Publications

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Bennett CR, Loomis JM, Klatzky RL, Giudice NA. Spatial updating of multiple targets: Comparison of younger and older adults. Mem Cognit 2017;Abstract
When walking without vision, people mentally keep track of the directions and distances of previously viewed objects, a process called spatial updating. The current experiment indicates that while people across a large age range are able to update multiple targets in memory without perceptual support, aging negatively affects accuracy, precision, and decision time. Participants (20 to 80 years of age) viewed one, three, or six targets (colored lights) on the floor of a dimly lit room. Then, without vision, they walked to a target designated by color, either directly or indirectly (via a forward turning point). The younger adults' final stopping points were both accurate (near target) and precise (narrowly dispersed), but updating performance did degrade slightly with the number of targets. Older adults' performance was consistently worse than the younger group, but the lack of interaction between age and memory load indicates that the effect of age on performance was not further exacerbated by a greater number of targets. The number of targets also significantly increased the latency required to turn toward the designated target for both age groups. Taken together, results extend previous work showing impressive updating performance by younger adults, with novel findings showing that older adults manifest small but consistent degradation of updating performance of multitarget arrays.
Bennett J, Wellman J, Marshall KA, McCague S, Ashtari M, DiStefano-Pappas J, Elci OU, Chung DC, Sun J, Wright FJ, Cross DR, Aravand P, Cyckowski LL, Bennicelli JL, Mingozzi F, Auricchio A, Pierce EA, Ruggiero J, Leroy BP, Simonelli F, High KA, Maguire AM. Safety and durability of effect of contralateral-eye administration of AAV2 gene therapy in patients with childhood-onset blindness caused by RPE65 mutations: a follow-on phase 1 trial. Lancet 2016;Abstract

BACKGROUND: Safety and efficacy have been shown in a phase 1 dose-escalation study involving a unilateral subretinal injection of a recombinant adeno-associated virus (AAV) vector containing the RPE65 gene (AAV2-hRPE65v2) in individuals with inherited retinal dystrophy caused by RPE65 mutations. This finding, along with the bilateral nature of the disease and intended use in treatment, prompted us to determine the safety of administration of AAV2-hRPE65v2 to the contralateral eye in patients enrolled in the phase 1 study. METHODS: In this follow-on phase 1 trial, one dose of AAV2-hRPE65v2 (1·5 × 10(11) vector genomes) in a total volume of 300 μL was subretinally injected into the contralateral, previously uninjected, eyes of 11 children and adults (aged 11-46 years at second administration) with inherited retinal dystrophy caused by RPE65 mutations, 1·71-4·58 years after the initial subretinal injection. We assessed safety, immune response, retinal and visual function, functional vision, and activation of the visual cortex from baseline until 3 year follow-up, with observations ongoing. This study is registered with ClinicalTrials.gov, number NCT01208389. FINDINGS: No adverse events related to the AAV were reported, and those related to the procedure were mostly mild (dellen formation in three patients and cataracts in two). One patient developed bacterial endophthalmitis and was excluded from analyses. We noted improvements in efficacy outcomes in most patients without significant immunogenicity. Compared with baseline, pooled analysis of ten participants showed improvements in mean mobility and full-field light sensitivity in the injected eye by day 30 that persisted to year 3 (mobility p=0·0003, white light full-field sensitivity p<0·0001), but no significant change was seen in the previously injected eyes over the same time period (mobility p=0·7398, white light full-field sensitivity p=0·6709). Changes in visual acuity from baseline to year 3 were not significant in pooled analysis in the second eyes or the previously injected eyes (p>0·49 for all time-points compared with baseline). INTERPRETATION: To our knowledge, AAV2-hRPE65v2 is the first successful gene therapy administered to the contralateral eye. The results highlight the use of several outcome measures and help to delineate the variables that contribute to maximal benefit from gene augmentation therapy in this disease. FUNDING: Center for Cellular and Molecular Therapeutics at The Children's Hospital of Philadelphia, Spark Therapeutics, US National Institutes of Health, Foundation Fighting Blindness, Institute for Translational Medicine and Therapeutics, Research to Prevent Blindness, Center for Advanced Retinal and Ocular Therapeutics, Mackall Foundation Trust, F M Kirby Foundation, and The Research Foundation-Flanders.

