Oral minocycline for the treatment of retinitis pigmentosa-associated cystoid macular edema: results of a phase I/II clinical trial.

PURPOSE: The etiology of retinitis pigmentosa (RP)-associated cystoid macular edema (CME) has been related to retinal neuroinflammation and microglial activation. Minocycline, a drug FDA-approved for anti-microbial indications, also inhibits microglial activation and expression of inflammatory mediators. This study investigates the safety and efficacy of oral minocycline as primary treatment for RP-associated CME. METHODS: A single-center, prospective, open-label phase I/II clinical trial enrolled five participants with RP-associated CME. Participants had lead-in assessments prior to the initiation of oral minocycline 100 mg twice daily for 12 months. Main outcome variables included changes in best-corrected visual acuity (BCVA) and retinal central subfield thickness (CST) measured using spectral domain optical coherence tomography relative to mean of pre-treatment measurements. RESULTS: The study drug was well tolerated and not associated with any severe adverse events. No significant changes in mean BCVA from study baseline were noted in either the study eye (+ 0.7 ± 4.1 letters at 6 months, - 1.1 ± 1.7 letters at 12 months) or the qualifying fellow eye (- 0.3 ± 3.4 letters at 6 months, - 0.3 ± 4.6 letters at 12 months) (p > 0.05 for all comparisons). Mean percentage changes in CST from baseline however decreased progressively with treatment (decreases at 6 and 12 months: study eyes 3.9 and 9.8%; qualifying fellow eyes 1.4 and 7.7%). Considering all eyes (n = 10), mean percentage CST decrease at 6 and 12 months was 2.7 ± 9.5% (p = 0.39) and 8.7 ± 9.5% (p = 0.02) respectively. CONCLUSION: Oral minocycline administration over 12 months was associated with no significant changes in mean BCVA and a small but progressive decrease in mean CST. TRIAL REGISTRATION: NCT02140164 (05/2014).

Investigations of Renal Function and Age-Related Macular Degeneration Phenotypes.

Purpose: To investigate potential associations between renal function and age-related macular degeneration (AMD) features as assessed with multimodal retinal imaging. Methods: A subset of participants included in a dark adaptation study with varying AMD severities had estimated glomerular filtration rate (eGFR) values (mL/min/1.73 m2) obtained from renal function laboratory testing of serum creatinine and cystatin C. Multimodal imaging from visit dates associated with serum samples was graded by the Wisconsin Reading Center for AMD features. Associations of eGFR with AMD features and severity grades, age, smoker status and rod-intercept time were investigated. Simple univariate analyses, age-corrected multivariate analyses, and a feature-selecting least absolute shrinkage and selection operator regression were performed for eGFR as a continuous dependent variable. Results: A total of 110 patients (mean age, 75.1 ± 9.4 years; mean eGFR, 70.7 ± 18.2 mL/min/1.73 m2) were included. In univariate analyses age (estimate, -1.16 units/year; 95% confidence interval [CI], -1.46 to -0.87; P < 0.0001), rod-intercept time (estimate, -0.54 units/minute; 95% CI, -0.81 to -0.27; P < 0.001) and subretinal drusenoid deposits (-11.12 units for subretinal drusenoid deposit presence in either eye; 95% CI, -20.23 to -2.01; P = 0.017) were associated with decreased renal function. However, in age-corrected multivariate models, age was the only significant variable associated with renal function, confirmed by least absolute shrinkage and selection operator regression. Conclusions: Accounting for age, renal function parameters did not show an association with AMD features. Translational Relevance: Bruch's membrane of the eye and the glomerular basement membrane of the kidney share physiologic similarities such that decreased renal function may demonstrate associations with AMD phenotypes.

10-YEAR FOLLOW-UP OF A SUBCLINICAL CHOROIDAL NEOVASCULAR MEMBRANE IN A PATIENT WITH AGE-RELATED MACULAR DEGENERATION.

