View details for DOI 10.1177/08830738251328423

View details for PubMedID 40455010

Abstract

Serial fundus photography is commonly used to differentiate between papilledema and pseudopapilledema, but there are limited data on the interrater reliability and accuracy of interpreting these images in children. The purpose of this study was to evaluate the agreement and accuracy of pediatric neuro-ophthalmologists in classifying fundus photographs of children with papilledema and pseudopapilledema.For this cross-sectional study, 3 masked experts (pediatric neuro-ophthalmologists) classified a multicenter image collection from children with a clinical diagnosis of either papilledema or pseudopapilledema, which was determined based on the results of history, examination, ancillary ophthalmic imaging, neuroimaging, and/or lumbar puncture. Fleiss kappa (κ) was calculated to assess interrater agreement; accuracy, sensitivity, and specificity were calculated to determine expert performance. Subgroup analyses according to papilledema grade and expert certainty were performed.Six hundred fifty-nine photographs from 171 children were included. The full data set, papilledema, and pseudopapilledema κ values were 0.36 (0.32-0.42), 0.40 (0.32-0.49), and 0.28 (0.22-0.34), respectively. Accuracy, sensitivity, and specificity ranged from 58.9% to 63.9%, 54.3% to 76.0%, and 56.1% to 62.6%, respectively, among the 3 experts. Grade 1 papilledema was associated with inaccurate agreement (misinterpretation as pseudopapilledema by all 3 experts) in 31.8% and disagreement in 59.0% of cases. Higher grades of papilledema were associated with higher rates of accurate agreement. All experts achieved high sensitivity in classifying photographs of moderate-to-high-grade papilledema (85%-94%).Overall agreement was low among pediatric neuro-ophthalmologists when classifying fundus photographs of children with papilledema and pseudopapilledema. When interpreting low-grade papilledema images, inaccurate agreement and disagreement were more likely than accurate agreement among experts. Our study highlights the limitations of interpreting fundus photographs of children with papilledema and pseudopapilledema in isolation, stressing the importance of obtaining a complete neuro-ophthalmologic history and examination, as well as other ancillary ophthalmic imaging, to guide decision making regarding systemic workup.

View details for DOI 10.1097/WNO.0000000000002316

View details for PubMedID 40378038

Abstract

Heterozygous deletions predicting haploinsufficiency for the Cysteine Rich Motor Neuron 1 (CRIM1) gene have been identified in two families with macrophthalmia, colobomatous, with microcornea (MACOM), an autosomal dominant trait. Crim1 encodes a type I transmembrane protein that is expressed at the cell membrane of lens epithelial and fiber cells at the stage of lens pit formation. Decreased Crim1 expression in the mouse reduced the number of lens epithelial cells and caused defective adhesion between lens epithelial cells and between the epithelial and fiber cells.We present three patients with heterozygous deletions and truncating variants predicted to result in haploinsufficiency for CRIM1 as further evidence for the role of this gene in eye defects, including retinal coloboma, optic pallor, and glaucoma. We used Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas9 to make a stable Danio rerio model of crim1 deficiency, generating zebrafish that were homozygous for a 2 basepair deletion, c.339_340delCT p.Leu112Leufs*, in crim1.Homozygous, crim1 -/- larvae demonstrated smaller eyes and small and misshapen lenses compared to controls, but we did not observe colobomas. Bulk RNA-Seq using dissected eyes from crim1 -/- larvae and controls at 72 h post fertilization showed significant downregulation of crim1 and chloride intracellular channel 4 (clic4) and upregulation of fibroblast growth factor 1b (fgf1b) and complement component 1, q subcomponent (c1q), amongst other dysregulated genes.Our work strengthens the association between haploinsufficiency for CRIM1 and eye defects and characterizes a stable model of crim1 loss of function for future research.

View details for DOI 10.3389/fcell.2025.1522094

View details for PubMedID 40114969

View details for PubMedCentralID PMC11922885

Abstract

Purpose: To evaluate risk factors associated with development of anti-adalimumab antibodies (AAA) in patients with non-infectious uveitis treated with adalimumab.Methods: A retrospective, cross-sectional, case-control study was done evaluating patients with non-infectious uveitis treated with adalimumab for at least 12 months and have undergone testing for AAA levels. Demographics, clinical characteristics, grading of ocular inflammation, and previous and concomitant immunomodulatory therapy were assessed. Univariate and multivariate analysis were done to estimate odds ratio (OR) with 95% confidence intervals for the various risk factors.Results: A total of 31 patients were included in the analysis, in which 12 patients who tested positive (Group 1) were matched with 19 patients who tested negative for AAA (Group 2). The groups differed significantly in terms of sex (female) (91.7% vs 52.6%, p=0.046), presence of systemic disease (91.7% vs 42.1%, p=0.008), and presence of anterior chamber inflammation at baseline (100% vs 63.2%, p=0.026). A history of interruption in anti-TNF therapy prior to starting or restarting adalimumab was found to have an increased odds for development of AAA (OR 16.89 [2.92, 107.11], p=0.008), as well as flare-ups (reactivation of disease) during adalimumab therapy (OR 6.77 [1.80, 61.80], p=0.027). Weekly dosing of adalimumab was shown to decrease odds of AAA development (OR 0.34 [0.02, 0.70], p=0.040), while concomitant anti-metabolite therapy was not shown to be a statistically significant protective factor (OR 2.22 [0.50, 9.96], p=0.148).Conclusions: History of interruption in anti-TNF therapy and flare during adalimumab were associated with development of AAA, while weekly dosing of adalimumab was protective against AAA. Identification of those with higher risk of developing AAA may guide in clinical decision making to optimize management for these patients.