Bennett CR, Bex PJ, Merabet LB. Assessing visual search performance using a novel dynamic naturalistic scene. J Vis 2021;21(1):5.Abstract
Daily activities require the constant searching and tracking of visual targets in dynamic and complex scenes. Classic work assessing visual search performance has been dominated by the use of simple geometric shapes, patterns, and static backgrounds. Recently, there has been a shift toward investigating visual search in more naturalistic dynamic scenes using virtual reality (VR)-based paradigms. In this direction, we have developed a first-person perspective VR environment combined with eye tracking for the capture of a variety of objective measures. Participants were instructed to search for a preselected human target walking in a crowded hallway setting. Performance was quantified based on saccade and smooth pursuit ocular motor behavior. To assess the effect of task difficulty, we manipulated factors of the visual scene, including crowd density (i.e., number of surrounding distractors) and the presence of environmental clutter. In general, results showed a pattern of worsening performance with increasing crowd density. In contrast, the presence of visual clutter had no effect. These results demonstrate how visual search performance can be investigated using VR-based naturalistic dynamic scenes and with high behavioral relevance. This engaging platform may also have utility in assessing visual search in a variety of clinical populations of interest.
Bennett CR, Bex PJ, Bauer CM, Merabet LB. The Assessment of Visual Function and Functional Vision. Semin Pediatr Neurol 2019;31:30-40.Abstract
The complete assessment of vision-related abilities should consider visual function (the performance of components of the visual system) and functional vision (visual task-related ability). Assessment methods are highly dependent upon individual characteristics (eg, the presence and type of visual impairment). Typical visual function tests assess factors such as visual acuity, contrast sensitivity, color, depth, and motion perception. These properties each represent an aspect of visual function and may impact an individual's level of functional vision. The goal of any functional vision assessment should be to measure the visual task-related ability under real-world scenarios. Recent technological advancements such as virtual reality can provide new opportunities to improve traditional vision assessments by providing novel objective and ecologically valid measurements of performance, and allowing for the investigation of their neural basis. In this review, visual function and functional vision evaluation approaches are discussed in the context of traditional and novel acquisition methods.
Benowitz LI, He Z, Goldberg JL. Reaching the brain: Advances in optic nerve regeneration. Exp Neurol 2017;287(Pt 3):365-373.Abstract

The optic nerve has been widely used to investigate factors that regulate axon regeneration in the mammalian CNS. Although retinal ganglion cells (RGCs), the projection neurons of the eye, show little capacity to regenerate their axons following optic nerve damage, studies spanning the 20(th) century showed that some RGCs can regenerate axons through a segment of peripheral nerve grafted to the optic nerve. More recently, some degree of regeneration has been achieved through the optic nerve itself by factors associated with intraocular inflammation (oncomodulin) or by altering levels of particular transcription factors (Klf-4, -9, c-myc), cell-intrinsic suppressors of axon growth (PTEN, SOCS3), receptors to cell-extrinsic inhibitors of axon growth (Nogo receptor, LAR, PTP-σ) or the intracellular signaling pathway activated by these receptors (RhoA). Other regulators of regeneration and cell survival continue to be identified in this system at a rapid pace. Combinatorial treatments that include two or more of these factors enable some retinal ganglion cells to regenerate axons from the eye through the entire length of the optic nerve and across the optic chiasm. In some cases, regenerating axons have been shown to innervate the appropriate central target areas and elicit postsynaptic responses. Many discoveries made in this system have been found to enhance axon regeneration after spinal cord injury. Thus, progress in optic nerve regeneration holds promise not only for visual restoration but also for improving outcome after injury to other parts of the mature CNS.

