Two-Year Outcomes After Variable Duration of Drug Cessation in Patients With Maculopathy Associated With Pentosan Polysulfate Use.

Importance: Prior retrospective studies have provided limited evidence on disease progression following drug cessation in patients with maculopathy associated with pentosan polysulfate (PPS). Objective: To evaluate the 2-year evolution of maculopathy associated with PPS use after drug cessation. Design, Setting, and Participants: This cohort study prospectively evaluated the natural history of patients with maculopathy associated with PPS use. Participants seen at the Emory Eye Center were enrolled between December 1, 2018, and December 1, 2019, and data were collected through November 30, 2021. Main Outcomes and Measures: The main outcomes were changes in visual function and structure. Visual function was assessed annually with refraction and Early Treatment Diabetic Retinopathy Study (ETDRS) best-corrected visual acuity (BCVA), mesopic microperimetry, and dark adaptometry. Structural outcomes included presence and extent of complete retinal pigment epithelium and outer retinal atrophy (cRORA), macular central subfield thickness (CST), and subfoveal choroidal thickness (SFCT). Results: Of the 12 participants (23 eyes), 11 (91.7%) were female (1 [8.3%] male), 11 (91.7%) were White (1 [8.3%] Black), and median (IQR) age at enrollment was 58 (47-64) years. Median (IQR) time from PPS discontinuation to initial visit was 0.6 (0.4-1.9) years. Median baseline ETDRS BCVA letter score was 83 (Snellen equivalent, 20/20) (IQR, 80-86.5 [20/25-20/20]), with a median 2-year change of -3 (IQR, -6 to -0.5; P = .08). Four eyes (17.4%) had a letter score decline of 15 or more, all associated with progressive cRORA. Median change in microperimetry average threshold was -3.5 dB (IQR, -4.1 to -2.5 dB; P = .001), and percent reduced threshold was 32.5% (IQR, 20.3%-52.8%; P = .004). Nine eyes (39%) had macular cRORA at baseline, with a median linearized growth rate of 0.23 mm/y (IQR, 0.22-0.25 mm/y). Two eyes (8.7%) without atrophy at baseline developed new-onset cRORA. Median baseline CST was 284 µm (IQR, 253-291 µm), with a median 2-year change of -5 µm (IQR, -13 to 0.5 µm; P = .0497). Median 2-year change in SFCT was 1 µm (IQR, -18 to 16 µm; P = .91). Conclusions and Relevance: The findings of this cohort study suggest that functional and structural deficits continue to progress in PPS-associated maculopathy even after drug cessation. Additional study is needed to determine whether these findings can be generalized to other patients with PPS-associated maculopathy and whether longer follow-up could determine subsequent disease course.

Daam2 Regulates Myelin Structure and the Oligodendrocyte Actin Cytoskeleton through Rac1 and Gelsolin.

