Faculty Bibliography

OBJECTIVE:Although keyhole transorbital approaches are gaining traction, their indications have not been adequately studied comparatively. In this study the authors have defined them also as transwing approaches-meaning that they use the different facies of the sphenoid wing for cranial entry-and sought to compare the four major ones: 1) lateral orbitocraniotomy through a lateral canthal incision (LatOrb); 2) modified orbitozygomatic approach through a palpebral incision (ModOzPalp); 3) modified orbitozygomatic approach through an eyebrow incision (ModOzEyB); and 4) supraorbital craniotomy through an eyebrow incision (SupraOrb), coupled with its expanded version (SupraTransOrb). METHODS:Cadaveric dissections were performed at the neuroanatomy lab. To delineate the skull base exposure, four formalin-fixed heads were used, with two sides dedicated to each approach. The outer limits were assessed via image guidance and were mapped and illustrated accordingly. A fifth head was dissected purely endoscopically, just to facilitate an overview of the transwing concept. Qualitative features were also rigorously examined. RESULTS:The LatOrb proves to be more versatile in the middle cranial fossa (MCF), whereas the anterior cranial fossa (ACF) exposure is limited to a small area above the sphenoid ridge. An anterior clinoidectomy is possible; however, the exposure of the roof of the optic canal is suboptimal. The ModOzPalp adequately exposes both the ACF and MCF. Its lateral trajectory allows the inferior to superior view, yet there is restricted access to the medial anterior skull base (olfactory groove). The ModOzEyB also provides extensive exposure of the ACF and MCF, but has a more superior to inferior trajectory compared to the ModOzPalp, making it more appropriate for pathology reaching the medial anterior skull base or even the contralateral side. The anterior clinoidectomy is performed with improved visualization of the optic canal. The SupraOrb provides mainly anterior cranial base exposure, with minimal middle fossa. An anterior clinoidectomy can be performed, but without any direct observation of the superior orbital fissure. Some MCF access can be accomplished if the lateral sphenoid wing is drilled inferiorly, leading to its highly versatile variant, the SupraTransOrb. CONCLUSIONS:All the aforementioned approaches use the sphenoid wing as skull base corridor from a specific orientation point; hence these are designated as transwing approaches. Their peculiarities mandate careful case selection for the effective and safe completion of the surgical goals.

Striatal dopamine axons co-release dopamine and gamma-aminobutyric acid (GABA), using GABA provided by uptake via GABA transporter-1 (GAT1). Functions of GABA co-release are poorly understood. We asked whether co-released GABA autoinhibits dopamine release via axonal GABA type A receptors (GABA_ARs), complementing established inhibition by dopamine acting at axonal D2 autoreceptors. We show that dopamine axons express α3-GABA_AR subunits in mouse striatum. Enhanced dopamine release evoked by single-pulse optical stimulation in striatal slices with GABA_AR antagonism confirms that an endogenous GABA tone limits dopamine release. Strikingly, an additional inhibitory component is seen when multiple pulses are used to mimic phasic axonal activity, revealing the role of GABA_AR-mediated autoinhibition of dopamine release. This autoregulation is lost in conditional GAT1-knockout mice lacking GABA co-release. Given the faster kinetics of ionotropic GABA_ARs than G-protein-coupled D2 autoreceptors, our data reveal a mechanism whereby co-released GABA acts as a first responder to dampen phasic-to-tonic dopamine signaling.

Lipid processing by the retinal pigment epithelium (RPE) is necessary to maintain retinal health and function. Dysregulation of retinal lipid homeostasis due to normal aging or age-related disease triggers lipid accumulation within the RPE, on Bruch's membrane (BrM), and in the subretinal space. In its role as a hub for lipid trafficking into and out of the neural retina, the RPE packages a significant amount of lipid into lipid droplets for storage and into apolipoprotein B (APOB)-containing lipoproteins (Blps) for export. Microsomal triglyceride transfer protein (MTP), encoded by the MTTP gene, is essential for Blp assembly. Herein we test the hypothesis that MTP expression in the RPE is essential to maintain lipid balance and retinal function using the newly generated RPEΔMttp mouse model. Using non-invasive ocular imaging, electroretinography, and histochemical and biochemical analyses we show that genetic depletion of Mttp from the RPE results in intracellular lipid accumulation, increased photoreceptor-associated cholesterol deposits, and photoreceptor cell death, and loss of rod but not cone function. RPE-specific reduction in Mttp had no significant effect on plasma lipids and lipoproteins. While APOB was decreased in the RPE, most ocular retinoids remained unchanged, with the exception of the storage form of retinoid, retinyl ester. Thus suggesting that RPE MTP is critical for Blp synthesis and assembly but is not directly involved in plasma lipoprotein metabolism. These studies demonstrate that RPE-specific MTP expression is necessary to establish and maintain retinal lipid homeostasis and visual function.

