October 2022

Moustafa GA, Liebman DL, Kabarriti G, Lorch AC, Vasan RA, Samal L, Nagykaldi ZJ, Osman NY, Kloek CE. Primary Care Provider Familiarity and Compliance with Preferred Practice Patterns for Comprehensive Eye Examinations. Am J Ophthalmol 2022;Abstract
PURPOSE: To assess primary care practitioners' (PCPs) familiarity with American Academy of Ophthalmology Preferred Practice Pattern (PPP) guidelines on the frequency of comprehensive eye examinations (CEEs) and explore their opinions and practices on counseling and referring patients for CEEs. DESIGN: Cross-sectional study. METHODS: Between February 1, 2019, and June 25, 2019, an anonymous survey was emailed to clinicians holding an MD, DO, PA, or NP degree, and residents at Brigham and Women's Hospital and University of Oklahoma. Descriptive statistics of participants' responses were reported. RESULTS: Regarding patient counseling on CEEs, 15.4% of PCPs reported "always", 48.1% "usually", and 36.5% "seldom" or "never" doing so. Few PCPs (11.1%) reported able to describe the guidelines and 63.9% were unaware of their existence. A strong majority of PCPs (90.7%) correctly referred a type 2 diabetic at their time of diagnosis, but a similar majority (77.8%) prematurely referred a newly-diagnosed type 1 diabetic. One in 7 (13.4%) PCPs would refer a patient with family history of glaucoma only upon developing visual/ocular symptoms. Compared to other providers, PAs/NPs were more likely to recommend unnecessary CEEs for low-risk individuals (p=0.009), while residents counseled patients less frequently (p=0.003), were less likely to be familiar with PPP guidelines (p=0.026), and less likely to recommend appropriate follow-ups for patients with family history of glaucoma (p=0.004). CONCLUSIONS: PCPs' awareness and familiarity with AAO CEE guidelines is variable and improves with provider age and experience. Efforts to improve PCP guideline awareness may be especially well-suited for residents and mid-level practitioners.
Oke I, Badami A, Kosteva KL, Wu K, Desai MA. Systemic Barriers in Receiving Electronically Prescribed Glaucoma Medications. J Glaucoma 2022;31(10):812-815.Abstract
PRCIS: Over a third of electronically prescribed glaucoma medications were not picked up within 1 month of patient request. Feedback-driven protocols may help minimize treatment interruptions attributed to electronic prescribing. PURPOSE: Glaucoma treatment relies on long-term medication compliance and many socioeconomic factors impact the ability of patients to receive their medications. This study aims to quantify treatment interruptions attributable to electronically prescribed medications and propose interventions to minimize this barrier. METHODS: This is a cross-sectional study of the electronic prescribing patterns at a tertiary care hospital serving a socioeconomically diverse patient population. Glaucoma medication refill requests received over a 6-week interval were reviewed and patient pharmacies were contacted 1 month after the request date to determine whether the medication was received by the patient. Patients who did not pick up the prescriptions were contacted and consented to participate in a survey to identify the barriers to acquiring the medications. RESULTS: Refill requests of 198 glaucoma medications met the inclusion criteria and the most common classes were prostaglandin analogs (44%) and alpha-2-agonists (21%). Medications were not obtained within 1 month in 71 (35.9%) cases. Prior authorization requirement was significantly associated with patients not obtaining their medication (odds ratio, 0.07; 95% confidence interval, 0.03-0.45). Patient reported challenges to successful receipt electronically prescribed medications included insurance coverage (32.2%) and pharmacy availability (22.6%). CONCLUSIONS: Approximately a third of electronically prescribed glaucoma medications were not received by patients within a month of refill request due to the need for prior authorization, insurance coverage, and pharmacy availability. A mechanism to alert providers and to address these barriers to medication access may minimize treatment interruption and disease progression.
