term, chorioretinal atrophy may lead to severe visual field loss in patients with AZOOR.