Reduced corneal sensation in individuals with type 2 diabetes mellitus (T2DM) leads to a dissociation between dry eye disease (DED) signs and symptoms, thereby affecting diagnostic accuracy. This study aimed to investigate the correlation between ocular surface signs and diabetic peripheral neuropathy (DPN) symptoms in patients with T2DM-associated DED.

The Michigan Neuropathy Screening Instrument Questionnaire (MNSIQ) was used to categorize patients with T2DM into MNSIQ-DPN and non-DPN groups. Ocular irritation symptoms were evaluated using the Ocular Surface Disease Index (OSDI) questionnaire. Ocular surface lesions were assessed via Cochet-Bonnet esthesiometry, corneal fluorescein staining (CFS), the Schirmer I tear test (SIT), tear meniscus height (TMH), noninvasive keratography break-up time (NIKf-BUT), and the meibomian gland loss (MGL) grade detected by OCULUS. Corneal nerve fiber parameters were evaluated using in vivo confocal microscopy (IVCM).

A total of 116 patients with T2DM, comprising 76 non-DPN patients and 40 MNSIQ-DPN patients, along with 51 age-matched participants without diabetes, were enrolled. Although OSDI scores were equivalent between MNSIQ-DPN patients and non-DPN patients, MNSIQ-DPN patients presented significantly more severe CFS (p < 0.001), meibomian gland dysfunction (MGD) (p < 0.001), corneal nerve fiber loss (p < 0.001), sensory dysfunction (p = 0.02), and corneal microneuromas (p < 0.001). The MNSIQ score was significantly positively correlated with CFS (p < 0.001); MGD (p < 0.01); corneal nerve fiber loss, including corneal nerve fiber density and length and branch density, in the paracentral (all p < 0.001) and inferior-whorl areas (p < 0.01, p < 0.05 and p < 0.01, respectively); and corneal microneuromas, characterized by increased microneuroma numbers (p < 0.001) and areas (p < 0.001) in these regions.

MNSIQ scores were significantly and robustly correlated with the presence of corneal epithelial defects, MGD, and nerve fiber loss in patients with T2DM. These findings suggest that DPN is a critical factor in diabetic ocular surface complications, highlighting the importance of the MNSIQ for assessing these conditions.

The aim of this review is to evaluate corneal microstructural changes and nephropathy in participants with diabetic peripheral neuropathy (DPN+) and without (DPN-) in each of type 1 (T1DM) and type 2 diabetes (T2DM). A systematic review of primary studies was conducted that quantified corneal sub-basal nerve plexus parameters using laser scanning in vivo corneal confocal microscopy (CCM) and DPN+ in at least five humans with diabetes mellitus. CCM parameters examined were corneal nerve fibre density (NFD), nerve branch density (NBD) and nerve fibre length (NFL). Weighted mean difference (±standard error) is reported. Twenty-six studies were included in this meta-analysis (18 for T1DM, 14 for T2DM). This comprised 1,357 participants with T1DM (573,784; DPN+, DPN-), 1,119 with T2DM (598,521; DPN+, DPN-) and 1,032 non-diabetic controls. Compared to T2DM, T1DM participants had larger differences in NFD (8.54 ± 0.83 vs 3.61 ± 0.41), NBD (11.92 ± 1.93 vs 3.56 ± 1.03) and NFL (4.24 ± 0.41 vs 1.65 ± 0.18) between DPN+ and DPN- groups. T1DM participants also had larger differences than T2DM participants in NBD (-21.26 ± 2.90 vs -6.15 ± 1.69) and NFL (-4.25 ± 0.59 vs -2.65 ± 0.31) between DPN- and non-diabetic controls, but smaller, insignificant difference, in NFD (-5.93 ± 0.90 vs -6.39 ± 0.92). eGFR was significantly different between DPN+ and DPN- in T1DM (p < 0.00001) but not in T2DM (p = 0.46). When comparing DPN- to DPN+, ACR was reduced in T1DM (-2.72 ± 1.14) and T2DM (-20.85 ± 8.91). Corneal sub-basal nerve changes and glomerular nephropathy likely precede peripheral neuropathy in T1DM and T2DM, with greater corneal neuropathy in T1DM. The current evidence suggests that CCM may be useful for monitoring the progression of diabetic neuropathy and nephropathy.

Unilateral herpes zoster ophthalmicus (HZO) results in bilateral corneal denervation in patients with corneal involvement, which correlates with corneal sensation loss. The study aimed to analyze bilateral corneal nerve changes in patients with acute unilateral HZO and no keratitis compared with healthy controls.

This was a prospective, single-center study. Using in vivo confocal microscopy (IVCM) and an automatized single image analysis software (ACCmetrics, University of Manchester, UK), seven corneal nerve parameters, including corneal nerve fiber density (CNFD; no/mm2), corneal nerve branch density (CNBD; no/mm2), corneal nerve fiber length (CNFL; mm/mm2), corneal nerve total branch density (CTBD; no/mm2), corneal nerve fiber area (CNFA; mm2/mm2), corneal nerve fiber width (CNFW; mm/mm2), and corneal nerve fiber fractal dimension (CFracDim) were analyzed. Additionally, central corneal sensitivity was measured.

Forty-six patients with HZO and 49 controls were recruited and compared. In the HZO group, ipsilateral and contralateral eyes presented a significant decrease (p < 0.001) in all seven IVCM parameters compared with controls: CNFD (13.25 ± 5.23 and 15.24 ± 4.70 vs. 23.54 ± 6.54), CNBD (14.67 ± 9.03 and 16.59 ± 7.98 vs. 31.72 ± 17.89), CNFL (8.42 ± 2.83 and 9.06 ± 2.69 vs. 13.08 ± 4.02), CTBD (27.11 ± 13.71 and 23.58 ± 12.69 vs. 46.88 ± 24.90), CNFA (0.0044 ± 0.002 and 0.0042 ± 0.001 vs. 0.0056 ± 0.002), CNFW (0.0213 ± 0.003 and 0.0221 ± 0.003 vs. 0.0222 ± 0.001) and CFracDim (1.39 ± 0.06 and 1.38 ± 0.06 vs. 1.45 ± 0.05). In the ipsilateral HZO eye group, a positive Hutchinson sign or a reduced corneal sensitivity was associated with more extensive corneal denervation. A significant negative correlation was found between patient age and CNFD (rho = - 0.312, p < 0.002), CNFL (rho = - 0.295, p = 0.004), and CFracDim (rho = - 0.284, p = 0.005).

Unilateral HZO in patients without apparent keratitis leads to bilateral subbasal nerve plexus alteration in the early days after disease onset, especially in those with a positive Hutchinson sign. Early follow-up of patients with HZO and bilateral application of preservative-free artificial tears during the initial months of symptom onset may help reduce the risk of developing neurotrophic keratopathy (NTK).

This study explores the role of corneal confocal microscopy (CCM) in detecting axonal degeneration in people with multiple sclerosis (pwMS) and its correlation with severity.

A literature search was conducted across PubMed, Scopus and Google Scholar. Differences in corneal nerve fiber density (CNFD), corneal nerve fiber branch density (CNBD), corneal nerve fiber length (CNFL), between pwMS and healthy controls were quantified using risk ratio (RR) and estimated using random effects models due to high observed heterogeneity. Random-effects meta-regression was utilized to evaluate the relationship between severity and CNFD, CNFL and CNBD.