Choudhury A, Reyes N, Galor A, Mehra D, Felix E, Moulton EA. Clinical neuroimaging of photophobia in individuals with chronic ocular surface pain. Am J Ophthalmol 2022;Abstract
PURPOSE: To examine neural mechanisms underlying photophobia in individuals with chronic ocular surface pain using functional magnetic resonance imaging (fMRI). DESIGN: Cross-sectional case/control analysis METHODS: 16 subjects from the Miami Veterans Affairs eye clinic underwent comprehensive ocular surface evaluations and were surveyed for ocular surface symptoms. Cases included subjects who reported chronic ocular surface pain symptoms and light sensitivity at least most of the time over one week. Controls included subjects without chronic ocular surface pain who reported no or minimal light sensitivity. All subjects viewed light stimuli during two fMRI scans, one before and one after topical anesthetic instillation, and rated their level of pain intensity to the stimulus at the end of each scan. Areas of brain activation in response to light stimuli presentation were correlated to pain responses and examined post- vs. pre-anesthesia. RESULTS: Cases (n=8) reported higher pain intensity ratings than controls (n=8) in response to light stimuli during fMRI. Case ratings correlated more with light-evoked activation in pain-related areas within the trigeminal brainstem, primary somatosensory cortex (S1), anterior mid-cingulate cortex (aMCC), and insula than with controls. Topical anesthesia led to varying responses in pain ratings among cases as well as decreased light-evoked activation in S1 and aMCC. CONCLUSIONS: The trigeminal nociceptive system may contribute to photophobia in individuals with chronic ocular surface pain. We demonstrate modulation of cortical structures in this pathway with topically applied anesthetic to the eyes. Further understanding of modulatory interactions that govern ocular surface pain and photophobia is critical for developing effective, precision-based therapies.
Houston KE, Paschalis EI. Feasibility of Magnetic Levator Prosthesis Frame Customization Using Craniofacial Scans and 3-D Printing. Transl Vis Sci Technol 2022;11(10):34.Abstract
Purpose: To determine the feasibility of a custom frame generation approach for nonsurgical management of severe blepharoptosis with the magnetic levator prosthesis (MLP). Methods: Participants (n = 8) with severe blepharoptosis (obscuring the visual axis) in one or both eyes who had previously been using a non-custom MLP had a craniofacial scan with a smartphone app to generate a custom MLP frame. A magnetic adhesive was attached to the affected eyelid. The custom MLP frame held a cylindrical magnet near the eyebrow above the affected eyelid, suspending it in the magnetic field while still allowing blinking. The spectacle magnet could be rotated manually, providing adjustable force via angular translation of the magnetic field. Fitting success and comfort were recorded, and interpalpebral fissure (IPF) was measured from video frames after 20 minutes in-office and one-week at-home use. Preference was documented, custom versus non-custom. Results: Overall, 88% of patients (7/8) were successfully fitted with a median 9/10 comfort (interquartile 7-10) and median ptosis improvement of 2.3 mm (1.3-5.0); P = 0.01). Exact binomial testing suggested, with 80% power, that the true population success rate was significantly greater than 45% (P = 0.05). Five participants took the custom MLP home for one week, with only one case of mild conjunctival redness which resolved without treatment. Highest to lowest force modulation resulted in a marginally significant median IPF adjustment of 1.5 mm (0.8 to 2.7; P = 0.06). All preferred the custom frame. Conclusions: The three-dimensional custom MLP frame generation approach using a smartphone app-based craniofacial scan is a feasible approach for clinical deployment of the MLP. Translational Relevance: First demonstration of customized frame generation for the MLP.
Noro T, Shah SH, Yin Y, Kawaguchi R, Yokota S, Chang K-C, Madaan A, Sun C, Coppola G, Geschwind D, Benowitz LI, Goldberg JL. Elk-1 regulates retinal ganglion cell axon regeneration after injury. Sci Rep 2022;12(1):17446.Abstract
Adult central nervous system (CNS) axons fail to regenerate after injury, and master regulators of the regenerative program remain to be identified. We analyzed the transcriptomes of retinal ganglion cells (RGCs) at 1 and 5 days after optic nerve injury with and without a cocktail of strongly pro-regenerative factors to discover genes that regulate survival and regeneration. We used advanced bioinformatic analysis to identify the top transcriptional regulators of upstream genes and cross-referenced these with the regulators upstream of genes differentially expressed between embryonic RGCs that exhibit robust axon growth vs. postnatal RGCs where this potential has been lost. We established the transcriptional activator Elk-1 as the top regulator of RGC gene expression associated with axon outgrowth in both models. We demonstrate that Elk-1 is necessary and sufficient to promote RGC neuroprotection and regeneration in vivo, and is enhanced by manipulating specific phosphorylation sites. Finally, we co-manipulated Elk-1, PTEN, and REST, another transcription factor discovered in our analysis, and found Elk-1 to be downstream of PTEN and inhibited by REST in the survival and axon regenerative pathway in RGCs. These results uncover the basic mechanisms of regulation of survival and axon growth and reveal a novel, potent therapeutic strategy to promote neuroprotection and regeneration in the adult CNS.