View details for DOI 10.1016/j.heliyon.2024.e29313

View details for PubMedID 38694084

Abstract

To ascertain whether the use of ultra-wide-field fluorescein angiography (UWFFA) at baseline visit alters the assessment of disease activity and localization, as well as the management of patients presenting to a tertiary uveitis clinic.Retrospective comparison of diagnostic approaches.Baseline visits of 158 patients who presented to the Uveitis Clinic at the Byers Eye Institute at Stanford between 2017 and 2022 were evaluated by three uveitis-trained ophthalmologists (I.K., A.B., and H.G.). Each eye had undergone clinical examination along with ultra-wide-field fundus photography (UWFFP) (Optos Plc, Dunfermline, Scotland, UK), spectral-domain optical coherence tomography (SD-OCT, Spectralis Heidelberg, Heidelberg Engineering, Heidelberg, Germany) and UWFFA (Optos Plc, Dunfermline, Scotland, UK) at the baseline visit. Investigators were asked to successively determine disease activity, localization of disease (anterior, posterior or both), and management decisions based on clinical examination and UWFFP and SD-OCT (Set 1) and Set 1 plus UWFFA (Set 2). The primary outcome was the percentage of eyes whose management changed based on the availability of UWFFA, compared with Set 1.The mean age of the patients was 46.9±22.4 (range, 7-96) and 91 (57.6%) were female. With Set 1 alone, 138 (55.2%) eyes were found to have active disease; localization was anterior in 58 (42.0%) eyes, posterior in 53 (38.4%) eyes and anterior + posterior in 27 (19.6%) eyes. With Set 2, 169 eyes of 107 patients had active anterior, posterior or pan-uveitis. In comparison with Set 1, assessment with Set 2 identified additional 31 (18.3%) eyes with active disease (p=0.006), and additional 31 (18.3%) eyes having disease in both anterior + posterior segments (p<0.001). Regarding the primary outcome, management was changed in 68 (27.4%) eyes in Set 2, compared to Set 1.Baseline UWFFA may alter assessment of disease activity, localization, and management decisions compared to clinical examination with only UWFFP and SD-OCT for eyes with uveitis. Thus, UWFFA may be considered as an essential tool in the evaluation of uveitis patients at the baseline visit.

View details for DOI 10.1016/j.ajo.2024.04.016

View details for PubMedID 38701875

Abstract

This analysis evaluated aqueous humour (AH) interleukin (IL)-6 concentrations and the association between AH IL-6 and visual outcomes in patients with neovascular age-related macular degeneration (nAMD) or diabetic macular oedema (DMO) receiving anti-vascular endothelial growth factor (VEGF) monotherapy.Post hoc analysis of the multicentre, double-masked, randomised HARBOR (NCT00891735) and READ-3 (NCT01077401) trials. HARBOR enrolled treatment-naïve nAMD patients. READ-3 enrolled treatment-naïve/previously treated DMO patients. HARBOR patients received ranibizumab 0.5 or 2.0 mg monthly or as needed; AH samples were collected at month 2, after two previous intravitreal injections. READ-3 patients received ranibizumab 0.5 or 2.0 mg as needed; AH samples were collected at baseline and months 3, 6, 9, and 12.association between AH IL-6 concentrations and month 24 best-corrected visual acuity (BCVA).In both trials (HARBOR, N = 36; READ-3, N = 137), patients with higher AH IL-6 concentrations had worse visual outcomes. HARBOR patients with low AH IL-6 concentrations at month 2 had a mean (95% CI) BCVA change at month 24 of +2.9 (-2.6, 8.3) letters, whereas patients with high AH concentrations had a mean (95% CI) BCVA change of -9.0 (-22.7, 4.7) letters. READ-3 patients with low AH concentrations at baseline had a mean (95% CI) BCVA change at month 12 of +9.3 (7.4, 11.3) letters, whereas patients with high AH concentrations had a mean (95% CI) BCVA change of +5.6 (2.2, 9.1) letters.Higher IL-6 AH concentrations may predict suboptimal visual responses to anti-VEGF monotherapy in patients with nAMD/DMO.

View details for DOI 10.1038/s41433-024-03015-2

View details for PubMedID 38622330

View details for PubMedCentralID 4176007

Abstract

Deep phenotyping of genetic retinal disease using multimodal adaptive optics ophthalmoscopy and protein structure variant analysis.In a patient with extensive atrophy of the retinal pigment epithelium and yellow deposits in the retina, genetic testing identified two CYP4V2 variants: c.802-8_810delinsGC and c.1169G > A, p.Arg390His. AI-generated protein structures indicated loss of CYP4V2 function. Reflectance confocal and multiple-scattering Adaptive Optics Scanning Light Ophthalmoscopy (AOSLO) captured crystalline deposits throughout the retina as well as previously unreported cyst-like structures that were mainly independent from the crystalline deposits. Sequential AOSLO imaging was conducted and revealed anatomical and morphological changes in the cysts and surrounding cellular structures.Cyst-like changes may represent a new BCD degenerative feature. Characterizing retinal genetic disease variants with protein structural modeling and phenotyping with AOSLO represents an advanced approach for clinical diagnosis and may serve as a biomarker of disease progression.

