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There is a reduction in corneal nerve fiber density and length in type 2 diabetes mellitus with chronic kidney disease compared with type 2 diabetes mellitus alone; however, this difference does not result in worse ocular surface discomfort or dry eye disease.This study aimed to determine the clinical impact of corneal nerve loss on ocular surface discomfort and markers of ocular surface homeostasis in people with type 2 diabetes mellitus without chronic kidney disease (T2DM-no CKD) and those with type 2 diabetes mellitus with concurrent chronic kidney disease (T2DM-CKD).Participants were classified based on estimated glomerular filtration rates into two groups: T2DM-CKD (n = 27) and T2DM-no CKD (n = 28).There was a significant difference between the T2DM-CKD and T2DM-no CKD groups in corneal nerve fiber density (14.9 ± 8.6 and 21.1 ± 7.1 no./mm 2 , respectively; P = .005) and corneal nerve fiber length (10.0 ± 4.6 and 12.3 ± 3.7 mm/mm 2 , respectively; P = .04). Fluorescein tear breakup time was significantly reduced in T2DM-CKD compared with T2DM-no CKD (8.1 ± 4.4 and 10.7 ± 3.8 seconds, respectively; P = .01), whereas ocular surface staining was not significantly different (3.5 ± 1.7 and 2.7 ± 2.3 scores, respectively; P = .12). In terms of ocular surface discomfort, there were no significant differences in the ocular discomfort score scores (12.5 ± 11.1 and 13.6 ± 12.1, respectively; P = .81) and Ocular Pain Assessment Survey scores (3.3 ± 5.4 and 4.3 ± 6.1, respectively; P = .37) between the T2DM-CKD and T2DM-no CKD.The current study demonstrated that corneal nerve loss is greater in T2DM-CKD than in T2DM-no CKD. However, these changes do not impact ocular surface discomfort or markers of ocular surface homeostasis.

The aim of this study was to investigate the reliability of subbasal corneal nerve plexus parameters of the inferior whorl compared with the central cornea with in vivo corneal confocal microscopy and to investigate the impact of inferior whorl pattern complexity on reproducibility.Subbasal corneal nerves of healthy controls (n = 10) and patients with chemotherapy-induced peripheral neuropathy (n = 10) were imaged with a laser scanning confocal microscope. Two masked, experienced observers and the original image taker were tasked with selecting representative images of the central cornea and inferior whorl for each participant. This was conducted on 2 occasions 1 week apart. Corneal nerve fiber length (CNFL) and fractal dimension (CNFrD) [central cornea: CNFL and CNFrD; inferior whorl region: inferior whorl length (IWL) and inferior whorl fractal dimension (IWFrD)] were analyzed. Intraclass correlation coefficient (ICC) was analyzed for interobserver and intraobserver reliability. Inferior whorl complexity was classified according to the ease of identification of the center point of convergence.Interobserver ICC was 0.992 for CNFL, 0.994 for CNFrD, 0.980 for IWL, and 0.954 for IWFrD. When analyzed by inferior whorl complexity, the interobserver reliability was similar for simple (0.987 for IWL; 0.960 for IWFrD) and complex patterns (0.967 for IWL; 0.949 for IWFrD). However, intraobserver ICC were reduced for complex (IWL 0.841-0.970; IWFrD 0.830-0.955) compared with simple patterns (IWL 0.931-0.970; IWFrD 0.921-0.969).Although the overall interobserver reliability was excellent for the central corneal and inferior whorl parameters, there was lower intraobserver reliability for the inferior whorl parameters for complex morphological patterns. To improve reliability, more sophisticated wide-field imaging of the inferior whorl may be needed.

Immune cell infiltration has been implicated in neurotoxic chemotherapy for cancer treatment. However, our understanding of immune processes is still incomplete and current methods of observing immune cells are time consuming or invasive. Corneal dendritic cells are potent antigen-presenting cells and can be imaged with in-vivo corneal confocal microscopy. Corneal dendritic cell densities and nerve parameters in patients treated with neurotoxic chemotherapy were investigated. Patients treated for cancer with oxaliplatin (n = 39) or paclitaxel (n = 48), 3 to 24 months prior to assessment were recruited along with 40 healthy controls. Immature (ImDC), mature (MDC) and total dendritic cell densities (TotalDC), and corneal nerve parameters were analyzed from in-vivo corneal confocal microscopy images. ImDC was increased in the oxaliplatin group (Median, Md = 22.7 cells/mm2) compared to healthy controls (Md = 10.1 cells/mm2, p = 0.001), but not in the paclitaxel group (Md = 10.6 cells/mm2). ImDC was also associated with higher oxaliplatin cumulative dose (r = 0.33, p = 0.04) and treatment cycles (r = 0.40, p = 0.01). There was no significant difference in MDC between the three groups (p > 0.05). Corneal nerve parameters were reduced in both oxaliplatin and paclitaxel groups compared to healthy controls (p

Aim: To determine the impact of chronic kidney disease on corneal nerve measures and dendritic cell counts in type 2 diabetes. Methods: In vivo corneal confocal microscopy images were used to estimate corneal nerve parameters and compared in people with type 2 diabetes with chronic kidney disease (T2DM-CKD) (n = 29) and those with type 2 diabetes without chronic kidney disease (T2DM-no CKD) (n = 29), along with 30 healthy controls. Corneal dendritic cell densities were compared between people with T2DM-CKD and those with T2DM-no CKD. The groups were matched for neuropathy status. Results: There was a significant difference in corneal nerve fiber density (p < 0.01) and corneal nerve fiber length (p = 0.04) between T2DM-CKD and T2DM-no CKD groups. The two diabetes groups had reduced corneal nerve parameters compared to healthy controls (all parameters: p < 0.01). Immature central dendritic cell density was significantly higher in the T2DM-CKD group compared to the T2DM-no CKD group ((7.0 (3.8–12.8) and 3.5 (1.4–13.4) cells/mm2, respectively, p < 0.05). Likewise, central mature dendritic cell density was significantly higher in the T2DM-CKD group compared to the T2DM-no CKD group (0.8 (0.4–2.2) and 0.4 (0.6–1.1) cells/mm2, respectively, p = 0.02). Additionally, total central dendritic cell density was increased in the T2DM-CKD group compared to T2DM-no CKD group (10.4 (4.3–16.1) and 3.9 (2.1–21.0) cells/mm2, respectively, p = 0.03). Conclusion: The study showed that central corneal dendritic cell density is increased in T2DM-CKD compared to T2DM-no CKD, with groups matched for peripheral neuropathy severity. This is accompanied by a loss of central corneal nerve fibers. The findings raise the possibility of additional local factors exacerbating central corneal nerve injury in people with diabetic chronic kidney disease.