BACKGROUND:Identification and referral of at-risk patients from primary care practitioners (PCPs) to eye care professionals remain a challenge. Approximately 1.9 million Americans suffer from vision loss as a result of undiagnosed or untreated ophthalmic conditions. In ophthalmology, artificial intelligence (AI) is used to predict glaucoma progression, recognize diabetic retinopathy (DR), and classify ocular tumors; however, AI has not yet been used to triage primary care patients for ophthalmology referral. OBJECTIVE:This study aimed to build and compare machine learning (ML) methods, applicable to electronic health records (EHRs) of PCPs, capable of triaging patients for referral to eye care specialists. METHODS:Accessing the Optum deidentified EHR data set, 743,039 patients with 5 leading vision conditions (age-related macular degeneration [AMD], visually significant cataract, DR, glaucoma, or ocular surface disease [OSD]) were exact-matched on age and gender to 743,039 controls without eye conditions. Between 142 and 182 non-ophthalmic parameters per patient were input into 5 ML methods: generalized linear model, L1-regularized logistic regression, random forest, Extreme Gradient Boosting (XGBoost), and J48 decision tree. Model performance was compared for each pathology to select the most predictive algorithm. The area under the curve (AUC) was assessed for all algorithms for each outcome. RESULTS:XGBoost demonstrated the best performance, showing, respectively, a prediction accuracy and an AUC of 78.6% (95% CI 78.3%-78.9%) and 0.878 for visually significant cataract, 77.4% (95% CI 76.7%-78.1%) and 0.858 for exudative AMD, 79.2% (95% CI 78.8%-79.6%) and 0.879 for nonexudative AMD, 72.2% (95% CI 69.9%-74.5%) and 0.803 for OSD requiring medication, 70.8% (95% CI 70.5%-71.1%) and 0.785 for glaucoma, 85.0% (95% CI 84.2%-85.8%) and 0.924 for type 1 nonproliferative diabetic retinopathy (NPDR), 82.2% (95% CI 80.4%-84.0%) and 0.911 for type 1 proliferative diabetic retinopathy (PDR), 81.3% (95% CI 81.0%-81.6%) and 0.891 for type 2 NPDR, and 82.1% (95% CI 81.3%-82.9%) and 0.900 for type 2 PDR. CONCLUSIONS:The 5 ML methods deployed were able to successfully identify patients with elevated odds ratios (ORs), thus capable of patient triage, for ocular pathology ranging from 2.4 (95% CI 2.4-2.5) for glaucoma to 5.7 (95% CI 5.0-6.4) for type 1 NPDR, with an average OR of 3.9. The application of these models could enable PCPs to better identify and triage patients at risk for treatable ophthalmic pathology. Early identification of patients with unrecognized sight-threatening conditions may lead to earlier treatment and a reduced economic burden. More importantly, such triage may improve patients' lives.

The availability of big data can transform the studies in biomedical research to generate greater scientific insights if expert labeling is available to facilitate supervised learning. However, data annotation can be labor-intensive and cost-prohibitive if pixel-level precision is required. Weakly supervised semantic segmentation (WSSS) with image-level labeling has emerged as a promising solution in medical imaging. However, most existing WSSS methods in the medical domain are designed for single-class segmentation per image, overlooking the complexities arising from the co-existence of multiple classes in a single image. Additionally, the multi-class WSSS methods from the natural image domain cannot produce comparable accuracy for medical images, given the challenge of substantial variation in lesion scales and occurrences. To address this issue, we propose a novel anomaly-guided mechanism (AGM) for multi-class segmentation in a single image on retinal optical coherence tomography (OCT) using only image-level labels. AGM leverages the anomaly detection and self-attention approach to integrate weak abnormal signals with global contextual information into the training process. Furthermore, we include an iterative refinement stage to guide the model to focus more on the potential lesions while suppressing less relevant regions. We validate the performance of our model with two public datasets and one challenging private dataset. Experimental results show that our approach achieves a new state-of-the-art performance in WSSS for lesion segmentation on OCT images.