View details for DOI 10.1016/j.ajoc.2025.102312

View details for PubMedID 40236510

View details for PubMedCentralID PMC11997262

Abstract

Cells and other microscopic phase objects can be visualized in the living retina, non-invasively, using non-confocal light detection schemes in adaptive optics scanning light ophthalmoscopes (AOSLOs). There is not yet widespread agreement regarding the origin of image contrast, nor the best way to render multichannel images. Here, we present data to support the interpretation that variations in the intensity of non-confocal images approximate a direct linear mapping of the prismatic deflection of the scanned beam. We advance a simple geometric framework in which local 2D image gradients are used to estimate the spherocylindrical refractive power for each element of the tissue. This framework combines all available information from the non-confocal image channels simultaneously, reducing noise and directional bias. We show that image derivatives can be computed with a scalable, separable gradient operator that minimizes directional errors; this further mitigates noise and directional bias as compared with previous filtering approaches. Strategies to render the output of split-detector gradient operations have been recently described for the visualization of immune cells, blood flow, and photoreceptors; our framework encompasses these methods as rendering astigmatic refractive power. In addition to astigmatic power, we advocate the use of the mean spherical equivalent power, which appears to minimize artifacts even for highly directional micro-structures such as immune cell processes. We highlight examples of positive, negative, and astigmatic power that match expectations according to the known refractive indices and geometries of the relevant structures (for example, a blood vessel filled with plasma acts as a negatively powered cylindrical lens). The examples highlight the benefits of the proposed scheme for the visualization of diverse phase objects including rod and cone inner segments, immune cells near the inner limiting membrane, flowing blood cells, the intravascular cell-free layer, and anatomical details of the vessel wall.

View details for DOI 10.1364/BOE.547734

View details for PubMedID 39958845

View details for PubMedCentralID PMC11828430

View details for DOI 10.1364/BOE.547734

View details for Web of Science ID 001406239600005

Abstract

Loss of retinal ganglion cells (RGCs) is central to the pathogenesis of optic neuropathies such as glaucoma. Increased RGC cAMP signaling is neuroprotective. We have shown that displacement of the cAMP-specific phosphodiesterase PDE4D3 from an RGC perinuclear compartment by expression of the modified PDE4D3 N-terminal peptide 4D3(E) increases perinuclear cAMP and protein kinase A activity in cultured neurons and in vivo RGC survival after optic nerve crush (ONC) injury. To explore mechanisms by which PDE4D3 displacement promotes neuroprotection, in this study mice intravitreally injected with an adeno-associated virus to express an mCherry-tagged 4D3(E) peptide were subjected to ONC injury and analyzed by single cell RNA-sequencing (scRNA-seq). 4D3(E)-mCherry expression was associated with an attenuation of injury-induced changes in gene expression, thereby supporting the hypothesis that enhanced perinuclear PKA signaling promotes neuroprotective RGC gene expression.

View details for DOI 10.1016/j.exer.2024.110017

View details for PubMedID 39097072

Abstract

Familial dilated cardiomyopathy is a prevalent cause of heart failure that results from the mutation of genes encoding proteins of diverse function. Despite modern therapy, dilated cardiomyopathy typically has a poor outcome and is the leading cause of cardiac transplantation. The phosphatase PP2A at cardiomyocyte perinuclear mAKAPβ signalosomes promotes pathological eccentric cardiac remodeling, as is characteristic of dilated cardiomyopathy. Displacement of PP2A from mAKAPβ, inhibiting PP2A function in that intracellular compartment, can be achieved by expression of a mAKAPβ-derived PP2A binding domain-derived peptide. To test whether PP2A anchoring disruption would be effective at preventing dilated cardiomyopathy-associated cardiac dysfunction, the adeno-associated virus gene therapy vector AAV9sc.PBD was devised to express the disrupting peptide in cardiomyocytes in vivo. Proof-of-concept is now provided that AAV9sc.PBD improves the cardiac structure and function of a cardiomyopathy mouse model involving transgenic expression of a mutant α-tropomyosin E54K Tpm1 allele, while AAV9sc.PBD has no effect on normal non-transgenic mice. At the cellular level, AAV9sc.PBD restores cardiomyocyte morphology and gene expression in the mutant Tpm1 mouse. As the mechanism of AAV9sc.PBD action suggests potential efficacy in dilated cardiomyopathy regardless of the underlying etiology, these data support the further testing of AAV9sc.PBD as a broad-based treatment for dilated cardiomyopathy.