Zang B, Rong SS, Ding XX, Zou B, Zang DX, Wang Y, Xu KM, Feng D, Li D. [The impact of diabetic retinopathy on vision-related quality of life]. Zhonghua Yan Ke Za Zhi 2022;58(10):760-768.Abstract
Objective: To assess the effect of diabetic retinopathy (DR) on vision-related quality of life (VRQoL) in patients with type 2 diabetes. Methods: In this cross-sectional study, patients with type 2 diabetes residing in 15 residency communities in Fushun, Liaoning province were enrolled from July 2012 to May 2013. We measured the VRQoL by the 25-item National Eye Institute Visual Function Questionnaire (NEI-VFQ-25). Patients were grouped according to their age, gender, presence of visual impairment, and affected eyes. NEI-VFQ-25 scores were compared between/among groups using the Wilcoxon rank-sum test or Kruskal-Wallis H test. The severity of DR in the eyes was graded into no DR, mild non-proliferative diabetic retinopathy (NPDR), moderate NPDR, severe NPDR, and proliferative diabetic retinopathy (PDR). Severity scores from both eyes were then summarized to create a single per-person grade ranging from 1 (no DR in either eye) to 7 (bilateral PDR). Generalized linear models were used to assess the linear relationship between NEI-VFQ-25 scores and DR severity. Locally weighted scatterplot smoothing plots were generated to evaluate the possible nonlinear associations between concatenated severity of DR and VRQoL. Results: A total of 1 537 patients were recruited, including 836 (54.4%) with no DR, 479 (31.2%) with mild NPDR, 90 (5.9%) with moderate NPDR, 72 (4.7%) with severe NPDR and 60 (3.9%) with PDR. Compared with patients with unilateral DR, bilaterally involved subjects were statistically significantly compromised in general vision [70.2 (66.5, 72.5) vs. 68.9 (63.9, 71.6), Z=90.222, P=0.038], near activities [90.5 (85.8, 94.0) vs. 88.8 (84.5, 92.5), Z=114.942, P=0.005], dependency [91.1 (85.6, 96.5) vs. 89.3 (83.8, 94.5), Z=91.934, P=0.033], mental health [80.0 (73.4, 84.9) vs. 77.5 (70.8, 82.0), Z=118.388, P=0.003], role difficulties [76.8 (70.1, 82.4) vs. 74.5 (67.6, 80.6), Z =90.791, P=0.036] and NEI-VFQ-25 composite [88.3 (84.2, 91.0) vs. 86.9 (82.8, 90.1), Z=96.207, P=0.024]. Scores on general vision (χ2=85.665), near activities (χ2=78.462), distance activities (χ2=145.489), social function (χ2=53.629), dependency (χ2=86.710), mental health (χ2=68.281), role difficulties (χ2=45.357), color vision (χ2=68.176), peripheral vision (χ2=116.179) and NEI-VFQ-25 composite (χ2=133.291) decreased gradually as DR severity increased (all P<0.001). On role difficulties, locally weighted scatterplot smoothing plots showed significant"turning points"from bilateral mild NPDR to mild NPDR/>mild NPDR (slope m=-4.7) and from moderate NPDR/≥moderate NPDR to severe NPDR/≥severe NPDR (slope m=-12.6). Conclusion: Both greater severity and bilaterality of DR were associated with lower vision-specific VRQoL, particularly role difficulties and mental health.