Purpose To determine the repeatability of TearLab and I-PEN osmometers in vivo and their accuracy in vitro. Design Prospective, single-visit study. Methods The tear osmolarity of 28 participants was evaluated with TearLab and I-PEN on two occasions in random order, over a 2-h period. Both eyes were measured in a randomised order. Coefficients of repeatability (CoR) were determined for each device, together with the bias and limits of agreement between them. For the in vitro experiment, the osmolarity was measured by both osmometers in five solutions (290, 297, 342, 338 and 383 mOsm/L) at two different temperatures (22 and 37°C) with a total of four consecutive measures. Results The CoRs for the TearLab and I-PEN in the right and left eyes were 26.2, 21.3, 33.6 and 28.3 mOsm/L, respectively. Across the first and second repeats, TearLab showed consistency of diagnosis for 50% of participants with 29% as dry eye positive, while I-PEN indicated 68% consistency of diagnosis with 57% dry eye positive. The instruments agreed on the diagnosis in 46.5% of cases. In vitro comparison showed that the average measurement errors for TearLab and I-PEN were -10 ± 13 and 31 ± 39 mOsm/L at 22°C, and 4 ± 13 and 20 ± 51 mOsm/L at 37°C. Conclusions In vitro, both instruments showed reasonable accuracy and repeatability at mid-range osmolarities, but repeatability generally declined at higher and lower levels. While TearLab accuracy remained consistent across the osmolarity range, measurement errors for I-PEN noticeably increased outside the mid-range. In vivo, both instruments displayed poor repeatability. This casts doubt on the value of utilising either instrument to establish osmolarity as a factor in the diagnosis of dry-eye, according to currently recommended diagnostic guidelines (TFOS DEWS II), if only a single measurement is taken from each eye.

The tear film is a thin, moist layer covering the ocular surface and is laden with proteins, peptides, lipids, mucins, electrolytes and cellular debris which function to maintain the healthy status of the ocular surface. In many cases of ocular or systemic disease, the integrity of this layer is changed and/or the balance of its constituents is disturbed. Since tears are easy and quick to collect and can be stored for long periods, they have the potential to be a valuable source of information relevant to many disease states. The purpose of this review is to collate information on the known biomarkers of systemic disease that have been identified in tears. The range of conditions covered includes diabetes mellitus, diabetic retinopathy, diabetic peripheral neuropathy, multiple sclerosis, Parkinson's disease, Alzheimer's disease, migraine, systemic sclerosis, cystic fibrosis, thyroid disorders and cancer.

Dry eye is considered an inflammatory disease. Gut microbiota are important in the regulation of low-grade chronic inflammation, including in the eye. Probiotics and prebiotics are increasingly used to regulate chronic-disease-associated gut dysbiosis. Therefore, this double-masked, randomized controlled clinical trial aimed to explore the potential of oral probiotics and prebiotics in the management of dry eye disease. In total, 41 participants with dry eye received probiotic and prebiotic supplements (treatment group, n = 23) or respective placebos (control group, n = 18) for 4 months. Dry eye symptoms and signs were evaluated using the Ocular Surface Disease Index (OSDI), Dry Eye Questionnaire 5, osmolarity, non-invasive keratograph break-up time (NIKBUT), ocular surface staining, tear meniscus height (TMH), lipid layer thickness, and conjunctival redness. After 4 months, the average OSDI score of the treatment group was significantly better compared to that of the controls (16.8 ± 5.9 vs. 23.4 ± 7.4; p < 0.001). The NIKBUT and TMH did not change significantly with treatment (p = 0.31 and p = 0.84) but reduced significantly for controls on average by −5.5 ± 1.0 secs (p = 0.03) and 0.2 ± 0.1 mm (p = 0.02). These data suggest that probiotics and prebiotics might be effective in the management of dry eye disease.

There is potential benefit in analysing corneal nerve tortuosity as a marker for assessment and progression of systemic diabetic neuropathy.The aim of this work was to determine whether tortuosity significantly differs in participants with type 1 (T1DM) and type 2 (T2DM) diabetes compared to controls and whether tortuosity differed according to neuropathy status.Corneal nerves of 164 participants were assessed across T1DM, T2DM and control groups. Images of corneal nerves were captured via in vivo corneal confocal microscopy. Diabetic neuropathy status was examined using the Total Neuropathy Score (TNS). Tortuosity was assessed with Cfibre v0.097. Results were compared between groups with a linear mixed model accounting for location of image and controlling for age, producing Tortuosity Factor (TF), an estimate of the marginal means of each group.Tortuosity was significantly reduced in the T1DM group compared to controls (TF = 0.241, 95%CI = 0.225-0.257 vs. TF = 0.272, 95%CI = 0.252-0.292; mean difference = -0.031, p = 0.02) and in the T2DM group compared to controls (TF = 0.261, 95%CI = 0.244-0.278 vs. TF = 0.289, 95%CI = 0.270-0.308; mean difference = -0.029, p = 0.03). Tortuosity did not significantly differ between participants with T1DM and T2DM accounting for age and TNS (TF = 0.240, 95%CI = 0.215-0.265 vs. 0.269, 95%CI = 0.244-0.293, mean difference = -0.029, p = 0.11). Tortuosity was significantly reduced in participants with neuropathy (TNS≥2) compared to participants with no neuropathy (TNS 2) (TF = 0.248, 95%CI = 0.231-0.265 vs. TF = 0.272, 95%CI = 0.260-0.283; mean difference = -0.024, p = 0.03).Tortuosity is significantly reduced in participants with T1DM and T2DM compared to age matched controls and in participants with neuropathy compared to those without neuropathy.