Bernabeu MO, Lu Y, Abu-Qamar O, Aiello LP, Sun JK. Estimation of Diabetic Retinal Microaneurysm Perfusion Parameters Based on Computational Fluid Dynamics Modeling of Adaptive Optics Scanning Laser Ophthalmoscopy. Front Physiol 2018;9:989.Abstract
Diabetic retinopathy (DR) is a leading cause of vision loss worldwide. Microaneurysms (MAs), which are abnormal outpouchings of the retinal vessels, are early and hallmark lesions of DR. The presence and severity of MAs are utilized to determine overall DR severity. In addition, MAs can directly contribute to retinal neural pathology by leaking fluid into the surrounding retina, causing abnormal central retinal thickening and thereby frequently leading to vision loss. Vascular perfusion parameters such as shear rate (SR) or wall shear stress (WSS) have been linked to blood clotting and endothelial cell dysfunction, respectively in non-retinal vasculature. However, despite the importance of MAs as a key aspect of diabetic retinal pathology, much remains unknown as to how structural characteristics of individual MAs are associated with these perfusion attributes. MA structural information obtained on high resolution adaptive optics scanning laser ophthalmoscopy (AOSLO) was utilized to estimate perfusion parameters through Computational Fluid Dynamics (CFD) analysis of the AOSLO images. The HemeLB flow solver was used to simulate steady-state and time-dependent fluid flow using both commodity hospital-based and high performance computing resources, depending on the degree of detail required in the simulations. Our results indicate that WSS is lowest in MA regions furthest away from the feeding vessels. Furthermore, areas of low SR are associated with clot location in saccular MAs. These findings suggest that morphology and CFD estimation of perfusion parameters may be useful tools for determining the likelihood of clot presence in individual diabetic MAs.
Berner D, Hoja U, Zenkel M, Ross JJ, Uebe S, Paoli D, Frezzotti P, Rautenbach RM, Ziskind A, Williams SE, Carmichael TR, Ramsay M, Topouzis F, Chatzikyriakidou A, Lambropoulos A, Sundaresan P, Ayub H, Akhtar F, Qamar R, Zenteno JC, Cruz-Aguilar M, Astakhov YS, Dubina M, Wiggs J, Ozaki M, Kruse FE, Aung T, Reis A, Khor CC, Pasutto F, Schlötzer-Schrehardt U. The protective variant rs7173049 at LOXL1 locus impacts on retinoic acid signaling pathway in pseudoexfoliation syndrome. Hum Mol Genet 2019;Abstract
LOXL1 (lysyl oxidase-like 1) has been identified as the major effect locus in pseudoexfoliation (PEX) syndrome, a fibrotic disorder of the extracellular matrix and frequent cause of chronic open-angle glaucoma. However, all known PEX-associated common variants show allele effect reversal in populations of different ancestry, casting doubt on their biological significance. Based on extensive LOXL1 deep sequencing, we report here the identification of a common noncoding sequence variant, rs7173049A>G, located downstream of LOXL1, consistently associated with a decrease in PEX risk (OR=0.63, p=6.33x10-31) in nine different ethnic populations. We provide experimental evidence for a functional enhancer-like regulatory activity of the genomic region surrounding rs7173049 influencing expression levels of ISLR2 (immunoglobulin superfamily containing leucine-rich repeat protein 2) and STRA6 (stimulated by retinoic acid receptor 6), apparently mediated by allele-specific binding of the transcription factor THRβ (thyroid hormone receptor beta). We further show that the protective rs7173049-G allele correlates with increased tissue expression levels of ISLR2 and STRA6 and that both genes are significantly downregulated in tissues of PEX patients together with other key components of the STRA6 receptor-driven retinoic acid signaling pathway. siRNA-mediated downregulation of retinoic acid signaling induces upregulation of LOXL1 and PEX-associated matrix genes in PEX-relevant cell types. These data indicate that dysregulation of STRA6 and impaired retinoid metabolismare involved in the pathophysiology of PEX syndrome and that the variant rs7173049-G, which represents the first common variant at the broad LOXL1 locus without allele effect reversal, mediates a protective effect through upregulation of STRA6 in ocular tissues.
