Corneal Keratocyte Density and Corneal Nerves Are Reduced in Patients With Severe Obesity and Improve After Bariatric Surgery

PurposeObesity is associated with peripheral neuropathy, which bariatric surgery may ameliorate. The aim of this study was to assess whether corneal confocal microscopy can show a change in corneal nerve morphology and keratocyte density in subjects with severe obesity after bariatric surgery.MethodsTwenty obese patients with diabetes (n = 13) and without diabetes (n = 7) underwent assessment of hemoglobin A1c (HbA1c), lipids, IL-6, highly sensitive C-reactive protein (hsCRP), and corneal confocal microscopy before and 12 months after bariatric surgery. Corneal nerve fiber density (CNFD), corneal nerve branch density (CNBD), corneal nerve fiber length (CNFL), and keratocyte density (KD) from the anterior, middle, and posterior stroma were quantified. Twenty-two controls underwent assessment at baseline only.ResultsCNFL (P < 0.001), CNBD (P < 0.05), and anterior (P < 0.001), middle (P < 0.001), and posterior (P < 0.001) keratocyte densities were significantly lower in obese patients compared to controls, and anterior keratocyte density (AKD) correlated with CNFL. Twelve months after bariatric surgery, there were significant improvements in body mass index (BMI; P < 0.001), HDL cholesterol (P < 0.05), hsCRP (P < 0.001), and IL-6 (P < 0.01). There were significant increases in CNFD (P < 0.05), CNBD (P < 0.05), CNFL (P < 0.05), and anterior (P < 0.05) and middle (P < 0.001) keratocyte densities. The increase in AKD correlated with a decrease in BMI (r = –0.55, P < 0.05) and triglycerides (r = –0.85, P < 0.001). There were no significant correlations between the change in keratocyte densities and corneal nerve fiber or other neuropathy measures.ConclusionsCorneal confocal microscopy demonstrates early small fiber damage and reduced keratocyte density in obese patients. Bariatric surgery leads to weight reduction and improvement in lipids and inflammation and an improvement in keratocyte density and corneal nerve regeneration.     

Small Nerve Fiber Damage and Langerhans Cells in Type 1 and Type 2 Diabetes and LADA Measured by Corneal Confocal Microscopy

PurposeIncreased corneal and epidermal Langerhans cells (LCs) have been reported in patients with diabetic neuropathy. The aim of this study was to quantify the density of LCs in relation to corneal nerve morphology and the presence of diabetic neuropathy and to determine if this differed in patients with type 1 diabetes mellitus (T1DM), type 2 diabetes mellitus (T2DM), and latent autoimmune diabetes of adults (LADA).MethodsPatients with T1DM (n = 25), T2DM (n = 36), or LADA (n = 23) and control subjects (n = 23) underwent detailed assessment of peripheral neuropathy and corneal confocal microscopy. Corneal nerve fiber density (CNFD), branch density (CNBD), length (CNFL) and total, immature and mature LC densities were quantified.ResultsLower CNFD (P < 0.001), CNBD (P < 0.0001), and CNFL (P < 0.0001) and higher LC density (P = 0.03) were detected in patients with T1DM, T2DM, and LADA compared to controls. CNBD was inversely correlated with mature (r = –0.5; P = 0.008), immature (r = –0.4; P = 0.02) and total (r = –0.5; P = 0.01) LC density, and CNFL was inversely correlated with immature LC density (r = –0.4; P = 0.03) in patients with T1DM but not in patients with T2DM and LADA.ConclusionsThis study shows significant corneal nerve loss and an increase in LC density in patients with T1DM, T2DM, and LADA. Furthermore, increased LC density correlated with corneal nerve loss in patients with T1DM.     