Substance P is a sensory neuropeptide increasingly used as a biomarker for ocular and systemic neuropathic conditions. Due to the limited studies on tear storage conditions compared to other bodily fluids including blood and urine, the aim of this study was to investigate whether different storage durations at 4 °C can impact on substance P concentrations prior to storage at -80 °C. This is important to assess potential practical limitations in the handling and storage of tear fluid essential.Tears were collected and pooled from both eyes of 31 healthy participants using the flush tears method. The samples were centrifuged and aliquoted into three sets of microcentrifuge tubes with each stored at 4 °C for2 h, 4 h or 6 h (Timepoints 1, 2 or 3). After each respective storage duration, the aliquoted samples were than stored at -80 °C before analysis, within 6 months. Tears were analyzed for the concentration of substance P and the total protein content (TPC).Substance P concentrations across the three timepoints were not significantly different (While the levels of substance P were stable while stored at 4 °C prior to proper -80 °C storage and analysis, future research should investigate the impact of other storage conditions such as ambient room temperature to optimize the feasibility of using tears for biomarker purposes in clinical settings.

Cancer is a global health problem and is one of the leading causes of death worldwide. Pleasingly, the rate of survival has improved and continues in an upward trend mainly due to better diagnosis and treatment modalities. In particular, the development of anticancer drugs including cytotoxic chemotherapy, hormonal agents and targeted therapies have provided the most effective treatment options in combatting cancerous cells. However, the antineoplastic mechanisms of these drugs can also lead to undesirable systemic and ocular side effects resulting from cytotoxicity, inflammation and neurotoxicity. While survival rates are projected to increase with time, the number of patients presenting with these side effects that can substantially impact quality of life will also rise. The current paper reviews the ocular surface and adnexal side effects of anticancer drugs, the appropriate management and possible interactions between drugs for ocular surface pathology treatment and the anticancer drugs.

AIM To examine the associations between continuous overlapping net glycaemic action (CONGA), percentage time in hyperglycaemia (%HG) or normoglycaemia (%NG) and peripheral nerve structure and function in type 1 diabetes. METHODS Twenty-seven participants with type 1 diabetes underwent continuous glucose monitoring followed by corneal confocal microscopy and nerve excitability assessments. CONGA, %HG (> 10.0 mmol/l) and %NG (3.9-10.0 mmol/l) were correlated against corneal nerve fibre length and density in the central cornea and inferior whorl region, corneal microneuromas, and a nerve excitability score while controlling for age, sex, diabetes duration and HbA1c . RESULTS An increase in CONGA [median 2.5 (2.0-3.1) mmol/l] or %HG (mean 46 ± 18%) was associated with a worse nerve excitability score (r = -0.433, P = 0.036 and r = -0.670, P = 0.0012, respectively). By contrast, greater %NG (51 ± 17%) correlated with better nerve excitability scores (r = 0.672, P = 0.0011). Logistic regression revealed that increasing %HG increased the likelihood of abnormal nerve function [odds ratio (OR) 1.11, 95% confidence interval (CI) 1.01-1.23; P = 0.037). An increase in CONGA and %HG were associated with worsening nerve conduction measures, whereas longer %NG correlated with improved nerve conduction variables. CONGA and %HG were associated with inferior whorl corneal nerve fibre length (r = 0.483, P = 0.034 and r = 0.591, P = 0.021, respectively) and number of microneuromas (r = 0.433, P = 0.047 and r = 0.516, P = 0.020, respectively). CONCLUSIONS Short-term measures of glucose control are associated with impaired nerve function and alterations in corneal nerve morphology.

To investigate the association between levels of MMP-9, a common marker of inflammation in tears, and changes to the meibomian glands accompanying soft contact lens (CL) wear.Flush tears were collected from: (1) three groups of CL wearers who had worn CLs on a daily basis for different durations (Short: 2 ± 1 years, Moderate: 5 ± 1 years and Long experience: 10 ± 2 years); (2) a group of previous CL wearers (PWs) who had ceased wear for at least 6 months; and (3) healthy non-wearers (NW) as a control group. Total MMP-9 and its inhibitor, tissue inhibitor of MMPs-1 (TIMP-1) concentration were established using sandwich enzyme-linked immunosorbent assay. The MMP-9: TIMP-1 ratio was calculated for every individual, and then the average of all ratios for each group were compared. The non-parametric statistical Kruskal Wallis one-way analysis of variance was used for comparison, with Dunn's testing post-hoc.Tear samples from 100 participants (51 females; mean age ± SD: 25.4 ± 4.1 years) were analysed. MMP-9 concentrations and MMP-9:TIMP-1 ratio were significantly different between groups (Kruskal Wallis p = 0.001 and p 0.001 respectively), while the concentration of TIMP-1 did not vary statistically between study groups (Kruskal Wallis, p = 0.32). Post hoc analysis indicated that only CL wearers with short experience had MMP-9 concentrations that were significantly high compared to NWs (23.1 ± 17.9 ng/mL and 4.1 ± 4.1 ng/mL, respectively, Dunn p 0.001). Additionally, the ratio of MMP-9 to TIMP-1 concentration was only significantly greater in CL wearers with short experience (mean ratio ± SD = 1.15 ± 0.76) when compared to NWs (0.19 ± 0.29, Dunn P 0.001), CL wearers with moderate experience (0.37 ± 0.41; P = 0.01) and PWs (0.38 ± 0.36; P = 0.02).The early years of CL wear appear to be associated with increased expression of MMP-9 relative to its inhibitor TIMP-1. This may be indicative of low-level inflammation during this phase of wear. The role this plays in propagating dry eye disease and MGD in CL wear requires further exploration.

