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a Representative IVCM images from one control subject and c one patient with dry eye disease. b Automated image analysis using ACCMetrics software of the same control subject and d dry eye disease patient. Main nerve fibers are indicated in red, nerve branches in blue, and branch points in green
Source publication
Purpose
To evaluate in vivo confocal microscopy (IVCM) features of corneal subbasal nerve plexus (SNP) in the setting of dry eye disease (DED) using fully automated software “ACCMetrics,” and to further investigate its diagnostic performance in discriminating DED patients.
Methods
IVCM exams of SNP in DED patients and matched control subjects were...
Citations
... Quantitative image analysis was performed via a validated automated nerve image analysis software (ACCMetrics Corneal Nerve Fiber Analyser V.2, University of Manchester, Manchester, UK) [25]. Assessed metrics include corneal nerve fiber density (number/mm 2 ), defined as the total number of main nerves per square millimeter; corneal nerve fiber length (mm/mm 2 ), defined as the total length of main nerves and nerve branches per square millimeter; corneal nerve branch density (number/mm 2 ), defined as the total number of main nerve branches per square millimeter; corneal nerve fiber area (mm/mm 2 ), defined as the total nerve fiber area [26]; corneal nerve fiber width (mm/mm 2 ), defined as the average nerve fiber width [26]; and corneal nerve fiber total branch density (number/mm 2 ), defined as the total number of branch points per square millimeter. Additionally, corneal nerve fractal dimension, defined as a "novel parameter that measures the structural complexity of corneal nerves", was assessed [27]. ...
... Quantitative image analysis was performed via a validated automated nerve image analysis software (ACCMetrics Corneal Nerve Fiber Analyser V.2, University of Manchester, Manchester, UK) [25]. Assessed metrics include corneal nerve fiber density (number/mm 2 ), defined as the total number of main nerves per square millimeter; corneal nerve fiber length (mm/mm 2 ), defined as the total length of main nerves and nerve branches per square millimeter; corneal nerve branch density (number/mm 2 ), defined as the total number of main nerve branches per square millimeter; corneal nerve fiber area (mm/mm 2 ), defined as the total nerve fiber area [26]; corneal nerve fiber width (mm/mm 2 ), defined as the average nerve fiber width [26]; and corneal nerve fiber total branch density (number/mm 2 ), defined as the total number of branch points per square millimeter. Additionally, corneal nerve fractal dimension, defined as a "novel parameter that measures the structural complexity of corneal nerves", was assessed [27]. ...
Background: We evaluate the relationship between corneal nerve structure and function in a veteran population. Methods: 83 veterans (mean age: 55 ± 5 years) seen at the Miami Veterans Affairs (VA) eye clinic were included in this study. Each individual filled out questionnaires to evaluate ocular symptoms (5-Item Dry Eye Questionnaire, DEQ5; Ocular Surface Disease Index, OSDI) and ocular pain (Numerical Rating Scale, NRS; Neuropathic Pain Symptom Inventory modified for the Eye, NPSI-Eye). The individuals also underwent an ocular surface examination that captured functional nerve tests including corneal sensation, corneal staining, and the Schirmer test for tear production. Corneal sub-basal nerve analysis was conducted using in vivo confocal microscopy (IVCM) images with corneal nerve density, length, area, width, and fractal dimension captured. IVCM and functional corneal metrics from the right eye were examined using correlational and linear regression analysis. Results: Most corneal structural metrics were not related to functional metrics, except for weak correlations between various IVCM metrics and tear production. In addition, corneal nerve fiber area was positively related to corneal sensation (r = 0.3, p = 0.01). On linear regression analyses, only the corneal fractal dimension remained significantly related to tear production (β = −0.26, p = 0.02) and only the corneal nerve fiber area remained significantly related to corneal sensation (β = 0.3, p = 0.01). Conclusions: Most corneal nerve structural metrics did not relate to functional metrics in our veteran population, apart from a few weak correlations between structural metrics and tear production. This suggests that using corneal nerve anatomy alone may be insufficient for predicting corneal function.