Bernstein CA, Nir R-R, Noseda R, Fulton AB, Huntington S, Lee AJ, Bertisch SM, Hovaguimian A, Buettner C, Borsook D, Burstein R. The migraine eye: distinct rod-driven retinal pathways' response to dim light challenges the visual cortex hyperexcitability theory. Pain 2019;160(3):569-578.Abstract
Migraine-type photophobia, most commonly described as exacerbation of headache by light, affects nearly 90% of the patients. It is the most bothersome symptom accompanying an attack. Using subjective psychophysical assessments, we showed that migraine patients are more sensitive to all colors of light during ictal than during interictal phase and that control subjects do not experience pain when exposed to different colors of light. Based on these findings, we suggested that color preference is unique to migraineurs (as it was not found in control subjects) rather than migraine phase (as it was found in both phases). To identify the origin of this photophobia in migraineurs, we compared the electrical waveforms that were generated in the retina and visual cortex of 46 interictal migraineurs to those generated in 42 healthy controls using color-based electroretinography and visual-evoked potential paradigms. Unexpectedly, it was the amplitude of the retinal rod-driven b wave, which was consistently larger (by 14%-19% in the light-adapted and 18%-34% in the dark-adapted flash ERG) in the migraineurs than in the controls, rather than the retinal cone-driven a wave or the visual-evoked potentials that differs most strikingly between the 2 groups. Mechanistically, these findings suggest that the inherent hypersensitivity to light among migraine patients may originate in the retinal rods rather than retinal cones or the visual cortex. Clinically, the findings may explain why migraineurs complain that the light is too bright even when it is dim to the extent that nonmigraineurs feel as if they are in a cave.
Berry JL, Polski A, Cavenee WK, Dryja TP, Murphree LA, Gallie BL. The Story: Characterization and Cloning of the First Tumor Suppressor Gene. Genes (Basel) 2019;10(11)Abstract
The gene is the first described human tumor suppressor gene and plays an integral role in the development of retinoblastoma, a pediatric malignancy of the eye. Since its discovery, the stepwise characterization and cloning of have laid the foundation for numerous advances in the understanding of tumor suppressor genes, retinoblastoma tumorigenesis, and inheritance. Knowledge of led to a paradigm shift in the field of cancer genetics, including widespread acceptance of the concept of tumor suppressor genes, and has provided crucial diagnostic and prognostic information through genetic testing for patients affected by retinoblastoma. This article reviews the long history of gene research, characterization, and cloning, and also discusses recent advances in retinoblastoma genetics that have grown out of this foundational work.
Berry RH, Qu J, John SWM, Howell GR, Jakobs TC. Synapse Loss and Dendrite Remodeling in a Mouse Model of Glaucoma. PLoS One 2015;10(12):e0144341.Abstract

It has been hypothesized that synaptic pruning precedes retinal ganglion cell degeneration in glaucoma, causing early dysfunction to retinal ganglion cells. To begin to assess this, we studied the excitatory synaptic inputs to individual ganglion cells in normal mouse retinas and in retinas with ganglion cell degeneration from glaucoma (DBA/2J), or following an optic nerve crush. Excitatory synapses were labeled by AAV2-mediated transfection of ganglion cells with PSD-95-GFP. After both insults the linear density of synaptic inputs to ganglion cells decreased. In parallel, the dendritic arbors lost complexity. We did not observe any cells that had lost dendritic synaptic input while preserving a normal or near-normal morphology. Within the temporal limits of these observations, dendritic remodeling and synapse pruning thus appear to occur near-simultaneously.

Besner S, Scarcelli G, Pineda R, Yun S-H. In Vivo Brillouin Analysis of the Aging Crystalline Lens. Invest Ophthalmol Vis Sci 2016;57(13):5093-5100.Abstract

Purpose: To analyze the age dependence of the longitudinal modulus of the crystalline lens in vivo using Brillouin scattering data in healthy subjects. Methods: Brillouin scans were performed along the crystalline lens in 56 eyes from 30 healthy subjects aged from 19 to 63 years. Longitudinal elastic modulus was acquired along the sagittal axis of the lens with a transverse and axial resolution of 4 and 60 μm, respectively. The relative lens stiffness was computed, and correlations with age were analyzed. Results: Brillouin axial profiles revealed nonuniform longitudinal modulus within the lens, increasing from a softer periphery toward a stiffer central plateau at all ages. The longitudinal modulus at the central plateau showed no age dependence in a range of 19 to 45 years and a slight decrease with age from 45 to 63 years. A significant intersubject variability was observed in an age-matched analysis. Importantly, the extent of the central stiff plateau region increased steadily over age from 19 to 63 years. The slope of change in Brillouin modulus in the peripheral regions were nearly age-invariant. Conclusions: The adult human lens showed no measurable age-related increase in the peak longitudinal modulus. The expansion of the stiff central region of the lens is likely to be the major contributing factor to age-related lens stiffening. Brillouin microscopy may be useful in characterizing the crystalline lens for the optimization of surgical or pharmacological treatments aimed at restoring accommodative power.