Corneal confocal microscopy (CCM) has been identified as a non-invasive technique to assess corneal nerve fiber morphology. It is not known how corneal nerve changes relate to measures of peripheral nerve function in diabetic peripheral neuropathy (DPN). The present study investigates the relationship between nerve structure and function in DPN.Fifty participants with type 1 diabetes (T1DM) and 29 healthy controls underwent CCM to assess corneal nerve fiber density (CNFD), branch density (CNBD), fiber length (CNFL), total branch density (CTBD), nerve fractal dimension (CNFrD) and inferior whorl length (IWL). The severity of DPN was assessed as Total Neuropathy Score (TNS). Motor nerve axonal excitability tests were conducted to assess axonal function.Significant correlations were noted between CNFD (rho = -0.783; P 0.01) or superexcitability (rho = 0.435; P 0.01) and TNS. CNFrD was significantly correlated with peak response to stimulus (r = 0.414; P 0.01) and superexcitability (r = -0.467; P 0.01) measurements.Corneal nerve loss demonstrates a significant association with axonal ion channel dysfunction in T1DM.Detection of altered corneal nerve morphology may lead to the earlier diagnosis of DPN.

To examine the effect of hydroxypropyl-guar nanoemulsion (HP-Guar nanoemulsion, Alcon Laboratories Ltd, Fort Worth, TX, USA) versus saline (0.9% sodium chloride; Pfizer Inc., Bentley WA Australia) on the comfort and tear film properties of people with dry eye disease both in the short-term (up to 2 h post-drop instillation) and longer-term (after 4 weeks of 4-times daily use), and to examine the effect on tear inflammatory markers after 4 weeks.This was a prospective, investigator-masked, randomised, cross-over dispensing study. Twenty participants with dry eye disease (5 males: 15 females) with average age 46.9 ± 14.4 (range 26 to 70) years were randomized to either HP-Guar nanoemulsion, or saline eye drops. Ocular symptoms, lipid layer thickness, tear evaporation, tear osmolarity and non-invasive break-up time were measured pre-drop instillation, 1 h and 2 h post-eye drop instillation, and after 4-weeks of 4-times daily drop use. Tear inflammatory mediators were measured pre-drop instillation and after 4-weeks. After 4-weeks, patients had a 4-week washout period and then crossed over to the alternate drop.With HP-Guar nanoemulsion, participants reported less grittiness/burning/stinging 1 h post eye drop instillation compared to baseline (79.5 ± 23.3 vs. 66.8 ± 27.7, p = 0.02); less dryness 1 h and 2 h post eye drop instillation compared to baseline (77.8 ± 23.0 and 76.2 ± 23.7 vs. 61.0 ± 27.1 respectively, p 0.01 for both); and greater overall satisfaction 1 h post drop instillation and after 4 weeks of daily use compared to baseline (80.4 ± 21.6 and 83.4 ± 16.6 vs. 68.6 ± 26.0 respectively, p ≤ 0.011 for both). With saline, participants reported less dryness after 4 weeks of daily use compared to baseline (74.2 ± 23.8 vs. 60.2 ± 24.0, p 0.01). For HP-Guar nanoemulsion, average lipid layer thickness was significantly thicker 2 h post drop-instillation (79.5 ± 21.7 nm) compared to baseline (63.7 ± 18.9 nm) and the 4-week assessment (62.4 ± 23.1 nm, p 0.01 for both). For saline, average lipid layer thickness was significantly thicker at 1 h and 2 h post eye drop instillation (76.0 ± 23.8 nm and 80.4 ± 24.8 nm) compared to baseline (61.0 ± 15.6 nm, p 0.01 for both). There was no difference in inflammatory mediators or other tear variables between drops or visits.HP-Guar nanoemulsion was more effective for improving a range of subjective dry eye symptoms both in the short and long-term compared to saline. Both HP-Guar nanoemulsion and saline transiently increased lipid layer thickness.

Neurotoxic chemotherapy has been shown to be associated with reduced corneal nerves and ocular surface discomfort. Substance P is a neuropeptide expressed by sensory nerves including those in the densely innervated cornea. It is involved in both pain signaling and the regulation of epithelial and neural health. While its levels in tear fluids have been used as a neuropathic biomarker in diabetes, investigations of tear concentrations of substance P in chemotherapy-induced peripheral neuropathy have not been explored. The current cross-sectional study assessed substance P expression in tears of patients following neurotoxic chemotherapy treatment. Patients treated with paclitaxel (n = 35) or oxaliplatin (n = 30) 3-24 months prior to assessment were recruited along with healthy controls (n = 25). Flush tear collection, in-vivo corneal confocal microscopy and neurotoxicity assessments were also conducted. Enzyme-linked immunosorbent assays were used to measure substance P concentrations in collected tears, while total protein content (TPC) was measured with the bicinchoninic acid method (BCA). General linear models were used for statistical analysis. Substance P concentration was reduced in paclitaxel-treated patients [Median (Interquartile range, IQR): 1.11 (0.20-2.24) ng/ml)] compared to the oxaliplatin group [4.28 (1.01-10.73) ng/ml, p = 0.02]. Substance P expressed as a proportion of TPC was also lower in the paclitaxel group [0.00006 (0.00001-0.00010) %] compared to the oxaliplatin group [0.00018 (0.00008-0.00040) %, p = 0.005]. Substance P concentration and its percentage in TPC were also reduced in the paclitaxel group when compared to healthy controls [4.61 (1.35-18.51) ng/ml, p = 0.02; 0.00020 (0.00006-0.00060) %, p = 0.04, respectively]. Higher cumulative dose of paclitaxel was correlated with a reduction in substance P concentrations (r = -0.40, p = 0.037), however no associations were found with corneal nerve parameters or neuropathy severity (p 0.05). While these findings show evidence for the dysregulation of tear film substance P following paclitaxel treatment, longitudinal studies should be conducted to investigate how substance P levels in tears change during treatment.