View details for DOI 10.1016/j.omtm.2024.101233

View details for PubMedID 38572067

View details for PubMedCentralID PMC10988123

View details for Web of Science ID 001313316200208

Abstract

Deep phenotyping of genetic retinal disease using multimodal adaptive optics ophthalmoscopy and protein structure variant analysis.In a patient with extensive atrophy of the retinal pigment epithelium and yellow deposits in the retina, genetic testing identified two CYP4V2 variants: c.802-8_810delinsGC and c.1169G > A, p.Arg390His. AI-generated protein structures indicated loss of CYP4V2 function. Reflectance confocal and multiple-scattering Adaptive Optics Scanning Light Ophthalmoscopy (AOSLO) captured crystalline deposits throughout the retina as well as previously unreported cyst-like structures that were mainly independent from the crystalline deposits. Sequential AOSLO imaging was conducted and revealed anatomical and morphological changes in the cysts and surrounding cellular structures.Cyst-like changes may represent a new BCD degenerative feature. Characterizing retinal genetic disease variants with protein structural modeling and phenotyping with AOSLO represents an advanced approach for clinical diagnosis and may serve as a biomarker of disease progression.

View details for DOI 10.1016/j.ajoc.2025.102312

View details for PubMedID 40236510

View details for PubMedCentralID PMC11997262

Abstract

Aberrant levels of the cysteine protease Calpain-2 have been linked to neurodegeneration, inflammation, and cancer, yet our understanding of this protease and its substrates remains limited. Systematic studies to identify Calpain-2 substrates have been largely confined to peptide libraries or in vitro studies, which fail to represent physiological cellular conditions and physiologically relevant substrates. To identify existing and novel Calpain-2 substrates, we used a genetic approach to knockout Calpain-2 in the THP-1 human monocyte-like cells, followed by proteomic and N-terminomic/TAILS mass spectrometry approaches to identify Calpain-2 substrates. We identified 51 substrates that may be cleaved directly by Calpain-2 or indirectly by downstream proteases. The direct cleavage of selected substrates by Calpain-2 was confirmed using in vitro assays. Finally, metabolomics analysis identified a role for Calpain-2 in the regulation of pyrimidine and glutathione metabolism. Our unbiased and quantitative mass spectrometry analytical pipeline provides new evidence on the physiological functions of Calpain-2 and its newly identified substrates in THP-1 cells.

View details for DOI 10.1002/pro.70144

View details for PubMedID 40277457

Abstract

There is a growing number of articles about conversational AI (i.e., ChatGPT) for generating scientific literature reviews and summaries. Yet, comparative evidence lags its wide adoption by many clinicians and researchers. We explored ChatGPT's utility for literature search from an end-user perspective through the lens of clinicians and biomedical researchers. We quantitatively compared basic versions of ChatGPT's utility against conventional search methods such as Google and PubMed. We further tested whether ChatGPT user-support tools (i.e., plugins, web-browsing function, prompt-engineering, and custom-GPTs) could improve its response across four common and practical literature search scenarios: (1) high-interest topics with an abundance of information, (2) niche topics with limited information, (3) scientific hypothesis generation, and (4) for newly emerging clinical practices questions. Our results demonstrated that basic ChatGPT functions had limitations in consistency, accuracy, and relevancy. User-support tools showed improvements, but the limitations persisted. Interestingly, each literature search scenario posed different challenges: an abundance of secondary information sources in high interest topics, and uncompelling literatures for new/niche topics. This study tested practical examples highlighting both the potential and the pitfalls of integrating conversational AI into literature search processes, and underscores the necessity for rigorous comparative assessments of AI tools in scientific research.

View details for DOI 10.1371/journal.pdig.0000849

View details for PubMedID 40354425

View details for Web of Science ID 001488156300090

View details for DOI 10.1080/01658107.2025.2495303

View details for Web of Science ID 001477892800001

Abstract

Background: Nonmydriatic ocular fundus photography has been studied with demonstrated benefit in the evaluation of emergency department neurological complaints, particularly in triaging headache and focal neurological deficits. Likewise, portable fundus camera usage may be practical for inpatients with neurological complaints, although feasibility has not been studied in a neurology teaching service. Purpose: The objective of this study is to determine if a portable, nonmydriatic fundus camera could be integrated into routine clinical care by neurology inpatient housestaff at a tertiary medical center. Research Design: Housestaff were asked to obtain fundus photographs for patients with specific indications for fundoscopy. Study Sample: During a 1-month pilot period, housestaff were successfully able to upload images from 21 patients, which were reviewed by a neuro-ophthalmology attending, with input from on-call ophthalmology if desired. Results: Surveys of housestaff before (n = 13) and after (n = 12) implementation demonstrated increased confidence in camera operation and in ocular structure identification, description, and interpretation. Thematic analysis on qualitative feedback suggested benefits in clinical (improving fundus visualization, aiding in triage, sharing images with offsite staff), health systems (reducing length of stay, reducing ophthalmology consultations, reduced unnecessary testing), and educational domains (facilitating group discussions of images, sharing photographs with patients). Conclusions: Overall, inpatient portable fundus photography was shown to be feasible and effective for rapid fundus visualization for neurological inpatients, enhancing the ability to share, document, and compare examinations among neurology housestaff. Further work is needed to confirm clinical and educational benefits of portable fundus photography usage by neurology residents, as suggested by this healthcare quality improvement pilot study.