Myelin is essential to neuronal health and CNS function, and oligodendrocytes (OLs) undergo a complex process of cytoskeletal remodeling to form compact myelin sheaths. We previously discovered that a formin protein, Dishevelled associated activator of morphogenesis 2 (Daam2), suppresses OL differentiation through Wnt signaling; however, its role in cytoskeletal control remains unknown. To investigate this, we used OL-specific Daam2 conditional knockout (Daam2 cKO) mice of either sex and found myelin decompaction during an active period of myelination in postnatal development and motor coordination deficits in adulthood. Using primary OL cultures, we found Daam2-depleted OLs showed morphologic dysregulation during differentiation, suggesting that Daam2 regulates the OL cytoskeleton. In vivo screening identified the actin regulators Rac1 and Gelsolin as possible effectors in Daam2-deficient OL cytoskeletal regulation. Using gain-of-function and loss-of-function (LOF) experiments in primary OLs, we found that Rac1 and Gelsolin operate downstream of Daam2 in OL differentiation, with Gelsolin and Daam2 promoting and inhibiting membrane spreading during late differentiation, respectively. In vivo experiments using Daam2 cKO mice revealed increased protein levels of Gelsolin in the developing white matter with no change in RNA levels, suggesting that Daam2 acts in a posttranslational manner to suppress Gelsolin levels. In vitro biochemical studies show Daam2 induces Gelsolin ubiquitination and degradation in OLs. Together, our studies show Daam2 is essential for formation of functional myelin through modulation of Gelsolin levels to regulate the OL cytoskeleton. These findings further demonstrate the critical role of cytoskeletal dynamics in myelination and reveal novel avenues for treatment of a variety of white matter diseases.SIGNIFICANCE STATEMENT Proper myelin formation is essential to CNS function, and oligodendrocytes (OLs) require extensive changes in the actin cytoskeleton to form myelin sheaths. Here, we show that the formin protein Dishevelled associated activator of morphogenesis 2 (Daam2) is necessary for myelin compaction during development and motor learning in adulthood. Further, we demonstrate that Daam2 regulates OL differentiation and morphology through actin regulators Rac1 and Gelsolin. Lastly, we find that Daam2 may control myelin compaction by modulating the ubiquitination and degradation of Gelsolin through recruitment of the E3 ubiquitin ligase Nedd4. These findings reveal novel pathways for regulating myelin structure and function during white matter development.

Risk Factors for Retinal Detachment in Acute Retinal Necrosis.

PURPOSE: Retinal detachment (RD) is associated with poor visual outcomes in patients with acute retinal necrosis (ARN). This research was undertaken to assess the risk factors for RD in ARN. DESIGN: Retrospective cohort study. SUBJECTS: Patients diagnosed with ARN at a tertiary referral center from 2010 to 2020. METHODS: A chart review was performed for all clinical and surgical encounters. Univariate and multivariate logistic analyses of demographic and clinical variables associated with RD were performed. Survival analyses with Kaplan-Meier estimates were performed to compare the time to RD in herpes simplex virus (HSV)- and varicella zoster virus (VZV)-associated ARN. MAIN OUTCOME MEASURES: Demographic information, clinical information (including visual acuity [VA]), intraocular pressure (IOP), intraocular inflammation level, the extent of retinitis, incidence and timing of retinal detachment, date of diagnosis, and treatments performed (including intravitreal injections of antiviral medications). RESULTS: Fifty-four eyes of 47 patients who were diagnosed with ARN were included, with equal proportions of eyes (n = 27; 50%) with VZV-ARN and HSV-ARN. Patients with VZV-ARN were, on average, older, more likely to be men, and more likely to be immunosuppressed compared with patients with HSV-ARN. The clinical characteristics, including the initial VA, initial IOP, anterior segment inflammation, clock hours, and posterior extent of retinitis, were similar between eyes with VZV- and HSV-ARN. In the univariate analysis of clinical and demographic variables associated with the development of RD, initial VA (P = 0.0083) and greater clock hours of retinitis (P = 0.009) were significantly associated with RD. These 2 variables remained significant in the multivariate logistic regression; worse VA at presentation had an odds ratio of 2.34 (95% confidence interval [CI], 1.01-5.44; P = 0.042), and greater clock hours of retinitis had an odds ratio of 1.23 (95% CI, 1.02-1.47; P = 0.025). A Kaplan-Meier survival analysis demonstrated no statistical difference in RD-free survival between HSV- and VZV-ARN. CONCLUSIONS: Patients with VZV-ARN were more likely to be older, male, and immunosuppressed compared with those with HSV-ARN, although no clear difference was observed in RD by viral etiology. Poor initial VA and clock hours of retinitis were significantly associated with RD development and may be relevant for patient counseling and prognosis.

Pentosan polysulfate maculopathy.