Betzler BK, Gunasekeran DV, Kempen J, Smith JR, McCluskey P, Nguyen QD, Pavesio C, Gupta V, Agrawal R. The Historical Evolution of Ocular Tuberculosis: Past, Present, and Future. Ocul Immunol Inflamm 2021;:1-7.Abstract
Ocular involvement is a rare manifestation of tuberculosis. Four key issues historically faced by clinicians when diagnosing and treating ocular tuberculosis - diagnostic uncertainty, naturally heterogeneous presentations, limitations of existing laboratory diagnostic tools, and non-uniform treatment guidelines - continue to test today's physicians. Unparalleled scientific and clinical developments over the past century have greatly expanded the knowledge surrounding this challenging ophthalmic condition. Experience with large volumes of cases at tuberculosis-endemic centres has led to recent growth in knowledge and physician experience, perhaps more so in developing countries. Looking forward, the role of diverse new technologies, including artificial intelligence and proteomics, will advance ocular tuberculosis research. Efforts have been made to address the lack of standardized nomenclature, diagnostic uncertainty, and unvalidated, geographically variable treatment guidelines.
Bever GJ, Jakobiec FA, Mendoza PR, Hatton MP. Congenital megacaruncle: a unique and innocent ocular adnexal anomaly. JAMA Ophthalmol 2013;131(12):1641-3.
Bharti K, den Hollander AI, Lakkaraju A, Sinha D, Williams DS, Finnemann SC, Bowes-Rickman C, Malek G, D'Amore PA. Cell culture models to study retinal pigment epithelium-related pathogenesis in age-related macular degeneration. Exp Eye Res 2022;222:109170.Abstract
Age-related macular degeneration (AMD) is a disease that affects the macula - the central part of the retina. It is a leading cause of irreversible vision loss in the elderly. AMD onset is marked by the presence of lipid- and protein-rich extracellular deposits beneath the retinal pigment epithelium (RPE), a monolayer of polarized, pigmented epithelial cells located between the photoreceptors and the choroidal blood supply. Progression of AMD to the late nonexudative "dry" stage of AMD, also called geographic atrophy, is linked to progressive loss of areas of the RPE, photoreceptors, and underlying choriocapillaris leading to a severe decline in patients' vision. Differential susceptibility of macular RPE in AMD and the lack of an anatomical macula in most lab animal models has promoted the use of in vitro models of the RPE. In addition, the need for high throughput platforms to test potential therapies has driven the creation and characterization of in vitro model systems that recapitulate morphologic and functional abnormalities associated with human AMD. These models range from spontaneously formed cell line ARPE19, immortalized cell lines such as hTERT-RPE1, RPE-J, and D407, to primary human (fetal or adult) or animal (mouse and pig) RPE cells, and embryonic and induced pluripotent stem cell (iPSC) derived RPE. Hallmark RPE phenotypes, such as cobblestone morphology, pigmentation, and polarization, vary significantly betweendifferent models and culture conditions used in different labs, which would directly impact their usability for investigating different aspects of AMD biology. Here the AMD Disease Models task group of the Ryan Initiative for Macular Research (RIMR) provides a summary of several currently used in vitro RPE models, historical aspects of their development, RPE phenotypes that are attainable in these models, their ability to model different aspects of AMD pathophysiology, and pros/cons for their use in the RPE and AMD fields. In addition, due to the burgeoning use of iPSC derived RPE cells, the critical need for developing standards for differentiating and rigorously characterizing RPE cell appearance, morphology, and function are discussed.