Multiple sclerosis (MS) is a neurological inflammatory disorder known to attack the heavily myelinated regions of the nervous system including the optic nerves, cerebellum, brainstem and spinal cord. This review will discuss the clinical manifestations and investigations for MS and other similar neurological inflammatory disorders affecting vision, as well as the effects of MS treatments on vision. Assessment of visual pathways is critical, considering MS can involve multiple components of the visual pathway, including optic nerves, uvea, retina and occipital cortex. Optical coherence tomography is increasingly being recognised as a highly sensitive tool in detecting subclinical optic nerve changes. Magnetic resonance imaging (MRI) is critical in MS diagnosis and in predicting long-term disability. Optic neuritis in MS involves unilateral vision loss, with characteristic pain on eye movement. The visual loss in neuromyelitis optica spectrum disorder tends to be more severe with preferential altitudinal field loss, chiasmal and tract lesions are also more common. Other differential diagnoses include chronic relapsing inflammatory optic neuropathy and giant cell arteritis. Leber's hereditary optic neuropathy affects young males and visual loss tends to be painless and subacute, typically involving both optic nerves. MS lesions in the vestibulocerebellum, brainstem, thalamus and basal ganglia may lead to abnormalities of gaze, saccades, pursuit and nystagmus which can be identified on eye examination. Medial longitudinal fasciculus lesions can cause another frequent presentation of MS, internuclear ophthalmoplegia, with failure of ipsilateral eye adduction and contralateral eye abduction nystagmus. Treatments for MS include high-dose corticosteroids for acute relapses and disease-modifying medications for relapse prevention. These therapies may also have adverse effects on vision, including central serous retinopathy with corticosteroid therapy and macular oedema with fingolimod.

Aim To investigate the expression of the keratinization-related protein, filaggrin, in the lid margin epithelium of contact lens (CL) wearers compared with nonwearers. Methods This was a cross-sectional study of 100 individuals with different exposures to CL wear: short, moderate, and long experience; previous CL wearers; and nonwearers as controls. Impression cytology samples were collected from the lid wiper (LW) area of the central upper lid margin. After fixing, an equal, random sample was selected from each group (n=13) for immunocytochemistry analysis using antihuman primary anybody (mouse filaggrin), then stained with secondary antibody (fluorescein isothiocyanate-conjugated donkey anti-mouse immunoglobulin G horseradish peroxidase) to detect filaggrin. Imaging was performed with the 3i-Vivo 2-photon microscope equipped with a Zeiss 20×-objective and SlideBook-reader software. Results Sixty-five samples from 65 participants (37 women; mean age±SD: 25.1±4.1 years) were collected. Filaggrin was detected in all 65 randomly selected immunostained marginal epithelium samples. All samples were similar in showing patchy areas of filaggrin immunostaining, regardless of CL wear, symptoms or epithelium morphology. Because the filaggrin immunostaining showed similar patterns across almost all the observed samples, comparison between subject groups was impractical. The presence of filaggrin in the healthy LW was additionally confirmed by an independent laboratory. Conclusion Filaggrin expression seems to be a normal part of epithelial cell differentiation in the lid margin and may not be a useful keratinization/stress biomarker in the marginal epithelium. Investigating other keratinization biomarkers that are not detected in the normal mucocutaneous junction/LW may help to understand the keratinization nature of LW epithelium changes in CL wearers.

Purpose: To evaluate the effect of age, gender and body mass index (BMI) on the levels of tear film neuromediators and corneal nerve parameters in healthy individuals.Methods: Twenty-six he...

PURPOSE To investigate the effect of soft contact lens (CL) wear on the morphology of the epithelial-lamina propria junction as well as the possible association with symptoms of discomfort. METHODS Ninety-two subjects were recruited, including 60 soft CL wearers, 16 previous wearers, and 16 non-wearers. Additionally, subjects were classified as symptomatic or asymptomatic using the Contact Lens Dry Eye Questionnaire 8 for the CL wearers (a score ≥ 12 was considered symptomatic) and the Dry Eye Questionnaire 5 for the previous wearers and non-wearers (a score ≥ 5 was considered symptomatic). In vivo confocal microscopy of the tarsal conjunctiva was performed on a single occasion. Papillae density, shortest diameter, longest diameter, area, circularity, lumen/wall brightness ratio, irregularity, reflectivity, inhomogeneous appearance of wall and inhomogeneous appearance of rete ridges were evaluated. Effects of CL wear, symptoms and their interaction were analysed using two-way analysis of variance. Correlations were investigated using Spearman's coefficient. Data are presented as mean (standard deviation) or median [interquartile range]. RESULTS Contact lens wearers, compared to previous wearers and non-wearers, showed higher circularity [0.65 (0.08) vs 0.59 (0.10) vs 0.57 (0.11), p = 0.003]. Subjects with symptoms, compared to asymptomatic participants, showed higher circularity [0.64 (0.08) vs 0.61 (0.10), p

Purpose: To determine the association between corneal dendritic cell (DC) density and corneal nerve morphology and tear film inflammatory mediators and neuromediators in healthy individuals. Methods: Flush tears were collected from 21 healthy participants aged 39.7 ± 9.9 years and analyzed for total protein content (TPC), substance P, matrix-metalloproteinase-9 (MMP-9), tissue inhibitor of MMPs-1 (TIMP-1), tumor necrosis factor-a (TNF-α) and interleukin-6 (IL-6). In vivo confocal microscopy was used to assess DC density and corneal nerve morphology. Corneal nerve variables measured were corneal nerve fiber length (CNFL), fiber density (CNFD), branch density (CNBD), fiber total branch density (CTBD), fiber area (CNFA), fiber width (CNFW) and fractal dimension (CNFrac). Results: Participants with DC density over 50 cells/mm2 correlated with CNBD-average (r = 0.7, p = 0.02), CNBD-high (r = 0.6, p = 0.02), CNBD-low (r = 0.6, p = 0.02) CTBD-average (r = 0.7, p = 0.01), CTBD-high (r = 0.6, p = 0.03), CTBD-low (r = 0.7, p = 0.01), CNFA-average (r = 0.7, p = 0.00), CNFA-high (r = 0.7, p = 0.01), CNFA-low (r = 0.8, p < 0.001), CNFrac-SD (r = -0.6, p = 0.04), CNFrac-low (r = 0.6, p = 0.04) and CNFL-low (r = 0.7, p = 0.02). The percentage of MMP-9 correlated with DC density in the entire cohort (r = 0.47, p = 0.03). Conclusions: Corneal nerve measures showed a strong correlation with higher DC density, suggesting that the number of cells maybe be modulated by the corneal nerves in the central cornea. MMP-9 also showed a moderate correlation with DC, supporting an inflammatory role.

