Translational Vision Science & Technology最新文献

Purpose: The corneal nerves within the sub-basal nerve plexus (SBNP) display a distinctive whorl-like pattern, a highly dynamic structure that could be a marker of diseases. Previous studies have reported a decrease in whorl nerve density in patients with diabetes, indicating an avenue for noninvasive monitoring of diabetic neuropathy. However, conflicting results have since been reported, highlighting the need for improved quantitative analysis of the corneal whorl. We present an automated algorithm to characterize the whorl shape and test the hypothesis that the whorl organization is affected by diabetic neuropathy.

Methods: The SBNP whorl was analyzed as a vector field, from which seven whorl metrics were calculated. The efficacy of these whorl metrics was demonstrated in synthetic images, ex vivo mouse corneas, and in a publicly available dataset of wide-field in vivo confocal microscopy (IVCM) images of diabetic and control subjects. Linear discriminant analysis and the Peacock test were used to test for statistical differences. Our analysis code is made freely available.

Results: Using our whorl metrics, we were able to quantify different whorl patterns in our patient population and statistically compare cohorts. We determined that whorl patterns tend to present bilaterally in patients (P < 0.001), but there were no significant differences between whorl patterns in patients with diabetes and control subjects, nor between patients with or without neuropathy symptoms.

Conclusions: We present a generalizable framework to statistically compare corneal nerve patterns in cohorts of patients.

Translational relevance: SBNP whorl patterns could serve as a noninvasive marker for ocular diseases, whereas few quantitative IVCM endpoints have been identified to date.

Purpose: Disorders of the anterior optic nerve cause quantifiable patterns, or archetypes (AT), in visual fields (VFs) obtained using standardized automated perimetry using stimulus size III (size III). VFs with stimulus size V (size V) can reduce retest variability in eyes with moderate to severe loss. We postulated that VF testing using both stimuli would show similar ATs in eyes with glaucoma and nonarteritic anterior ischemic optic neuropathy (NAION).

Methods: We used 1969 same-day pairs of 24-2 size III and size V VFs from two datasets. QRK207 is the largest NAION study to date, and the VIPII study measured same-day VFs across many stimulus sizes. We censored raw sensitivities of less than 21 dB for size III and 24 dB for size V and age-standardized to total deviations, before archetypal analysis (AA). We compared the ATs between the two stimuli and the combined data.

Results: Using 14 ATs for both glaucoma and NAION, AA captured similar patterns between the two stimuli in both diseases with 87% of AT pairings having a cosine similarity of 0.8 or greater. The combined ATs retained the patterns in the separate stimuli VFs.

Conclusions: AA shows that size V VFs provide quantifiable patterns of loss similar to size III. This aids in comparing stimulus sizes for monitoring VF patterns in disease progression.

Translational relevance: AA shows similar quantifiable patterns of VF loss with size III or size V, supporting the use of size V to monitor eyes with moderate to severe VF loss.

Purpose: To investigate the toxicity of terpinen-4-ol (T4O) on primary cultured human corneal epithelial cells (HCECs).

Methods: HCECs were exposed to various concentrations (0%-0.1%) of T4O for 15 minutes to 72 hours. Cell viability was assessed using the CCK8 kit and cell counting. Intracellular reactive oxygen species (ROS) were measured after 15 to 60 minutes of T4O exposure. Changes in cell morphology and cytoplasmic actin filaments were observed using phase contrast microscopy and immunocytochemistry. The expression levels of proteins involved in cell survival pathways (mTOR, Akt, Bcl-xL, and BAX) were evaluated by Western blot analysis.

Results: T4O induced dose-dependent toxicity in HCECs. Exposure to 0.05% T4O for 15 minutes significantly decreased cell viability. Lower concentrations (0.025% and 0.0125%) also caused significant toxicity with longer exposure times. Prolonged exposure enhanced cytotoxicity, with 0.05% T4O reducing viability by half after 24 hours and 0.1% T4O causing complete cell death. Increased intracellular ROS and decreased levels of phosphorylated mTOR, phosphorylated Akt, and Bcl-xL, along with increased BAX expression, accompanied this toxicity. F-actin staining revealed significant changes in cell adhesion.

Conclusions: Our study demonstrates that T4O exposure causes significant toxicity in HCECs, depending on concentration and incubation time. This toxic response is associated with increased ROS and decreased cell survival pathway activity.

Translational relevance: The corneal epithelial toxicity data of T4O revealed in this study may be useful in the future use of tea tree oil or the development of tee tree oil-containing eyelid scrub products for treating eyelid demodex infestation.

Purpose: For structure-function research at the transition of aging to age-related macular degeneration, we refined the current consensus optical coherence tomography (OCT) nomenclature and evaluated a novel review software for investigational high-resolution OCT imaging (HR-OCT; <3 µm axial resolution).