A total of 8 studies were included with 351 pwMS. CNFD and CNFL were lower in pwMS compared to controls (Hedge's G Effect Size = -1.53, 95 % CI:2.62, -0.44, p = .01). Meta-regression analysis showed that CNFD (Mean b = -1.93, 95 % CI (-3.32, -0.55), p = .01), CNBD (Mean b = -33.36, 95 % CI (-48.90, -17.82), p < .01) and CNFL (Mean b = -2.31, 95 % CI (-2.94, -1.68) p < .01) had significant associations with Multiple Sclerosis Severity Score (MSSS) but not with Extended Disability Severity Score (EDSS).

CCM can be a non-invasive imaging biomarker for axonal degeneration in pwMS.

Background: Although prediabetes increases the risk of developing diabetes, its role in neuropathy remains unclear. We aim to assess alterations in the corneal nerve structure and function in prediabetes and risk factors for corneal nerve loss. Methods: An examination of IVCM and corneal sensitivity was conducted on a cohort of 75 participants, comprising 23 controls, 32 prediabetes, and 20 Type 2 diabetes. Semiautomatic analysis was employed to quantify the corneal nerve fiber length (CNFL), corneal nerve fiber density (CNFD), and dendritic cell (DC) density. Results: CNFL and CNFD were lower in prediabetes and Type 2 diabetes than in the controls, and they were associated with DC density. CNFL and CNFD were lower in Type 2 diabetes than in prediabetes. DC density was higher in prediabetes and Type 2 diabetes than in controls. However, there were no differences in corneal sensitivity between controls and prediabetes. Multivariable regression analysis demonstrated an association between reduced CNFL and age, BMI, fasting plasma glucose (FPG), and uric acid (UA) levels in prediabetes. In Type 2 diabetes, age, HbA1c, blood urea nitrogen (BUN), creatinine (Cr), and triglyceride levels exhibited associations with reduced CNFL. Conclusions: Corneal nerve damage was detected in prediabetes using IVCM. The patients with prediabetes showed signs of nerve structure damage, and the corneal nerve structure damage occurred before the nerve function changes. Immune cells also participate in the occurrence and development of DCN and are related to the corneal neuropathy. Understanding the corneal nerve fiber condition through IVCM may prove crucial in monitoring prediabetic neuropathy.

This study investigates nerve fiber dysfunction in type 1 diabetes (T1D) patients and identifies risk factors for diabetic peripheral neuropathy (DPN). It evaluates the relationship between current perception threshold (CPT) tests and nerve conduction velocity (NCV), and assesses CPT's diagnostic accuracy for early DPN detection.

This study enrolled 110 patients with T1D and 26 healthy controls between January 2020 and December 2021, in accordance with predefined inclusion/exclusion criteria. CPT testing at 2000 Hz, 250 Hz, and 5 Hz assessed Aβ, Aδ, and C fiber function, while NCV was measured in 47 patients. Subgroups were stratified by disease duration (>5 years vs ≤5 years). Multivariate logistic regression identified DPN risk factors, and CPT-NCV correlation was analyzed using Chi-square and Kappa tests. Receiver operating characteristic (ROC) curves evaluated CPT diagnostic efficacy.

The incidence of DPN in 110 T1D patients was 78%, with no significant difference between disease duration subgroups (78.3% vs. 78.0%). Neurological abnormalities were significantly more common in the lower extremities compared to the upper extremities (67.27% vs. 49.09%, P < 0.05). Multivariate logistic regression analysis revealed that a waist-to-hip ratio (WHR) greater than 0.85 was an independent risk factor for DPN (OR = 3.01, 95% CI: 1.03-8.80, P < 0.05). Patients with a disease duration >5 years demonstrated significantly higher 2000Hz abnormality rates (68.09% vs. 46.15%, P < 0.05) and more severe neurological lesions (57.45% vs. 35.90%, P < 0.05). In contrast, those with disease duration ≤5 years exhibited elevated 5Hz abnormality rates (30.77% vs. 10.64%, P < 0.05) with predominantly milder lesions (56.41% vs. 31.91%, P < 0.05). Statistical analyses demonstrated a significant association between CPT and NCV (P<0.001), with moderate diagnostic consistency further supported by Cohen's Kappa Test (κ=0.515, P<0.001). ROC curve analysis demonstrated that CPT exhibited moderate diagnostic accuracy in detecting DPN at the 5Hz, with an area under the curve (AUC) of 0.723.

CPT showed moderate diagnostic accuracy for early unmyelinated (C) fibers detection, routine CPT screening in high-risk groups (central obesity/short disease duration) enables timely intervention to prevent irreversible damage.

This study aimed to assess the impact of diabetes mellitus (DM) on the corneal nerve, ocular surface, and tear cytokine and substance P (SP) levels and to compare the findings with those in control subjects.

This cross-sectional study included 23 patients diagnosed with DM within the last 5 years and who had no systemic involvement, including diabetic retinopathy, and 22 control subjects. The ocular surface and tear film were assessed using the Ocular Surface Disease Index (OSDI) questionnaire, ocular surface staining, Schirmer, and corneal sensitivity. In vivo confocal microscopy was used to assess the architecture of the corneal nerves. The tear levels of cytokines were examined by Luminex and SP levels were measured by ELISA.

Both groups had similar OSDI scores, ocular surface staining, Schirmer, and corneal sensitivity measurements. The patient group had higher corneal nerve tortuosity (p = 0.015) but showed no significant difference in short or long nerve fibre density compared with the control group. Tear IL-6 and IL-8 levels were higher in the DM group (p = 0.002 and p = 0.01, respectively), whereas tear SP levels were lower in the DM group (p = 0.05). The tear SP level exhibited a strong positive correlation with total and long nerve fibre parameters (both p = 0.00).

The study results indicated that DM affected corneal nerve structure, tear SP, and inflammatory cytokine levels. The corneal nerves were affected and the tear SP level decreased even in patients without peripheral neuropathy, which is one of the most common complications of DM. In addition, ocular surface inflammation was observed in patients with DM, despite no ocular surface symptoms.

To explore the relationship between dry eye disease and type 1 diabetes mellitus (DM) and also to identify whether diabetic peripheral neuropathy (DPN) was a significant predictor for the development of dry eye disease.

This prospective cross sectional study involved patients with type 1 DM and aged- and sex-matched healthy controls. All of the participants underwent dry eye tests including meibomian gland function. Based on neurologic examination and electromyography findings, diabetic patients were grouped as DPN + and DPN-. All findings were compared and predictive factors for dry eye disease were identified.

Of the 97 patients with type 1 DM, 42 (43.3%) were diagnosed as DPN. In patients with DM, there was a significant increase in the ocular surface disease index, corneal surface staining, eyelid margin abnormality and meibomian gland dysfunction and a significant decrease in tear break-up time and Schirmer's I test (p < 0.05). Measurements of dry eye tests were more severe with the presence of DPN (p < 0.05). Age of the patients, duration of DM and HbA1c level were significantly correlated with ocular surface and meibomian gland dysfunction parameters (p < 0.05). Age of the patients (p < 0.001), duration of DM (p = 0.001), HbA1c level (p = 0.036) and presence of DPN (p < 0.001) were found to be the independent and significant predictors of dry eye disease.