View details for DOI 10.1177/19418744251317260

View details for PubMedID 39895825

View details for PubMedCentralID PMC11780609

Abstract

The increasing incidence of ophthalmic diseases has led the need for multiple dosage regimens, which can cause patient discomfort and noncompliance due to the frequency of medication administration. Still, ophthalmic drug delivery methods, such as eye drops and intravitreal injection, pose challenges, such as poor bioavailability, short half-life, and patient compliance. In this study, we introduce a novel refillable intracapsular drug-eluting reservoir for the long-term management of ocular diseases. This device, made of medical-grade silicone and stainless steel, has features to contour the lens capsule to facilitate microincisional implantation. Rheological and mechanical analyses of the silicone revealed the optimized conditions for the device construction and its application compliance for ocular intracapsular implantation. Furthermore, in vitro release studies exhibit controlled drug release, the kinetics of which were along with Fickian diffusion, while ex vivo implantation testing shows that the device can be easily delivered and placed at the time of cataract surgery. Taken altogether, the developed implant holds significant potential for improving therapeutic outcomes while offering a practical surgical application and compliance of patients.

View details for DOI 10.1021/acsami.5c03985

View details for PubMedID 40331902

Abstract

This study evaluates the second-year outcomes of an AI-based diabetic retinopathy (DR) detection program (Stanford Teleophthalmology Autonomous Testing and Universal Screening (STATUS)) implemented in primary care and endocrinology clinics in Northern California. We focused on assessing improvements following implementation of an intervention-based framework to increase AI system gradability and patient encounters.A retrospective analysis was conducted involving diabetic patients aged 18 years and older with no prior DR diagnosis or examination in the past year. These patients presented for routine DR screening in primary care or endocrinology clinics. In its second year, the STATUS program expanded to additional sites and introduced an intervention-based framework, including targeted training protocols, to enhance screening accuracy and efficiency. Our study measured AI system gradability and tracked patient encounters over Year 2.The AI system's gradability increased from 62.3% in Year 1 to 71.2% in Year 2, comparable to non-mydriatic gradability rates observed in clinical trials. Patient encounters increased by 21.9%, indicating expanded reach and improved accessibility. Interventions, including enhanced training protocols and camera utilization reports, effectively improved screening efficiency.The second-year outcomes of the STATUS AI-based DR screening program demonstrate significant improvements in image gradability by the AI system as well as in patient encounter numbers. These findings highlight the potential of interventional methods to continually improve the outcomes of AI-based screening programs and offer a scalable solution to the growing burden of diabetic retinopathy. The success of STATUS supports further integration and expansion of AI-based screening in clinical practice for early detection and management of DR, improving patient outcomes.

View details for DOI 10.1097/IAE.0000000000004499

View details for PubMedID 40334205

View details for DOI 10.1016/j.oret.2017.03.002

Abstract

Brain response to repetitive stimuli generates steady-state evoked potentials (ssEP) that vary depending on the experimental conditions. To analyze these responses, Fourier measurements extracted from ssEP data require statistical techniques to differentiate neural responses across various experimental conditions within the same participant(s). In this study, we introduce new statistical methods to compare multiple dependent clusters of discrete Fourier measurements corresponding to multiple experimental conditions.We present two statistics: 1) The first statistic is derived from repeated measures analysis of variance (ANOVA) for complex numbers, used to compare multiple dependent circular clusters of Fourier estimates under the assumption of equal variance across the clusters. 2) The second statistic is employed when either the assumption of circularity within the clusters or the assumption of equal variance across the clusters is violated. In this case, we derive the statistic from the rank-sum Friedman test to compare multiple related clusters of complex numbers.We demonstrated the validity of the statistics using simulated and empirical ssEP data. Our methods offer robust statistical tools that maintain a constant Type-I error of 0.05 in all conditions, including equal or unequal variance-covariance matrix of the real and imaginary components of Fourier estimates across the circular and elliptical clusters, even in the presence of outliers in the dataset. Furthermore, our statistics demonstrate a lower Type-II error compared to repeated measures multivariate analysis of variance (rmMANOVA).The statistical methods enable us to compare multiple dependent clusters of Fourier estimates corresponding to multiple experimental conditions within the same participant(s), whether or not the variance is equal across the circular or elliptical clusters, even with outliers in the dataset.

View details for DOI 10.1016/j.compbiomed.2025.110117

View details for PubMedID 40198991

Abstract

Intervention strategies for post-mild traumatic brain injury (mTBI) ocular motor disorders vary across disciplines and include watchful waiting, vestibular rehabilitation, vision rehabilitation/vision therapy, and optical intervention. However, evidence supporting their effectiveness is limited, highlighting the need for high-quality randomized controlled trials with standardized testing, diagnostic criteria, and reassessment of ocular motor function after intervention.Ocular motor disorders occur frequently after mTBI.This study aimed to conduct a scoping review of interventions for mTBI-related ocular motor disorders in children and adults.The following electronic bibliographic databases were searched: PubMed, Embase, PEDro, OVID, Clinical Key, Google Scholar, and REHABDATA.Intervention studies published in English between 2003 and 2024 involving mTBI participants who had an ocular motor assessment prior to intervention were included in this study.Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews guidelines were followed for reporting. Study population, intervention, and outcomes were extracted and synthesized in tabular and graphical formats.Sixty-seven eligible studies were included, with only three (4%) judged as low risk of bias. Intervention strategies included watchful waiting (n = 31, 46%), vestibular rehabilitation (n = 13, 19%), vision rehabilitation/vision therapy (n = 10, 15%), optical intervention (n = 4, 6%), and alternative interventions or multifaceted interventions (n = 9, 14%). Among the studies providing statistically supported results, improvements in one or more ocular motor outcome domains were reported in nearly 80% of the studies on watchful waiting (19/24) and 100% of the studies on vestibular rehabilitation (4/4), vision rehabilitation/vision therapy (7/7), or optical intervention (1/1).Although post-mTBI ocular motor deficits improved with watchful waiting strategy, vestibular rehabilitation, vision rehabilitation/vision therapy, and optical interventions, most studies had significant risk of bias. This review emphasizes the necessity for high-quality randomized controlled trials with standardized testing protocols and diagnostic criteria and reassessment of ocular motor functions after intervention to evaluate the effectiveness of these interventions in different age groups and recovery stages.