Corneal nerves in diabetes—The role of the in vivo corneal confocal microscopy of the subbasal nerve plexus in the assessment of peripheral small fiber neuropathy

The cornea's intense innervation is responsible for corneal trophism and ocular surface hemostasis maintenance. Corneal diabetic neuropathy affects subbasal nerve plexus, with progressive alteration of nerves' morphology and density. The quantitative analysis of nerve fibers can be performed with in vivo corneal confocal microscopy considering the main parameters such as corneal nerve fibers length, corneal nerve fibers density, corneal nerve branching density, tortuosity coefficient, and beadings frequency. As the nerve examination permits the detection of early changes occurring in diabetes, the in vivo corneal confocal microscopy becomes, over time, an important tool for diabetic polyneuropathy assessment and follow-up. In this review, we summarize the actual evidence about corneal nerve changes in diabetes and the relationship between the grade of alterations and the duration and severity of the disease. We aim at understanding how diabetes impacts corneal nerves and how it correlates with sensorimotor peripheral polyneuropathy and retinal complications. We also attempt to analyze the safety of the most common surgical procedures such as cataract and refractive surgery in diabetic patients and to highlight the specific risk factors. We believe that information about the corneal nerve fibers' condition obtained from the in vivo subbasal nerve plexus investigation may be crucial in monitoring peripheral small fiber polyneuropathy and that it will help with decision-making in ophthalmic surgery in diabetic patients.     

糖尿病患者角膜朗格汉斯细胞与神经纤维病理改变的研究

目的：探讨糖尿病神经病变患者角膜上皮下朗格汉斯细胞（ Langerhans cell,LCs）与神经纤维病理改变的关系,分析其发病机制,并提出免疫机制在此过程中的可能作用。方法：选取60例糖尿病神经病变患者和32例健康对照者,分析角膜神经纤维形态、数量、长度、角膜知觉和LC细胞密度,并分析二者的相关性。结果：糖尿病神经病变患者角膜神经纤维数量和长度、分支数量明显降低,神经纤维弯曲度明显增加。糖尿病神经病变患者角膜中央和周边上皮下的LC密度与正常对照组相比升高（ P＜0．05）。同时相关性分析结果显示：LC密度和神经纤维密度（r＝0．461,P＝0．011）、长度（r＝0．519,P＝0．002）间存在线性相关。同时糖尿病神经病变患者角膜中央的知觉较对照组明显减退（ P＜0．05）。结论：糖尿病神经病变患者角膜下神经纤维明显受损,角膜知觉减退,LC细胞数量增加,提示这种改变可能是免疫机制介导所致。     

In vivo confocal microscopic study of corneal innervation in Sjögren's Syndrome with or without small fiber neuropathy

PurposeTo study changes in the subbasal nerve plexus by In vivo confocal microscopy (IVCM) in Sjögren's Syndrome (SS) with or without associated Small Fiber Neuropathy (SFN), in order to prevent diagnostic delay.MethodsSeventy-one patients with SS, including 19 with associated SFN, 20 healthy volunteers and 20 patients with Meibomian gland dysfunction (MGD) were included in this retrospective case-control study. IVCM was used to investigate subbasal nerve plexus density and morphology.ResultsCorneal sensitivity as evaluated with the Cochet-Bonnet aesthesiometer was significantly reduced in the SS group versus the control group (P = 0.026) and the MGD group (P = 0.037). The number of inflammatory cells was significantly increased in the SS group to 86.2 ± 82.1 cells/mm² compared to the control group (P < 0.001). The density of the subbasal nerve plexus was significantly reduced to 16.7 ± 6.5 mm/mm² in the SS group compared to the control group (P < 0.005) and the MGD group (P = 0.042). The tortuosity of the nerves in the SS group was significantly increased compared to the control group (P < 0.001) and the MGD group (P = 0.025). The average number of subbasal nerve plexus neuromas was significantly increased in the SS group compared to the control group (P = 0.001), with a significant increase in the average number of neuromas in SS patients with associated SFN compared to SS patients without SFN (P = 0.008).ConclusionIVCM can be useful to detect corneal nerve changes in SS patients and may allow earlier diagnosis of the disease and to consider new therapeutic approaches.     