Type 1 DM was found to be significantly associated with ocular surface abnormalities including meibomian gland dysfunction. Furthermore, age of the patients, duration of DM, HbA1c level and presence of DPN were predictive factors of dry eye disease in type 1 DM.

Diabetic peripheral neuropathy (DPN) is a common complication of diabetes, posing a significant risk for foot ulcers and amputation. Corneal confocal microscopy (CCM) is a rapid, noninvasive method to assess DPN by analysing corneal nerve fibre morphology. However, selecting high-quality representative images remains a critical challenge.

In this study, we propose a fully automated CCM image-selection algorithm based on deep learning feature extraction using ResNet-18 and unsupervised clustering. The algorithm consistently identifies representative images by balancing non-redundancy and representativeness, ensuring objectivity and reproducibility.

When validated against manual selection by researchers with varying expertise levels, the algorithm demonstrated superior performance in distinguishing DPN and reduced inter-observer variability. It completed the analysis of hundreds of images within 1 s, significantly enhancing diagnostic efficiency. Compared with traditional manual selection, the proposed method achieved higher diagnostic accuracy for key morphological parameters, including corneal nerve fibre density, length, and branch density.

The algorithm is open source and compatible with standard CCM workflows, offering researchers and clinicians a robust and efficient tool for DPN diagnosis. Further, multicentre studies are needed to validate these findings in diverse populations.

Peripheral neuropathy is a common cause of morbidity in diabetes. Despite recent advancements in early diagnosis methods, there is a need for practical, highly sensitive, and cost-effective screening methods in clinical practice. This study summarizes evidence from systematic reviews and meta-analyses on the diagnostic accuracy of validated screening methods for diabetic peripheral neuropathy. Two independent reviewers assessed methodological quality and bias using AMSTAR and ROBIS tools. Seven reviews with 19,531 participants were included. The monofilament test showed inconsistent sensitivity (S: 0.53-0.93) and specificity (Sp: 0.64-1.00), along with high variability in its application. Neuropad exhibited high S (86%, 95% CI 79-91). However, variations in the interpretation of results across the included studies may have impacted its Sp (65%, 95% CI 51-76). The Ipswich touch test exhibited adequate diagnostic accuracy (S: 0.77, Sp: 0.96, DOR: 75.24) but lacked comparison with gold standard tests. In vibration perception studies, the biothesiometer outperformed the tuning fork (S: 0.61-0.80 vs. 0.10-0.46). In general, heterogeneity was observed due to varied reference tests, thresholds, and patient differences. The development of automated analysis methods, as well as determination of predictive value of the combination of screening tools, is needed for further studies. Based on the study results, we suggest that clinicians should select screening tools tailored to their patient population, clinical setting, and available resources, as no single test can be universally recommended for all clinical scenarios.

Corneal confocal microscopy is a noninvasive imaging technique to analyze corneal nerve fibers and corneal inflammatory cells (CICs). The amount of CICs is a potential biomarker of disease activity in chronic autoinflammatory diseases. To date, there are no standardized criteria for the morphological characterization of CICs. The aim was to establish a protocol for a standardized morphological classification of CICs based on a literature search and to test this protocol for applicability and reliability.

A systematic review of the literature about definitions of CICs was conducted. Existing morphological descriptions were translated into a structured algorithm and applied by raters. Subsequently, the protocol was optimized by reducing and defining the criteria of the cell types. The optimized algorithm was applied by 4 raters. The interrater reliability was calculated using Fleiss kappa (K).

A systematic review of the literature revealed no uniform morphological criteria for the differentiation of the individual cell types in CICs. Our first protocol achieved only a low level of agreement between 3 raters (K = 0.09; 1062 rated cells). Our revised protocol was able to achieve a higher interrater reliability with 3 (K = 0.64; 471 rated cells) and 4 (K = 0.61; 628 rated cells) raters.

The indirect use of criteria from the literature leads to a high error rate. By clearly defining the individual cell types and standardizing the protocol, reproducible results were obtained, allowing the introduction of this protocol for the future evaluation of CICs in the corneal confocal microscopy.

In this Prentice Medal Award lecture, I shall recount my career in vision science in the context of three types of inspiration-"being inspired," "personal inspiration," and "inspiring others." My research has derived inspiration from a variety of sources, such as contemporary and historical research doyens in the ophthalmic field and beyond, artists, Greek philosophers, and abstract constructs such as principles and adages. A given moment of inspiration can range from being a profound experience to a subtle realization during a quiet moment of reflection. Here I shall recount the primary research domains of vision science that have defined my academic career in the context of the three types of inspiration defined above. These research domains are ophthalmic markers of diabetic neuropathy, ocular response to contact lens wear, contact lens-induced parainflammation, contact lens-associated microbial keratitis, grading scales for contact lens complications, contact lens prescribing surveys, material properties of contact lenses, contact lens compliance, history of contact lenses, ocular thermography, and ophthalmic bibliometrics. The notions of "being inspired" and "personal inspiration" are necessarily subjective, although I have endeavored to present them here in a scientific context. Conversely, the notion of "inspiring others" can be objectively gauged, at least in part, by counting article citations or the number of times articles are read online or downloaded from a journal website. In conclusion, my research in the vision sciences has been inspired by others, derived from personal ideas, and perhaps in turn has inspired others.

Neurotrophic keratopathy is an uncommon degenerative corneal disorder characterized by compromised corneal sensory innervation resulting in the formation of epithelial defects and nonhealing corneal ulcers. Various treatment modalities are available to stabilize disease progression, improve patient well-being, and prevent vision loss. For eligible patients, medical and surgical reinnervation have emerged as pioneering therapies, holding promise for better management. We present a comprehensive review of the disorder, providing an update relevant to ophthalmologists on pathogenesis, diagnosis, treatment options, and novel therapies targeting pathophysiological pathways.

Deficiency of neurotropic factors is implicated in diabetic neuropathy (DN). Netrin-1 is a neurotropic factor, but its association with DN has not been explored. We have assessed the association between serum netrin-1 levels and early diabetic neuropathy assessed by quantifying corneal nerve fiber loss using corneal confocal microscopy.

A total of 72 participants with type 2 diabetes, without and with corneal nerve fiber loss (DN- n = 42, DN+ n = 30), and 45 healthy controls were studied. Serum netrin-1 levels were measured by enzyme-linked immunosorbent assay, and corneal nerve morphology was assessed using corneal confocal microscopy.

Corneal nerve fiber density, branch density, fiber length and serum netrin-1 levels were significantly lower in the DN- and DN+ groups compared with controls (P < 0.001). Netrin-1 levels correlated with corneal nerve fiber length in the DN+ group (r = 0.51; P < 0.01). A receiver operating characteristic curve analysis showed that a netrin-1 cut-off value of 599.6 (pg/mL) had an area under the curve of 0.85, with a sensitivity of 76% and specificity of 74% (P < 0.001; 95% confidence interval 0.76-0.94) for differentiating patients with and without corneal nerve loss.

Serum netrin-1 levels show a progressive decline with increasing severity of small nerve fiber damage in patients with diabetes. Netrin-1 could act as a biomarker for small nerve fiber damage in DN.

