Faculty Bibliography

PURPOSE/UNASSIGNED:Eyes with age-related macular degeneration (AMD) and some healthy aged eyes exhibit risk-indicating delays in rod-mediated dark adaptation (RMDA) and prolonged long spectral channel (LSC) lifetimes by fluorescence lifetime imaging ophthalmoscopy (FLIO) in the Early Treatment Diabetic Retinopathy Study (ETDRS) outer ring, especially nasally. To learn FLIO's potential for AMD detection, we correlate FLIO to RMDA. METHODS/UNASSIGNED:The ALSTAR2 follow-up cohort underwent FLIO, color fundus photography, two-wavelength autofluorescence (for macular pigment optical density [MPOD]), visual function testing, including RMDA (rod intercept time [RIT]). AMD was staged by the Age-Related Eye Disease Study (AREDS) 9-step at baseline and follow-up. In pseudophakic eyes with high-quality FLIO, mean intensity maps and meridian plots were created. Vision data were analyzed using linear regression and Spearman's r. RESULTS/UNASSIGNED:Of 155 eyes (155 participants [75 ± 5.0 years; 60.7% female participants]), 67 eyes were healthy, 38 had early (e)AMD, and 50 had intermediate (i)AMD (P = 0.02). LSC lifetimes were longest in iAMD in all ETDRS regions (P < 0.01) and short spectral channel (SSC) lifetimes in inner and outer rings (P < 0.01). The LSC pattern manifested in 65 of 88 AMD eyes and 30 of 67 healthy eyes. Lifetimes were longest on the nasal meridian and shortest on temporal. LSC lifetimes in the inner and outer rings correlated strongly with RIT (r = 0.68). A stable subgroup had short LSC lifetimes and short RIT. SSC correlated weakly with MPOD. CONCLUSIONS/UNASSIGNED:Prolonged lifetimes in AMD exhibit spatial asymmetry, suggesting mechanisms beyond retinal cells and including choroid. Lifetimes correlate with delayed RMDA, potentially indicating risk for AMD onset and early progression. Further research into SSC signal sources is warranted.

IMPORTANCE/UNASSIGNED:High-quality evidence regarding suppressive valacyclovir treatment in herpes zoster ophthalmicus (HZO) is necessary to guide care. OBJECTIVE/UNASSIGNED:To determine whether suppressive valacyclovir compared with placebo delays the occurrence of new or worsening stromal keratitis (SK), endothelial keratitis (EK), iritis, or dendriform epithelial keratitis (DEK) during 12 months of treatment and if treatment benefit persisted at 18 months (secondary end point). DESIGN, SETTING, AND PARTICIPANTS/UNASSIGNED:The Zoster Eye Disease Study (ZEDS) was a randomized clinical trial conducted in 95 sites from November 2017 to June 2024. Immunocompetent, nonpregnant adults with a history of an HZO rash, documented active keratitis or iritis within 1 year, and an estimated glomerular filtration rate of 45 mL/min/1.73 m2 or greater were eligible. After determined to be eligible, participants were randomized in 4 strata: age at onset (<60 years vs ≥60 years) and disease duration (<6 months vs ≥6 months). INTERVENTIONS/UNASSIGNED:A total of 12 months of double-masked daily valacyclovir, 1000 mg, or placebo. MAIN OUTCOMES AND MEASURES/UNASSIGNED:The primary outcome was time to first occurrence within 12 months of new or worsening SK, EK, iritis, or DEK. RESULTS/UNASSIGNED:A total of 527 participants (median [IQR] age, 60 [50-68] years; 266 female [50.5%]; 266 in the valacyclovir group; 261 in the placebo group) were randomized in 4 strata; 481 completed 12 months, and 460 completed 18 months. Data were analyzed by intention to treat. At 12 months, primary end points occurred in 86 participants (33%) assigned to placebo and 74 (28%) assigned to valacyclovir, and at 18 months in 104 participants (40%) assigned to placebo and 86 (32%) assigned to valacyclovir. The hazard ratio (HR) of the primary end point at 12 months was 0.77 for participants taking valacyclovir vs placebo (HR, 0.77; adjusted 95% CI, 0.56-1.05; P = .09) and 0.73 at the secondary end point at 18 months (HR, 0.73; adjusted 95% CI, 0.55-0.97; P = .03). There was a reduction of multiple other secondary end points at 12 months (HR, 0.70; 95% CI, 0.52-0.95; P = .02) and 18 months (HR, 0.72; 95% CI, 0.55-0.95; P = .02). CONCLUSIONS AND RELEVANCE/UNASSIGNED:Although the primary outcome did not show a benefit of suppressive valacyclovir treatment, secondary study outcomes showed treatment superiority at the 18-month end point and reduced number of multiple episodes of keratitis or iritis at both 12 and 18 months. These results support consideration of 1 year of suppressive valacyclovir treatment for HZO. TRIAL REGISTRATION/UNASSIGNED:ClinicalTrials.gov Identifier: NCT03134196.