A progression sequence for age-related macular degeneration onset may be determinable with consensus neuroanatomical nomenclature augmented by drusen biology and eye-tracked clinical imaging. This narrative review proposes to supplement the Early Treatment of Diabetic Retinopathy Study (sETDRS) grid with a ring to capture high rod densities. Published photoreceptor and retinal pigment epithelium (RPE) densities in flat mounted aged-normal donor eyes were recomputed for sETDRS rings including near-periphery rich in rods and cumulatively for circular fovea-centered regions. Literature was reviewed for tissue-level studies of aging outer retina, population-level epidemiology studies regionally assessing risk, vision studies regionally assessing rod-mediated dark adaptation (RMDA), and impact of atrophy on photopic visual acuity. The 3 mm-diameter xanthophyll-rich macula lutea is rod-dominant and loses rods in aging whereas cone and RPE numbers are relatively stable. Across layers, the largest aging effects are accumulation of lipids prominent in drusen, loss of choriocapillary coverage of Bruch's membrane, and loss of rods. Epidemiology shows maximal risk for drusen-related progression in the central subfield with only one third of this risk level in the inner ring. RMDA studies report greatest slowing at the perimeter of this high-risk area. Vision declines precipitously when the cone-rich central subfield is invaded by geographic atrophy. Lifelong sustenance of foveal cone vision within the macula lutea leads to vulnerability in late adulthood that especially impacts rods at its perimeter. Adherence to an sETDRS grid and outer retinal cell populations within it will help dissect mechanisms, prioritize research, and assist in selecting patients for emerging treatments.

PURPOSE/UNASSIGNED:Metformin has been suggested to protect against the development of age-related macular degeneration (AMD) in multiple observational studies. However, the association between metformin and geographic atrophy (GA), a debilitating subtype of AMD, has not been analyzed. METHODS/UNASSIGNED:We conducted a case-control study of patients ages 60 years and older with new-onset International Classification of Diseases (ICD) coding of GA in the Merative MarketScan Commercial and Medicare Databases between 2017 and 2021. Cases were matched with propensity scores estimated by age, region, hypertension, and Charlson Comorbidity Index to a control without GA of the same year. Exposure to metformin was assessed for cases and controls in the year prior to their index visit. Conditional multivariable logistic regression, adjusting for AMD risk factors, was used to calculate odd ratios and 95% confidence intervals (CIs). This study design and analysis were repeated in a sample of patients without diabetes. RESULTS/UNASSIGNED:In the full sample, we identified 10,505 cases with GA and 10,502 matched controls without GA. In total, 1149 (10.9%) cases and 1277 (12.2%) controls were exposed to metformin, and in multivariable regression, metformin decreased the odds of new-onset ICD coding of GA by 12% (95% CI, 0.79-0.99). In the sample of patients without diabetes, we identified 7611 cases with GA and 7608 matched controls without GA. Twenty-nine (0.4%) cases and 63 (0.8%) controls were exposed to metformin, and in multivariable regression, metformin decreased the odds of new-onset ICD coding of GA by 47% (95% CI, 0.33-0.83). CONCLUSIONS/UNASSIGNED:Metformin may hold promise as a noninvasive, alternative agent to prevent the development of GA. This finding is notable due to shortcomings in recently approved therapeutics for GA and metformin's overall ease of use and few adverse effects. Additional studies are required to explore our findings further and motivate a clinical trial.