There has been a growing application of in vivo confocal microscopy (IVCM) in the examination of corneal microstructure, including different corneal layers and corneal nerve fibers in health and in pathological conditions. Corneal nerves forming the sub-basal nerve plexus (SBNP) beneath the corneal basal epithelial cell layer in particular have been intensively researched in health and disease as a marker for corneal neurophysioanatomical and degenerative changes. One intriguing feature in the SBNP that is found inferior to the corneal apex, is a whorl-like pattern (or vortex) of nerves, which represents an anatomical landmark. Evidence has indicated that the architecture of this 'whorl region' is dynamic, changing with time in healthy individuals but also in disease conditions such as in diabetic neuropathy and keratoconus. This review summarizes the known information regarding the characteristics and significance of the whorl region of nerves in the corneal SBNP, as a potential area of high relevance for future disease monitoring and diagnostics.

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).

To compare, between Alzheimer's disease (AD) patients and healthy individuals, corneal subbasal nerve plexus (CSNP) parameters and corneal sensitivities.

Twenty-two patients who were followed up with Alzheimer's disease (Alzheimer's group) and 18 age- and gender-matched healthy individuals (control group) were included in this cross-sectional study. CSNP parameters, including nerve fiber length (NFL), nerve fiber density (NFD), and nerve branch density (NBD), were evaluated using in vivo confocal microscopy. Corneal sensitivity was evaluated using a Cochet-Bonnet esthesiometer. The results were compared between the two groups.

In the Alzheimer's group, NFL was 12.2 (2.4) mm/mm2, NFD was 12.5 [3.1] fibers/mm2, and NBD was 29.7 [9.37] branches/mm2. In the control group, NFL was 16.5 (2.0) mm/mm2, NFD was 25.0 [3.13] fibers/mm2, and NBD was 37.5 [10.9] branches/mm2. All three parameters were significantly lower in the Alzheimer's group compared to the control group (p < 0.001, p < 0.001, and p = 0.001, respectively). Similarly, corneal sensitivity was significantly lower in the Alzheimer's group (55.0 [5.0] mm) compared to the control group (60.0 [5.0] mm) (p < 0.001).

We determined that, in AD, corneal sensitivity decreases significantly, in parallel with the decrease in corneal nerves. Changes in the corneal nerve plexus and a decrease in corneal sensitivity may be used in the early diagnosis and follow-up of AD. In addition, ocular surface problems secondary to these changes should also be kept in mind.

This study aimed to investigate corneal limbus changes in patients with type 2 diabetes mellitus (DM) using in vivo confocal microscopy (IVCM) and explore the correlation between their ocular manifestations and systemic status.

Fifty-five patients with type 2 DM and 20 age-matched controls were included. The following IVCM parameters were compared between the 2 groups: palisades of Vogt (POV), corneal epithelial thickness (CET), basal cell density (BCD), subbasal nerve plexus, and dendritic cell density. All subjects underwent blood and urine sampling for laboratory analysis, including fasting blood glucose, glycated hemoglobin, total cholesterol (TC), triglycerides (TG), low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, C-reactive protein, urinary albumin-to-creatinine ratio, urine albumin, and urine creatinine. The correlations between IVCM parameters and blood biomarkers were detected. Receiver operating characteristic curve was used for selecting the cutoff value of risk factors for corneal stem cell injury in patients with DM.

Compared with controls, patients with DM displayed a significant reduction of POV (superior region, P = 0.033; inferior region, P = 0.003; nasal region, P < 0.001; temporal region, P < 0.001), central CET (44.8 ± 3.6 μm vs. 51.9 ± 3.6 μm, P < 0.001), central corneal BCD (7415.5 ± 563.2 cells/mm 2 vs. 9177.9 ± 977.8 cells/mm 2 , P < 0.001), and peripheral corneal BCD (6181.3 ± 416.5 cells/mm 2 vs. 8576.3 ± 933.2 cells/mm 2 , P < 0.001). Dendritic cell density (41.0 ± 33.7 cells/mm 2 vs. 24.6 ± 7.8 cells/mm 2 , P = 0.001) was significantly higher in the DM group. The following weak correlations were shown between IVCM parameters and blood biomarkers: central corneal BCD was negatively correlated with DM duration (r = -0.3, P = 0.024), TC (r = -0.36, P = 0.007), and LDL (r = -0.39, P = 0.004). The presence of POV in the superior region was negatively correlated with TC (r = -0.34, P = 0.011) and LDL (r = -0.31, P = 0.022). Cutoff values of 1.215 mmol/L for HDL, 1.59 mmol/L for TG, or 4.75 mmol/L for TC were established to distinguish patients with a high risk from a low risk for stem cell damage.

Patients with type 2 DM displayed a lower positive rate of typical POV and a decrease in BCD, CET, and subbasal nerve density. The most relevant indicators for stem cell phenotypes were DM duration, TC, and LDL. Lipid status in diabetic patients could be a predictor of risk for developing corneal limbal stem cell deficiency. Further studies with larger sample sizes or basic research are needed to verify the results.

Distal sensory polyneuropathy (DSP) is characterised by length-dependent, sensory-predominant symptoms and signs, including potentially disabling symmetric chronic pain, tingling and poor balance. Some patients also have or develop dysautonomia or motor involvement depending on whether large myelinated or small fibres are predominantly affected. Although highly prevalent, diagnosis and management can be challenging. While classic diabetes and toxic causes are well-recognised, there are increasingly diverse associations, including with dysimmune, rheumatological and neurodegenerative conditions. Approximately half of cases are initially considered idiopathic despite thorough evaluation, but often, the causes emerge later as new symptoms develop or testing advances, for instance with genetic approaches. Improving and standardising DSP metrics, as already accomplished for motor neuropathies, would permit in-clinic longitudinal tracking of natural history and treatment responses. Standardising phenotyping could advance research and facilitate trials of potential therapies, which lag so far. This review updates on recent advances and summarises current evidence for specific treatments.

No guidelines are available on the preferred method for analyzing corneal confocal microscopy (CCM) data. Manual, semiautomatic, and automatic analyzes are all currently in use. The purpose of the present study was threefold. First, we aimed to investigate the different methods for CCM analysis in patients with and without small fiber neuropathy (SFN). Second, to determine the correlation of different methods for measuring corneal nerve fiber length (CNFL) and nerve fiber area (NFA). Finally, we investigated the added value of automatic NFA analysis.

We included 20 healthy controls and 80 patients with sarcoidosis, 31 with established SFN and 49 without SFN. The CNFL was measured using CCMetrics, ACCMetrics, and NeuronJ. NFA was measured with NFA FIJI and ACCMetrics NFA.

CNFL and NFA could not distinguish sarcoidosis with and without SFN or healthy controls. CCMetrics, NeuronJ, and ACCMetrics CNFL highly correlated. Also, NFA FIJI and ACCMetrics NFA highly correlated. Reproducing a nonlinear formula between CNFL and NFA confirmed the quadratic relation between NFA FIJI and ACCMetrics CNFL. CCMetrics and NeuronJ instead showed a square root relationship and seem to be less comparable owing to differences between automatic and manual techniques.

ACCMetrics can be used for fully automatic analysis of CCM images to optimize efficiency. However, CNFL and NFA do not seem to have a discriminatory value for SFN in sarcoidosis. Further research is needed to determine the added value and normative values of NFA in CCM analysis.