... IVCCM is becoming an indispensable ophthalmic imaging technique that obtains high-resolution visualization of corneal SNPs and keratocytes [17]. The software ACCMetrics by the University of Manchester offers quantified analyses of SNPs, and the nerve metrics have been proved to be reproducible and repeatable [13,[18][19][20][21]. This methodology has been applied in longitudinal studies and helps gain a full scope of information on the time-dependent trends of corneal regenerative capacity after SMILE surgery [5]. ...
Purpose
The corneal cap thickness is a vital parameter designed in small incision lenticule extraction (SMILE). The purpose was to investigate the changes in corneal subbasal nerve plexus (SNP) and stromal cells with different cap thicknesses and evaluate the optimized design for the surgery.
Methods
In this prospective, comparative, non-randomized study, a total of 108 eyes of 54 patients who underwent SMILE were allocated into three groups with different corneal cap thicknesses (110 μm, 120 μm or 130 μm group). The SNP and stromal cell morphological changes obtained from in vivo corneal confocal microscopy (IVCCM) along with their refractive outcomes were collected at 1 week, 1 month, 3 months and 6 months postoperatively. One-way analysis of variance (ANOVA) was used to compare the parameters among the three groups.
Results
The SNPs in the three groups all decreased after surgery and revealed a gradual increasing trend during the 6-month follow-up. The values of the quantitative nerve metrics were significantly lower in the 110 μm group than in the 120 μm and 130 μm groups, especially at 1 week postoperatively. No difference was detected between the 120 μm and 130 μm groups at any time point. Both Langerhans cells and keratocytes were activated after surgery, and the activation was alleviated during the follow-up.
Conclusions
The SMILE surgeries with 110 μm, 120 μm or 130 μm cap thickness design achieved good efficacy, safety, accuracy and stability for moderate to high myopic correction while the thicker corneal cap was more beneficial for corneal nerve regeneration.
... Quantitative image analysis was performed via a validated automated nerve image analysis software (ACCMetrics Corneal Nerve Fiber Analyser V.2, University of Manchester, Manchester, United Kingdom) [23]. Assessed metrics include: corneal nerve fiber density (number/mm 2 ) defined as the total number of main nerves per square millimeter, corneal nerve fiber length (mm/mm 2 ) defined as the total length 4 of main nerves and nerve branches per square millimeter, corneal nerve branch density (number/mm 2 ) defined as the total number of main nerve branches per square millimeter, corneal nerve fiber area (mm/mm 2 ) defined as the total nerve fiber area [24], corneal nerve fiber width (mm/mm 2 ) defined as the average nerve fiber width [24], corneal nerve fiber total branch density (number/mm²) defined as the total number of branch points per square millimeter, and corneal nerve fractal dimension defined as a "novel parameter that measures the structural complexity of corneal nerves" [25]. The mean of the three values (one for each analyzed image) obtained for each parameter was calculated for the right eye. ...
... Quantitative image analysis was performed via a validated automated nerve image analysis software (ACCMetrics Corneal Nerve Fiber Analyser V.2, University of Manchester, Manchester, United Kingdom) [23]. Assessed metrics include: corneal nerve fiber density (number/mm 2 ) defined as the total number of main nerves per square millimeter, corneal nerve fiber length (mm/mm 2 ) defined as the total length 4 of main nerves and nerve branches per square millimeter, corneal nerve branch density (number/mm 2 ) defined as the total number of main nerve branches per square millimeter, corneal nerve fiber area (mm/mm 2 ) defined as the total nerve fiber area [24], corneal nerve fiber width (mm/mm 2 ) defined as the average nerve fiber width [24], corneal nerve fiber total branch density (number/mm²) defined as the total number of branch points per square millimeter, and corneal nerve fractal dimension defined as a "novel parameter that measures the structural complexity of corneal nerves" [25]. The mean of the three values (one for each analyzed image) obtained for each parameter was calculated for the right eye. ...