Corneal structure and sensitivity in type 1 diabetes mellitus

PURPOSE: Corneal wound healing is impaired in diabetic cornea. The purpose of this study was to examine patients with type 1 diabetes mellitus for changes in corneal morphology and to correlate corneal sensitivity, subbasal nerve morphology, and degree of polyneuropathy with each other. METHODS: Forty-four eyes of 23 patients with diabetes and nine control eyes were included. Corneal sensitivity was tested with a Cochet-Bonnet esthesiometer (Luneau, Paris, France), and corneal morphology and epithelial and corneal thickness were determined by in vivo confocal microscopy. The density of subbasal nerves was evaluated by calculating the number of long subbasal nerve fiber bundles per confocal microscopic field. The degree of polyneuropathy was evaluated using the clinical part of the Michigan Neuropathy Screening Instrument (MNSI) classification, and retinopathy was evaluated using fundus photographs. RESULTS: A reduction of long nerve fiber bundles per image was noted to have occurred already in patients with mild to moderate neuropathy, but corneal mechanical sensitivity was reduced only in patients with severe neuropathy. Compared with control subjects the corneal thickness was increased in patients with diabetes without neuropathy. The epithelium of patients with diabetes with severe neuropathy was significantly thinner than that of patients with diabetes without neuropathy. CONCLUSIONS: Confocal microscopy appears to allow early detection of beginning neuropathy, because decreases in nerve fiber bundle counts precede impairment of corneal sensitivity. Apparently, the cornea becomes thicker in a relatively early stage of diabetes but does not further change with the degree of neuropathy. A reduction in neurotrophic stimuli in severe neuropathy may induce a thin epithelium that may lead to recurrent erosions.     

Corneal Nerves Alteration Associated with Corneal Complications after Pars Plana Vitrectomy

PurposeTo evaluate the effect of corneal nerves assessment on predicting corneal complications following pars plana vitrectomy (PPV).MethodsIn this prospective single-center cohort study, 94 patients (94 eyes) received PPV, and were divided into postoperative groups with and without corneal complications. All eyes had corneal nerve fiber length (CNFL), corneal nerve fiber density, and branch density of corneal nerve fibers assessed and calculated with Image J preoperatively. Multivariate logistic regression analysis was used to identify corneal nerve fiber parameters that correlated to post-operative corneal complications. Receiver operator characteristic curve analysis was performed to identify the optimal cut-off point of the corneal fibers’ parameters for predicting corneal complications after PPV.ResultsEleven eyes (11.70%) developed corneal complications at 1 week after PPV. There was significant difference between CNFL (19.44 ± 6.88 vs. 26.84 ± 7.53, p = 0.003), corneal nerve fiber density (28.82 ± 9.91 vs. 37.10 ± 10.16, p = 0.013) and branch density of corneal nerve fibers (55.84 ± 21.08 vs. 82.04 ± 31.89, p = 0.01) in two groups, respectively. Receiver operator characteristic analysis showed that the optimal cutoff value of CNFL to predict corneal complications following PPV was <26.495 mm/mm².ConclusionsThe decrease of CNFL may predict corneal complications following PPV. Regular preoperative corneal confocal microscopy test in PPV patients could be considered.     

Correlation of diabetic retinopathy and corneal neuropathy using confocal microscopy

Purpose/Aim: To employ corneal confocal microscopy to assess differences in the extent of corneal nerve fiber alterations between diabetic patients classed according to retinopathy status and nondiabetic patients. Materials and Methods: Two hundred seventy-eight corneas of 139 patients with type 2 diabetes mellitus and 94 corneas of 47 age-matched control participants were scanned using corneal confocal microscopy. Images of the subbasal nerve plexus were collected and analyzed for nerve fiber density (NFD), nerve branch density (NBD), nerve fiber length (NFL), and nerve fiber tortuosity (NFT). Diabetic patients were categorized into three groups according to the classification of diabetic retinopathy (DR) proposed in the Early Treatment of Diabetic Retinopathy Study, based on indirect fundoscopy, fundus photography, and fluorescein angiography findings. A separate classification into four groups according to the severity of peripheral diabetic neuropathy (DN) was also used, based on the results of clinical and electrodiagnostic examinations. Results: Average NFD, NBD, and NFL differed significantly according to DR status and were found to be lower, whereas NFT was found to be higher in diabetic patients than control participants. A positive correlation between diabetic corneal neuropathy and peripheral DN was also found. Conclusions: Nerve fiber alterations of the subbasal nerve plexus of diabetic corneas appear to progress in parallel with DR and peripheral DN. Corneal confocal microscopy could possibly represent a promising adjuvant technique for the early diagnosis and assessment of human DN.     