Chang TC, Calderon-Candelario RA, Berrocal AM, Briceño CA, Chen J, Shoham-Hazon N, Berco E, Solá-Del Valle D, Vanner EA. LGBTQ+ Identity and Ophthalmologist Burnout. Am J Ophthalmol 2022;Abstract
PURPOSE: To evaluate lesbian, gay, bisexual, transgender, questioning and other sexual/gender minority (LGBTQ+) orientation as a burnout risk factor among an international ophthalmologist cohort. METHODS: An anonymous, cross-sectional electronic survey was distributed via an internet platform to characterize the relationship between demographic factors, including LGBTQ+ orientation, and burnout as measured by the Copenhagen Burnout Inventory (CBI). Univariable data analysis (linear) by sexual orientation was performed and variables with association with p-value < 0.15 in univariable analysis were included in the multiple linear regression modeling. RESULTS: A total of 403 ophthalmologists participated in the survey, the majority self-identified as "White" (69.2%), were from North America (72.0% United States, 18.6% Canada), and were evenly distributed between age of 30 and 65 years. Overall, 13.2% of participants identified as LGBTQ+, 98.2% as cisgender. Approximately 12% had witnessed or experienced LGBTQ+-related workplace discrimination or harassment. The personal and work-related burnout scores and confidence limits of those identified as LGBTQ+ were higher and non-overlapping than those reported as non-LGBTQ+. Multivariable analysis identified significant risk factors for higher personal and work-related burnout scores: LGBTQ+ (11.8 and 11.1, P = .0005 and .0023), female gender (5.36 and 4.83, P = .0153 and .0434), older age (19.1 and 19.2, P = .0173 and .0273) and caretaker stress (6.42 and 5.97, P = .0085 and .0239). CONCLUSIONS: LGBTQ+ orientation is a burnout risk factor among ophthalmologists, and LGBTQ+ workplace discrimination may be a contributing factor. Support from ophthalmology organization to address LGBTQ+-, gender- and age-related work-place discrimination may decrease burnout.
Lu Y-C, Tsai Y-H, Chan Y-H, Hu C-J, Huang C-Y, Xiao R, Hsu C-J, Vandenberghe LH, Wu C-C, Cheng Y-F. Gene therapy with a synthetic adeno-associated viral vector improves audiovestibular phenotypes in Pjvk-mutant mice. JCI Insight 2022;7(20)Abstract
Recessive PJVK mutations that cause a deficiency of pejvakin, a protein expressed in both sensory hair cells and first-order neurons of the inner ear, are an important cause of hereditary hearing impairment. Patients with PJVK mutations garner limited benefits from cochlear implantation; thus, alternative biological therapies may be required to address this clinical difficulty. The synthetic adeno-associated viral vector Anc80L65, with its wide tropism and high transduction efficiency in various inner ear cells, may provide a solution. We delivered the PJVK transgene to the inner ear of Pjvk mutant mice using the synthetic Anc80L65 vector. We observed robust exogenous pejvakin expression in the hair cells and neurons of the cochlea and vestibular organs. Subsequent morphologic and audiologic studies demonstrated significant restoration of spiral ganglion neuron density and hair cells in the cochlea, along with partial recovery of sensorineural hearing impairment. In addition, we observed a recovery of vestibular ganglion neurons and balance function to WT levels. Our study demonstrates the utility of Anc80L65-mediated gene delivery in Pjvk mutant mice and provides insights into the potential of gene therapy for PJVK-related inner ear deficits.