Our study improves the knowledge about CCM software and pathophysiology of SFN.

Diabetic neuropathy is a common complication of diabetes that affects up to 50% of patients during the course of the disease; 20-30% of the patients also develop neuropathic pain. The mechanisms underlying neuropathy are not known in detail, but both metabolic and vascular factors may contribute to the development of neuropathy. The development of the most common type of neuropathy is insidious, often starting distally in the toes and feet and gradually ascending up the leg and later also involving fingers and hands. The symptoms are mainly sensory with either sensory loss or positive symptoms with different types of paresthesia or painful sensations. In more advanced cases motor dysfunction may occur, causing gait disturbances and falls. The diagnosis of neuropathy is based on history and a careful examination, which includes a sensory examination of both large and small sensory nerve fiber function, as well as an examination of motor function and deep tendon reflexes of the lower limbs. Attention needs to be paid to the feet including examination of the skin, joints, and vascular supply. Nerve conduction studies are rarely needed to make a diagnosis of neuropathy. In patients with clear motor deficit or with an asymmetrical presentation, additional electrophysiological examination may be necessary. Early detection of diabetic neuropathy is important to avoid further irreversible injury to the peripheral nerves.

To assess the associations between glucose metabolism status and a range of continuous measures of glycaemia with corneal nerve fibre measures, as assessed using corneal confocal microscopy.

We used population-based observational cross-sectional data from the Maastricht Study of N=3471 participants (mean age 59.4 years, 48.4% men, 14.7% with prediabetes, 21.0% with type 2 diabetes) to study the associations, after adjustment for demographic, cardiovascular risk and lifestyle factors, between glucose metabolism status (prediabetes and type 2 diabetes vs normal glucose metabolism) plus measures of glycaemia (fasting plasma glucose, 2 h post-load glucose, HbA1c, skin autofluorescence [SAF] and duration of diabetes) and composite Z-scores of corneal nerve fibre measures or individual corneal nerve fibre measures (corneal nerve bifurcation density, corneal nerve density, corneal nerve length and fractal dimension). We used linear regression analysis, and, for glucose metabolism status, performed a linear trend analysis.

After full adjustment, a more adverse glucose metabolism status was associated with a lower composite Z-score for corneal nerve fibre measures (β coefficients [95% CI], prediabetes vs normal glucose metabolism -0.08 [-0.17, 0.03], type 2 diabetes vs normal glucose metabolism -0.14 [-0.25, -0.04]; linear trend analysis showed a p value of 0.001), and higher levels of measures of glycaemia (fasting plasma glucose, 2 h post-load glucose, HbA1c, SAF and duration of diabetes) were all significantly associated with a lower composite Z-score for corneal nerve fibre measures (per SD: -0.09 [-0.13, -0.05], -0.07 [-0.11, -0.03], -0.08 [-0.11, -0.04], -0.05 [-0.08, -0.01], -0.09 [-0.17, -0.001], respectively). In general, directionally similar associations were observed for individual corneal nerve fibre measures.

To our knowledge, this is the first population-based study to show that a more adverse glucose metabolism status and higher levels of glycaemic measures were all linearly associated with corneal neurodegeneration after adjustment for an extensive set of potential confounders. Our results indicate that glycaemia-associated corneal neurodegeneration is a continuous process that starts before the onset of type 2 diabetes. Further research is needed to investigate whether early reduction of hyperglycaemia can prevent corneal neurodegeneration.

Small-fiber neuropathy (SFN) is known to be associated with Sjögren disease (SjD), and in vivo corneal confocal microscopy can identify features compatible with SFN. Here, we performed a descriptive study to identify features of SFN of the corneal subbasal nerve plexus using in vivo confocal microscopy.

We recruited 10 participants from the Sjögren's International Collaborative Clinical Alliance (SICCA), 1 new participant (in an effort to expand the SICCA cohort), and 22 healthy controls. All participants underwent slit-lamp examination and in vivo confocal microscopy of the central corneal subbasal nerve plexus centered about the central whorl to create a 30-image montage. Each image was analyzed with automated software (ACCmetrics, Manchester, United Kingdom) to produce 7 nerve metrics. We performed t-tests and age-adjusted regressions to make comparisons of nerve metrics between participants with SjD and healthy controls.

Most nerve metrics were significantly lower in participants with SjD compared with healthy controls. The mean corneal nerve fiber density was found to be 3.5 mm/mm 2 in participants with SjD compared with 10.6 mm/mm 2 in healthy controls (95% confidence interval, -8.4 to -0.93; P = 0.02). Within the 11 participants with SjD, 22 eyes were analyzed on confocal microscopy, and 16 of those eyes (from 9 individuals) did not have an identifiable central whorl. Within the 22 healthy controls, 22 eyes (right eye alone) were analyzed on confocal microscopy, and 21 of those eyes had an identifiable central whorl.

SjD exhibits lower corneal nerve metrics compared with healthy controls. These findings suggest that features compatible with SFN can distinguish SjD from healthy controls and may serve as a potential novel biomarker in identifying SjD.

Rheumatoid arthritis (RA) is a multisystem autoimmune disorder characterized by articular and extra-articular manifestations. Neuropathy is a poorly studied manifestation of RA. The aim of this study was to utilize the rapid non-invasive ophthalmic imaging technique of corneal confocal microscopy to identify whether there is evidence of small nerve fibre injury and immune cell activation in patients with RA.

Fifty consecutive patients with RA and 35 healthy control participants were enrolled in this single-centre, cross-sectional study conducted at a university hospital. Disease activity was assessed with the 28-Joint Disease Activity Score and erythrocyte sedimentation rate (DAS28-ESR). Central corneal sensitivity was measured with a Cochet-Bonnet contact corneal esthesiometer. A laser scanning in vivo corneal confocal microscope was used to quantify corneal nerve fibre density (CNFD), nerve branch density (CNBD), nerve fibre length (CNFL), and Langerhans cell (LC) density.

Corneal sensitivity (P = 0.01), CNFD (P = 0.02), CNBD (P < 0.001), and CNFL (P < 0.001) were lower, and mature (P = 0.001) and immature LC densities (P = 0.011) were higher in patients with RA compared to control subjects. CNFD (P = 0.016) and CNFL (P = 0.028) were significantly lower in patients with moderate to high (DAS28-ESR > 3.2) compared to mild (DAS28-ESR ≤ 3.2) disease activity. Furthermore, the DAS28-ESR score correlated with CNFD (r = -0.425; P = 0.002), CNBD (ρ = -0.362; P = 0.010), CNFL (r = -0.464; P = 0.001), total LC density (ρ = 0.362; P = 0.010) and immature LC density (ρ = 0.343; P = 0.015).

This study demonstrates reduced corneal sensitivity, corneal nerve fibre loss and increased LCs which were associated with the severity of disease activity in patients with RA.

In the Diabetes Control and Complications Trial (DCCT), the minimal nerve conduction (NC) criterion for diabetic sensorimotor polyneuropathy (DSPN) was abnormality of NC in more than one peripheral nerve without specifying the attributes of NCs to be evaluated. In the present study, we assess individual and composite scores of NCs meeting the DCCT criterion and signs for improved diagnosis and assessment of DSPN severity.