Biomarkers of in vivo limbal stem cell function

PurposeTo evaluate in vivo parameters as biomarkers of limbal stem cell function and to establish an objective system that detects and stage limbal stem cell deficiency (LSCD).MethodsA total of 126 patients (172 eyes) with LSCD and 67 normal subjects (99 eyes) were included in this observational cross-sectional comparative study. Slit-lamp biomicroscopy, in vivo laser scanning confocal microscopy (IVCM), and anterior segment optical coherence tomography (AS-OCT) were performed to obtain the following: clinical score, cell morphology score, basal cell density (BCD), central corneal epithelial thickness (CET), limbal epithelial thickness (LET), total corneal nerve fiber length (CNFL), corneal nerve fiber density (CNFD), corneal nerve branch density (CNBD), and tortuosity coefficient. Their potential correlations with the severity of LSCD were investigated, and cutoff values were determined.ResultsAn increase clinical score correlated with a decrease in central cornea BCD, limbal BCD, CET, mean LET, maximum LET, CNFL, CNFD, CNBD, and tortuosity coefficient. Regression analyses showed that central cornea BCD, CET and CNFL were the best parameters to differentiate LSCD from normal eyes (Coef = 3.123, 3.379, and 2.223; all p < 0.05). The rank correlation analysis showed a similar outcome between the clinical scores and the central cornea BCD (ρ = 0.79), CET (ρ = 0.82), and CNFL (ρ = 0.71). A comprehensive LSCD grading formula based on a combination of these parameters was established.ConclusionsA comprehensive staging system combining clinical presentation, central cornea BCD, CET, and CNFL is established to accurately and objectively diagnose LSCD and stage its severity.     

Pigment Epithelium-Derived Factor Peptide Promotes Corneal Nerve Regeneration: An In Vivo and In Vitro Study

PurposeTo investigate the potential of a pigment epithelium-derived factor (PEDF) peptide 44-mer to promote nerve regeneration in a rabbit corneal nerve injury model to demonstrate its neurotrophic ability in cultivated mouse trigeminal neuron cells.MethodsSubconjunctival or intrastromal injection of 44-mer on the cornea was performed in a rabbit model of corneal nerve injury created by corneal epithelial debridement. Immunocytochemical analysis (44-mer, anti-tubulin III, SMI312, CD11b, and α-SMA) and in vivo confocal microscopy were performed. Corneal sensation was estimated using a Cochet-Bonnet corneal esthesiometer. Primary cultivated mouse trigeminal neurons were used to examine the in vitro neurotrophic ability of 44-mer. The cellular morphology and the immunocytochemical staining with anti-tubulin III and SMI312 in different concentrations of 44-mer were compared, and a quantitative assessment of neurite outgrowth was performed.ResultsImmunohistochemical staining showed the retention of 44-mer in the corneal stroma for at least 7 days after a single dose of corneal intrastromal injection and promoted corneal nerve regeneration revealed by in vivo confocal microscopy. Corneal esthesiometer demonstrated gradual recovery of the corneal sensation in 44-mer-treated eyes with a lower corneal touch threshold than wounded vehicles and closer to baseline at 3 weeks after corneal injury (P < 0.001). In vitro studies showed a dose-dependent neurotrophic effect of 44-mer in cultivated trigeminal neuron cells.ConclusionsThe 44-mer showed in vivo and in vitro corneal neurotrophic abilities. Our results suggest that intrastromal injection of 44-mer into the corneal stroma may have a potential role in treating diseases related to corneal nerve damage.     