Method: Volume electron microscopy, immunolocalizations, histology, and investigational devices informed a refined OCT nomenclature for a custom ImageJ-based review tool to assess retinal band visibility. We examined effects on retinal band visibility of automated real-time averaging (ART) 9 and 100 (11 eyes of 10 healthy young adults), aging (10 young vs 22 healthy aged), and age-related macular degeneration (AMD; 22 healthy aged, 17 early (e)AMD, 15 intermediate (i)AMD). Intrareader reliability was assessed.

Results: Bands not included in consensus nomenclature are now visible using HR-OCT: inner plexiform layer (IPL) 1-5, outer plexiform layer (OPL) 1-2, outer segment interdigitation zone 1-2 (OSIZ, including hyporeflective outer segments), and retinal pigment epithelium (RPE) 1-5. Cohen's kappa was 0.54-0.88 for inner and 0.67-0.83 for outer retinal bands in a subset of 10 eyes. IPL-3-5 and OPL-2 visibility benefitted from increased ART. OSIZ-2 and RPE-1,2,3,5 visibility was worse in aged eyes than in young eyes. OSIZ-1-2, RPE-1, and RPE-5 visibility decreased in eAMD and iAMD compared to healthy aged eyes.

Conclusions: We reliably identified 28 retinal bands using a novel review tool for HR-OCT. Image averaging improved inner retinal band visibility. Aging and AMD development impacted outer retinal band visibility.

Translational significance: Detailed knowledge of anatomic structures visible on OCT will enhance precision in research, including AI training and structure-function analyses.

Purpose: To compare the effects of bacteriophages (phages) and vancomycin on Enterococcus faecalis-induced biofilms on the intraocular lens.

Methods: E. faecalis strains EF24, GU02, GU03, and phiEF14H1 were used. The expression of the enterococcus surface protein (esp) gene was analyzed using polymerase chain reaction. Phages or vancomycin was added to the biofilms formed on culture plates or acrylic intraocular lenses. The biofilms were quantified after staining with crystal violet. The structure of the biofilms was analyzed using scanning electron microscopy.

Results: E. faecalis strains EF24, GU02, and GU03 formed biofilms on cell culture plates; however, the esp-negative GU03 strain had a significantly lower biofilm-forming ability than the esp-positive strains EF24 and GU02. The addition of phiEF14H1 resulted in a significant reduction in biofilm mass produced by both EF24 and GU02 compared with the untreated control. However, the addition of vancomycin did not degrade the biofilms. Phages significantly degraded biofilms and reduced the viable EF24 and GU02 bacteria on the intraocular lens.

Conclusions: Phages can degrade biofilms formed on the intraocular lens and destroy the bacteria within it. Thus, phage therapy may be a new treatment option for refractory and recurrent endophthalmitis caused by biofilm-forming bacteria.

Translational relevance: Phage therapy, a novel treatment option for refractory and recurrent endophthalmitis caused by biofilm-forming bacteria, effectively lyses E. faecalis-induced biofilms.

Purpose: Optical coherence tomography (OCT)-derived measurements of the optic nerve head (ONH) from different devices are not interchangeable. This poses challenges to patient follow-up and collaborative studies. Here, we present a device-agnostic method for the extraction of OCT biomarkers using artificial intelligence.

Methods: ONH-centered OCT volumes from the Heidelberg SPECTRALIS, ZEISS CIRRUS HD-OCT 5000, and Topcon 3D OCT-1000 Mark I/II and 3D OCT-2000 devices were annotated by trained graders. A convolutional neural network (CNN) was trained on these segmented B-scans and utilized to obtain several ONH biomarkers, such as the retinal nerve fiber layer (RNFL) and the minimal rim width (MRW). The CNN results were compared between different devices and to the manufacturer-reported values using an independent test set.

Results: The intraclass correlation coefficient (ICC) for the circumpapillary retinal nerve fiber layer (cpRNFL) at 3.4 mm reported by the CIRRUS and 3D OCT-2000 was 0.590 (95% confidence interval [CI], -0.079 to 0.901), and our CNN resulted in a cpRNFL ICC of 0.667 (95% CI, -0.035 to 0.939). The cpRNFL at 3.5 mm on the CIRRUS, 3D OCT-2000, and SPECTRALIS generated by the CNN resulted in an ICC of 0.656 (95% CI, 0.055-0.922). Comparing the global mean MRWs from the SPECTRALIS between CNN and manufacturer yielded an ICC of 0.983 (95% CI, 0.917-0.997). The CNN ICC for the MRW among the CIRRUS, 3D OCT-2000, and SPECTRALIS was 0.917 (95% CI, 0.947-0.981).

Conclusions: Our device-agnostic feature extraction from ONH OCT scans showed a higher reliability than the measures generated by the manufacturers for cpRNFL. MRW measurements compared very well among the manufacturers.

Translational relevance: This open-source software can robustly extract a wide range of biomarkers from any OCT device, removing the dependency on manufacturer-specific algorithms, which has significant implications for patient follow-up and collaborative research.