Evaluated were 13 attributes and 6 composite NC scores and signs and symptoms in 395 healthy subjects (HS) and 388 persons with diabetes (DM).

Percent abnormality between subjects with DM and HS was remarkably different among individual attributes and the six composite NC scores. For diagnosis of DSPN using the DCCT criterion, assessment of conduction velocities (CVs) and distal latencies (DLs) provided sensitive diagnoses of DSPN. NC amplitudes provided stronger measures of severity. In studied cohorts, DSPN was staged: N0, no NC abnormality using NC score 2 (CVs and DLs), 60.0%; N1, NC abnormality only, 18.4%; N2, NC abnormality and signs of feet or legs, 16.3%; and N3, NC abnormality and signs of thighs, 5.3%.

For sensitive and standard diagnosis of DSPN using the DCCT NC criterion, specifically defined composite scores of CVs and DLs, e.g., score 2, is recommended. A composite score of amplitudes, e.g., score 4, provides a stronger measure of neuropathy severity. Also, provided are HS reference values of evaluated attributes of NCs and estimates of staged severity of DSPN of mid North American DM cohorts.

Nutrients, required by human bodies to perform life-sustaining functions, are obtained from the diet. They are broadly classified into macronutrients (carbohydrates, lipids, and proteins), micronutrients (vitamins and minerals) and water. All nutrients serve as a source of energy, provide structural support to the body and/or regulate the chemical processes of the body. Food and drinks also consist of non-nutrients that may be beneficial (e.g., antioxidants) or harmful (e.g., dyes or preservatives added to processed foods) to the body and the ocular surface. There is also a complex interplay between systemic disorders and an individual's nutritional status. Changes in the gut microbiome may lead to alterations at the ocular surface. Poor nutrition may exacerbate select systemic conditions. Similarly, certain systemic conditions may affect the uptake, processing and distribution of nutrients by the body. These disorders may lead to deficiencies in micro- and macro-nutrients that are important in maintaining ocular surface health. Medications used to treat these conditions may also cause ocular surface changes. The prevalence of nutrition-related chronic diseases is climbing worldwide. This report sought to review the evidence supporting the impact of nutrition on the ocular surface, either directly or as a consequence of the chronic diseases that result. To address a key question, a systematic review investigated the effects of intentional food restriction on ocular surface health; of the 25 included studies, most investigated Ramadan fasting (56%), followed by bariatric surgery (16%), anorexia nervosa (16%), but none were judged to be of high quality, with no randomized-controlled trials.

Damage to small nerve fibers is common in diabetic polyneuropathy (DPN), and the diagnosis of DPN relies on subjective symptoms and signs in a combination with objective confirmatory tests, typically electrophysiology or intraepidermal nerve fiber density (IENFD) from skin biopsy. Corneal confocal microscopy (CCM) has been introduced as a tool to detect DPN. However, it is unclear if CCM can reliably be used to diagnose DPN and how the technique compares with other commonly used measures of small fiber damage, such as IENFD, cold detection threshold (CDT), and warm detection threshold (WDT). Therefore, we assessed and compared the use of CCM, IENFD, CDT, and WDT in the diagnosis of DPN in patients with type 2 diabetes.

In this cohort study, the participants underwent detailed neurologic examination, electrophysiology, quantification of IENFD, CCM, and quantitative sensory testing. Definition of DPN was made in accordance with the Toronto criteria for diabetic neuropathy (without relying on IENFD and thermal thresholds).

A total of 214 patients with at least probable DPN, 63 patients without DPN, and 97 controls without diabetes were included. Patients with DPN had lower CCM measures (corneal nerve fiber length [CNFL], nerve fiber density, and branch density), IENFD, CDT, and WDT compared with patients without DPN (p ≤ 0.001, <0.001, 0.002, p < 0.001, p = 0.003, and <0.005, respectively), whereas there was no difference between controls and patients with diabetes without DPN. All 3 CCM measures showed a very low diagnostic sensitivity with CNFL showing the highest (14.4% [95% CI 9.8-18.4]) and a specificity of 95.7% (88.0-99.1). In comparison, the sensitivity of abnormal CDT and/or WDT was 30.5% (24.4-37.0) with a specificity of 84.9% (74.6-92.2). The sensitivity of abnormal IENFD was highest among all measures with a value of 51.1% (43.7-58.5) and a specificity of 90% (79.5-96.2). CCM measures did not correlate with IENFD, CDT/WDT, or neuropathy severity in the group of patients with DPN.

CCM measures showed the lowest sensitivity compared with other small fiber measures in the diagnosis of DPN. This indicates that CCM is not a sensitive method to detect DPN in recently diagnosed type 2 diabetes.

This study provides Class III evidence that CCM measures aid in the detection of DPN in recently diagnosed type 2 diabetics but with a low sensitivity when compared with other small fiber measures.

It remains unknown why some people with diabetes develop painful neuropathies while others experience no pain. This study aimed to validate a novel method for assessing the function of small sensory nerves in diabetes to further elucidate this phenomenon. The function of large and small nerves was assessed using a novel perception threshold tracking technique in 3 well-characterized groups (n = 60) with type 1 diabetes, namely, (1) painful diabetic peripheral neuropathy (T1DM + PDPN), (2) painless diabetic peripheral neuropathy (T1DM + DPN), and (3) no neuropathy (T1DM - DPN), and healthy controls (n = 20). Electrical currents with different shapes, duration, and intensities were applied by 2 different skin electrodes activating large and small fibers, respectively. The minimal current needed to activate the fibers were analyzed as the rheobase of the stimulus-response function. Nerve fiber selectivity was measured by accommodation properties of stimulated nerves. The rheobase of both fiber types were highest for T1DM + PDPN, followed by T1DM + DPN, T1DM - DPN, and healthy controls, indicating that the nerve properties are specific in individuals with diabetes and pain. There was an overall significant difference between the groups ( P < 0.01). The accommodation properties of stimulated fibers were different between the 2 electrodes ( P < 0.05) apart from in the group with T1DM + PDPN, where both electrodes stimulated nerves displaying properties similar to large fibers. Perception threshold tracking reveals differences in large and small nerve fiber function between the groups with and without diabetes, DPN, and pain. This indicates that the methods have potential applications in screening DPN and explore further the features differentiating painful from nonpainful DPN.

The quantification of intraepithelial corneal basal nerve parameters by in vivo confocal microscopy represents a promising modality to identify the earliest manifestations of diabetic peripheral neuropathy. However, its diagnostic accuracy is hampered by its dependence on neuron length, with minimal consideration for other parameters, including the origin of these nerves, the corneal stromal-epithelial nerve penetration sites. This study sought to utilize high-resolution images of murine corneal nerves to analyze comprehensively the morphological changes associated with type 2 diabetes progression.

βIII-Tubulin immunostained corneas from prediabetic and type 2 diabetic mice and their respective controls were imaged by scanning confocal microscopy and analyzed automatically for nerve parameters. Additionally, the number and distribution of penetration sites was manually ascertained and the average length of the axons exiting them was computed.