DR早期视网膜神经纤维层和角膜神经的变化及其相关性

目的:观察无视网膜微血管病变的糖尿病患者的视网膜神经纤维层(RNFL)和角膜神经纤维(CNF)变化,以及两者变化的相关性.方法:收集40例40眼2型糖尿病患者,经散瞳眼底检查未发现糖尿病视网膜病变,均接受光学相干断层扫描(OCT)检查和活体角膜共聚焦显微镜(IVCM)检查.另收集年龄匹配的80例80眼健康正常眼为对照,分为40例40眼只行OCT检查的RNFL对照组和40例40眼只行IVCM检查的CNF对照组.利用OCT观察视乳头上方、下方、颞侧、鼻侧和平均RNFL厚度,用IVCM观察角膜上皮下角膜神经纤维长度和角膜神经密度.结果:糖尿病组的视乳头上方、颞侧、鼻侧及平均RNFL与对照组比较,差异无统计学意义(P>0.05),但视乳头下方RNFL糖尿病组比RNFL对照组减少,差异有统计学意义(P=0.003).糖尿病组的角膜神经纤维长度、角膜神经密度均比CNF对照组减少(P<0.01).糖尿病组中,平均RNFL与角膜神经纤维长度和角膜神经密度呈正相关(r=0.518,P<0.01;r=0.484,P=0.002),下方RNFL与角膜神经纤维长度和角膜神经密度呈正相关(r=0.607,P<0.01;r=0.573,P<0.01).结论:糖尿病患者在未发现糖尿病视网膜病变前同时存在视网膜神经纤维层和角膜神经的丢失,视网膜神经纤维层变薄主要表现在下方象限,视网膜神经纤维层的变薄与角膜神经的减少呈正相关.     

Análisis de nervios estromales en pacientes con queratocono

ObjectiveTo evaluate the differences in stromal corneal nerves between normal patients and keratoconus patients.Material and methodsA total of 140 eyes of 70 normal patients (group A) and 122 eyes of 87 keratoconus patients (group B) were examined with the confocal microscope, with a central scan of the total corneal thickness being taken. The morphology and thickness of the corneal stromal nerves were evaluated by using the Navis v. 3.5.0. software. Nerve thickness was obtained from the mean between the widest and the narrowest portions of each stromal nerve.ResultsCorneal stromal nerves were observed as irregular linear hyper-reflective structures with wide and narrow portions in all cases. Mean corneal stromal nerves thickness in group A was 5.7 ± 1.7 (range from 3.3 to 10.4 μ), mean corneal stromal nerves thickness in group B was 7.2 ± 1.9 (range from 3.5 to 12.0 μ). There was a statistical significant difference (P<.05) in stromal corneal nerves thickness between group A and group B.ConclusionStromal corneal nerves morphology was similar in both groups, but stromal nerves were thicker in keratoconus patients.     

Corneal nerve tortuosity in diabetic patients with neuropathy

PURPOSE: Corneal confocal microscopy is a reiterative, rapid, noninvasive in vivo clinical examination technique capable of imaging corneal nerve fibers. Nerve fiber tortuosity may indicate a degenerative and attempted regenerative response of nerve fibers to diabetes. The purpose of this study was to define alterations in the tortuosity of corneal nerve fibers in relation to age, duration of diabetes, glycemic control, and neuropathic severity. METHODS: The cornea and collected images of the subbasal nerve plexus of 18 diabetic patients (stratified into mild, moderate, and severe neuropathic groups using conventional clinical measures of neuropathy) and 18 age-matched nondiabetic control subjects were scanned, and a novel mathematical paradigm was applied to quantify the extent of nerve tortuosity, which was termed the tortuosity coefficient (TC). RESULTS: TC was significantly different between the four clinical groups (F(3) = 12.2, P < 0.001). It was significantly greater in the severe neuropathic group than in control subjects (P < 0.003) and in the mild (P < 0.004) and moderate (P < 0.01) neuropathic groups. TC did not correlate significantly with the age (r = -0.003, P > 0.05), duration of diabetes (r = -0.219, P > 0.05), or hemoglobin A1c (HbA1c; r = 0.155, P > 0.05) of diabetic patients. CONCLUSIONS: Corneal confocal microscopy allows rapid, noninvasive in vivo evaluation of corneal nerve tortuosity. This morphologic abnormality relates to the severity of somatic neuropathy and may reflect an alteration in the degree of degeneration and regeneration in diabetes.     