Bhattacharya S, García-Posadas L, Hodges RR, Makarenkova HP, Masli S, Dartt DA. Alteration in nerves and neurotransmitter stimulation of lacrimal gland secretion in the TSP-1 mouse model of aqueous deficiency dry eye. Mucosal Immunol 2018;11(4):1138-1148.Abstract
The purpose of this study is to determine neural, vascular, protein secretion, and cellular signaling changes with disease progression in lacrimal glands of the thrombospondin-1 (TSP-1) mouse model of dry eye compared to C57BL/6 wild-type (WT) mice. Neural innervation was reduced in TSP-1 lacrimal glands compared to WT controls, whereas the number of blood vessels was increased. Intracellular Ca stores and the amount of lysosomes, mitochondria, and secretory granules, but not the endoplasmic reticulum, were reduced in TSP-1 compared to WT acini at 12 weeks of age. Ex vivo high KCl-evoked secretion was decreased in TSP-1 compared to WT lacrimal gland tissue pieces. The α-adrenergic agonist-stimulated response was increased in TSP-1 at 4 and 24 weeks but decreased at 12 weeks, and the ATP and MeSATP-stimulated peak [Ca] responses were decreased at 24 weeks. These changes were observed prior to the appearance of mononuclear infiltrates. We conclude that in the lacrimal gland the absence of TSP-1: injures peripheral nerves; blocks efferent nerve activation; decreases protein secretion; and alters intracellular Ca stores. Through these effects the absence of TSP-1 leads to disruption of ocular surface homeostasis and development of dry eye.
Bian Y, Ma KK, Hall NE, Alice Lorch TE, Miller JW, Dana R, Yin J. Neurotrophic Keratopathy in the United States: an IRIS® Registry (Intelligent Research in Sight) Analysis. Ophthalmology 2022;Abstract
PURPOSE: To describe the characteristics of neurotrophic keratopathy (NK) in the US. DESIGN: Retrospective database study. SUBJECTS: 31,915 eyes from 27,483 patients with a diagnosis of NK. METHODS: Retrospective analysis of visits associated with a diagnosis of NK between 2013 and 2018 using the American Academy of Ophthalmology IRIS® Registry (Intelligent Research in Sight). MAIN OUTCOME MEASURES: Demographic information, prevalence, visual acuity (VA), concomitant diagnosis and procedure codes, risk factors impacting visual acuity closest after NK onset date. RESULTS: Mean age at initial diagnosis of NK was 68.0 (SD=16.0) years. 58.91% of patients were female (p<0.0001). Presentation was unilateral in 58.14%, bilateral in 16.13%, and unspecified in 25.73%. Average 6-year prevalence of NK in the IRIS Registry was 21.34 cases per 100,000 patients. Mean logMAR VA was 0.60 (SD=0.79) prior to diagnosis, and 0.88 (SD=0.94) after diagnosis (p<0.0001). Most common concomitant diagnoses included herpetic keratitis (33.70%), diabetes (31.59%), and corneal dystrophy (14.28%). Common procedures for NK management included the use of amniotic membrane (29.90%), punctal plugs (29.65%), and bandage contact lenses (22.67%). Age, male sex, Black race, Hispanic or Latino ethnicity, unilateral involvement, concomitant diagnoses of diabetes, corneal transplant, or herpetic keratitis were significantly associated with worse VA. CONCLUSION: Based on the IRIS Registry, the prevalence of NK is 21.34 cases per 100,000 patients. VA was significantly worse after NK diagnosis compared to other time points. NK was most commonly associated with herpetic keratitis and diabetes. Worse VA in NK patients was associated with several demographic characteristics, history of diabetes, corneal transplant, and herpetic keratitis.