AIMS To investigate changes in corneal nerve morphology in Type 2 diabetes and to establish relationships between in vivo corneal confocal microscopy and markers of peripheral nerve structure and function. PARTICIPANTS AND METHODS We recruited 57 participants with Type 2 diabetes and 26 healthy controls of similar age and sex distribution. We also recruited a disease control group of 54 participants with Type 1 diabetes. All participants were assessed for distal symmetrical polyneuropathy using the Total Neuropathy Score. In vivo corneal confocal microscopy was used to assess corneal nerve fibre length, corneal nerve fibre density, corneal nerve branch density and inferior whorl length. Peripheral nerve structure was assessed using median nerve ultrasonography. Large fibre function was assessed according to median nerve axonal excitability. Small fibre function was assessed using SudoscanTM and the Survey of Autonomic Symptoms. RESULTS Corneal nerve fibre length, fibre density and branch density and inferior whorl length were significantly lower in individuals with Type 2 diabetes compared to controls (P

Dry eye disease is one of the most common conditions encountered in optometric practice, affecting up to 50% of certain populations with a greater predisposition for women, those of Asian ethnicity...

Dry eye disease is one of the most common, chief-complaints presenting in clinical practice, with a prevalence of up to 50%. Evaporative dry eye, as a result of meibomian gland dysfunction, is thought to be the biggest component factor. Treatments for meibomian gland dysfunction aim to restore tear film homoeostasis and include warm compress therapy, eyelid hygiene, in-office meibomian gland expression and lipid-containing, artificial tears. A recent introduction to the in-office treatments available for meibomian gland dysfunction has been low-level light therapy, also known as photobiomodulation. The technique involves applying red, or near infra-red, radiation using low-power light sources and is suggested to promote tissue repair, decrease inflammation, and relieve pain. This work aims to review the available literature on the efficacy and safety of photobiomodulation in meibomian gland dysfunction and dry eye disease, as well as what is currently known about its mechanism of action.

Survival rates of cancer has improved with the development of anticancer drugs including systemic chemotherapeutic agents. However, long-lasting side effects could impact treated patients. Neurotoxic anticancer drugs are specific agents which cause chemotherapy-induced peripheral neuropathy (CIPN), a debilitating condition that severely deteriorates quality of life of cancer patients and survivors. The ocular surface is also prone to neurotoxicity but investigation into the effects of neurotoxic chemotherapy on the ocular surface has been more limited compared to other systemic etiologies such as diabetes. There is also no standardized protocol for CIPN diagnosis with an absence of a reliable, objective method of observing nerve damage structurally. As the cornea is the most densely innervated region of the body, researchers have started to focus on corneal neuropathic changes that are associated with neurotoxic chemotherapy treatment. In-vivo corneal confocal microscopy enables rapid and objective structural imaging of ocular surface microscopic structures such as corneal nerves, while esthesiometers provide means of functional assessment by examining corneal sensitivity. The current article explores the current guidelines and gaps in our knowledge of CIPN diagnosis and the potential role of in-vivo corneal confocal microscopy as a diagnostic or prognostic tool. Corneal neuropathic changes with neurotoxic anticancer drugs from animal research progressing through to human clinical studies are also discussed, with a focus on how these data inform our understanding of CIPN.

BACKGROUND AND PURPOSE There is a strong association between the metabolic syndrome in diabetes and the development of peripheral neuropathy; however, the pathophysiological mechanisms remain unknown. METHODS Participants with type 2 diabetes and metabolic syndrome (T2DM/MetS, n = 89) and type 2 diabetes alone (T2DM; n = 59) underwent median nerve ultrasound and excitability studies to assess peripheral nerve structure and function. A subset of T2DM/MetS (n = 24) and T2DM (n = 22) participants underwent confocal microscopy to assess central and inferior whorl corneal nerve structure. Neuropathy severity was assessed using the modified Toronto Clinical Neuropathy Score (mTCNS). Diabetes groups were similar for age, sex distribution, diabetes duration, hemoglobin A1c , insulin treatment, and renal function. Sixty healthy controls similar for age and sex distribution were recruited for comparison. RESULTS Participants with T2DM/MetS manifested with a greater mTCNS compared to T2DM (p

Diagnosis and monitoring of keratoconus is increasingly being conducted with the aid of imaging equipment such as corneal aberrometry. There is a need to also know the confidence with which ocular aberration measurements can be made.To assess the repeatability of lower- and higher-order aberration measurements in patients with keratoconus using the irx3 wavefront aberrometer (Imagine Eyes, Orsay, France) and evaluate correlations with corneal curvature.The irx3 wavefront aberrometer was used to measure bilateral lower- and higher-order ocular aberrations on 33 participants with keratoconus. Three measurements were taken from each eye to determine the repeatability of lower-order aberrations (quantified as sphere and cylinder in dioptres) and higher-order aberration co-efficients (up to eighth order in micrometres), coma, trefoil and total higher-order aberration root mean square (in micrometres). Corneal curvature was measured using the Pentacam HR system (OCULUS, Wetzlar, Germany).Repeat measurements for lower-order aberrations resulted in larger co-efficients of repeatability than higher-order aberrations. Similarly, larger co-efficients of repeatability between repeated measures across all Zernike co-efficients were observed in eyes with severe keratoconus (that is, corneal curvature 52-D) compared to eyes with flatter corneas. The difference between repeated measures tended to be significant for the lower-order aberrations regardless of corneal curvature. The highest correlations with corneal curvature for right and left eyes respectively, were identified for total higher-order aberration root mean square (r = 0.92, p 0.001 and r = 0.91, p 0.001), followed closely by coma (r = -0.93, p 0.001 and r = -0.86, p 0.001) and the Z (3, -1) co-efficient (r = -0.92, p 0.001 and r = -0.86, p 0.001 for right and left eyes, respectively).Lower-order aberrations tended to be less repeatable, indicating that instrument variability must be considered when monitoring progression. Total higher-order aberration root mean square and third-order aberrations, in particular the vertical coma Z (3, -1) co-efficient, demonstrated a stronger correlation with corneal curvature than the lower-order aberrations.