Purpose: To evaluate the relationship between corneal nerve structure and function in a veteran population. Methods: 83 veterans (mean age: 55 ± 5 years) seen at the Miami Veterans Affairs (VA) eye clinic were included in the study. Each individual filled out questionnaires to evaluate ocular symptoms (5-Item Dry Eye Questionnaire, DEQ5, Ocular Surface Disease Index, OSDI) and ocular pain (Numerical Rating Scale, NRS, Neuropathic Pain Symptom Inventory modified for the Eye, NPSI-Eye). Individuals also underwent an ocular surface examination that captured functional nerve tests including corneal sensation, corneal staining, and Schirmer test for tear production. Corneal sub-basal nerve analysis was conducted using in vivo confocal microscopy (IVCM) images with corneal nerve density, length, area, width, and fractal dimension captured. IVCM and functional corneal metrics from the right eye were examined using correlational and linear regression analysis. Results: Most corneal structural metrics were not related to functional metrics, except for weak correlations between various IVCM metrics and tear production. In addition, corneal nerve fiber area was positively related to corneal sensation (r = 0.3, p = 0.01). On linear regression analyses, only corneal fractal dimension remained significantly related to tear production (β = -0.26, p = 0.02) and only corneal nerve fiber area remained significantly related to corneal sensation (β = 0.3, p = 0.01). Conclusions: Most corneal nerve structural metrics did not relate to functional metrics in our veteran population, apart from a few weak correlations between structural metrics and tear production. This highlights caution in using corneal nerve anatomy to predict corneal function.
... 6,7 The increased width of nerve fibers might be due to nerve swelling caused by neuroinflammation, stimulating the release of neurotrophic factors, which in turn causes compensatory nerve hypertrophy. 50,51 We also observed activated stromal keratocytes in the majority of NCP patients. Keratocytes transform from a silent state to an activated phenotype influenced by cytokines and growth factors, 52 in response to tissue insult such as neuroinflammation. ...
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
Twenty NCP patients and twenty age-matched controls were recruited. All subjects were evaluated by corneal sensitivity, Schirmer's test, tear break-up time, corneal and ocular surface staining, Ocular Surface Disease Index and Ocular Pain Assessment Survey questionnaires, as well as IVCM examinations for corneal nerves, microneruomas, 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 two 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, RHOGDI and P70S6K signaling pathways. Compared to controls, the NCP cohort presented with significantly decreased corneal sensitivity (P<0.001), decreased corneal nerve fiber length (P=0.003), corneal nerve fiber density (P=0.006), nerve fiber fractal dimension (P=0.033), as well as increased in corneal nerve fiber width (P=0.002), increased length, total area and perimeter of microneuromas (P<0.001, P<0.001, P=0.019), smaller corneal epithelial size (P=0.017), and higher nerve growth factor level in tears (p=0.006).
Conclusions
These clinical manifestations, imaging features, and molecular characterizations would contribute to the diagnostics and potential therapeutic targets for NCP.
... 38 Corneal nerves have an essential role in the tear secretion reflex and the maintenance of ocular surface health. 39 Corneal nerve fibres are shorter in length and less dense in patients with DE than in normal subjects, [40][41][42] and corneal nerve morphology is closely related to DE symptoms and visual quality. 43 44 Therefore, at baseline and week 4, we will perform in vivo confocal microscopy (IVCM) to take a primary look at the morphological changes of corneal subbasal nerves. ...
... The average values are taken for statistical analyses. 41 Adverse events Any adverse events will be recorded. EA-related adverse events include local bleeding, subcutaneous hematoma, pain, itch, infection and generalised symptoms such as dizziness and palpitation during the treatment. ...