Quantitative corneal neural imaging using in vivo confocal microscopy in cases of congenital corneal anesthesia: A prospective analysis and clinical correlation

Purpose:Congenital corneal anesthesia (CCA) is a rare clinical entity that poses a diagnostic dilemma, particularly in the pediatric age group with very little literature on this. Accurate initial diagnosis, evaluation, early identification of risk factors, aggressive systemic workup, and appropriate therapy are paramount to prevent visual loss due to long-term complications of corneal anesthesia. The purpose of the study was to estimate and compare the corneal neural architecture using real time, in vivo confocal microscopy (IVCM) in patients with CCA as against a control population.Methods:This was a retrospective nonconsecutive, comparative clinical case series in a tertiary hospital in South India from June 2015 to December 2018.Methods:IVCM was accomplished in cooperative children in whom central cornea was relatively clear. The clearest three to five images from each eye were selected, and the nerves were analyzed for length, thickness, density, dichotomous pattern, and beading. Statistical analysis was done using Origin v7.0 (Origin Lab Corporation, Northampton, MA, USA).Results:In total, 15 eyes of 11 cases and 20 eyes of 10 controls were imaged. Measurements on corneal nerve density showed a significant difference (P = 0.0005), cases having a lower mean (3.85 ± 1.38 mm per mm²) compared to the controls (6.74 ± 1.75 mm per mm²). Measurements on corneal nerve length (P = 0.28), thickness (P = 0.45), and presence of beading (P = 0.97) and dichotomous pattern (P = 0.07) did not reveal a significant difference between cases and controls.Conclusion:There is a strong relationship between the functional loss (absent corneal sensation) and anatomical decrease (reduced subbasal nerve density) of corneal nerves in congenital corneal anaesthesia.     

角膜激光共焦显微镜在糖尿病视网膜病变中的应用

目的　探讨角膜激光共焦显微镜在观察糖尿病视网膜病变（diabetic retinopathy,DR）患者角膜上皮下神经丛、角膜细胞密度及形态变化中的价值。方法　选取确诊的DR患者94例（114眼）,其中非增生型糖尿病视网膜病变（non-proliferative diabetic retinopathy,NPDR）患者41例（52眼,NPDR组）、增生型糖尿病视网膜病变（proliferative diabetic retinopathy,PDR）患者53例（62眼,PDR组）,收治时间2016年1月至2017年4月,同期糖尿病无眼底改变的患者40例（40眼）作为对照组,三组均采用角膜激光共焦显微镜进行检测,对比各组角膜上皮下神经丛、角膜细胞密度及形态的变化。结果　NPDR组和PDR组患者的角膜基底层、浅基质层、中基质层、深基质层的细胞密度均显著低于对照组（均为P<0.05）;PDR组患者的角膜基底层、浅基质层、中基质层、深基质层的细胞密度均显著低于NPDR组（均为P<0.05）;NPDR组和PDR组患者的角膜内皮细胞密度、六边形细胞比例、神经纤维密度、神经纤维长度均显著低于对照组（均为P<0.05）,NPDR组和PDR组患者的内皮细胞变异率、神经分支密度均显著高于对照组（均为P<0.05）;PDR组患者的角膜内皮细胞密度、六边形细胞比例、神经纤维密度、神经纤维长度分别为（1962.0±117.3）个·mm^-2、46.1%±5.5%、（15.4±3.3）根·mm^-2、（6.2±2.7）mm·mm^-2,均显著低于NPDR组的（2381.4±144.0）个·mm^-2、58.2%±7.0%、（20.6±3.8）根·mm^-2、（8.6±2.4）mm·mm^-2（均为P<0.05）,PDR组患者的内皮细胞变异率、神经分支密度均显著高于NPDR组（均为P<0.05）。结论　角膜激光共焦显微镜能有效观察DR患者角膜上皮下神经丛、角膜细胞密度及形态变化,为临床诊断、治疗提供指导。     

Small fiber neuropathy in the cornea of Covid-19 patients associated with the generation of ocular surface disease