Professor Fiona J Stapleton (Figure 1) is a UK‐trained optometrist who has become one of the most influential women in optometry. Professor Stapleton is a clinical scientist and researcher with exp...

Measurement of corneal nerve tortuosity is associated with dry eye disease, diabetic retinopathy, and a range of other conditions. However, clinicians measure tortuosity on very different grading scales that are inherently subjective. Using in vivo confocal microscopy, 253 images of corneal nerves were captured and manually labelled by two researchers with tortuosity measurements ranging on a scale from 0.1 to 1.0. Tortuosity was estimated computationally by extracting a binarised nerve structure utilising a previously published method. A novel U-Net segmented adjacent angle detection (USAAD) method was developed by training a U-Net with a series of back feeding processed images and nerve structure vectorizations. Angles between all vectors and segments were measured and used for training and predicting tortuosity measured by human labelling. Despite the disagreement among clinicians on tortuosity labelling measures, the optimised grading measurement was significantly correlated with our USAAD angle measurements. We identified the nerve interval lengths that optimised the correlation of tortuosity estimates with human grading. We also show the merit of our proposed method with respect to other baseline methods that provide a single estimate of tortuosity. The real benefit of USAAD in future will be to provide comprehensive structural information about variations in nerve orientation for potential use as a clinical measure of the presence of disease and its progression.

In 2019 Clinical and Experimental Optometry celebrated its 100th anniversary – a historic milestone, one to be truly proud of as a profession. The immediate past Editor‐in‐Chief, Professor H Barry ...

To investigate the influence of blinking on tear film parameters, ocular surface characteristics, and dry eye symptomology.A total of 154 participants were recruited in an age, gender and ethnicity-matched cross-sectional study, of which 77 exhibited clinically detectable incomplete blinking, and 77 did not. Blink rate, dry eye symptomology, tear film parameters, and ocular surface characteristics were assessed in a single clinical session.Overall, a higher proportion of participants exhibiting incomplete blinking fulfilled the TFOS DEWS II dry eye diagnostic criteria (64% versus 44%, p = 0.02), with an odds ratio (95% CI) of 2.2 (1.2-4.2) times. Participants exhibiting incomplete blinking had higher Ocular Surface Disease Index scores (18 ± 13 versus 12 ± 9, p = 0.01), and greater levels of meibomian gland dropout (41.3 ± 15.7% versus 27.5 ± 14.1%, p 0.001). Furthermore, poorer tear film lipid layer thickness, non-invasive tear film stability, expressed meibum quality, eyelid notching, and anterior blepharitis grades were also observed in those exhibiting incomplete blinking (all p 0.05). Blink frequency did not correlate significantly with any ocular surface parameters (all p 0.05).Incomplete blinking was associated with a two-fold increased risk of dry eye disease. The greater levels of meibomian gland dropout, as well as poorer expressed meibum quality and tear film lipid layer thickness, observed would suggest that incomplete blinking may predispose towards the development of evaporative dry eye.

To determine the utility of corneal confocal microscopy and tear neuromediator analysis in the diagnosis of diabetic peripheral neuropathy (DPN) as a result of type 1 and type 2 diabetes.Seventy individuals with either type 1 diabetes or type 2 diabetes (T1D/T2D) underwent corneal confocal microscopy to assess the corneal nerve morphology. The concentration of substance P and calcitonin gene-related peptide (CGRP) in tears was measured by enzyme-linked immunosorbent assay. Motor excitability studies were conducted on the median nerve to assess axonal ion channel function. Based on total neuropathy score (TNS), participants were stratified into DPN (DPN+ve; TNS ≥ 2; T1D, n = 19; T2D, n = 16) and without DPN (DPN-ve; TNS ≤ 1; T1D, n = 19; T2D, n = 16). Areas under the receiver operating characteristic curves (AUCs) were calculated to obtain specificity and sensitivity of the measures to diagnose DPN.In T1D, the concentration of substance P and confocal microscopy measures were significantly reduced (Corneal confocal microscopy parameters provide a better diagnostic ability to detect DPN in T1D and T2D than nerve excitability measures or concentrations of tear neuromediators. The concentration of substance P could also be useful in diagnosing DPN but for T1D only.

SIGNIFICANCE This cross-sectional study presented a link between contact lens wear and changes on the cellular morphology characteristics of the lid wiper (LW) epithelium, which was not visible by LW staining. PURPOSE The aim of this study was to establish if the duration of contact lens (CL) wear affects the cellular morphology of the LW epithelium. METHODS This was a cross-sectional study of 100 individuals with different exposures to CL wear: short, moderate, and long experience of CL wear; previous CL wearers; and nonwearers (NWs) as controls. Impression cytology samples were collected from the central upper lid margin (LW area). After fixing, samples were stained with periodic acid-Schiff and haematoxylin for cell morphology analysis and subsequently graded according to the Nelson 0- to 3-point scale. Lid wiper staining was assessed with the aid of lissamine green and graded using the Korb (0- to 3-point) scale. One-way Kruskal-Wallis analysis followed by the Dunn multiple-comparisons test was used for statistical comparison. RESULTS The Nelson grade for LW epithelium morphology was significantly different between groups (P = .003). Abnormal epithelial morphology as defined by grade 2 or 3 was evident in 66.7% of CL wearers with short experience and 76.5% of CL wearers with moderate experience. This was significantly higher than NWs of whom only 21.5% showed greater than grade 1 (P = .02 and .005, respectively). There was no significant difference between NWs and other groups. Lid wiper staining did not significantly differ between groups (P = .50) or correlate with the Nelson grade (Spearman r = 0.02, P = .08). CONCLUSIONS Metaplasia of the LW epithelium was significantly greater in the early to moderate stages of CL. This supports the view that mechanical irritation is responsible for LW changes in CL wear. Ceasing CL wear seems to lead to recovery. Lid wiper staining did not reflect the underlying morphological changes.