Bicket AK, Mihailovic A, E J-Y, Nguyen A, Mukherjee MR, Friedman DS, Ramulu PY. Gait in Elderly Glaucoma: Impact of Lighting Conditions, Changes in Lighting, and Fear of Falling. Transl Vis Sci Technol 2020;9(13):23.Abstract
Purpose: The purpose of this study was to characterize the impact of lighting changes on gait in elderly patients with glaucoma and evaluate whether associations are mediated by fear of falling (FOF). Methods: Gait initiation and parameters measured with the GAITRite Electronic Walkway were captured in normal indoor light, then in dim light, and again in normal light (normal post dim [NPD]). Participants' right and left eye visual fields (VFs) were merged into integrated VF (IVF) sensitivities. FOF was evaluated using a Rasch-analyzed questionnaire. Multivariable regression models evaluated whether IVF sensitivity was associated with lighting-dependent gait changes and if this relationship was mediated by FOF. Results: In 213 participants (mean age = 71.4 years), gait initiation in dim light took longer with more VF damage ( = 0.02). Greater VF damage was associated with slower gait in dim ( < 0.001) and NPD ( = 0.003) lighting, as well as shorter strides ( = 0.02), broader stance ( = 0.003), and more variable stride velocity and length in all lighting (all < 0.03). When moving from normal to dim lighting, those with more VF damage slowed gait and cadence, shortened stride length, and lengthened double support time (all < 0.001). Velocity, cadence, and double support time did not return to baseline in NPD lighting (all < 0.05). Fear of falling did not appear to mediate the relationship between IVF sensitivity and lighting-dependent gait changes. Conclusions: Patients with more VF damage demonstrate gait degradation in extreme or changing lighting, which is not mediated by FOF. Translational Relevance: Quantitative spatiotemporal gait evaluation reveals lighting-associated impairment, supporting patient-reported difficulty with nonideal lighting and equipping providers to advise patients about limitations.
Binenbaum G, Chang MY, Heidary G, Morrison DG, Trivedi RH, Galvin JA, Pineles SL. Botulinum Toxin Injection for the Treatment of Strabismus: A Report by the American Academy of Ophthalmology. Ophthalmology 2021;128(12):1766-1776.Abstract
PURPOSE: To review the available evidence comparing the effectiveness of extraocular muscle botulinum toxin type A (BTXA) injection with eye muscle surgery for restoring ocular alignment in children and adults with nonparalytic, nonrestrictive horizontal strabismus. METHODS: Literature searches in the PubMed Cochrane Library, and clinical trial databases with no date restrictions, but limited to articles published in English, were conducted last on January 10, 2021. The searches yielded 515 citations, 40 of which were reviewed in full text by the first author. Fourteen articles met the criteria for inclusion (randomized or nonrandomized comparative studies, or case series with a minimum 50 patients; evaluating extraocular muscle BTXA injection for initial or repeat treatment of horizontal, nonparalytic, nonrestrictive strabismus; with at least 6 months of follow-up) and were graded by a methodologist. RESULTS: The 14 included studies consisted of 2 randomized clinical trials, 3 nonrandomized comparative studies, and 9 case series. All 5 comparative studies were graded level II evidence, and the 9 case series were graded level III evidence. Successful motor outcomes after BTXA injection were relatively consistent across 4 of the 5 comparative studies at 60%, when adjustment was made for differential selection bias in 1 of the studies. In the 4 studies, successful motor outcomes after surgery ranged from 66% to 77% with a mean follow-up of 23 to 75 months, and the outcomes were not significantly different from those after BTXA injection. In the fifth level II study, success was significantly higher with BTXA injection than with surgery (94% vs. 72%). The level III BTXA case series demonstrated higher motor success rates of 87% to 89% when children were treated in 2 muscles at a time; rates were lower in adults treated with single-muscle BTXA injection. CONCLUSIONS: Extraocular muscle injection of BTXA achieves a high rate of successful motor alignment, comparable with that achieved after eye muscle surgery for nonparalytic, nonrestrictive horizontal strabismus. Good alignment may require multiple BTXA injections, and it is not yet clear whether sensory outcomes are equivalent for BTXA injections versus eye muscle surgery in young children.
