BACKGROUND: Patients with Parkinson\'s disease (PD) suffer from serious quality of life problems. Diabetes has been demonstrated as an independent risk element for PD, aggravating its severity and accelerating its progression. There are currently no suitable biomarkers to reveal the impact of diabetes on PD. The purpose of our research was to study the impact of diabetes on PD using corneal confocal microscopy (CCM), a non-invasive and objective test.
METHODS: Fourteen PD patients with diabetes (PD-DM), 60 PD patients without diabetes (PD-NDM), and 30 healthy controls (HC) were included in the study. The clinical symptoms of patients with PD were assessed using the Unified Parkinson\'s Disease Rating Scale-3 (UPDRS-3) and the Parkinson\'s Disease Autonomic Symptom Prognosis Scale (SCOPA-AUT). Participants underwent CCM to quantify the corneal nerve fibres.
RESULTS: Corneal nerve fibre density (CNFD) and corneal nerve fibre length (CNFL) in patients with PD were lower than HC. Furthermore, CNFD in PD-DM was lower than in PD-NDM (P < 0.01). We also assessed the relationship between CCM parameters and clinical scores. CNFL and Hamilton anxiety (HAMA) have a negative correlation (r = -0.261, P = 0.032), but this study did not observe a significant correlation between CCM parameters and SCOPA-AUT. Additionally, CNFD could distinguish PD-DM from PD-NDM, achieving an area under the curve of 75.06% (95% CI, 61.76%-88.36%).
CONCLUSIONS: The CCM could be served as an objective and sensitive biomarker to investigate the impact of diabetes in PD.

OBJECTIVE: To explore variations in systemic and ocular parameters among patients with diabetes, both with and without diabetic peripheral neuropathy (DPN) and to identify sensitive indicators for DPN diagnosis.
METHODS: Ninty-five patients with type 2 diabetes mellitus (T2DM) were involved in this cross-sectional study, including 49 without DPN and 46 with DPN. Ocular parameters were obtained using optical coherence tomography angiography (OCTA) and corneal confocal microscopy (CCM).
RESULTS: Patients with DPN presented with significantly higher HbA1c (p < 0.05) and glycated albumin (GA, p < 0.01) levels, increased prevalence of diabetic retinopathy (DR, p < 0.05), and lower serum albumin (ALB, p < 0.01) and red blood cell (RBC, p < 0.05) levels. Ocular assessments revealed reduced corneal nerve fiber length (CNFL, p < 0.001) and enlarged foveal avascular zone (FAZ) area (p < 0.05) in DPN group. Logistic regression analysis indicated a significant association of presence of DR, RBC, GA, ALB, CNFL and DPN (p < 0.05, respectively). In the binary logistic regression for DPN risk, all three models including the presence of DR and CNFL exhibited the area under the curve (AUC) exceeding 0.8.
CONCLUSIONS: The study establishes a strong correlation between ocular parameters and DPN, highlighting CCM\'s role in early diagnosis. Combining systemic and ocular indicators improves DPN risk assessment and early management.

Purpose: Diabetes mellitus has been associated with increased dry eye disease (DED) and exacerbates DED\'s pathology. This preliminary short-term study aimed to evaluate the effects of 3% Diquafosol Sodium ophthalmic solution (DQS) on ocular surface inflammation and corneal nerve density in diabetic dry eye (DDE) patients. Methods: In this perspective, participants used 1 drop of 3% DQS (Diquas; Santen Pharmaceutical Co., Ltd., Osaka, Japan) 6 times daily for 8 weeks. Non-invasive tear breakup time (NITBUT), tear film lipid layer (TFLL), conjunctival hyperemia [redness score (RS)], corneoconjunctival staining (CFS), corneal sensitivity (CS), Meibomian gland quality (MGQ) and Meibomian gland expressibility (MGEx), corneal nerve fiber density (CNFD), and Standard Patient Evaluation Eye Dryness (SPEED) questionnaire were assessed at baseline, at weeks 4, and up to 8 weeks. Matrix metalloproteinase-9 (MMP-9) of tear samples was measured at baseline and weeks 8. Results: The mean age was 61.27 ± 11.68 years. At baseline NITBUT = 5.89 ± 2.81 s, tear meniscus height = 0.17 ± 0.05 mm, TFLL = 2.74 ± 0.51, CFS = 4.35 ± 0.68, CS = 53.83 ± 9.63 mm, MMP-9 = 49.10 ± 10.42 ng/mL, RS = 1.65 ± 0.44, MGEx = 1.85 ± 0.72, MGQ = 2.65 ± 0.50, CNFD = 20.36 ± 8.20 no./mm2, and SPEED = 12.62 ± 3.91. At week 4, significant improvements were found in all parameters except RS (1.59 ± 0.46, P = 0.172) and CNFD (21.46 ± 8.41, P = 0.163). Finally, at week 8, all parameters had significant improvements. Conclusion: Preliminary short-term findings suggest that treatment of DDE patients with DQS was found to be safe and efficacious in improving dry eye parameters. In addition, inflammatory marker and corneal nerve density were significantly improved. This study was registered with ClinicalTrials.gov (NCT05193331).