Xu C, Saini C, Wang M, Devlin J, Wang H, Greenstein SH, Brauner SC, Shen LQ. Combined Model of OCT Angiography and Structural OCT Parameters to Predict Paracentral Visual Field Loss in Primary Open-Angle Glaucoma. Ophthalmol Glaucoma 2022;Abstract
PURPOSE: To assess a model combining optical coherence tomography angiography (OCTA) and optical coherence tomography (OCT) parameters to predict the severity of paracentral visual field (VF) loss in primary open-angle glaucoma (POAG). DESIGN: Cross-sectional study. PARTICIPANTS: Forty-four patients with POAG and 42 control subjects underwent OCTA and OCT imaging with a swept-source OCT device. METHODS: The circumpapillary microvasculature was quantified for vessel density (cpVD) and flow (cpFlow) after delineation of Bruch's membrane opening and removal of large vessels. Retinal nerve fiber layer thickness (RNFLT) and Bruch's membrane opening-minimum rim width (BMO-MRW) were measured from structural OCT. Paracentral total deviation (PaTD) was defined as the average of the total deviation values within the central 10 degrees on Humphrey VF testing (24-2) for upper and lower hemifields. The OCT and OCTA parameters were measured in the affected hemisphere corresponding to the hemifield with lower PaTD for POAG patients. Models were created to predict affected PaTD based on RNFLT alone; RNFLT and BMO-MRW; OCTA alone; or RNFLT, BMO-MRW and OCTA parameters. The models were compared using coefficient of determination (r2) and Bayesian information criterion (BIC) score. BIC decrease of ≥6 indicates strong evidence for model improvement. MAIN OUTCOME MEASURES: Performance of models containing OCT and OCTA parameters in predicting PaTD. RESULTS: POAG and controls were similar in age and gender (65.9±9.5 years and 38.4% male overall, p≥0.56 for both). Average RNFLT, minimum RNFLT, average BMO-MRW, minimum BMO-MRW, cpVD, and cpFlow were all significantly lower (all p<0.001) in the affected hemisphere in POAG patients compared to controls. In POAG patients, the average mean deviation was -4.33±3.25 dB; the PaTD of the affected hemifield averaged -4.55±5.26 dB and correlated significantly with both OCTA and structural OCT parameters (r≥0.43, p≤0.004 for all). The model containing RNFLT, BMO-MRW, and OCTA parameters was superior in predicting affected PaTD (r2=0.47, BIC=290.7), with higher r2 and lower BIC compared to all three other models. CONCLUSIONS: A combined model of OCTA and structural OCT parameters can predict the severity of paracentral visual field loss of the affected hemifield, supporting clinical utility of OCTA in POAG patients with paracentral VF loss.
Lee D, Tomita Y, Negishi K, Kurihara T. Therapeutic roles of PPARα activation in ocular ischemic diseases. Histol Histopathol 2022;:18542.Abstract
Ocular ischemia is one of the leading causes of blindness. It is related to various ocular diseases and disorders, including age-related macular degeneration, diabetic retinopathy, glaucoma, and corneal injury. Ocular ischemia occurs due to an abnormal supply of oxygen and nutrients to the eye, resulting in ocular metabolic dysfunction. These changes can be linked with pathologic conditions in the eye, such as inflammation, neovascularization, and cell death, ultimately leading to vision loss. The current treatment care for ocular ischemia is limited. Peroxisome proliferator-activated receptor α (PPARα) is a nuclear receptor protein functioning in regulating lipid metabolism, fatty acid oxidation, and glucose homeostasis. Recently, PPARα activation has been suggested as a useful therapeutic target in treating ocular ischemia. However, its applications have not been well summarized. In this review, we cover an overview of the therapeutic roles of PPARα activation in various ocular ischemic conditions with recent experimental evidence and further provide clinical implications of its therapeutic applications. Our review will enable more approaches to comprehensively understand the therapeutic roles of PPARα activation for preventing ocular ischemic diseases.
Wu M, Matar DY, Yu Z, Karvar M, Chen Z, Ng B, Knoedler S, Darwish O, Agarwal S, Orgill DP, Panayi AC. Xenogenic induction of adipose tissue and maintenance through pre- and post-conditioning using external volume expansion. Biomed Mater 2022;17(6)Abstract
External volume expansion (EVE) has been shown to improve fat graft survival. In this study, we investigated the xenogenic implantation of human allograft adipose matrix (AAM) in non-immunocompromised mice in combination with pre- and post-conditioning with EVE to assess long-term adipose tissue survival. Sixty-eight recipient sites in thirty-four eight-week-old wild type (C57BL/6J) mice were separated into four groups. Thirty-four sites received no conditioning and either a subcutaneous injection of 300 μl saline (n= 17; PBS group) or AAM (n= 17; AAM group). Thirty-four sites received pre-conditioning with EVE (Day -7-3 pre-grafting) and 300 μl of AAM. Seventeen of these sites received immediate post-conditioning (Day 1-5 post-grafting) and 17 delayed post-conditioning (Day 28-32 post-grafting). Tissue was harvested at week 12 for analysis. At 12 weeks, immediate and delayed post-conditioning enabled higher volume retention (p= 0.02 andp< 0.0001, respectively). Adipose Stem Cells were greater in the AAM+Del-EVE group compared to the AAM (p= 0.01). Microvessel density was lower in the AAM group compared to the AAM+Imm-EVE (p= 0.04) and AAM+Del-EVE group (p= 0.02). Macrophage infiltration was lower in the AAM+Imm-EVE (p= 0.002) and AAM+Del-EVE (p= 0.003) groups compared to the AAM group. PCR analysis and Western blotting identified a significantly higher expression of PPAR-γ, LPL and VEGF with delayed-conditioning. Pre- and post-conditioning, particularly delayed-post-conditioning, of the recipient site optimized the microenvironment allowing significant adipogenesis and survival of neo-adipose tissue through robust angiogenesis. This study supports that xenogenic transplantation of adipose matrix allows adipose tissue formation and survival with EVE as an adjuvant.