Purpose: Traditional visual acuity (VA) measurements depend on subjective responses, which can be unreliable, especially with uncooperative participants. Objective measurements with visual evoked potentials (VEP) address this issue but can overestimate VA in amblyopia. This study aims to establish the P300 component of the event-related potential as an objective VA test for amblyopia and compare its performance to subjective (psychophysical) and VEP-based VA estimates.

Methods: Psychophysical, VEP-based, and P300-based VA estimates were obtained for amblyopic and fellow eyes of 18 participants (aged 19-65) in a bicentric study. VEP-based VA was determined from the spatial frequency threshold derived from occipital cortex pattern-pulse responses to check-sizes ranging from 0.048° to 8.95°. P300 responses were collected using visual oddball sequences with circular optotypes. The threshold was estimated from the sigmoid function of parietal P300 amplitude versus optotype gap size. Mean VA values for amblyopic eyes were compared across methods.

Results: VEP-based VA of the amblyopic eyes overestimated psychophysical VA by 0.18 ± 0.06 logMAR (P = 0.0016). In contrast, P300-based VA showed no significant difference from psychophysical VA (0.00 ± 0.04 logMAR, P > 0.05).

Conclusions: In amblyopia, P300-based optotype VA aligns more closely with psychophysical VA than VEP-based VA, suggesting that P300-based VA is a valid objective alternative for estimating VA in amblyopic eyes.

Translational relevance: This study highlights the potential of P300-based VA testing as a reliable and objective method for assessing VA in amblyopic eyes, offering a promising tool for clinical and research applications where traditional methods fall short.

Purpose: To assess whether corneal nerve analysis can identify and differentiate patients with multiple sclerosis (MS) from those with epilepsy.

Methods: Participants with MS (n = 83), participants with epilepsy (n = 50), and healthy controls (HCs) (n = 20) underwent corneal confocal microscopy (CCM) and quantification of automated corneal nerve fiber length (ACNFL), automated corneal nerve fractal dimension (ACNFrD), and ACNFrD/ACNFL ratio of the subbasal nerve plexus.

Results: ACNFL (MS: P < 0.0001; epilepsy: P = 0.002) and ACNFrD (MS: P < 0.0001; epilepsy: P = 0.025) were significantly lower and the ACNFrD/ACNFL ratio (MS: P < 0.0001; epilepsy: P = 0.018) was significantly higher compared to HCs. ACNFL (P = 0.001), ACNFrD (P = 0.0003), and ACNFrD/ACNFL ratio (P = 0.006) were significantly lower in patients with MS compared to those with epilepsy. ACNFL had the highest diagnostic utility for identifying patients with MS (sensitivity/specificity 0.86/0.85, area under the curve [AUC] 0.90, P < 0.0001), and ACNFrD had the highest diagnostic utility for identifying patients with epilepsy (sensitivity/specificity 0.78/0.75, AUC 0.76, P = 0.0008). ACNFrD had the highest diagnostic utility for differentiating patients with MS from epilepsy (sensitivity/specificity 0.66/0.65, AUC 0.70, <0.0001).

Conclusions: Corneal neurodegeneration occurs in and is characterized by a distinct pattern that differentiates patients with MS and epilepsy.

Translational relevance: CCM identifies and differentiates patients with MS and epilepsy, albeit with moderate performance. Further validation, with a larger sample size, is needed.

Purpose: To compare the efficacy of thin plate spline (TPS) and Gaussian interpolation methods in generating hill of visions (HOVs) for patients with X-linked retinitis pigmentosa (XLRP).

Methods: Visual field data from 78 eyes of 39 patients with XLRP were acquired using the Octopus 900 Pro. TPS, Gaussian, and Universal Kriging interpolation methods were implemented to generate HOVs. The volume of the entire grid (VTot), a 30-degree region (V30), and the volume ratio (VRatio) were calculated. Pearson correlation and Bland-Altman limit of agreement (LOA) analysis were performed to assess the concordance. An undersampled grid was used to assess the accuracy of the interpolation by comparing the interpolated value to the actual measured value.

Results: There were strong positive correlations (R > 0.99, P < 0.001), and LOA analysis revealed minimal differences between the three methods. Gaussian interpolation performed the fastest (P < 0.0001).

Conclusions: TPS and Gaussian interpolation methods demonstrated a high degree of concordance in generating HOVs for patients with XLRP. The choice of methods depends on the specific needs and priorities of researchers and clinicians, factoring in speed, accessibility, ease of implementation, and the ability to fine-tune the interpolation.

Translational relevance: Accurate HOV analysis is crucial for monitoring and assessing visual field loss progression. TPS and Gaussian interpolation methods are equally effective in generating HOV representations for patients with XLRP. The choice of method can be based on specific needs of researchers or clinicians, enabling more personalized treatment strategies and better disease management.