BACKGROUND: To investigate the role of neutrophils in corneal nerve regeneration.
METHODS: A mouse model simulating corneal nerve injury was established and samples from corneal scraping with and without neutrophil closure were collected. These samples were used for corneal nerve staining, ribonucleic acid sequencing, and bioinformatics. Differential expression analysis was used to perform enrichment analysis to identify any significant differences between these two groups. The differential genes were then intersected with neutrophil-associated genes and a protein-protein interaction network was constructed using the intersected genes. The immune infiltration between the two groups was examined along with the immune cell variation between the high and low gene expression groups.
RESULTS: Neutrophil removal delays corneal epithelial and nerve regeneration. A total of 546 differential genes and 980 neutrophil-associated genes, with 27 genes common to both sets were obtained. Molecular Complex Detection analysis yielded five key genes, namely integrin subunit beta 2 (ITGB2), matrix metallopeptidase 9 (MMP9), epidermal growth factor (EGF), serpin family E member 1 (SERPINE1), and plasminogen activator urokinase receptor (PLAUR). Among these genes, ITGB2, SERPINE1, and PLAUR exhibited increased expression in the neutrophil-confined group, while MMP9 and EGF showed decreased expression, with MMP9 and EGF displaying a more significant difference. Immune infiltration was also observed between the two groups, revealing significant differences in the infiltration of M0 macrophages, activated mast cells, and neutrophils. Moreover, the neutrophil levels were lower in the groups with low MMP9 and EGF expressions and higher in the high-expression group.
CONCLUSIONS: Neutrophil confinement might significantly affect the MMP9 and EGF expression levels. Strategies to inhibit MMP9 could potentially yield therapeutic benefits.

UNASSIGNED: 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).
UNASSIGNED: Prospective nonrandomized comparative trial.
UNASSIGNED: 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.
UNASSIGNED: 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).
UNASSIGNED: 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.

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.

OBJECTIVE: To observe corneal nerve fibers and densitometry after small incision lenticule extraction (SMILE), femtosecond laser-assisted laser in situ keratomileusis (FS-LASIK) and laser-assisted subepithelial keratomileusis (LASEK) for high myopia.
METHODS: This is a prospective, cross-sectional research study. Patients with high myopia (equivalent spherical lens: -6.00 and -11.00D) who underwent laser corneal refractive surgery were divided into three groups: SMILE, FS-LASIK and LASEK. Scheimpflug imaging of corneal nerves in five areas was observed by confocal microscopy before and 6, 12 months after surgery. Corneal densitometry was measured by Pentacam anterior segment analysis system.
RESULTS: Overall, 59 patients were enrolled. The nerve density in the central area did not recover to the preoperative level in three groups until 12 months. The density and length of corneal nerves in central and lower area were better in the SMILE group 6 months postoperatively (p = 0.01), while nerve density did not differ significantly among three groups 12 months postoperatively (p = 0.18). Nerve fibers in central and temporal region were wider in LASEK than that in other two groups at 6- and 12-month follow-up. Corneal densitometry in the central 6 mm diameter was significantly higher in the LASEK group compared with other two groups 6 months postoperatively (p = 0.04). Twelve months postoperatively, corneal densitometry in range of all zone was lower in SMILE than in FS-LASIK and LASEK (p = 0.01, 0.03, 0.04).
CONCLUSIONS: Compared with FS-LASIK and LASEK, SMILE-treated eyes with high myopia had certain advantages in nerve density, length and nerve connection way and had better corneal transparency after operation.

