Quality of Life and Symptomatology in Neuropathic Corneal Pain in Comparison With Dry Eye Syndrome.

PURPOSE: To investigate and compare the quality of life (QoL) and symptomatology between neuropathic corneal pain (NCP) and dry eye disease (DED). METHODS: We recruited 150 patients, comprising 50 patients with NCP and 100 patients with DED. Patients' symptoms and QoL were evaluated using the Ocular Pain Assessment Survey and Ocular Surface Disease Index questionnaires. Ocular surface assessments were also performed. RESULTS: Patients with NCP demonstrated significantly lower Oxford and National Eye Institute scores for ocular surface and corneal staining, respectively, and a better tear break-up time than patients with DED. However, patients with NCP reported significantly worse scores on most of the Ocular Pain Assessment Survey questions and significantly more severe overall pain (P = 0.019), maximal and average ocular pain and nonocular pain (all P < 0.05). The NCP group reported significantly worse QoL in all aspects of daily living (all P < 0.001). Patients with NCP spent more time thinking about their eye pain and reported significantly higher pain intensities than patients with DED when exposed to chemical and mechanical stimuli (all P ≤ 0.008). Burning sensation and photophobia were significantly more frequent in patients with NCP (P = 0.032 and P = 0.012, respectively). Similarly, the NCP group reported significantly worse total Ocular Surface Disease Index scores, significantly more frequent vision-related function impairment and painful or sore eyes than the DED group (P = 0.029, P = 0.031, and P = 0.014, respectively). CONCLUSIONS: Compared with DED, NCP is more debilitating, leading to more severe and frequent symptoms, and greater negative impact on all aspects of QoL.

Potential therapeutic effects of peroxisome proliferator-activated receptors on corneal diseases.

The cornea is an avascular tissue in the eye that has multiple functions in the eye to maintain clear vision which can significantly impair one's vision when subjected to damage. Peroxisome proliferator-activated receptors (PPARs), a family of nuclear receptor proteins comprising three different peroxisome proliferator-activated receptor (PPAR) isoforms, namely, PPAR alpha (α), PPAR gamma (γ), and PPAR delta (δ), have emerged as potential therapeutic targets for treating corneal diseases. In this review, we summarised the current literature on the therapeutic effects of PPAR agents on corneal diseases. We discussed the role of PPARs in the modulation of corneal wound healing, suppression of corneal inflammation, neovascularisation, fibrosis, stimulation of corneal nerve regeneration, and amelioration of dry eye by inhibiting oxidative stress within the cornea. We also discussed the underlying mechanisms of these therapeutic effects. Future clinical trials are warranted to further attest to the clinical therapeutic efficacy.

One-Step Intraoperative Optical Coherence Tomography Guided Tunnel, Mushroom Femtosecond Laser Big Bubble Deep Anterior Lamellar Keratoplasty.

The aim of our study is to investigate the feasibility and outcomes of using a femtosecond laser (FSL) platform (Ziemer LDV Z8) for deep anterior lamellar keratoplasty (DALK), enabling the creation of mushroom-shaped graft-host junctions, lamellar cuts, and intrastromal tunnels, to facilitate the big bubble, in one step. We included wet lab experiments on nine porcine eyes to assess the laser accuracy and cuts depth using an anterior segment (AS) OCT. This was followed by an interventional prospective case series on 10 eyes with variant corneal pathologies. The Z8 system, with in-built intraoperative optical coherence tomography (iOCT), guided corneal scans and directed the cuts. ASOCT showed visible mushroom configurations, lamellar cuts, and tunnels. Deviations from the target were 1.6%, 2.6%, and 3.5%. Anterior lamellar removal was easy in all clinical cases, including corneal scarring. The intrastromal tunnel was found at the preset location and the mushroom configuration was acquired. A big bubble was achieved in all cases. Type 1, 2, and 3 bubbles were formed in eight, one, and one case, respectively. We describe a new approach to DALK in which the in-built iOCT-guided FSL enables safe, precise, controlled, and reproducible desired cuts in one step. The preliminary clinical outcomes were favorable.