Introduction
Dry eye (DE) is a multifactorial ocular surface disease causing considerable medical, social and financial implications. Currently, there is no recognised long-term, effective treatment to alleviate DE. Clinical evidence shows that electroacupuncture (EA) can improve DE symptoms, tear secretion and tear film stability, but it remains controversial whether it is just a placebo effect. We aim to provide solid clinical evidence for the EA treatment of DE.
Methods and analysis
This is a multicentre, randomised, sham-controlled trial. A total of 168 patients with DE will be enrolled and randomly assigned to EA or sham EA groups to receive 4-week consecutive treatments and follow-up for 24 weeks. The primary outcome is the change in the non-invasive tear break-up time (NIBUT) from baseline to week 4. The secondary outcomes include tear meniscus height, the Schirmer I test, corneal and conjunctival sensation, the ocular surface disease index, corneal fluorescein staining, the numerical rating scale and the Chinese DE-related quality of life scale.
Ethics and dissemination
The trial protocol and informed consent were approved by the Ethics Committee of Yueyang Hospital of Integrated Traditional Chinese and Western Medicine Affiliated to Shanghai University of Traditional Chinese Medicine (identifier: 2021–119), Shanghai Eye Disease Prevention and Treatment Center (identifier: 2022SQ003) and Eye and ENT Hospital of Fudan University (identifier: 2022014).
Trial registration number
NCT05552820 .
... 21,22 (2) Chronic inflammation that occurred postoperatively stimulates the release of neurotrophic factors, which in turn causes compensatory peripheral nerve hypertrophy. 23,24 (3) The smaller nerve fibers in the central ablation zone or optical zone were ablated or removed, whereas the thicker nerve bundles in the corneal periphery were preserved. ...
Purpose
To evaluate the impact of corrected refractive power on corneal denervation and ocular surface in SMILE and LASIK.
Setting
Singapore National Eye Center, Singapore.
Design
A prospective study.
Methods
Eighty-eight eyes undergoing SMILE or LASIK were divided into low-moderate (MRSE<-6.0 D) and high myopic (MRSE≥-6.0 D) groups. In-vivo confocal microscopy and clinical assessments were performed preoperatively and 1, 3, 6, and 12 months postoperatively.
Results
In SMILE, high myopic treatment presented with significantly greater reduction in corneal nerve fiber area (CNFA) and nerve fiber fractal dimension (CFracDim) compared to low-moderate myopic treatment (both P <0.05). There was a significant and negative correlation between the corrected MRSE and the reduction of corneal nerve fiber density (CNFD), corneal nerve branch density (CNBD), corneal nerve fiber length, CNFA and CFracDim after SMILE ( r =-0.38 to -0.66, all P <0.05). In LASIK, a significant correlation between the MRSE and the changes of CNBD, corneal nerve fiber total branch density, CNFA ( r =-0.37 to -0.41), and corneal nerve fiber width ( r =0.43) was observed (all P <0.05). Compared to SMILE, LASIK had greater reduction of CNBD and CNFA for every diopter increase in the corrected MRSE. High myopic SMILE, compared to low-moderate myopic SMILE, resulted in significantly lower tear break-up time at 1 and 6 months (both P <0.05). The changes in CNFA and CFracDim were significantly associated with Schirmer’s test values (both P <0.001).
Conclusions
Postoperative corneal denervation was related to corrected refractive power in both SMILE and LASIK. With the same refractive correction, LASIK led to more prominent corneal denervation.
... Further studies are needed to focus on components of tear fluid such as mucin or inflammatory factors. In addition, both false-negative and false-positive errors are possible in detecting corneal nerve with ACCMetrics, including the failure to detect thin nerve fibers and the erroneous recognition of other structures such as dendritic cells (45). Third, patients in our study used necessary antibiotics and anti-inflammatory agents after FS-LASIK, which could influence ocular surface status. ...
Purpose
To assess the effect of combination therapy with 3% diquafosol tetrasodium (DQS) and sodium hyaluronate (HA) for dry eye after femtosecond laser-assisted in situ keratomileusis (FS-LASIK).