Interest has grown over the past decade in using in vivo confocal microscopy to analyse the morphology of corneal nerves and their changes over time. Advances in computational modelling techniques have been applied to automate the estimation of sub-basal nerve structure. These objective methods have the potential to quantify nerve density (and length), tortuosity, variations in nerve thickness, as well as temporal changes in nerve fibres such as migration patterns. Different approaches to automated nerve analysis, methods proposed and how they were validated in previous literature are reviewed. Improved understanding of these approaches and their limitations will help improve the diagnostic leverage of emerging developments for monitoring the onset and progression of a broad class of systemic diseases, including diabetes.

To compare non-invasive break-up time (NIBUT) when measured with the Tearscope-Plus™ and the Oculus® Keratograph 5M, and to compare lipid layer thicknesses (LLT) when measured with the Tearscope-Plus™ and the LipiView®. This study also set out to establish the repeatability of these methods.The following measurements were taken from both eyes of 24 participants on two occasions: non-invasive keratograph break-up time using the Oculus® (NIKBUT-1 and NIKBUT-average), NIBUT using the Tearscope-Plus™, and LLT using the LipiView® (minimum, maximum, and average) and Tearscope-Plus™. The Tearscope-Plus™ grades were converted to nanometers.There were no significant differences between eyes (Tearscope-Plus™ NIBUT: p = 0.52; NIKBUT-1: p = 0.052; NIKBUT-average: p = 0.73; Tearscope-Plus™ LLT: p = 0.13; LipiView® average, maximum, or minimum: p = 0.68, 0.39 and 0.50, respectively) or days (Tearscope-Plus™ NIBUT: p = 0.32; NIKBUT-1: p = 0.65; NIKBUT-average: p = 0.54; Tearscope-Plus™ LLT: p = 0.26; LipiView® average, maximum, or minimum: p = 0.20, 0.09, and 0.10, respectively). LLT was significantly greater with the Tearscope-Plus™ (80.4 ± 34.0 nm) compared with the LipiView® average (56.3 ± 16.1 nm, p = 0.007), minimum (50.1 ± 15.8 nm, p 0.001) but not maximum (67.2 ± 19.6 nm, p = 0.55). NIBUT was significantly greater with the Tearscope-Plus™ (15.9 ± 10.7 seconds) compared to the NIKBUT-1 (8.2 ± 3.5 seconds, p = 0.006) but not NIKBUT-average (10.9 ± 3.9 seconds, p = 0.08).The Tearscope-Plus™ is not interchangeable with either the Oculus® K5M measurement of tear stability (NIKBUT-1) or the LipiView® maximum and minimum lipid thickness.

This work aims to characterize the relationship between tear film neuropeptide substance P and the structural integrity of the sub-basal nerve plexus in diabetes.Seventeen healthy control participants and nine participants with diabetes were recruited in this cross-sectional study. Total protein content and substance P concentrations were determined in the flush tears of participants. Corneal nerve morphology was assessed by capturing the corneal sub-basal nerve plexus using the Heidelberg Retinal Tomograph II with the Rostock Corneal Module (Heidelberg Engineering GmbH, Heidelberg, Germany) in the central cornea. Corneal nerve fiber density (CNFD) was measured using ACCMetrics (M.A. Dabbah, Imaging Science and Biomedical Engineering, Manchester, UK) on eight captured images. Comparisons between groups were made using independent samples t-tests. Correlations between parameters were analyzed using Pearson's correlations.Substance P concentrations were significantly higher in the tears of the control group compared to participants with diabetes (4150 ± 4752 and 1473 ± 1671 pg/mL, respectively, P = .047). There was no significant difference in total protein content between the groups (3.4 ± 1.8 and 2.6 ± 1.7 mg/mL in the control and diabetes groups, respectively, P = .262). CNFD was significantly lower in the participants with diabetes compared to the control group (16.1 ± 5.7 and 21.5 ± 7.0 mm/mm, respectively, P = .041). There was a moderate correlation between substance P and CNFD (r = 0.48, P = .01).Substance P is expressed at a significantly lower level in the tears of people with diabetes compared with healthy controls. The positive correlation between substance P and corneal nerve density indicates that substance P may be a potential biomarker for corneal nerve health.

Aims Patients with chronic kidney disease (CKD) in type 2 diabetes typically manifest with severe peripheral neuropathy. Corneal confocal microscopy is a novel technique that may serve as a marker of nerve injury in peripheral neuropathy. This study examines the changes that occur in corneal nerve morphology as a result of peripheral neuropathy due to renal dysfunction in people with type 2 diabetes. Methods Sixty-two participants (mean age, 62 ± 12 years) with type 2 diabetes and 25 age-matched healthy controls underwent a comprehensive assessment of neuropathy using the total neuropathy score (TNS). The corneal sub-basal nerve plexus was imaged using corneal confocal microscopy. Corneal nerve fiber length, fiber density, branch density, total branch density, nerve fractal dimension, inferior whorl length and inferior whorl nerve fractal dimension were quantified. Based on the eGFR, participants were classified into those with diabetic CKD (eGFR Results Participants with diabetic CKD had significantly lower corneal nerve fiber density (P = 0.037), length (P = 0.036) and nerve fractal dimension (P = 0.036) compared to those without CKD. Multiple linear regression analysis revealed that reduced corneal nerve fiber density (s coefficient = 0.098, P = 0.017), length (s coefficient = 0.006, P = 0.008) and nerve fractal dimension (s coefficient = 0.001, P = 0.007) was associated with low eGFR levels when adjusted for age, duration of diabetes and severity of neuropathy. Conclusion Corneal confocal microscopy detects corneal nerve loss in patients with diabetic CKD and reduction in corneal nerve parameters is associated with the decline of kidney function.