The earliest detectable changes included a significant increase in nerve density (6.06 ± 0.41% vs 8.98 ± 1.99%, P = 0.03) and branching (2867.8 ± 271.3/mm² vs 4912.1 ± 1475.3/mm² , P = 0.03), and in the number of penetration sites (258.80 ± 20.87 vs 422.60 ± 63.76, P = 0.0002) at 8 weeks of age. At 16 weeks, corneal innervation decreased, most notably in the periphery. The number of penetration sites remained significantly elevated relative to controls throughout the monitoring period. Similarly, prediabetic mice exhibited an increased number of penetration sites (242.2 ± 13.55 vs 305.6 ± 30.96, P = 0.003) without significant changes to the nerves.

Our data suggest that diabetic peripheral neuropathy may be preceded by a phase of neuron growth rather than regression, and that the peripheral cornea is more sensitive than the center for detecting changes in innervation.

Dementia is characterized by progressive cognitive decline, memory impairment, and disability. Alzheimer's disease (AD) accounts for 60-70% of cases, followed by vascular and mixed dementia. Qatar and the Middle East are at increased risk owing to aging populations and high prevalence of vascular risk factors. Appropriate levels of knowledge, attitudes, and awareness amongst health care professionals (HCPs) are the need of the hour, but literature indicates that these proficiencies may be inadequate, outdated, or markedly heterogenous. In addition to a review of published quantitative surveys investigating similar questions in the Middle East, a pilot cross-sectional online needs-assessment survey was undertaken to gauge these parameters of dementia and AD among healthcare stakeholders in Qatar between 19 April and 16 May 2022. Overall, 229 responses were recorded between physicians (21%), nurses (21%), and medical students (25%), with two-thirds from Qatar. Over half the respondents reported that >10% of their patients were elderly (>60 years). Over 25% reported having contact with >50 patients with dementia or neurodegenerative disease annually. Over 70% had not undertake related education/training in the last 2 years. The knowledge of HCPs regarding dementia and AD was moderate (mean score of 5.3 ± 1.5 out of 7) and their awareness of recent advances in basic disease pathophysiology was lacking. Differences existed across professions and location of respondents. Our findings lay the groundwork for a call-to-action for healthcare institutions to improve dementia care within Qatar and the Middle East region.

To investigate whether SARS-CoV-2 causes morphological changes in the corneal sub-basal nerve plexus (CSNP) of post-COVID-19 patients using in vivo confocal microscopy (IVCM).

A total of 70 participants were included in the study and were divided into three groups. Post-COVID-19 patients with neurological manifestations were considered Group 1 (n = 24), and post-COVID-19 patients without neurological manifestations were considered Group 2 (n = 24). Healthy control participants were considered Group 3 (n = 22). The parameters of the CSNP, including nerve fibre density (NFD), nerve branch density (NBD), and nerve fibre length (NFL), were investigated in all participants using IVCM. Additionally, corneal sensitivity was tested by corneal esthesiometry.

The mean NFD, NBD, and NFL values of Group 1 (16.12 ± 4.84 fibre/mm², 27.97 ± 9.62 branch/mm², and 11.60 ± 2.89 mm/mm²) were significantly lower than those of Group 2 (19.55 ± 3.01 fibre/mm², 40.44 ± 7.16 branch/mm², and 15.92 ± 2.08 mm/mm²) and Group 3 (25.24 ± 3.75 fibre/mm², 44.61 ± 11.80 branch/mm², and 17.76 ± 3.32 mm/mm²) (p < 0.05 for all). Except the mean NFD value (p < 0.001), there were no significant differences in terms of the mean NBD and NFL values between Group 2 and Group 3 (p = 0.445, p = 0.085). The value of the mean corneal sensitivity was significantly higher in Group 3 (59.09 ± 1.97 mm) compared to Group 1 (55.21 ± 1.02 mm) and Group 2 (55.28 ± 1.18 mm) (p < 0.001, p < 0.001) but there was no significant difference between Group 1 and Group 2 (p = 1.000).

In post-COVID-19 patients, the mean parameters of CSNP were lower than in the control group. These differences were more pronounced in patients who had neurological manifestations of COVID-19.

To evaluate changes in conjunctiva-associated lymphoid tissues (CALTs) in patients with type 2 diabetic mellitus (T2DM).

Thirty-two patients with T2DM and 32 healthy volunteers underwent comprehensive examinations. In vivo confocal microscopy and Image J were used to observe and evaluate the patients' CALT-related parameters. Conjunctival impression cytology (CIC) samples of the tarsal conjunctiva were collected from the patients, and CD4+ and CD8+ cells were evaluated by immunofluorescence staining.

The diabetes group showed higher diffuse lymphocyte density(p < .001), follicular density(p < .001) and parafollicular lymphocyte density(p < .001). The percentages of CD4+ cells (p < .001) and CD8+ cells (p < .001) in the diabetes group were higher than those in the control group. CALT-related parameters of the diabetic patients with diabetic retinopathy showed higher degrees of activation than those of the diabetic patients without diabetic retinopathy.

CALT activation is observed in patients with T2DM, and the activation is more obvious in patients with diabetic retinopathy.

Retrospectively registered, ChiCTR2100046030.

Corneal nerves play a key role in maintaining ocular surface integrity. Corneal nerve damage, from local or systemic conditions, can lead to ocular discomfort, pain, and, if poorly managed, neurotrophic keratopathy. Omega-3 polyunsaturated fatty acids (PUFAs) are essential dietary components that play a key role in neural development, maintenance, and function. Their potential application in modulating ocular and systemic inflammation has been widely reported. Omega-3 PUFAs and their metabolites also have neuroprotective properties and can confer benefit in neurodegenerative disease. Several preclinical studies have shown that topical administration of omega-3 PUFA-derived lipid mediators promote corneal nerve recovery following corneal surgery. Dietary omega-3 PUFA supplementation can also reduce corneal epithelial nerve loss and promote corneal nerve regeneration in diabetes. Omega-3 PUFAs and their lipid mediators thus show promise as therapeutic approaches to modulate corneal nerve health in ocular and systemic disease. This review discusses the role of dietary omega-3 PUFAs in maintaining ocular surface health and summarizes the possible applications of omega-3 PUFAs in the management of ocular and systemic conditions that cause corneal nerve damage. In examining the current evidence, this review also highlights relatively underexplored applications of omega-3 PUFAs in conferring neuroprotection and addresses their therapeutic potential in mediating corneal nerve regeneration.

These are the guidelines for diagnosis and treatment of diabetic neuropathy and diabetic foot.The position statement summarizes characteristic clinical symptoms and techniques for diagnostic assessment of diabetic neuropathy, including the complex situation of the diabetic foot syndrome. Recommendations for the therapeutic management of diabetic neuropathy, especially for the control of pain in sensorimotor neuropathy, are provided. The needs to prevent and treat diabetic foot syndrome are summarized.

Continuous glucose monitoring (CGM) has revealed that glycemic variability and low time in range are associated with albuminuria and retinopathy. We have investigated the relationship between glucose metrics derived from CGM and a highly sensitive measure of neuropathy using corneal confocal microscopy in participants with type 1 and type 2 diabetes.

A total of 40 participants with diabetes and 28 healthy controls underwent quantification of corneal nerve fiber density (CNFD), corneal nerve branch density (CNBD), corneal nerve fiber length (CNFL) and inferior whorl length (IWL) and those with diabetes underwent CGM for four consecutive days.