IMPORTANCE/UNASSIGNED:Evidence regarding suppressive valacyclovir treatment on postherpetic neuralgia is necessary to guide care. OBJECTIVE/UNASSIGNED:To test the hypothesis that suppressive treatment with 1000 mg/d of oral valacyclovir for 12 months reduces the prevalence, severity, and duration of postherpetic neuralgia compared with placebo at 12 and 18 months in participants with herpes zoster ophthalmicus (HZO). DESIGN, SETTING, AND PARTICIPANTS/UNASSIGNED:Multicenter, placebo-controlled randomized clinical trial including 527 immunocompetent, nonpregnant adults with history of HZO rash, documented keratitis, or iritis within 1 year and an estimated glomerular filtration rate of 45 mL/min/1.73 m2 or greater. The study was conducted at 95 participating sites (in Canada, New Zealand, and the US) from November 2017 to June 2024 and participant visits occurred every 3 months. INTERVENTION/UNASSIGNED:Treatment with 1000 mg/d of valacyclovir or placebo for 12 months. MAIN OUTCOMES AND MEASURES/UNASSIGNED:Prevalence of postherpetic neuralgia, severity as determined by pain score (a score of ≥3 on a scale of 1-10), pain duration (≥3 months after HZO onset), and total daily dose of pain medication. RESULTS/UNASSIGNED:Of the 527 participants (490 completed 12 months of treatment and 460 completed 18 months), 73 (14%) had postherpetic neuralgia and were analyzed by age at HZO onset (<60 years or ≥60 years) and disease duration (recent [<6 months] or chronic [≥6 months]). Of the 73 participants with postherpetic neuralgia (34 in the valacyclovir group and 39 in the placebo group), the mean age was 62.4 years (SD, 13.6 years), 59% were female, 5% were Black or African American, and 10% were Hispanic. The prevalence of postherpetic neuralgia at 12 months was not reduced by valacyclovir (12/32 [38%]) compared with placebo (14/35 [40%]) (between-group difference, 2.5% [95% CI, -20.8% to 25.8%]; P>.99). The participants who were younger than 60 years at HZO onset and had a chronic disease duration had lower pain scores in the valacyclovir group (mean score, 0.3 [SD, 0.9]) vs the placebo group (mean score, 0.8 [SD, 1.9]) at 12 months (P = .045) and at 18 months (mean score, 0.2 [SD, 0.9] vs 1.0 [SD, 2.3], respectively; P = .02). There was a decrease in pain duration in the valacyclovir group at 18 months (mean, 13.6 [SD, 11.4] months) vs the placebo group (mean, 18.7 [SD, 29.5] months) (linear mixed-effects model between-group difference, -3.39 months [95% CI, -6.73 to -0.04 months]; P = .046). The total daily dose of neuropathic pain medication was lower in the valacyclovir group (mean, 271.4 [SD, 593.8] mg/d) vs the placebo group (mean, 363.4 [SD, 592.2] mg/d) at 12 months (linear mixed-effects model P = .006) and at 18 months (mean, 209.0 [SD, 412.8] mg/d vs 286.2 [SD, 577.9] mg/d, respectively; linear mixed-effects model P = .01). CONCLUSIONS AND RELEVANCE/UNASSIGNED:One year of suppressive treatment with valacyclovir was associated with a lower dosage of neuropathic pain medication. Participants in the valacyclovir group, who were younger at HZO onset and had a chronic disease duration, had lower pain scores. These secondary outcomes support consideration of 1 year of suppressive treatment with valacyclovir to reduce dosage of pain medications and pain due to HZO. TRIAL REGISTRATION/UNASSIGNED:ClinicalTrials.gov Identifier: NCT03134196.