Design
Prospective nonrandomized comparative trial.
Methods
The prospective study included 80 eyes of 40 patients who underwent FS-LASIK with or without preoperative dry eye. Patients were divided into a combination group and a HA group according to their willingness and the doctor’s advice. The combination group was treated with DQS six times a day and HA four times a day, and the HA group was treated with HA four times a day after FS-LASIK. Ocular surface disease index (OSDI), ocular symptom score, vision-related score, environmental score, tear meniscus height (TMH), first non-invasive tear breakup time (NIBUT-First), average non-invasive tear breakup time (NIBUT-Ave), tear breakup time (TBUT), Schirmer I test (SIT), corneal fluorescein staining score (CFS), bulbar redness score, limbal redness score, lipid layer grade (LLG), meiboscore, lid margin abnormality, corneal sensitivity, and corneal nerve parameters were examined before surgery and at 1 week and 1 month after surgery. Surface regularity index (SRI) was also examined before surgery and at 1 month postoperatively.
Results
OSDI score ( p = 0.024) and vision-related score ( p = 0.026) were significantly lower in the combination group than in the HA group at 1 month after FS-LASIK, especially in patients with preoperative dry eye symptoms. The increasements of CFS ( p = 0.018), bulbar redness score ( p = 0.021), and limbal redness score ( p = 0.009) were significantly lower in the combination group than in the HA group at 1 week after FS-LASIK. But other ocular surface parameters showed no difference between both groups at 1 week and 1 month after FS-LASIK. LLG was significantly higher in the combination group than in the HA group at 1 week ( p = 0.004) and 1 month ( p < 0.001) after surgery, especially in patients with high meiboscore. Additional DQS significantly improved corneal sensitivity in patients without preoperative dry eye symptoms at 1 month after FS-LASIK ( p = 0.041).
Conclusion
The combination therapy with DQS and HA significantly relieved subjective symptoms, improved ocular surface status, and had the potential to promote corneal nerve growth in patients after FS-LASIK.
... Despite the advances in image analysis, manual or semiautomatic methodologies remain the most commonly used methods for analyzing corneal nerve tortuosity from IVCM images [37]. However, these techniques are subjective, time consuming and heavily dependent on the experience of the evaluator, which might not deliver reproducible outcomes [38]. These limitations show the need to create new automatic analysis systems that are able to provide reliable results. ...
... Conventionally, corneal nerve abnormalities have been commonly identified through arduous manual or semiautomatic evaluation processes [50][51][52]. Such approaches result in time-consuming and subjective outcomes, with limited inter-rater reliability across observers [38]. As expected, in this type of tool, the operator's ability has a high impact on the accuracy of the measurements. ...
An automated tool for corneal nerve fiber tortuosity quantification from in vivo confocal microscopy (IVCM) is described and evaluated. The method is a multi-stage process based on the splitting of the corneal nerve fibers into individual segments, whose endpoints are an extreme or intersection of white pixels on a binarized image. Individual segment tortuosity is quantified in terms of the arc-chord ratio. Forty-three IVCM images from 43 laser-assisted in situ keratomileusis (LASIK) surgery patients were used for evaluation. Images from symptomatic dry eye disease (DED) post-LASIK patients, with (n=16) and without (n=7) ocular pain, and non-DED post-LASIK controls (n=20) were assessed. The automated tortuosity measure was compared to a manual grading one, obtaining a moderate correlation (Spearman’s rank correlation coefficient = 0.49, p=0.0008). The new tortuosity index was significantly higher in post-LASIK patients with ocular pain than in control patients (p=0.001), while no significant differences were detected with manual measurement (p>0.28). The tortuosity quantification was positively correlated with the ocular surface disease index (OSDI) and a numeric rating scale (NRS) assessing pain (p=0.0012 and p=0.0051, respectively). The results show good performance of the proposed automated methodology for the evaluation of corneal nerve tortuosity.