Bingham CM, Sivak-Callcott JA, Gurka MJ, Nguyen J, Hogg JP, Feldon SE, Fay A, Seah L-L, Strianese D, Durairaj VD, Uddin J, Devoto MH, Harris M, Saunders J, Osaki TH, Looi A, Teo L, Davies BW, Elefante A, Shen S, Realini T, Fischer W, Kazim M. Axial Globe Position Measurement: A Prospective Multicenter Study by the International Thyroid Eye Disease Society. Ophthal Plast Reconstr Surg 2016;32(2):106-12.Abstract

PURPOSE: Identify a reproducible measure of axial globe position (AGP) for multicenter studies on patients with thyroid eye disease (TED). METHODS: This is a prospective, international, multicenter, observational study in which 3 types of AGP evaluation were examined: radiologic, clinical, and photographic. In this study, CT was the modality to which all other methods were compared. CT AGP was measured from an orthogonal line between the anterior lateral orbital rims to the cornea. All CT measurements were made at a single institution by 3 individual clinicians. Clinical evaluation was performed with exophthalmometry. Three clinicians from each clinical site assessed AGP with 3 different exophthalmometers and horizontal palpebral width using a ruler. Each physician made 3 separate measurements with each type of exophthalmometer not in succession. All photographic measurements were made at a single institution. AGP was measured from lateral photographs in which a standard marker was placed at the anterior lateral orbital rim. Horizontal and vertical palpebral fissure were measured from frontal photographs. Three trained readers measured 3 separate times not in succession. Exophthalmometry and photography method validity was assessed by agreement with CT (mean differences calculation, intraclass correlation coefficients [ICCs], Bland-Altman figures). Correlation between palpebral fissure and CT AGP was assessed with Pearson correlation. Intraclinician and interclinician reliability was evaluated using ICCs. RESULTS: Sixty-eight patients from 7 centers participated. CT mean AGP was 21.37 mm (15.96-28.90 mm) right and 21.22 mm (15.87-28.70 mm) left (ICC 0.996 and 0.995). Exophthalmometry AGP fell between 18 mm and 25 mm. Intraclinician agreement across exophthalmometers was ideal (ICC 0.948-0.983). Agreement between clinicians was greater than 0.85 for all upright exophthalmometry measurements. Photographic mean AGP was 20.47 mm (10.92-30.88 mm) right and 20.30 mm (8.61-28.72 mm) left. Intrareader and interreader agreement was ideal (ICC 0.991-0.989). All exophthalmometers' mean differences from CT ranged between -0.06 mm (±1.36 mm) and 0.54 mm (±1.61 mm); 95% confidence interval fell within 1 mm. Magnitude of AGP did not affect exophthalmometry validity. Oculus best estimated CT AGP but differences from other exophthalmometers were not clinically meaningful in upright measurements. Photographic AGP (right ICC = 0.575, left ICC = 0.355) and palpebral fissure do not agree with CT. CONCLUSIONS: Upright clinical exophthalmometry accurately estimates CT AGP in TED. AGP measurement was reliably reproduced by the same clinician and between clinicians at multiple institutions using the protocol in this study. These findings allow reliable measurement of AGP that will be of considerable value in future outcome studies.

Birnbaum FA, Neeson C, Solá-Del Valle D. Microinvasive Glaucoma Surgery: An Evidence-Based Review. Semin Ophthalmol 2021;36(8):772-786.Abstract
PURPOSE: Interest in micro-invasive glaucoma surgery (MIGS) has exploded over the last 8 years with an increase in MIGS procedures of at least 400% in the United States, according to Medicare data. MIGS is an umbrella term that can cover many different types of surgeries. This review focuses on peer-reviewed evidence for Trabectome®, iStent inject®, Kahook Dual Blade®, XEN® Gel Stent, and Hydrus®. METHODS: We present key recent studies evaluating the efficacy and safety of MIGS in various types of glaucoma patients with different stages of disease. CONCLUSION: We conclude that MIGS is generally safe and efficacious, although only some MIGS have been studied through randomized clinical trials. When comparing and contrasting the different MIGS procedures, large prospective studies are not yet the norm. High-quality large prospective studies involving MIGS will be an important next step as ophthalmologists decide how to incorporate MIGS into their surgical armamentarium.

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