PURPOSE/UNASSIGNED:Age-related macular degeneration (AMD) is a multifactorial disease, and studies have implicated the role of gut microbiota in its pathogenesis. However, characterization of microbiome dysbiosis and associated microbial-derived metabolomic profiles across AMD stages remains unknown. In this pilot study, we explored how gut microbiome composition and gut-derived metabolites differ in AMD. METHODS/UNASSIGNED:Our pilot study analyzed fasted stool samples that were collected from 22 patients at a tertiary academic center. Subjects were classified as control, intermediate AMD, or advanced AMD based on clinical presentation. 16S rRNA amplicon sequencing and standard chromatography-mass spectrometry methods were used to identify bacterial taxonomy composition and abundance of short-chain fatty acids (SCFAs) and bile acids (BAs), respectively. Genetic testing was used to investigate the frequency of 14 high-risk single nucleotide polymorphisms (SNPs) associated with AMD in the AMD cohort. RESULTS/UNASSIGNED:Forty-three differentially abundant genera were present among the control, intermediate, and advanced groups. Taxa with known roles in immunologic pathways, such as Desulfovibrionales (q = 0.10) and Terrisporobacter (q = 1.16e-03), were in greater abundance in advanced AMD patients compared to intermediate. Advanced AMD patients had decreased abundance of 12 SCFAs, including acetate (P = 0.002), butyrate (P = 0.04), and propionate (P = 0.01), along with 12 BAs, including taurocholic acid (P = 0.02) and tauroursodeoxycholic acid (P = 0.04). Frequencies of high-risk SNPs were not significantly different between the intermediate and advanced AMD groups. CONCLUSIONS/UNASSIGNED:This pilot study identifies distinct gut microbiome compositions and metabolomic profiles associated with AMD and its stages, providing preliminary evidence of a potential link between gut microbiota and AMD pathogenesis. To validate these findings and elucidate the underlying mechanisms, future research with larger cohorts and more comprehensive sampling is strongly recommended.

PURPOSE:Risk factors for the development of rhegmatogenous retinal detachments (RRDs) in the early postoperative period after open globe repair are not well understood. RRDs are often diagnosed late after open globe injuries, which can negatively affect visual prognosis. The authors assessed the incidence and risk factors that predict the development of this complication. METHODS:The authors conducted a retrospective case-control study of all open globe injuries at a single ocular trauma center from January 2016 to September 2021 where at baseline the retina was attached. Cases were defined as postoperative RRDs that developed within 90 days of open globe repair. RESULTS:Of 96 eyes included, 40 (41.7%) subsequently developed RRD. Univariate analysis revealed initial visual acuity of light perception or worse (odds ratio 7.64; 95% CI, 3.03-19.22; P < 0.01), Zone 3 injuries (odds ratio 7.54; 95% CI, 2.64-21.54; P < 0.01), no view of the lens (odds ratio 4.26; 95% CI, 1.77-10.26; P < 0.01), and the presence of injuries external to the globe (odds ratio 5.33; 95% CI, 2.09-13.63; P < 0.01) to be associated with early RRD development. On multivariate analysis, presenting visual acuity of light perception ( P < 0.001), the presence of external injuries ( P = 0.001), and Zone 3 injuries ( P = 0.037) remained significant. Of the 40 patients with early retinal detachment, 34 (85%) remained attached after repair, with variable visual outcomes. CONCLUSION:Presenting visual acuity of light perception, Zone 3 injuries, and external injuries to the globe confer increased risk of early postoperative RRD after open globe repair. The majority of RRDs can be successfully repaired.

Type 3 macular neovascularization (MNV) is a unique form of neovascular age-related macular degeneration (AMD) that presents distinct pathogenetic features, clinical manifestations, and prognostic considerations when compared to types 1 and 2 MNV. Insights gained from clinicopathological correlations, bridging in vivo examination techniques with ex vivo histological analysis, have significantly enhanced our comprehension of this MNV phenotype, shaped current management strategies and influenced future directions for therapeutics. The particularities of type 3 MNV, which may largely stem from its origin from the retinal vasculature, are critically important for predicting the disease course. Our current understanding suggests that type 3 MNV occurs in response to retinal pigment epithelium (RPE) disruption and photoreceptor loss when neovessels originating from the deep capillary plexus are accompanied by activated Müller glia as they infiltrate sub-retinal pigment epithelium basal laminar deposits. Dysregulation of angiogenic and angiostatic factors are thought to play a key role in its pathogenesis. The prognosis for type 3 MNV is likely bilateral involvement and progression towards macular atrophy. It may be imperative for practitioners to distinguish type 3 MNV from other mimicking pathologies such as intraretinal microvascular anomalies, which are also part of the type 3 disease spectrum. For instance, deep retinal age-related microvascular anomalies (DRAMA) may present with similar features on multimodal imaging yet may necessitate distinct management protocols. Distinguishing between these conditions may be vital for implementing tailored treatment regimens and improving patient outcomes in the diverse landscape of AMD phenotypes in the future.

