Faculty Bibliography

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.

En face optical coherence tomography (OCT) is a practical and informative imaging modality to noninvasively visualize distinct retinal and choroidal layers by providing coronal images using boundary-specific segmentation. Ongoing research with this method is generating breakthroughs in the illustration of new perspectives of retinal disease. The clinical value of en face OCT as an advanced retinal imaging tool is growing steadily and it has unveiled many new insights into the pathoanatomy of retinal disorders. Moreover, this modality can capture various en face OCT biomarkers that correspond to different cell or tissue subtypes, which were previously only identified through histological or electron microscopy methods, underscoring the significance of this technique in providing valuable pathoanatomical information. In this comprehensive review, we will systematically summarize the en face OCT findings across a broad spectrum of retinal diseases, including disorders of the vitreoretinal interface and retinal vascular system (e.g. paracentral acute middle maculopathy or PAMM and diabetic retinopathy), in addition to the en face OCT features of other conditions such as age-related macular degeneration, pachychoroid disease spectrum, myopic degeneration, uveitis and inflammatory disorders, inherited retinal dystrophies, and drug toxicity. We will discuss and highlight the unique clinical and pathoanatomical findings uncovered with en face OCT of each these diseases mentioned above.

PURPOSE/OBJECTIVE:We describe a case of bilateral, multiple, branch retinal artery occlusions (BRAO) associated with carotid webs. METHODS:A thorough chart review was conducted for the patient. Relevant literature was systematically reviewed. RESULTS:Eight cases of fibromuscular dysplasia (FMD) associated with retinal artery occlusions have been reported. Two additional cases of FMD with other ocular involvement have been described. No cases of carotid webs associated with retinal artery occlusions were found. CONCLUSION/CONCLUSIONS:Carotid webs, an uncommon variant of FMD, are a recognized causative etiology of arterial, ischemic stroke. The case described here of bilateral, multifocal BRAOs represents a unique manifestation of this variant of FMD. This diagnosis should be considered in the setting of an otherwise unrevealing BRAO workup, as recognition of this association may be sight and life-saving.

PURPOSE/UNASSIGNED:To assess corneal resistance to enzymatic digestion after rose bengal (RB)/green light and RB/green light followed by riboflavin (RF)/ultraviolet A (UV-A) cross-linking (CXL), with or without oxygen. METHODS/UNASSIGNED:Ex vivo porcine corneal buttons (n = 144) underwent CXL with RB/green or RB/green-RF/UV-A under atmospheric 21% oxygen conditions or in a nitrogen chamber with 0.1% oxygen (hypoxic conditions) to test 10- and 15-J/cm2 fluences. After CXL, corneas were digested with 0.3% collagenase A, and mean digestion times (MDTs) were recorded. RESULTS/UNASSIGNED:For the non-irradiated control group, the MDT was 19.75 ± 1.34 hours. Under atmospheric oxygen conditions, RB/green CXL yielded MDTs of 33.69 ± 1.4 and 34.38 ± 1.31 hours with fluences of 10 and 15 J/cm2, respectively. RB/green + RF/UV-A showed MDTs of 39.56 ± 1.93 and 51.94 ± 4.2 hours for combined fluences of 10 + 10 J/cm2 and 15 + 15 J/cm2, respectively. Hypoxic RB/green MDTs were 33.88 ± 1.02 and 34.06 ± 1.57 hours, and RB/green + RF/UV-A MDTs were 39.62 ± 2.5 and 50.35 ± 1.59 hours for the same respective fluences. No significant differences were observed between the control groups and corresponding intervention groups (all P > 0.05). CONCLUSIONS/UNASSIGNED:CXL via RB/green and RB/green-RF/UV-A significantly enhanced corneal collagenase digestion resistance, irrespective of oxygen presence. These findings could help optimize infectious keratitis therapy CXL protocols. TRANSLATIONAL RELEVANCE/UNASSIGNED:Our findings aid the understanding of the molecular mechanisms underlying the therapeutic effect of CXL and may contribute to refining accelerated PACK-CXL protocols and other CXL treatment strategies.