Topical and oral peroxisome proliferator-activated receptor-α agonist ameliorates diabetic corneal neuropathy.

Diabetic corneal neuropathy (DCN) is a common diabetic ocular complication with limited treatment options. In this study, we investigated the effects of topical and oral fenofibrate, a peroxisome proliferator-activated receptor-α agonist, on the amelioration of DCN using diabetic mice (n = 120). Ocular surface assessments, corneal nerve and cell imaging analysis, tear proteomics and its associated biological pathways, immuno-histochemistry and western blot on PPARα expression, were studied before and 12 weeks after treatment. At 12 weeks, PPARα expression markedly restored after topical and oral fenofibrate. Topical fenofibrate significantly improved corneal nerve fibre density (CNFD) and tortuosity coefficient. Likewise, oral fenofibrate significantly improved CNFD. Both topical and oral forms significantly improved corneal sensitivity. Additionally, topical and oral fenofibrate significantly alleviated diabetic keratopathy, with fenofibrate eye drops demonstrating earlier therapeutic effects. Both topical and oral fenofibrate significantly increased corneal ß-III tubulin expression. Topical fenofibrate reduced neuroinflammation by significantly increasing the levels of nerve growth factor and substance P. It also significantly increased ß-III-tubulin and reduced CDC42 mRNA expression in trigeminal ganglions. Proteomic analysis showed that neurotrophin signalling and anti-inflammation reactions were significantly up-regulated after fenofibrate treatment, whether applied topically or orally. This study concluded that both topical and oral fenofibrate ameliorate DCN, while topical fenofibrate significantly reduces neuroinflammation.

Comparative Study of Primary SMILE, SMILE Enhancement, and Femtosecond Laser-Assisted LASIK on Higher Order Aberrations and Corneal Densitometry.

PURPOSE: To compare differences in corneal densitometry (CD) and higher order aberrations (HOAs) in eyes that underwent small incision lenticule extraction (SMILE) and femtosecond laser-assisted laser in situ keratomileusis (FS-LASIK) for the treatment of myopia and myopic astigmatism at postoperative months 3, 6, and 12, and to evaluate their changes in a separate cohort of eyes after SMILE enhancement. METHODS: In this prospective, randomized, paired-eye clinical trial, consecutive eligible participants were randomized to undergo SMILE or FS-LASIK in either eye. Main outcome measures were CD and HOAs preoperatively and at 3, 6, and 12 months postoperatively. A separate cohort of consecutive patients who had SMILE and underwent enhancement were also included for comparison. RESULTS: For CD, no significant differences were found between SMILE and FS-LASIK up to month 12. For HOA measured by wavefront aberrometry, both SMILE and FS-LASIK had an increase in total root mean square (RMS) HOAs, spherical aberration (SA), and vertical coma up to month 12. SMILE had an additional increase in vertical quatrefoil, and FS-LASIK had an increase in horizontal coma at month 12. FS-LASIK had higher SA than SMILE, whereas SMILE had higher vertical quatrefoil than FS-LASIK at month 12. Central and posterior zone CD had significantly decreased after SMILE enhancement compared to after primary SMILE up to 2 years after enhancement. RMS HOAs, lower order aberrations, and SA were all increased after SMILE enhancement compared to after primary SMILE. CONCLUSIONS: SMILE induced lower SA but higher vertical quatrefoil than FS-LASIK at 1 year. Both SMILE and FS-LASIK had similar increases in RMS HOAs and vertical coma up to 1 year. There were no differences in CD between both groups. SMILE enhancement additionally had decreased central and posterior CD but greater RMS HOAs and SA compared to primary SMILE. [J Refract Surg. 2024;40(5):e291-e303.].

Analyzing genetic diversity in luffa and developing a Fusarium wilt-susceptible linked SNP marker through a single plant genome-wide association (sp-GWAS) study.