The pachychoroid disease spectrum is a phenotype characterized by alterations in choroidal vasculature which result in outer retinal and choriocapillaris damage and visual loss. The presence of pachyvessels is one of the key features of the pachychoroid phenotype. Recent imaging studies suggest that pachyvessels may form because of choroidal venous congestion in one or more quadrants. The formation of intervortex anastomosis may function as a compensatory mechanism to dissipate the increased venous pressure, while outflow obstruction has been hypothesized to occur at the site of the vortex vein exiting the sclera. This review aims to summarize recent imaging findings and discuss evolution in the understanding of pathogenesis of the pachychoroid disease spectrum. We have summarized notable treatment trials in central serous chorioretinopathy and polypoidal choroidal vasculopathy and included an update of the current diagnostic and management strategies of the entities that are part of the pachychoroid disease spectrum.

High-density microelectrode arrays have opened new possibilities for systems neuroscience, but brain motion relative to the array poses challenges for downstream analyses. We introduce DREDge (Decentralized Registration of Electrophysiology Data), a robust algorithm for the registration of noisy, nonstationary extracellular electrophysiology recordings. In addition to estimating motion from action potential data, DREDge enables automated, high-temporal-resolution motion tracking in local field potential data. In human intraoperative recordings, DREDge's local field potential-based tracking reliably recovered evoked potentials and single-unit spike sorting. In recordings of deep probe insertions in nonhuman primates, DREDge tracked motion across centimeters of tissue and several brain regions while mapping single-unit electrophysiological features. DREDge reliably improved motion correction in acute mouse recordings, especially in those made with a recent ultrahigh-density probe. Applying DREDge to recordings from chronic implantations in mice yielded stable motion tracking despite changes in neural activity between experimental sessions. These advances enable automated, scalable registration of electrophysiological data across species, probes and drift types, providing a foundation for downstream analyses of these rich datasets.

Adipose-derived leptin contributes to energy homeostasis by balancing food intake and motor output, but how leptin acts in brain motor centers remains poorly understood. We investigated the influence of leptin on neuronal activity in two basal ganglia nuclei involved in motor control: the substantia nigra pars compacta (SNc) and pars reticulata (SNr). Using a mouse reporter line to identify cells expressing leptin receptors (LepRs), we found that in both sexes, a majority of SNc dopamine neurons express a high level of LepR. Whole-cell recording in ex vivo midbrain slices from male wild-type mice showed that leptin activates SNc dopamine neurons directly and increases somatodendritic dopamine release. Although LepR expression in SNr GABA output neurons was low, leptin also activated these cells. Additional experiments showed that the influence of leptin on SNr neurons is indirect and involves D1 dopamine receptors and TRPC3 channels. Administration of leptin to male mice increased locomotor activity, consistent with activation of dopamine neurons in the SNc coupled to previously reported amplification of axonal dopamine release by leptin in striatal slices. These findings indicate that in addition to managing energy homeostasis through its actions as a satiety hormone, leptin also promotes axonal and somatodendritic dopamine release that can influence motor output.Significance statement Dopamine neurons regulate motivated behaviors, but how they are influenced by metabolic hormones, like leptin, is incompletely understood. We show here that leptin increases the activity of substantia nigra (SN) pars compacta dopamine neurons directly, and that this enhances somatodendritic dopamine release. Leptin also increases the activity of GABAergic neurons in the SN pars reticulata, but does so indirectly via D1 dopamine receptors activated by locally released dopamine. Consistent with increased nigral dopamine neuron activity and previous evidence showing that leptin amplifies striatal dopamine release, systemic leptin increases locomotor behavior. This increase in motor activity complements the well-established inhibitory effect of leptin on food intake and adds an additional dimension to the regulation of energy balance by this hormone.