PURPOSE/OBJECTIVE:To assess 5-years trends in the rate of immediate sequential bilateral cataract surgery (ISBCS) and surgeon characteristics associated with performing ISBCS. SETTING/METHODS:100% Medicare Fee-for-service beneficiaries from 2018-2022. DESIGN/METHODS:Cross-sectional study. METHODS:ISBCS cases were identified among patients aged ≥ 65 years undergoing bilaterally performed cataract surgery (BPCS). Cochrane Armitage trend test was used to assess patient and surgeon characteristics over time. Multivariable logistic regression was used to evaluate surgeon characteristics associated with performing ISBCS. RESULTS:Among 1,190,169 BPCS, 3,954 (0.33%) were ISBCS. Quarterly ISBCS rate increased from 2.12 to 5.5 per 1,000 BPCS (p<0.001). Among 10,290 surgeons, 1,119 (10.87%) performed ISBCS on some patients. Proportion of surgeons performing ISBCS per 1,000 cataract surgeons increased from 15.63 during the first quarter of 2018 to 26.55 during the last quarter of 2022 (p<0.001). Among the ISBCS surgeons, the proportion of ISBCS cases per 1,000 BPCS doubled from 17.20 in 2018 to 35.50 in 2022 (p<0.001). On multivariable analysis, surgeons in the highest surgical volume quartile (OR: 1.21; 95% CI: 1.01-1.45; Ref: lowest quartile), recent graduates (0-10 years OR: 2.43, 95% CI: 1.87-3.15; Ref: ≥ 31 years) and surgeons in West (OR: 2.408, 95% CI: 2.052-2.826; Ref: South) had higher odds of performing ISBCS. CONCLUSIONS:There was an increased rate of ISBCS possibly suggesting greater interest among patients and surgeons. Although the overall ISBCS rate remained low, the number of surgeons performing ISBCS increased. Higher volume surgeons, recent graduates, and those practicing in the West were more likely to perform ISBCS.

PURPOSE/OBJECTIVE:To investigate the light transmission (LT) of UV-A and green light through infected corneas saturated with riboflavin or rose bengal in an ex vivo porcine model for infectious keratitis. SETTING/METHODS:University of Zurich and EMPA. DESIGN/METHODS:Laboratory study. METHODS:Ex vivo porcine eyes (n=162) were divided into three groups: control eyes, eyes infected with Staphylococcus aureus, and eyes infected with Pseudomonas aeruginosa. Corneas remained either uninfected, or were infected with S. aureus, and P. aeruginosa, respectively, and were either left untreated, or were instilled with 0.1% riboflavin or 0.1% rose bengal. Corneal buttons were prepared, and corneal LT was measured at 365 nm and 522 nm using a spectrophotometer. LTs were calculated and compared. Transmission electron microscopy (TEM) was used to visualize structural damage and bacteria within infected corneas. RESULTS:Riboflavin-saturated corneas infected by S. aureus or P. aeruginosa (LT = 0.77% [0.41-1.87] and 0.81% [0.23, 1.46]) exhibited 3.18-fold and 3.02-fold lower LTs than uninfected corneas (LT = 2.45% [2.15, 5.89]) (both p-values < 0.001). No LT difference was found between rose bengal-saturated corneas infected by S. aureus or P. aeruginosa and uninfected corneas (all LTs = 0.01% [0.01-0.01]; both p-values = 0.08). TEM showed bacteria on corneal stroma borders and occasionally inside the stroma. CONCLUSION/CONCLUSIONS:Our results indicate that the amount of light arriving at the corneal endothelium is substantially reduced in infected corneas. The total fluence of clinical PACK-CXL protocols can be safely increased substantially while maintaining a low risk of corneal endothelial damage.