Pentosan polysulfate sodium (PPS), a semisynthetic sulfated polysaccharide, is the only FDA-approved oral therapy for interstitial cystitis. Recent studies have described a progressive, vision-threatening macular condition associated with long-term PPS use. We reviewed all publications concerning PPS maculopathy to consolidate known clinical features and to evaluate the strength of this association. Current literature supports a strong dose-dependent association between PPS exposure and a progressive maculopathy impacting the retinal pigment epithelium (RPE) and RPE-photoreceptor interface that may worsen even after drug cessation. Initial symptoms may include prolonged dark adaptation and difficulty reading with relative visual acuity preservation. Fundus examination often shows macular pigment clumps corresponding to lesions of focal RPE thickening. Fundus autofluorescence most clearly depicts the condition, with a distinctive pattern of hypo- and hyperautofluorescent spots in the posterior pole that sometimes extends to the retinal periphery. Many cases also show a characteristic peripapillary hypoautofluorescent halo. Near infrared reflectance may aid in early detection. RPE atrophy, cystoid macular edema, and macular neovascularization may also occur, potentially resulting in loss of central acuity. This newly described association implies significant public health risk. Ophthalmologists should screen PPS users with multimodal retinal imaging, and prescribers should minimize dose and duration of PPS use.

Patient Perceptions of SARS-CoV-2 Exposure Risk and Association With Continuity of Ophthalmic Care.

Importance: Patient perceptions regarding the risks of obtaining in-person ophthalmic care during the coronavirus disease 2019 (COVID-19) pandemic may affect adherence to recommended treatment plans and influence visual outcomes. A deeper understanding of patient perspectives will inform strategies to optimize adherence with vision-preserving therapies. Objective: To evaluate perceptions of COVID-19 exposure risk and their association with appointment attendance among patients at high risk of both reversible and irreversible vision loss from lapses in care. Design, Setting, and Participants: This survey study included a nonvalidated telephone survey designed in April and May of 2020 and a retrospective medical record review conducted in parallel with survey administration from May 22 to August 18, 2020. Participants were recruited from 2 tertiary eye care centers (Emory Eye Center in Atlanta, Georgia, and W.K. Kellogg Eye Center in Ann Arbor, Michigan). The study included a random sample of patients with diagnoses of exudative age-related macular degeneration (AMD) or diabetic retinopathy (DR) who received an intravitreal injection between January 6 and March 13, 2020, and were scheduled for a second injection between March 13 and May 6, 2020. Main Outcomes and Measures: Association between perceptions regarding COVID-19 risks and loss to follow-up. Results: Of 1004 eligible patients, 423 (42%) were successfully contacted, and 348 (82%) agreed to participate (participants' mean [SD] age, 75 [12] years; 195 women [56%]; 287 White [82%] patients). Respondents had a mean (SD) of 2.7 (1.1) comorbidities associated with severe COVID-19, and 77 (22%) knew someone with COVID-19. Of all respondents, 163 (47%) were very concerned or moderately concerned about vision loss from missed treatments during the pandemic. Although 208 (60%) believed the COVID-19 virus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), exposure at the eye clinic was extremely unlikely or unlikely, 49 (14%) believed it was extremely likely or likely. Seventy-eight participants (22%) were lost to follow-up. Concern regarding COVID-19 exposure during clinic visits (odds ratio [OR], 3.9; 95% CI, 1.8-8.4) and diagnosis of DR (vs AMD) (OR, 8.130; 95% CI, 3.367-20.408) were associated with an increase in likelihood of loss to follow-up. Conclusions and Relevance: Among patients at high risk for vision loss from lapses in care, many expressed concerns regarding the effect of the pandemic on their ability to receive timely care. Survey results suggest that fear of SARS-CoV-2 exposure was associated with a roughly 4-fold increase in the odds of patient loss to follow-up. These results support the potential importance of clearly conveying infection-control measures.

Outcomes of Combination Systemic and Intravitreal Antiviral Therapy for Acute Retinal Necrosis.