... One study reported a reduction in the corneal nerve length and density after cataract surgery [6]. Previous studies reported that the corneal subbasal nerve density and length tended to decrease in DED, indicating damaged nerve fibers [7]. They indicated that cataract surgery aggravated the eye dryness by damaging the corneal nerves. ...
This study aimed to evaluate the change patterns in corneal intrinsic aberrations and nerve density after cataract surgery in dry eye disease. The preoperative, 1- and 3-month postoperative dry eye-related parameters were obtained by the Oculus keratograph and the ocular surface disease index questionnaire. The corneal intrinsic aberrations were measured using the Pentacam HR system. In vivo confocal microscopy was performed to observe the vortical and peripheral corneal nerves. An artificial intelligence technique run by the deep learning model generated the corneal nerve parameters. Corneal aberrations on the anterior and total corneal surfaces were significantly increased at 1 month compared with the baseline (p < 0.05) but gradually returned to the baseline by 3 months (p > 0.05). However, the change in posterior corneal aberration lasted up to 3 months (p < 0.05). There was a significant decrease in the corneal vortical nerve maximum length and average density after the operation (p < 0.05), and this damage lasted approximately 3 months. The corneal vortical nerve maximum length and average density were negatively correlated with the anterior corneal surface aberrations before and 1 month after the operation (correlation coefficients, CC = −0.26, −0.25, −0.28; all p < 0.05). Corneal vortex provided a unique site to observe long-term corneal nerve injury related to eye dryness. The continuous damage to the corneal vortical nerve may be due to the continuous dry eye state.
... In recent years, with the increase in the understanding of DED and the progress of ocular surface assessment methods, in vivo confocal microscopy (IVCM) has proven to be useful to observe corneal microstructure in DED patients [3][4][5][6][7]. Patients with DED have observed alterations in subbasal corneal nerves in IVCM, including reduced density, high tortuosity, more branches and Langerhans cells (LC) [8][9][10][11][12][13][14][15][16][17], which correlates with DED symptoms, ocular surface staining [14,18], and the severity of dry eye [4,8,14]. A recent review proposed that corneal neuroma (sometimes referred to as micro neuromas), which may serve as a diagnostic biomarker, is a pathological feature of the ocular surface disease [19], and their presence may be related to the symptoms of photophobia and neuropathic ocular pain (NOP) [8,19]. ...
Our purpose is to demonstrate the changes in cornea nerve parameters and symptoms and signs in dry eye disease (DED) patients after oral vitamin B1 and mecobalamin treatment. In this randomized double-blind controlled trial, DED patients were randomly assigned to either the treatment group (oral vitamin B1 and mecobalamin, artificial tears) or the control group (artificial tears). Corneal nerve parameters via in vivo confocal microscopy (IVCM), DED symptoms, and signs were assessed at baseline and 1 and 3 months post-treatment. In total, 398 eyes from 199 patients were included. In the treatment group, there were significant improvements in corneal nerve length, width, and neuromas, the sign of conjunctival congestion score (CCS), symptoms of dryness, pain, photophobia, blurred vision, total symptom score, and OSDI (OSDI) at 1/3 months post-treatment (all p < 0.05). Patients who received vitamin B1 and mecobalamin showed greater improvement in CCS, dryness scores at 1 month (p < 0.05), corneal fluorescein staining (CFS) (p = 0.012), photophobia (p = 0.032), total symptom scores (p = 0.041), and OSDI (p = 0.029) at 3 months. Greater continuous improvement in CFS (p = 0.045), dryness (p = 0.033), blurred vision (p = 0.031) and total symptom scores (p = 0.023) was demonstrated at 3 months than at 1 month post-treatment in the treatment group. We found that oral vitamin B1 and mecobalamin can improve corneal nerve length, width, reflectivity and the number of neuromas in IVCM, thereby repairing epithelial cells and alleviating some ocular symptoms. Thus, vitamin B1 and mecobalamin are potential treatment options for patients with DED.