PurposeTo describe the association between Sars-CoV-2 infection and small fiber neuropathy in the cornea identified by in vivo corneal confocal microscopy.MethodsTwenty-three patients who had overcome COVID-19 were recruited to this observational retrospective study. Forty-six uninfected volunteers were also recruited and studied as a control group. All subjects were examined under in vivo confocal microscopy to obtain images of corneal subbasal nerve fibers in order to study the presence of neuroma-like structures, axonal beadings and dendritic cells. The Ocular Surface Disease Index (OSDI) questionnaire and Schirmer tear test were used as indicators of Dry Eye Disease (DED) and ocular surface pathology.ResultsTwenty-one patients (91.31%) presented alterations of the corneal subbasal plexus and corneal tissue consistent with small fiber neuropathy. Images from healthy subjects did not indicate significant nerve fiber or corneal tissue damage. Eight patients reported increased sensations of ocular dryness after COVID-19 infection and had positive DED indicators. Beaded axons were found in 82.60% of cases, mainly in patients reporting ocular irritation symptoms. Neuroma-like images were found in 65.22% patients, more frequently in those with OSDI scores >13. Dendritic cells were found in 69.56% of patients and were more frequent in younger asymptomatic patients. The presence of morphological alterations in patients up to 10 months after recovering from Sars-CoV-2 infection points to the chronic nature of the neuropathy.ConclusionsSars-CoV-2 infection may be inducing small fiber neuropathy in the ocular surface, sharing symptomatology and morphological landmarks with DED and diabetic neuropathy.     

Visualization of microneuromas by using in vivo confocal microscopy: An objective biomarker for the diagnosis of neuropathic corneal pain?

PurposeThe diagnosis of neuropathic corneal pain (NCP) is challenging, as it is often difficult to differentiate it from conventional dry eye disease (DED). In addition to eye pain, NCP can present with similar signs and symptoms of DED. The purpose of this study is to find an objective diagnostic sign to identify patients with NCP, using in vivo confocal microscopy (IVCM).MethodsThis was a comparative, retrospective, case-control study. Patients with clinical diagnosis of NCP (n = 25), DED (n = 30), and age- and sex-matched healthy controls (n = 16), who underwent corneal imaging with IVCM (HRT3/RCM) were included. Central corneal IVCM scans were analyzed by 2 masked observers for nerve density and number, presence of microneuromas (terminal enlargements of subbasal corneal nerve) and/or nerve beading (bead-like formation along the nerves), and dendritiform cell (DC) density.ResultsThere was a decrease in total nerve density in both NCP (14.14 ± 1.03 mm/mm²) and DED patients (12.86 ± 1.04 mm/mm²), as compared to normal controls (23.90 ± 0.92 mm/mm²; p < 0.001). However, total nerve density was not statistically different between NCP and DED patients (p = 0.63). Presence of nerve beading was not significantly different between patients and normal controls (p = 0.15). Interestingly, microneuromas were observed in all patients with NCP, while they were not present in any of the patients with conventional DED (sensitivity and specificity of 100%). DC density was significantly increased in both NCP (71.89 ± 16.91 cells/mm²) and DED patients (111.5 ± 23.86 cells/mm²), as compared to normal controls (24.81 ± 4.48 cells/mm² (p < 0.05). However, there was no significant difference in DC density between DED and NCP patients (p = 0.31).ConclusionIVCM may be used as an adjunct diagnostic tool for the diagnosis of NCP in the presence of neuropathic symptoms. Microneuromas may serve as a sensitive and specific biomarker for the diagnosis of NCP.     

The pattern of the inferocentral whorl region of the corneal subbasal nerve plexus is altered with age

PurposeTo describe the pattern of the nerves in the inferocentral whorl region of the human corneal subbasal nerve plexus (SBNP) in health and diseases known to affect the subbasal nerves.MethodsLaser-scanning in vivo confocal microscopy (IVCM) was used to image the SBNP bilaterally in 91 healthy subjects, 39 subjects with type 2 diabetes mellitus (T2DM), and 43 subjects with Parkinson's disease (PD). Whorl regions were classified according to nerve orientation relative to age and health/disease status.ResultsOf 346 examined eyes, 300 (86.7%) had an identifiable whorl pattern. In healthy subjects, a clockwise nerve orientation of the whorl was most common (67.9%), followed by non-rotatory or ‘seam’ morphology (21.4%), and counterclockwise (10.7%). The clockwise orientation was more prevalent in healthy subjects than in T2DM or PD (P < 0.001). Healthy individuals below 50 years of age had a predominantly clockwise orientation (93.8%) which was reduced to 51.9% in those over 50 years (P < 0.001). Age but not disease status explained whorl orientation in T2DM and PD groups. Moreover, whorl orientation is bilaterally clockwise in the young, but adopts other orientations and becomes asymmetric across eyes with age. Finally, we report reflective ‘dot-like’ features confined to the whorl region of the subbasal plexus, sometimes appearing in close association with subbasal nerves and present in 84–93% of examined eyes regardless of disease status, eye or sex.ConclusionSubbasal nerves in the inferocentral whorl region are predominantly clockwise in young, healthy corneas. With aging and conditions of T2DM and PD, counterclockwise and non-rotatory configurations increase in prevalence, and bilateral symmetry is lost. Mechanisms regulating these changes warrant further investigation.     