PURPOSE: Determine the efficacy of combination intravitreal and systemic antiviral therapy for the treatment of acute retinal necrosis (ARN) and risk factors impacting visual acuity (VA) and retinal detachment (RD) outcomes. DESIGN: Single-center retrospective case series. PARTICIPANTS: Patients with an ARN diagnosis based on clinical features and polymerase chain reaction confirmation who were treated at a tertiary referral, university-based academic practice. METHODS: Patient records were reviewed for demographic information including age and gender. Snellen VA, disease findings including RD outcomes, optic nerve involvement, and treatments were recorded. Incidence rates of major VA and RD outcomes were calculated based on the number of events and exposure times. Cox proportional hazards regression modeling and survival analyses were used to identify factors related to VA and RD outcomes over time. MAIN OUTCOME MEASURES: Logarithm of the minimal angle of resolution VA, 2-line or more VA gain, severe vision loss (SVL) of 20/200 or worse, RD development, and fellow eye involvement. RESULTS: Twenty-three eyes of 21 patients (11 male, 10 female) were reviewed. Thirteen patients (62%) had herpes simplex virus and 8 patients (38%) had varicella zoster virus. The event rate for 2-line or more VA gain was 0.49 events/eye-year (95% confidence interval [CI], 0.26-0.86 events/eye-year), whereas the rate of SVL was 0.61 events/eye-year (95% CI, 0.34-1.02 events/eye-year). Retinal detachment development was observed at a rate of 0.59 events/eye-year (95% CI, 0.33-1.00 events/eye-year). Thirteen of 23 eyes (57%) demonstrated RD with a mean time of 120 days after ARN diagnosis. With each additional quadrant of retina involved, a greater risk of RD development over time was observed (hazard ratio, 2.21; 95% CI, 1.12-4.35). Nine percent of eyes progressed with additional quadrantic involvement, despite combination systemic and intravitreal antiviral therapy; however, none of the 19 patients demonstrating unilateral ARN showed fellow-eye involvement after initiation of therapy. CONCLUSIONS: Combination intravitreal and systemic antiviral therapy for ARN can be effective in improving VA and limiting retinitis progression. Each additional quadrant of retina involved was associated with a 2.2-fold greater risk of RD, which may impact monitoring, timing of intervention, and patient counseling.

The Daam2-VHL-Nedd4 axis governs developmental and regenerative oligodendrocyte differentiation.

Dysregulation of the ubiquitin-proteasomal system (UPS) enables pathogenic accumulation of disease-driving proteins in neurons across a host of neurological disorders. However, whether and how the UPS contributes to oligodendrocyte dysfunction and repair after white matter injury (WMI) remains undefined. Here we show that the E3 ligase VHL interacts with Daam2 and their mutual antagonism regulates oligodendrocyte differentiation during development. Using proteomic analysis of the Daam2-VHL complex coupled with conditional genetic knockout mouse models, we further discovered that the E3 ubiquitin ligase Nedd4 is required for developmental myelination through stabilization of VHL via K63-linked ubiquitination. Furthermore, studies in mouse demyelination models and white matter lesions from patients with multiple sclerosis corroborate the function of this pathway during remyelination after WMI. Overall, these studies provide evidence that a signaling axis involving key UPS components contributes to oligodendrocyte development and repair and reveal a new role for Nedd4 in glial biology.

Successful Treatment of Full-Thickness Macular Hole in Polypoidal Choroidal Vasculopathy with Anti-VEGF Therapy.

PURPOSE: To report a case of an 86-year-old man with a full thickness macular hole (FTMH) secondary to polypoidal choroidal vasculopathy (PCV) treated with bevacizumab. METHODS: A retrospective case report is presented. RESULTS: An 86-year-old male presented with a five-month history of metamorphopsia and decreased vision in his right eye and was found to have active exudation secondary to PCV with a concurrent FTMH. After four treatments with intravitreal bevacizumab, the FTMH resolved without surgical intervention. CONCLUSIONS: The patient's FTMH resolved with solely pharmacologic treatment as a result of treating his PCV with intravitreal bevacizumab. MH formation secondary to PCV is a rare finding, but may be successfully treated with pharmacologic therapy without surgical intervention.