BACKGROUND: Luffa (Luffa spp.) is an economically important crop of the Cucurbitaceae family, commonly known as sponge gourd or vegetable gourd. It is an annual cross-pollinated crop primarily found in the subtropical and tropical regions of Asia, Australia, Africa, and the Americas. Luffa serves not only as a vegetable but also exhibits medicinal properties, including anti-inflammatory, antidiabetic, and anticancer effects. Moreover, the fiber derived from luffa finds extensive applications in various fields such as biotechnology and construction. However, luffa Fusarium wilt poses a severe threat to its production, and existing control methods have proven ineffective in terms of cost-effectiveness and environmental considerations. Therefore, there is an urgent need to develop luffa varieties resistant to Fusarium wilt. Single-plant GWAS (sp-GWAS) has been demonstrated as a promising tool for the rapid and efficient identification of quantitative trait loci (QTLs) associated with target traits, as well as closely linked molecular markers. RESULTS: In this study, a collection of 97 individuals from 73 luffa accessions including two major luffa species underwent single-plant GWAS to investigate luffa Fusarium wilt resistance. Utilizing the double digest restriction site associated DNA (ddRAD) method, a total of 8,919 high-quality single nucleotide polymorphisms (SNPs) were identified. The analysis revealed the potential for Fusarium wilt resistance in accessions from both luffa species. There are 6 QTLs identified from 3 traits, including the area under the disease progress curve (AUDPC), a putative disease-resistant QTL, was identified on the second chromosome of luffa. Within the region of linkage disequilibrium, a candidate gene homologous to LOC111009722, which encodes peroxidase 40 and is associated with disease resistance in Cucumis melo, was identified. Furthermore, to validate the applicability of the marker associated with resistance from sp-GWAS, an additional set of 21 individual luffa plants were tested, exhibiting 93.75% accuracy in detecting susceptible of luffa species L. aegyptiaca Mill. CONCLUSION: In summary, these findings give a hint of genome position that may contribute to luffa wild resistance to Fusarium and can be utilized in the future luffa wilt resistant breeding programs aimed at developing wilt-resistant varieties by using the susceptible-linked SNP marker.

Blood-Derived Eye Drops for the Treatment of Corneal Neuropathic Pain.

Blood-derived preparations, including autologous or allogenic serum, umbilical cord serum/plasma, and platelet-rich plasma eye drops, contain various growth factors, cytokines, and immunoglobulins that resemble natural tears. These components play important roles in corneal cell migration, proliferation, and wound healing. Blood-derived eye drops have demonstrated clinical effectiveness across a spectrum of ocular surface conditions, encompassing dry eye disease, Sjögren's syndrome, graft-versus-host disease, and neuropathic corneal pain (NCP). Currently, management of NCP remains challenging. The emergence of blood-derived eye drops represents a promising therapeutic approach. In this review, we discuss the benefits and limitations of different blood-derived eye drops, their mechanisms of action, and treatment efficacy in patients with NCP. Several studies have demonstrated the clinical efficacy of autologous serum eye drops in relieving pain and pain-like symptoms, such as allodynia and photoallodynia. Corneal nerve parameters were also significantly improved, as evidenced by increased nerve fiber density, length, nerve reflectivity, and tortuosity, as well as a decreased occurrence of beading and neuromas after the treatment. The extent of nerve regeneration correlated with improvement in patient-reported photoallodynia. Cord plasma eye drops also show potential for symptom alleviation and corneal nerve regeneration. Future directions for clinical practice and research involve standardizing preparation protocols, establishing treatment guidelines, elucidating underlying mechanisms, conducting long-term clinical trials, and implementing cost-effective measures such as scaling up manufacturing. With ongoing advancements, blood-derived eye drops hold promise as a valuable therapeutic option for patients suffering from NCP.

Applications of Imaging Technologies in Fuchs Endothelial Corneal Dystrophy: A Narrative Literature Review.