PURPOSE: To provide long-term, natural history data of a case of a subclinical choroidal neovascular membrane (CNVM) in the setting of age-related macular degeneration. METHODS: Retrospective review of the 10-year clinical course of a patient including multimodal imaging. RESULTS: A 75-year-old white female with macular degeneration presented with visual acuity of 20/25 in the right eye and 20/40 in the left eye. In the left eye, a retinal pigment epithelial detachment with associated subretinal and intraretinal fluid was found on spectral domain optical coherence tomography. Fluorescein angiography was consistent with a predominately classic CNVM, which was well-visualized on indocyanine green angiography. Treatment was initiated with bevacizumab for 10 months that reduced the amount of subretinal and intraretinal fluid, but progressive geographic atrophy developed over the subsequent 9 years reducing vision to 20/100. Interestingly, at initial presentation, a nonexudative fibrovascular pigment epithelial detachment was detected in the right (contralateral) eye. This was monitored with multimodal imaging twice yearly for 10 years without any signs of exudation, and vision remained 20/25. Optical coherence tomography angiography revealed a remarkably similar appearance of the subclinical CNVM compared with indocyanine green angiography 10 years prior, suggesting anatomical stability. CONCLUSION: The advent of optical coherence tomography angiography has increased the detection of subclinical CNVMs. Recent evidence suggests that subclinical CNVMs have a high rate of progression to exudation over 1 year, which raises the question of whether early treatment is beneficial. This case provides 10-year follow-up with multimodal imaging (fluorescein angiography, indocyanine green angiography, optical coherence tomography, and optical coherence tomography angiography) of a subclinical CNVM, which remained stable and without exudation, suggesting that they may be closely observed.

LONGITUDINAL CHANGES IN EYES WITH HYDROXYCHLOROQUINE RETINAL TOXICITY.

PURPOSE: To characterize functional and structural changes in hydroxychloroquine (HCQ) retinal toxicity after drug cessation. METHODS: Twenty-two patients (91% female; mean age 58.7 ± 11.4 years; mean duration of HCQ treatment 161.1 ± 90 months; mean dose 5.9 ± 1.9 mg/kg) with detected HCQ retinopathy were monitored for 6 months to 82 months after HCQ cessation with multimodal imaging including spectral domain optical coherence tomography and fundus autofluorescence imaging at 488 nm (standard) and 787 nm (near-infrared autofluorescence). Tests of visual function including visual acuity, Humphrey visual field testing, and multifocal electroretinography (mfERG) were performed. Study eyes were categorized into four separate severity stages by qualitative grading of spectral domain optical coherence tomography macular scans taken at the time of HCQ cessation. Changes in outcome measures between drug cessation and last follow-up visit were computed and compared between eyes of different severity stages. RESULTS: Study eyes (n = 44) were categorized based on optical coherence tomography criteria into: Stage 1 (subtle changes confined to parafoveal region; n = 14), Stage 2 (clear localized changes in parafovea; n = 17), Stage 3 (extensive parafoveal changes; n = 7), and Stage 4 (foveal involvement, n = 6). Visual acuity measurements across follow-up were stable in Stage 1 and Stage 2 eyes but decreased significantly in Stage 3 and 4 eyes. Humphrey visual field measures were also stable in stages 1 and 2 but deteriorated in Stage 3 eyes. mfERG testing demonstrated significant improvement in the R1/R2 ratio after HCQ cessation in Stage 1 eyes (mean change = -0.86 ± 0.79, P = 0.03) but did not change significantly in eyes of higher stages. Decreases in macular thickness in ≥1 of 9 Early Treatment Diabetic Retinopathy Study subfields on spectral domain optical coherence tomography were found in eyes of all stages, with Stage 2 eyes demonstrating thinning in most subfields (eight of nine subfields). In eyes with a measurable central foveal ellipsoid zone band island (9 of 17 Stage 2 eyes and 7 of 7 Stage 3 eyes), progressive decrease in the foveal ellipsoid zone band length was observed in 6 of 9 (67%) Stage 2 eyes and 6 of 7 (86%) Stage 3 eyes. Changes indicative of progressing retinopathy were detected in 17% of Stage 1 eyes, 46% of Stage 2 eyes, and 43% of Stage 3 eyes on standard fundus autofluorescence imaging, and in 17% of Stage 1 eyes, 38% of Stage 2 eyes, and 14% of Stage 3 eyes on near-infrared autofluorescence imaging. CONCLUSION: Eyes with detected HCQ retinopathy do not demonstrate general stability in retinal structure and function after HCQ cessation but instead demonstrate a range of changes during follow-up whose magnitudes correlate with retinopathy severity at the time of cessation. After cessation, eyes with only subtle and localized retinopathy were mostly stable and may show some functional improvement, whereas more severely affected eyes continued to progress. These findings provide evidence that early detection and prompt cessation in HCQ retinopathy may be needed to arrest retinopathy progression and to optimize long-term outcomes.