View details for DOI 10.1097/OPX.0000000000002237

View details for PubMedID 39951336

Abstract

Concussed adolescents often report visual symptoms, especially for moving targets, but the mechanisms resulting in oculomotor deficits remain unclear. We objectively measured accommodative and vergence responses to a moving target in concussed adolescents and controls.Thirty-two symptomatic concussed participants (mean age, 14.4 ± 2.6 years; mean days since concussion, 107 days; range, 36-273 days) and 32 healthy controls (mean age, 12.7 ± 2.1 years) viewed a movie binocularly (closed-loop) and monocularly (vergence open-loop), as well as a Difference of Gaussians (DoG) target binocularly (accommodation open-loop). The movie or DoG target sinusoidally moved toward and away from participants at a 0.1-hertz (Hz) frequency at four separate stimulus amplitudes (1.50 diopters [D], 1.00 D, 0.50 D, 0.25 D) around a 2.50-D midpoint. Accommodation and vergence were continuously measured at 50 Hz using the PowerRef 3. Fourier analysis was used to assess the response amplitudes at the 0.1-Hz frequency. A 2 × 3 analysis of variance with the factors group (concussed, control) and viewing condition (binocular, monocular, DoG) was conducted on response amplitudes.Across groups, accommodative and vergence responses were significantly higher in binocular than monocular conditions (P < 0.001), but not DoG conditions. Compared to controls, concussed participants had significantly reduced monocular accommodative responses (P < 0.012; e.g., at 1.50 D, controls = 1.09 ± 0.47 D and concussed = 0.80 ± 0.36 D, P = 0.011). No group differences were observed for vergence responses in any viewing condition.Accommodative and vergence responses to the moving target were largely driven by disparity cues for both groups, with only minimal improvements in the presence of additional blur cues. Concussed participants showed reduced accommodative responses to a 0.1-Hz stimulus in monocular conditions, indicating mild accommodative deficits in the absence of disparity cues.

View details for DOI 10.1167/iovs.65.12.45

View details for PubMedID 39475939

Abstract

Brimonidine has shown neuroprotective effects in animal studies, but clinical trials failed to demonstrate effective endpoints. Here, we used a newly developed in vivo calcium imaging method to measure RGC function of brimonidine in mice optic nerve crush (ONC) models. To transduce RGCs in vivo, wild-type C57Bl/6j mice were treated with intravitreal AAV2-mSncg-jGCaMP7s, a live-cell Ca2+ tracer. RGCs are defined as 10 subtypes according to different responses to UV light. Mice were treated with topical brimonidine or placebo three times daily for two weeks after ONC. The calcium signals of live-cell RGCs were measured with the Heidelberg cSLO system. Ganglion cell complex (GCC) thickness and IOP were examined at different timepoints after treatment. RGCs were counted after RBPMS immunostaining. Live calcium imaging showed ONC significantly decreased RGC number at 14 days post-ONC compared to controls. The topical brimonidine administration changed calcium signal responses of RGC to UV light in ONC mice. It showed brimonidine partly prevented the decrease of survival ON-RGCs percent after ONC. Single RGC analysis showed a lower conversion percent of ON-RGCs to OFF-RGCs with brimonidine administration after ONC. However, no significant differences in RGC survival, IOP or GCC thickness were noted between eyes treated with brimonidine or placebo. In the acute ONC mice model, in vivo calcium imaging revealed that brimonidine maintained the Ca2+ activation of ON-RGCs to UV stimulation, inhibiting the conversion of survival ON-RGCs to OFF-RGCs. This indicates that ON-RGCs may be more resilient to acute optic nerve injury based on the calcium imaging method.

View details for DOI 10.1016/j.exer.2025.110355

View details for PubMedID 40127747

Abstract

Elevated intraocular pressure (IOP) is the primary risk factor for glaucoma, a leading cause of irreversible blindness worldwide. IOP homeostasis is maintained through a balance between aqueous humor production and its drainage through the trabecular meshwork (TM)/Schlemm's Canal (SC) outflow pathway. Prior studies by our laboratory reported a key role of mechanical forces and primary cilia (PC)-dependent stretch-induced autophagy in IOP homeostasis. However, the precise mechanism regulating this process remains elusive. In this study, we investigated the upstream signaling pathway orchestrating autophagy activation during cyclic mechanical stretch (CMS) in primary cultured human TM cells, using biochemical and cell biological analyses. Our results indicate that TM cells express catalytic subunits of class IA PI3Ks (PIK3CA, B, and D), and that inhibition of class IA isoforms, but not class II and III, significantly prevent CMS-induced autophagy. Importantly, PIK3CA was found to localize in the PC. Furthermore, we identified a coordinated action of Class IA PI3Ks along INPP4A/B, a 4' inositol phosphatase, responsible for the formation of PI(3,4)P2 and PI(3)P and stretch-induced autophagy in TM cells. These findings contribute to a deeper understanding of the molecular mechanisms underlying IOP homeostasis.