OBJECTIVE: To investigate corneal sub-basal nerve morphology changes in primary Sjogren\'s syndrome (SS) dry eye (SSDE) patients and determine the association with disease severity at microstructural level.
METHODS: Twenty-eight eyes of 17 SSDE and 82 eyes of 47 age- and sex-matched non-SS dry eye (NSSDE) patients were included. The Ocular Surface Disease Index questionnaire (OSDI), Schirmer\'s test (ST), tear meniscus height (TMH), non-invasive breakup time (NIBUT), meibomian gland (MG) morphology, and ocular staining score (OSS) were assessed. In vivo confocal microscopy was performed to observe corneal sub-basal nerve morphology (length, reflectivity, width, and tortuosity). Associations between clinical features and nerve parameters were analysed.
RESULTS: SSDE patients more frequently had increased nerve reflectivity (151.12 ± 17.07 vs. 139.37 ± 14.31 grey value), width (4.45 ± 0.87 vs. 3.92 ± 0.81 μm), tortuosity (132.90 ± 8.04 vs. 129.50 ± 7.33 degree), and higher reflectivity, width, and total nerve grades than NSSDE individuals (all P < 0.05). Significant associations were found between nerve reflectivity/width and anti-SSA [OR = 1.139 (1.013-1.281)/1.802 (1.013-4.465)]/labial gland biopsy [OR = 1.046 (1.002-1.161)/1.616 (1.020-3.243)]. Higher nerve width was associated with increased OSDI [β = 0.284 (0.187-0.455)], MG score [β = 0.185 (0.109-0.300)] and OSS [β = 0.163 (0.020-0.345)], but decreased NIBUT [β =  - 0.247 (- 0.548 ~  - 0.154)]. Higher nerve total grade was associated with increased OSDI [β = 0.418 (0.157-0.793)] and OSS [β = 0.287 (0.027-0.547)], but decreased ST [β =  - 0.410 (-0.857 ~  - 0.138)].
CONCLUSIONS: Corneal nerve morphology changes associated with clinical features in SS patients. These changes may facilitate severity evaluation and management of the disease.

BACKGROUND: Dry eye syndrome (DES) is a common disease with various clinical manifestations. DES had a significant association with diabetes. Blink reflex (BR) is also known as trigeminal nerve facial reflex. The stimulation of corneal nerves is one of the origins of BR stimulation. The parasympathetic fibers sent out through the facial nerve are the outlet of tear reflexes. BR can be used to assess the function of the corneal nerve closed-loop; however, whether the BR changes in these patients is unclear.
OBJECTIVE: To understand the morphology and function of the corneal nerve in patients with dry eyes having diabetes or not.
METHODS: This study enrolled 131 patients who visited the inpatient and outpatient services of ophthalmology and endocrinology departments between January 2019 to August 2020 with subjective symptoms of dry eyes and non-dry eye reasons, as well as volunteers such as colleagues. The patients were divided into four groups: DEwDM, with dry eyes having type 2 diabetes mellitus (T2DM); DMnDE, with T2DM not having dry eyes; DEnDM, with dry eyes not having diabetes; and nDMnDE, with neither dry eyes nor diabetes. The tear film break-up time, Schirmer I test, in vivo confocal microscopy, and BR were performed.
RESULTS: The DEwDM, DMnDE, DEnDM, and nDMnDE groups included 56, 22, 33, and 20 patients, respectively. Sex and age were not statistically different among the four groups. The nerve fiber length (NFL) of patients in the DEwDM, DEnDM, and DMnDE groups reduced (P < 0.001, P = 0.014, and P = 0.001, respectively). No significant difference in corneal nerve fiber density (NFD) (P = 0.083) and corneal nerve branch density (NBD) (P = 0.195) was found among the four groups. The R1 Latency of blink reflexes increased only in the DEwDM group (P = 0.008, P = 0.001, P < 0.001, compared with the DMnDE, DEnDM, and nDMnDE groups, respectively). The NBD and R1 Latency were different between DEwDM and DEnDM groups in patients with moderate and severe dry eyes.
CONCLUSIONS: The corneal nerve morphology changed in patients with dry eyes or diabetes, or with both, while the function of corneal nerve closed-loop reduced only in those with dry eyes and diabetes.

UNASSIGNED: This study aimed to evaluate the features of corneal nerve with in vivo confocal microscopy (IVCM) among patients with non-neurological autoimmune (NNAI) diseases.
UNASSIGNED: We systematically searched PubMed, Web of Science, and Cochrane Central Register of Controlled Trials for studies published until May 2021. The weighted mean differences (WMDs) of corneal nerve fiber length (CNFL), corneal nerve fiber density (CNFD), corneal nerve branch density (CNBD), tortuosity, reflectivity, and beadings per 100 μm with a 95% CI between NNAI and control group were analyzed using a random-effects model.
UNASSIGNED: The results showed 37 studies involving collective totals of 1,423 patients and 1,059 healthy controls were ultimately included in this meta-analysis. The pooled results manifested significantly decreased CNFL (WMD: -3.94, 95% CI: -4.77--3.12), CNFD (WMD: -6.62, 95% CI: -8.4--4.85), and CNBD (WMD: -9.89, 95% CI: -14--5.79) in NNAI patients. In addition, the NNAI group showed more tortuous corneal nerve (WMD: 1.19, 95% CI:0.57-1.81). The comparison between NNAI patients and healthy controls in beadings per 100 μm corneal nerve length was inconsistent. No significant difference was found in the corneal nerve fiber reflectivity between NNAI and the control group (WMD: -0.21, 95% CI: -0.65-0.24, P = 0.361).
UNASSIGNED: The parameters and morphology of corneal nerves observed by IVCM proved to be different in NNAI patients from healthy controls, suggesting that IVCM may be a non-invasive technique for identification and surveillance of NNAI diseases.