Orbital Roof Reconstruction Using Nylon Foil Implants.

PURPOSE: To describe a surgical technique of orbital roof reconstruction with a thin nylon foil implant. METHODS: This study is a description of a surgical technique with a retrospective chart review of 3 consecutive patients treated with a nylon foil implant for a complete superior orbital defect after meningioma resection via craniotomy approach. RESULTS: The nylon foil reconstruction achieved an anatomically stable orbit without globe dystopia, pulsatile proptosis, cerebrospinal fluid leak, or other serious cranio-orbital problems, in all cases. Postoperative visual acuity, pain, extraocular motility, proptosis, and globe position remained stable or improved in each case. There were no complications related to the orbital roof reconstruction. CONCLUSIONS: Nylon foil implantation was an effective and inexpensive surgical technique for orbital roof reconstruction after tumor resection in this small series.

Longitudinal Study of Dark Adaptation as a Functional Outcome Measure for Age-Related Macular Degeneration.

PURPOSE: To investigate the natural history of dark adaptation (DA) function as measured by the change in rod intercept time (RIT) over 4 years and to correlate RIT change with age-related macular degeneration (AMD) severity. DESIGN: Longitudinal, single-center, observational study. PARTICIPANTS: A total of 77 participants aged ≥50 years with a range of AMD severities. METHODS: Participants each contributing a single study eye to the analysis were assigned into person-based AMD severity groups based on fundus characteristics (drusen, pigmentary changes, late AMD, and subretinal drusenoid deposits [SDDs]). The DA function was assessed in study eyes at baseline and 3, 6, 12, 18, 24, 36, and 48 months. Mean change in DA function over time was calculated using the slope of linear regression fits of longitudinal RIT data. Patient-reported responses on a Low Luminance Questionnaire (LLQ) were obtained at baseline and yearly. Nonparametric statistical testing was performed on all comparisons. MAIN OUTCOME MEASURE: The RIT, defined as the time taken after a photobleach for visual sensitivity to recover detection of a 5×10-3 cd/m2 stimulus (a decrease of 3 log units), was monitored in study eyes over 4 years, and the mean rate of change was computed. RESULTS: Longitudinal analysis of 65 study eyes followed on the standard testing protocol (mean age, 71±9.3 years; 49% were female) revealed that higher rates of RIT prolongation were correlated with AMD severity group assignment at baseline (P = 0.026) and with severity group assignments at year 4 (P = 0.0011). Study eyes that developed SDD during follow-up demonstrated higher rates of RIT prolongation relative to those that did not (P < 0.0001). Overall, higher rates of RIT prolongation were significantly correlated with greater 4-year decreases in LLQ scores (total mean score, P = 0.0032). CONCLUSIONS: Longitudinal decline in DA function, which correlated with patient-reported functional deficits, was accelerated in eyes with greater AMD severity and especially in eyes with SDD both at baseline and at 4 years. The RIT prolongation as a measure of changing DA function may be a functional outcome measure in AMD clinical studies.