View details for DOI 10.1007/s00018-025-05615-x

View details for PubMedID 39985671

View details for PubMedCentralID PMC11846827

Abstract

The cornea serves to protect the eye from external insults and refracts light to the retina. Maintaining ocular homeostasis requires constant epithelial renewal and an efficient healing process following injury. Corneal wound healing is a dynamic process involving several key cell populations and molecular pathways. Immediately after a large corneal epithelial injury involving limbal stem cells, conjunctival epithelial cells migrate toward the center of the wound guided by the newly formed electrical field (EF). Proliferation and transdifferentiation play a critical role in corneal epithelial regeneration. Corneal nerve endings migrate through the EF, connect with the migrating epithelial cells, and provide them with multiple growth factors. Finally, the migrated epithelial cells undergo differentiation, which is also regulated by corneal nerve endings. All these processes require energy and effective cellular cross-talk between different cell lines and extracellular matrix molecules. We provide an overview of the roles and interactions between corneal wound regeneration components that may help develop fascinating new targeted therapeutic strategies to enhance corneal wound healing with less injury-related corneal opacity and neovascularization.

View details for DOI 10.1038/s41433-025-03619-2

View details for PubMedID 39939391

View details for PubMedCentralID 7697722

Abstract

Approved by the FDA in 2021, varenicline solution is the first nasal spray specifically designed to enhance basal tear film production for treating dry eye disease (DED). However, there is a lack of data comprehensively comparing its safety profile to conventional DED therapies. Herein, we assess whether ocular adverse events (AEs) are disproportionately reported with the real-world use of varenicline solution.This observational, population-based pharmacovigilance study analyzed the Food and Drug Administration Adverse Event Reporting System (FAERS) data (inception-April 2024) using reporting odds ratio (ROR), with significance defined as a 95% CI lower bound > 1.0. Nasal saline and systane were the controls.A total of 1,125 AE reports were associated with varenicline solution. No disproportionate reporting of specific ocular AEs was observed when comparing varenicline solution with nasal saline. However, when compared with systane, varenicline solution showed higher odds of lacrimation (ROR = 2.18, 95%CI = 1.46-3.26, p < 0.0001), visual impairment (ROR = 2.27, 95%CI = 1.24-4.16, p = 0.0085), and photophobia (ROR = 7.50, 95%CI = 3.68-15.27, p < 0.0001).Although a direct causal relationship for higher RORs cannot be established for varenicline solution compared to systane, our findings provide evidence for potential risk signals and highlight the crucial role of post-marketing pharmacovigilance in monitoring long-term safety.

View details for DOI 10.1080/14740338.2025.2460454

View details for PubMedID 39921610

Abstract

There remain limited therapies to treat thyroid eye disease (TED) orbital fibrosis, highlighting the urgency to develop novel targets. Transforming growth factor-β1 (TGF-β1)-induced myofibroblast transdifferentiation from orbital fibroblasts are important pathogenetic factor of TED. Endoplasmic reticulum (ER) stress may play a role in TED pathogenesis since it has been linked to liver, kidney, heart and lung fibrotic remodelling. We would evaluate the role of thioredoxin domain containing 5 (TXNDC5), a fibroblast-enriched ER protein, in TGF-β1-induced myofibroblast transdifferentiation from TED orbital fibroblasts.Orbital fibroblasts from patients with TED were treated with TGF-β1 to investigate ER stress-relative gene expression especially for TXNDC5. To determine if TXNDC5 is involved in TGF-β1-induced fibrosis, we transfected TED orbital fibroblasts by lentivirus with a small hairpin RNA of pLKO-TXNDC5 gene (shTXNDC5) to knockdown TXNDC5 protein expression levels. After transfection of shTXNDC5 in TED orbital fibroblast followed by TGF-β1 treatment, we analysed TGF-β1-induced fibrosis protein expression.We measured increased TXNDC5 gene and protein expression in primary TED orbital fibroblasts. TXNDC5 protein levels were increased in TED orbital fibroblasts under TGF-β1 stimulation (2.5, 5, 10 and 20 ng/mL). Moreover, TXNDC5 knockdown of attenuated TGFβ1 (5 ng/mL)-induced myofibroblast transdifferentiation and extracellular matrix protein upregulation whereas increasing TXNDC5 expression by a recombinant protein of TXNDC5 (rhTXNDC5) addition increased alpha smooth muscle actin, fibronectin and connective tissue growth factor protein expression.In conclusion, targeting TXNDC5 may be a novel therapeutic approach against TGF-β1-induced myofibroblast transdifferentiation in TED orbital fibroblasts.