Fuchs endothelial corneal dystrophy (FECD) is a complex genetic disorder characterized by the slow and progressive degeneration of corneal endothelial cells. Thus, it may result in corneal endothelial decompensation and irreversible corneal edema. Moreover, FECD is associated with alterations in all corneal layers, such as thickening of the Descemet membrane, stromal scarring, subepithelial fibrosis, and the formation of epithelial bullae. Hence, anterior segment imaging devices that enable precise measurement of functional and anatomical changes in the cornea are essential for the management of FECD. In this review, the authors will introduce studies on the application of various imaging modalities, such as anterior segment optical coherence tomography, Scheimpflug corneal tomography, specular microscopy, in vitro confocal microscopy, and retroillumination photography, in the diagnosis and monitoring of FECD and discuss the results of these studies. The application of novel technologies, including image processing technology and artificial intelligence, that are expected to further enhance the accuracy, precision, and speed of the imaging technologies will also be discussed.

Effects of Different Capsulotomy and Fragmentation Energy Levels on the Generation of Oxidative Stress Following Femtosecond Laser-Assisted Cataract Surgery.

PURPOSE: This study was conducted to evaluate the effects of different capsulotomy and fragmentation energy levels on the production of oxidative free radicals following femtosecond laser-assisted cataract surgery (FLACS) with a low-energy platform. METHODS: The experimental study included 60 porcine eyes (12 groups). In each group, capsulotomies with 90% or 150% energy, and fragmentations with 90%, 100%, or 150% energy or 150% with high spot density, respectively, were performed. Control samples were obtained from non-lasered eyes at the beginning (five eyes) and end (five eyes) of the experiment. In the clinical study, 104 eyes were divided into 5 groups, and they received conventional phacoemulsification (20 eyes), FLACS with 90% capsulotomy and 100% fragmentation energy levels without NSAIDs (16 eyes), FLACS with 90% (26 eyes) or 150% (22 eyes) capsulotomy energy levels, respectively, with a 100% fragmentation energy level and NSAIDs, and FLACS with 90% capsulotomy and 150% fragmentation energy levels and NSAIDs (20 eyes). Aqueous samples were analyzed for their malondialdehyde (MDA) and superoxide dismutase (SOD) levels. RESULTS: In the experimental study, there were no significant differences in the MDA and SOD levels between the groups with different capsulotomy energy levels. An increase in the fragmentation energy from 100% to 150% led to significantly higher MDA levels in the groups with both 90% (p = 0.04) and 150% capsulotomy energy levels (p = 0.03), respectively. However, increased laser spot densities did not result in significant changes in MDA or SOD levels. In the clinical study, all four of the FLACS groups showed higher MDA levels than the conventional group. Similarly, the increase in the fragmentation energy from 100% to 150% resulted in significantly elevated levels of MDA and SOD, respectively. CONCLUSIONS: Although increasing the FSL capsulotomy energy level may not have increased free radicals, higher fragmentation energy levels increased the generation of aqueous free radicals. However, fragmentation with high spot density did not generate additional oxidative stress. Increased spot density did not generate additional oxidative stress, and this can be helpful for dense cataracts.

Deep learning for detection of Fuchs endothelial dystrophy from widefield specular microscopy imaging: a pilot study.

BACKGROUND: To describe the diagnostic performance of a deep learning (DL) algorithm in detecting Fuchs endothelial corneal dystrophy (FECD) based on specular microscopy (SM) and to reliably detect widefield peripheral SM images with an endothelial cell density (ECD) > 1000 cells/mm2. METHODS: Five hundred and forty-seven subjects had SM imaging performed for the central cornea endothelium. One hundred and seventy-three images had FECD, while 602 images had other diagnoses. Using fivefold cross-validation on the dataset containing 775 central SM images combined with ECD, coefficient of variation (CV) and hexagonal endothelial cell ratio (HEX), the first DL model was trained to discriminate FECD from other images and was further tested on an external set of 180 images. In eyes with FECD, a separate DL model was trained with 753 central/paracentral SM images to detect SM with ECD > 1000 cells/mm2 and tested on 557 peripheral SM images. Area under curve (AUC), sensitivity and specificity were evaluated. RESULTS: The first model achieved an AUC of 0.96 with 0.91 sensitivity and 0.91 specificity in detecting FECD from other images. With an external validation set, the model achieved an AUC of 0.77, with a sensitivity of 0.69 and specificity of 0.68 in differentiating FECD from other diagnoses. The second model achieved an AUC of 0.88 with 0.79 sensitivity and 0.78 specificity in detecting peripheral SM images with ECD > 1000 cells/mm2. CONCLUSIONS: Our pilot study developed a DL model that could reliably detect FECD from other SM images and identify widefield SM images with ECD > 1000 cells/mm2 in eyes with FECD. This could be the foundation for future DL models to track progression of eyes with FECD and identify candidates suitable for therapies such as Descemet stripping only.