CNBD was significantly lower in patients with high glycemic variability (GV) compared to low GV (median (range) (25.0 (19.0-37.5) vs 38.6 (29.2-46.9); P = 0.007); in patients who spent >4% compared to <4% time in level 1 hypoglycemia (54-69 mg/dL) (25.0 (22.9-37.5) vs 37.5 (29.2-46.9); P = 0.045) and in patients who spent >1% compared to <1% time in level 2 hypoglycemia (<54 mg/dL) (25.0 (19.8-41.7) vs 35.4 (28.1-44.8); P = 0.04). Duration in level 1 hypoglycemia correlated with CNBD (r = -0.342, P = 0.031). Duration in level 1 (181-250 mg/dL) and level 2 (>250 mg/dL) hyperglycemia did not correlate with CNFD (P > 0.05), CNBD (P > 0.05), CNFL (P > 0.05) or IWL (P > 0.05).

Greater GV and duration in hypoglycemia, rather than hyperglycemia, are associated with nerve fiber loss in diabetes.

Nerve conduction studies (NCS) are the current objective measure for diagnosis of peripheral neuropathy in type 2 diabetes but do not assess nerve structure. This study investigated the utility of peripheral nerve ultrasound as a marker of the presence and severity of peripheral neuropathy in type 2 diabetes.

A total of 156 patients were recruited, and nerve ultrasound was undertaken on distal tibial and distal median nerves. Neuropathy severity was graded using the modified Toronto Clinical Neuropathy Scale (mTCNS) and Total Neuropathy Score (TNS). Studies were undertaken by a single ultrasonographer blinded to nerve conduction results.

A stepwise increase in tibial nerve cross-sectional area (CSA) was noted with increasing TNS grade (p &lt; 0.001) and each mTCNS quartile (p &lt; 0.001). Regression analysis demonstrated a correlation between tibial nerve CSA and neuropathy severity (p &lt; 0.001). Using receiver operator curve analysis, tibial nerve CSA of &gt;12.88 mm yielded a sensitivity of 70.5% and specificity of 85.7% for neuropathy detection. Binary logistic regression revealed that tibial nerve CSA was a predictor of abnormal sural sensory nerve action potential amplitude (odds ratio = 1.239, 95% confidence interval [CI] = 1.142-1.345) and abnormal neuropathy score (odds ratio = 1.537, 95% confidence interval [CI] = 1.286-1.838).

Tibial nerve ultrasound has good specificity and sensitivity for neuropathy diagnosis in type 2 diabetes. The study demonstrates that tibial nerve CSA correlates with neuropathy severity. Future serial studies using both ultrasound and NCS may be useful in determining whether changes in ultrasound occur prior to development of nerve conduction abnormalities and neuropathic symptoms.

Diabetes mellitus (DM) is a group of metabolic diseases that is known to cause structural and functional ocular complications. In the human cornea, DM-related complications affect the epithelium, stroma, and nerves. Monocarboxylate transporters (MCTs) are a family of proton-linked plasma membrane transporters that carry monocarboxylates across plasma membranes. In the context of corneal health and disease, their role, presence, and function are largely undetermined and solely focused on the most common MCT isoforms, 1 through 4. In this study, we investigated the regulation of MCT1, 2, 4, 5, 8, and 10, in corneal DM, using established 3D self-assembled extracellular matrix (ECM) in vitro models. Primary stromal corneal fibroblasts were isolated from healthy (HCFs), type I (T1DMs), and type II (T2DMs) DM donors. Monoculture 3D constructs were created by stimulating stromal cells on transwells with stable vitamin C for two or four weeks. Coculture 3D constructs were created by adding SH-SY5Y neurons at two different densities, 12 k and 500 k, on top of the monocultures. Our data showed significant upregulation of MCT1 at 4 weeks for HCF, T1DM, and T2DM monocultures, as well as the 500 k nerve cocultures. MCT8 was significantly upregulated in HCF and T1DM monocultures and all of the 500 k nerve cocultures. Further, MCT10 was only expressed at 4 weeks for all cocultures and was limited to HCFs and T1DMs in monocultures. Immunofluorescence analysis showed cytoplasmic MCT expression for all cell types and significant downregulation of both MCT2 and MCT4 in HCFs, when compared to T1DMs and T2DMs. Herein, we reveal the existence and modulation of MCTs in the human diabetic cornea in vitro. Changes appeared dependent on neuronal density, suggesting that MCTs are very likely critical to the neuronal defects observed in diabetic keratopathy/neuropathy. Further studies are warranted in order to fully delineate the role of MCTs in corneal diabetes.

The assessment of the corneal nerve fibre plexus with corneal confocal microscopy (CCM) is an upcoming but still experimental method in the diagnosis of early stage diabetic peripheral neuropathy (DPN). Using an innovative imaging technique-Heidelberg Retina Tomograph equipped with the Rostock Cornea Module (HRT-RCM) and EyeGuidance module (EG)-we were able to look at greater areas of subbasal nerve plexus (SNP) in order to increase the diagnostic accuracy. The aim of our study was to evaluate the usefulness of EG instead of single image analysis in diagnosis of early stage DPN.

This prospective study was performed on 60 patients with type 2 diabetes mellitus, classified equally into two subgroups based on neuropathy deficient score (NDS): patients without DPN (group 1) or with mild DPN (group 2). The following parameters were analysed in the two subgroups: corneal nerve fibre length (CNFL; mm/mm²), corneal nerve fibre density (CNFD; no./mm²), corneal nerve branch density (CNBD; no./mm²). Furthermore, we compared the data calculated with the novel mosaic, EG-based method with those received from single image analysis using different quantification tools.

Using EG we did not find a significant difference between group 1 and group 2: CNFL (16.81 ± 5.87 mm/mm² vs. 17.19 ± 7.19 mm/mm², p = 0.895), CNFD (254.05 ± 115.36 no./mm² vs. 265.91 ± 161.63 no./mm², p = 0.732) and CNBD (102.68 ± 62.28 no./mm² vs. 115.38 ± 96.91 no./mm², p = 0.541). No significant difference between the EG method of analysing the SNP and the single image analysis of 10 images per patient was detected.

On the basis of our results it was not possible to differentiate between early stages of large nerve fibre DPN in patients with type 2 diabetes mellitus via SNP analysis. To improve sensitivity and specificity of this method newer technologies are under current evaluation.

ClinicalTrials.gov Identifier NCT05326958.

Distal symmetric polyneuropathy (DPN), particularly chronic sensorimotor DPN, represents one of the most frequent complications of diabetes, affecting 50% of diabetic patients and causing an enormous financial burden. Whilst diagnostic methods exist to detect and monitor this condition, they have significant limitations, mainly due to their high subjectivity, invasiveness, and non-repeatability. Corneal confocal microscopy (CCM) is an in vivo, non-invasive, and reproducible diagnostic technique for the study of all corneal layers including the sub-basal nerve plexus, which represents part of the peripheral nervous system. We reviewed the current literature on the use of CCM as an instrument in the assessment of diabetic patients, particularly focusing on its role in the study of sub-basal nerve plexus alterations as a marker of DPN. CCM has been demonstrated to be a valid in vivo tool to detect early sub-basal nerve plexus damage in adult and pediatric diabetic patients, correlating with the severity of DPN. Despite its great potential, CCM has still limited application in daily clinical practice, and more efforts still need to be made to allow the dissemination of this technique among doctors taking care of diabetic patients.