View details for DOI 10.1136/bmjophth-2024-001693

View details for PubMedID 39721966

Abstract

Visual impairment caused by retinal ganglion cell (RGC) axon damage or degeneration affects millions of individuals throughout the world. While some progress has been made in promoting long-distance RGC axon regrowth following injury, it remains unclear whether RGC axons can properly reconnect with their central targets to restore visual function. Additionally, the regenerative capacity of many RGC subtypes remains unknown in part due to a lack of available genetic tools. Here, we use a new mouse line that labels On direction-selective RGCs (oDSGCs) and characterize the survival and regenerative potential of these cells following optic nerve crush (ONC). In parallel, we use a previously characterized mouse line to answer these same questions for M1 intrinsically photosensitive RGCs (ipRGCs). We find that both M1 ipRGCs and oDSGCs are resilient to injury but do not display long-distance axon regrowth following Lin28a overexpression. Unexpectedly, we found that M1 ipRGC, but not oDSGC, intraretinal axons exhibit ectopic branching and are misaligned near the optic disc between one- and three-weeks following injury. Additionally, we observe that numerous ectopic presynaptic specializations associate with misguided ipRGC intraretinal axons. Taken together, these results reveal insights into the injury response of M1 ipRGCs and oDSGCs, providing a foundation for future efforts seeking to restore visual system function following injury.

View details for DOI 10.1016/j.expneurol.2022.114176

View details for PubMedID 35870522

Abstract

To determine if visuocortical development in premature infants with high bilirubin levels is more adversely affected than that in full-term infants.57 preterm infants were managed using institutional guidelines for hyperbilirubinemia. At 12-months corrected age, Vernier acuity, contrast sensitivity, and grating acuity measured using the sweep visual evoked potential (sVEP) were correlated to total serum/plasma bilirubin (TSB) levels in the first week of life.As TSB levels increased, Vernier acuity worsened in infants <34 weeks' gestation compared with those >34 to <37 weeks' gestation (p < 0.001). Contrast sensitivity varied as a function of TSB levels (Spearman correlation 0.63, p < 0.001). Grating acuity was unaffected.Vernier acuity in preterm infants <34 weeks' gestation is more vulnerable to the effects of bilirubin, suggesting that the extrastriate visual cortex is primarily affected by bilirubin. Therefore, guidelines for management of hyperbilirubinemia in preterm infants (<34 weeks' gestation) should be revised.

View details for DOI 10.1038/s41372-025-02213-4

View details for PubMedID 39910190

View details for PubMedCentralID 4197714

Abstract

Immaturities exist at multiple levels of the developing human visual pathway, starting with immaturities in photon efficiency and spatial sampling in the retina and on through immaturities in early and later stages of cortical processing. Here we use Steady-State Visual Evoked Potentials (SSVEPs) and controlled visual stimuli to determine the degree to which sensitivity to horizontal retinal disparity is limited by the visibility of the monocular half-images, the ability to encode absolute disparity or the ability to encode relative disparity. Responses were recorded from male and female human participants at average ages of 5.3 +/- 1.6 months, 4.7 +/- 1.3 years, and 25.3 +/ -6 years. Horizontal disparity sensitivity was measured using planar stereograms that modulated absolute disparity and in stereograms portraying disparity gratings that additionally contained relative disparity. Disparity thresholds for absolute disparity changed little over development, but those for relative disparity changed by a factor of ∼10. SSVEPs were also recorded in response to contrast and blur modulation of dynamic random dot patterns to measure sensitivity to the spatio-temporal content of the monocular half-images. Equating subjective contrast and blur levels between infants, children and adults based on these measurements did not equate disparity sensitivity. The protracted developmental sequence for horizontal relative disparity coding shown in our measurements is not simply inherited from immaturities in encoding absolute disparity or retinal image contrast, but rather reflects immaturities in the computations needed to represent relative disparity that likely involve extra-striate cortical areas where relative disparity is first extracted.Significance Statement The lateral separation of the eyes creates horizontal image disparities that provide the primary cue for depth. These disparities reflect the distance of a point from the plane of fixation (absolute disparities) or depth relationships between two or more points in the image (relative disparity). By recording SSVEPs driven by disparity modulation and stimuli that contain only absolute disparity versus those that also contain relative disparity, we find that sensitivity to absolute disparity develops to near adult levels within the first 6 months of life, but that relative disparity develops beyond 5 years of age. These developmental changes are dissociable from changes in the visibility of the half-images and reflect specific immaturities in disparity processing.

View details for DOI 10.1523/JNEUROSCI.0216-24.2024

View details for PubMedID 39794129

Abstract

Organizing the continuous stream of visual input into categories like places or faces is important for everyday function and social interactions. However, it is unknown when neural representations of these and other visual categories emerge. Here, we used steady-state evoked potential electroencephalography to measure cortical responses in infants at 3-4 months, 4-6 months, 6-8 months, and 12-15 months, when they viewed controlled, gray-level images of faces, limbs, corridors, characters, and cars. We found that distinct responses to these categories emerge at different ages. Reliable brain responses to faces emerge first, at 4-6 months, followed by limbs and places around 6-8 months. Between 6 and 15 months response patterns become more distinct, such that a classifier can decode what an infant is looking at from their brain responses. These findings have important implications for assessing typical and atypical cortical development as they not only suggest that category representations are learned, but also that representations of categories that may have innate substrates emerge at different times during infancy.

View details for DOI 10.7554/eLife.100260

View details for PubMedID 39714017

View details for PubMedCentralID PMC11666245