Neuropathic Corneal Pain: Tear Proteomic and Neuromediator Profiles, Imaging Features, and Clinical Manifestations.

PURPOSE: To investigate the tear proteomic and neuromediator profiles, in vivo confocal microscopy (IVCM) imaging features, and clinical manifestations in neuropathic corneal pain (NCP) patients. DESIGN: Cross-sectional study. METHODS: A total of 20 NCP patients and 20 age-matched controls were recruited. All subjects were evaluated by corneal sensitivity, Schirmer test, tear break-up time, and corneal and ocular surface staining, Ocular Surface Disease Index and Ocular Pain Assessment Survey questionnaires were administered, as well as IVCM examinations for corneal nerves, microneruomas, and epithelial and dendritic cells. Tears were collected for neuromediator and proteomic analysis using enzyme-linked immunosorbent assay and data-independent acquisition mass spectrometry. RESULTS: Burning and sensitivity to light were the 2 most common symptoms in NCP. A total of 188 significantly dysregulated proteins, such as elevated metallothionein-2, creatine kinases B-type, vesicle-associated membrane protein 2, neurofilament light polypeptide, and myelin basic protein, were identified in the NCP patients. The top 10 dysregulated biological pathways in NCP include neurotoxicity, axonal signaling, wound healing, neutrophil degradation, apoptosis, thrombin signaling mitochondrial dysfunction, and RHOGDI and P70S6K signaling pathways. Compared to controls, the NCP cohort presented with significantly decreased corneal sensitivity (P < .001), decreased corneal nerve fiber length (P = .003), corneal nerve fiber density (P = .006), and nerve fiber fractal dimension (P = .033), as well as increased corneal nerve fiber width (P = .002), increased length, total area and perimeter of microneuromas (P < .001, P < .001, P = .019), smaller corneal epithelial size (P = .017), and higher nerve growth factor level in tears (P = .006). CONCLUSIONS: These clinical manifestations, imaging features, and molecular characterizations would contribute to the diagnostics and potential therapeutic targets for NCP.

Neuropathic Corneal Pain after Coronavirus Disease 2019 (COVID-19) Infection.

INTRODUCTION: This is a case report of a patient with neuropathic corneal pain after coronavirus disease 2019 (COVID-19) infection. METHODS: A previously healthy 27-year-old female presented with bilateral eye pain accompanied by increased light sensitivity 5 months after COVID-19 infection. She was diagnosed with neuropathic corneal pain based on clear corneas without fluorescein staining, alongside the presence of microneuromas, dendritic cells, and activated stromal keratocytes identified bilaterally on in vivo confocal microscopy. RESULTS: The patient's tear nerve growth factor, substance P, and calcitonin gene-related peptide levels were 5.9 pg/mL, 2978.7 pg/mL, and 1.1 ng/mL, respectively, for the right eye and 23.1 pg/mL, 4798.7 pg/mL, and 1.2 ng/mL, respectively, for the left eye, suggesting corneal neuroinflammatory status. After 6 weeks of topical 0.1% flurometholone treatment, decreased microneuroma size, less extensive dendritic cells, and reduced tear nerve growth factor and substance P levels were observed. The scores on the Ocular Pain Assessment Survey showed an improvement in burning sensation and light sensitivity, decreasing from 80% and 70% to 50% for both. CONCLUSIONS: Neuropathic corneal pain is a potential post-COVID-19 complication that warrants ophthalmologists' and neurologists' attention.