Silpa-Archa S, Sapthanakorn W, Foster SC. ISOLATED RETINAL VASCULITIS: Prognostic Factors and Expanding the Role of Immunosuppressive Treatment in Retinal Vasculitis Associated With Positive QuantiFERON-TB Gold Test. Retina 2022;42(10):1897-1908.Abstract
PURPOSE: To identify prognostic factors for poor visual outcomes in patients with isolated retinal vasculitis and to elucidate the outcome of immunosuppressive treatment without the use of antituberculosis drugs for patients with retinal vasculitis associated with a positive QuantiFERON-TB Gold In-Tube (QFT) test. METHODS: A retrospective chart review was performed of patients presenting with retinal vasculitis. After the diagnosis of active retinal vasculitis had been confirmed by fluorescein angiography and other possible causes of retinal vasculitis had been excluded, patients were categorized into two groups by their QFT result. Potential associated factors between the poor and good visual outcome groups were statistically analyzed by the chi-square test and logistic regression model with generalized estimating equations. RESULTS: Seventy-three eyes (48 patients) were enrolled in this study. After univariate analysis, multivariate logistic regression analysis was performed and revealed that logMAR visual acuity at the initial visit ( P = 0.01) and outer retinal disruption ( P = 0.03) were the two factors significantly associated with poor visual outcomes. Systemic corticosteroids were administered without the use of antituberculosis drugs to all 16 cases of presumed tuberculous retinal vasculitis associated with positive QFT (26 eyes), 10 (63%) of whom were given nonsteroidal immunosuppressive drugs and achieved inflammatory control and treatment success. CONCLUSION: Risk factors leading to poor visual outcome in patients with isolated retinal vasculitis have been identified. Immunosuppressive treatment without antituberculosis drugs seems to be a promising regimen for selected patients with presumed tuberculous retinal vasculitis under vigilant care.
Kuo A, Checa A, Niaudet C, Jung B, Fu Z, Wheelock CE, Singh SA, Aikawa M, Smith LE, Proia RL, Hla T. Murine endothelial serine palmitoyltransferase 1 (SPTLC1) is required for vascular development and systemic sphingolipid homeostasis. Elife 2022;11Abstract
Serine palmitoyl transferase (SPT), the rate-limiting enzyme in the de novo synthesis of sphingolipids (SL), is needed for embryonic development, physiological homeostasis, and response to stress. The functions of de novo SL synthesis in vascular endothelial cells (EC), which line the entire circulatory system, are not well understood. Here, we show that the de novo SL synthesis in EC not only regulates vascular development but also maintains circulatory and peripheral organ SL levels. Mice with an endothelial-specific gene knockout of SPTLC1 (Sptlc1 ECKO), an essential subunit of the SPT complex, exhibited reduced EC proliferation and tip/stalk cell differentiation, resulting in delayed retinal vascular development. In addition, Sptlc1 ECKO mice had reduced retinal neovascularization in the oxygen-induced retinopathy model. Mechanistic studies suggest that EC SL produced from the de novo pathway are needed for lipid raft formation and efficient VEGF signaling. Post-natal deletion of the EC Sptlc1 also showed rapid reduction of several SL metabolites in plasma, red blood cells, and peripheral organs (lung and liver) but not in the retina, part of the central nervous system (CNS). In the liver, EC de novo SL synthesis was important for acetaminophen-induced rapid ceramide elevation and hepatotoxicity. These results suggest that EC-derived SL metabolites are in constant flux between the vasculature, circulatory elements, and parenchymal cells of non-CNS organs. Taken together, our data point to the central role of the endothelial SL biosynthesis in maintaining vascular development, neovascular proliferation, non-CNS tissue metabolic homeostasis, and hepatocyte response to stress.

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