Although cell-free DNA (cfDNA) prenatal screening is widely used and has high sensitivity and specificity, there are circumstances in which the screening does not provide an interpretable result. Although this is relatively uncommon, it happens enough that clinical implications and potential reasons for follow-up should be studied and assessed. This study was designed to evaluate outcomes for pregnancies with nonreportable results on cfDNA screening tests. This study was a secondary analysis of the data from a multicenter prospective observational study of cfDNA screening for aneuploidy and 22q11.2 deletion syndrome. All patients were tested for trisomies 13, 18, and 21, as well as the 22q11.2 deletion syndrome, and all patients had confirmatory testing on the newborns in addition to collecting obstetric and perinatal outcomes. Inclusion criteria were women older than 18 years and at greater than 9 weeks of gestation with a singleton pregnancy. Exclusion criteria were having received cfDNA screening results before enrollment, organ transplant, ovum donation, vanishing twin, or being unwilling to provide a newborn sample. The primary outcome was the rate of adverse obstetrical and perinatal outcomes, including aneuploidy; preterm birth at less than 28, 34, or 37 weeks' gestation; preeclampsia; small for gestational age birth; and a composite outcome that included preterm birth before 37 weeks, preeclampsia, stillbirth at greater than 20 weeks, and small for gestational age. Final analyses included 17,851 individuals who had cfDNA screening, confirmatory genetic testing on the newborn, and obstetrical and perinatal outcomes recorded. Nonreportable results were found in 602 individuals (3.4%) after the first draw, with 32.2% of these due to low fetal fraction. Another third of the cohort had patterns where the risk of aneuploidy was uninterpretable but with an adequate fetal fraction, and in the final third, the fetal fraction could not be measured. Of the original 602 cases of nonreportable findings, 427 had a second draw, with 112 of these (26.2%) again having nonreportable results. There were no significant differences in baseline characteristics of age and parity for those with successful versus nonreportable test results; gestational age was significantly higher in individuals with nonreportable results (14.4 vs 13.4 weeks, P < 0.001), as was body mass index (26.2 vs 31.3), and the rate of chronic hypertension (4.0% vs 9.7%). In this cohort, there were 133 genetically confirmed trisomies, with 100 fetuses with trisomy 21, 18 individuals with trisomy 18, and 15 individuals with trisomy 13. Overall, the rate of aneuploidy was 1.7% in individuals with nonreportable results, versus 0.7% in those with reported results (P = 0.013; adjusted odds ratio [aOR] 2.1; 95% confidence interval [CI], 1.1-4.0). Rates of preterm birth were also higher in those with nonreportable test results, with delivery at less than 34 weeks at 1.5% in those with a test result, 4.6% in those with one nonreportable test result and 6.9% in those with a second nonreportable test result (aOR, 2.2 and 2.7; 95% CI, 1.4-3.4 and 1.2-6.0, respectively). Preeclampsia showed a similar trend, with rates climbing from 3.9% in those with a reported result to 9.4% with 1 nonreportable result and 16.8% with 2 (aOR, 1.4 and 2.0; 95% CI, 1.0-1.9 and 1.1-3.7, respectively). Chances of live birth were significantly reduced in pregnancies with a nonreportable results (aOR, 0.20; 95% CI, 0.13-0.30), with the chances decreasing more after a second nonreportable test result (aOR, 0.11; 95% CI, 0.06-0.23). The study found that nonreportable cfDNA screening results are associated with an increased risk for aneuploidy, preterm birth, and preeclampsia, with a gradient of increased risk with a second failed test. This adds to literature with conflicting findings surrounding obstetrical complications in those with altered cfDNA levels and with most studies largely focused on characteristics that may be predictive of a nonreportable result rather than outcomes associated with nonreportable results. These results can inform clinicians who have patients with nonreportable test results in a way that may help them provide better care; future research should focus on more fully understanding the adverse outcomes associated with nonreportable tests to maximize this ability for clinicians in the future. Further research should also focus on specific populations or diagnoses to understand if there are fundamental differences in different groups of individuals.

PURPOSE:To determine whether peripapillary atrophy (PPA) area is an indicator of glaucomatous structural and functional damage and progression. METHODS:In this retrospective longitudinal analysis from ongoing prospective study we qualified 71 eyes (50 subjects) with glaucoma. All subjects had a comprehensive ophthalmic examination, visual field (VF), and spectral-domain optical coherence tomography (OCT) testing in at least three visits. PPA was manually delineated on en face OCT optic nerve head scans, while observing the corresponding cross-sectional images, as the hyper-reflective area contiguous with the optic disc. RESULTS:The mean follow-up duration was 4.4 ± 1.4 years with an average of 6.8 ± 2.2 visits. At baseline, PPA area was significantly associated only with VF's mean deviation (MD; P = 0.041), visual field index (VFI; P = 0.041), superior ganglion cell inner plexiform layer (GCIPL; P = 0.011), and disc area (P = 0.011). Longitudinally, PPA area was negatively and significantly associated with MD (P = 0.015), VFI (P = 0.035), GCIPL (P = 0.009), superior GCIPL (P = 0.034), and disc area (P = 0.007, positive association). CONCLUSIONS:Longitudinal change in PPA area is an indicator of glaucomatous structural and functional progression but PPA area at baseline cannot predict future progression. TRANSLATIONAL RELEVANCE:Longitudinal changes in peripapillary atrophy area measured by OCT can be an indicator of structural and functional glaucoma progression.

PURPOSE/OBJECTIVE:To present the early post-operative evolution of retained subretinal perfluoro-n-octane (PFO) as captured on OCT. METHODS:Case report of a patient. RESULTS:A 58-year-old woman was noted to have subretinal PFO after undergoing autologous retinal graft for macular hole closure under PFO tamponade. Serial OCT identified the subretinal PFO as early as the first postoperative day and demonstrates progressive consolidation and encapsulation of the PFO bubble by the surrounding outer retina. CONCLUSION/CONCLUSIONS:Subretinal PFO is usually seen several weeks in the postoperative course once the gas endotamponade has resorbed sufficiently for OCT imaging. In this case, PFO tamponade enabled its imaging early. Its subsequent evolution into the classic "omega sign" may suggest a granulomatous encapsulation of the PFO bubble.