Gradient three-dimensional current collector with lithiophilic nanolayer regulation for efficient lithium metal anode construction.

Metallic lithium (Li) is highly desirable for Li battery anodes due to its unique advantages. However, the growth of Li dendrites poses challenges for commercialization. To address this issue, researchers have proposed various three-dimensional (3D) current collectors. In this study, the selective modification of a 3D Cu foam scaffold with lithiophilic elements was explored to induce controlled Li deposition. The Cu foam was selectively modified with Ag and Sn to create uniform Cu foam (U-Cu) and gradient lithiophilic Cu foam (G-Cu) structures. Density Functional Theory (DFT) calculations revealed that Ag exhibited a stronger binding energy with Li compared to Sn, indicating superior Li induction capabilities. Electrochemical testing demonstrated that the half cell with the G-Cu@Ag electrode exhibited excellent cycling stability, maintaining 550 cycles with an average Coulombic efficiency (CE) of 97.35%. This performance surpassed that of both Cu foam and G-Cu@Sn. The gradient modification of the current collectors improved the utilization of the 3D scaffold and prevented Li accumulation at the top of the scaffold. Overall, the selective modification of the 3D Cu foam scaffold with lithiophilic elements, particularly Ag, offers promising prospects for mitigating Li dendrite growth and enhancing the performance of Li batteries.

Incisional surface quality of electron-beam irradiated cornea-extracted lenticule for stromal keratophakia: high nJ-energy vs. low nJ-energy femtosecond laser.

Introduction: Corneal lenticules can be utilized as an additive material for stromal keratophakia. However, following extraction, they must be reimplanted almost immediately or cryopreserved in lenticule banks. Electron-beam (E-beam) irradiated corneas permit room-temperature storage for up to 2 years, enabling keratophakia to be performed on demand. This study aims to compare the performance of high nano Joule (nJ)-energy (VisuMax) and low nJ-energy (FEMTO LDV) femtosecond laser systems on the thickness consistency and surface quality and collagen morphology of lenticules produced from fresh and E-beamed corneas. Methods: A total of 24 lenticules with -6.00 dioptre power were cut in fresh human donor corneas and E-beamed corneas with VisuMax and FEMTO LDV. Before extraction, the thickness of the lenticules was measured with anterior segment-optical coherence tomography (AS-OCT). The incisional surface roughness of extracted lenticules was analyzed using atomic force microscopy (AFM) and scanning electron microscopy (SEM). Multiphoton microscopy was then used to assess the surface collagen morphometry. Results: The E-beamed lenticules that were cut using FEMTO LDV were significantly thicker than the fresh specimens as opposed to those created with VisuMax, which had a similar thickness as the fresh lenticules. On the vertex, they were ∼11% thicker than the fresh lenticules. The surface roughness (Rq) of E-beamed lenticules incised with FEMTO LDV did not differ significantly from the fresh lenticules. This contrasted with the VisuMax-fashioned lenticules, which showed notably smoother surfaces (∼36 and ∼20% lower Rq on anterior and posterior surfaces, respectively) on the E-beamed than the fresh lenticules. The FEMTO LDV induced less cumulative changes to the collagen morphology on the surfaces of both fresh and E-beamed lenticules than the VisuMax. Conclusion: It has been previously demonstrated that the low nJ-energy FEMTO LDV produced a smoother cutting surface compared to high nJ-energy VisuMax in fresh lenticules. Here, we showed that this effect was also seen in the E-beamed lenticules. In addition, lower laser energy conferred fewer changes to the lenticular surface collagen morphology. The smaller disparity in surface cutting quality and collagen disturbances on the E-beamed lenticules could be beneficial for the early visual recovery of patients who undergo stromal keratophakia.