反复玻璃体腔注射雷珠单抗与阿柏西普对黄斑水肿患者角膜神经的影响

目的:探讨反复玻璃体腔注射雷珠单抗与阿柏西普对黄斑水肿患者角膜神经的影响。方法:选取2021-06/2022-06在我院进行玻璃体腔注射抗血管内皮生长因子(VEGF)药物治疗的患者64例64眼,其中糖尿病性黄斑水肿20例20眼,湿性年龄相关性黄斑变性19例19眼,视网膜静脉阻塞25例25眼。采取3+PRN治疗方案,注药前和每次玻璃体腔注药后1mo时采用共聚焦显微镜采集角膜上皮基底膜下神经丛图像,测量角膜神经纤维长度和密度。结果:玻璃体腔注射阿柏西普的患者注药前后术眼角膜神经纤维密度无显著变化(P>0.05),但第2、3次注药后角膜神经纤维长度均低于注药前(均P<0.01);玻璃体腔注射雷珠单抗的患者注药前后术眼角膜神经纤维密度和长度均无显著变化(均P>0.05)。第3次注药后,两组患者术眼角膜神经纤维长度和密度均无显著差异(均P>0.05)。结论:反复玻璃体内注射抗VEGF药物会一定程度影响角膜神经,对多次注射抗VEGF药物的患者需关注角膜神经变化。     

In vivo corneal confocal microscopic analysis in patients with keratoconus

AIM:To quantify corneal ultrastructure using laser scanning in vivo confocal microscopy (IVCM) in patients with keratoconus and control subjects.METHODS: Unscarred corneas of 78 keratoconic subjects without a history of contact lens use and 36 age-matched control subjects were evaluated with slit-lamp examination (SLE), corneal topography and laser scanning IVCM. One eye was randomly chosen for analysis. Anterior and posterior stromal keratocyte, endothelial cell and basal epithelial cell densities and sub-basal nerve structure were evaluated.RESULTS: IVCM qualitatively demonstrated enlarged basal epithelial cells, structural changes in sub-basal and stromal nerve fibers, abnormal stromal keratocytes and keratocyte nuclei, and pleomorphism and enlargement of endothelial cells. Compared with control subjects, significant reductions in basal epithelial cell density (5817±306 cells/mm² vs 4802±508 cells/mm², P<0.001), anterior stromal keratocyte density (800±111 cells/mm² vs 555±115 cells/mm², P<0.001), posterior stromal keratocyte density (333±34 cells/mm² vs 270±47 cells/mm², P<0.001), endothelial cell density (2875±223 cells/mm² vs 2686±265 cells/mm², P<0.001), sub-basal nerve fiber density (31.2±8.4 nerves/mm² vs 18.1±9.2 nerves/mm², P<0.001), sub-basal nerve fiber length (21.4±3.4 mm/mm² vs 16.1±5.1 mm/mm², P<0.001), and sub-basal nerve branch density (median 50.0 (first quartile 31.2 - third quartile 68.7) nerve branches/mm² vs median 25.0 (first quartile 6.2 - third quartile 45.3) nerve branches/mm², P<0.001) were observed in patients with keratoconus.CONCLUSION: Significant microstructural abnormalities were identified in all corneal layers in the eyes of subjects with keratoconus using IVCM. This non-invasive in vivo technique provides an important means to define and follow progress of microstructural changes in patients with keratoconus.