Corneal nerve changes by anti-glaucoma medications examined by in vivo confocal microscopy

AIM:To evaluate the effects of antiglaucoma eye drops on corneal nerves by in vivo confocal microscopy(IVCM).METHODS:This study comprised 79 patients diagnosed with glaucoma and 16 healthy control individuals.Among the glaucoma patients,54 were treated with medication,while 25 remained untreated.Central corneal images were evaluated by IVCM,and then ACCMetrics was used to calculate the following parameters:corneal nerve fiber density(CNFD),branch density(CNBD),fiber length(CNFL),total branch density(CTBD),fiber area(CNFA),fiber width(CNFW),and fractal dimension(CNFrD).The correlation between IVCM parameters and drugs was evaluated using non-parametric measurements of Spearman’s rank correlation coefficient.RESULTS:The CNFD was reduced in glaucoma groups compared to healthy subjects(P<0.01).Patients using anti-glaucoma medications exhibited poorer confocal parameters compared to untreated patients.As the number of medications and usage count increased,CNFD,CNBD,CNFL,CTBD,CNFA,and CNFrD experienced a decline,while CNFW increased(all P<0.01).For the brinzolamide-therapy group,there was a significant decrease in CNFD and CNFL compared to the other monotherapy groups(P<0.001).In the absence of medication,CNFD in males was lower than that in females(P<0.05).Among patients under medication therapy,CNFD remained consistent between males and females.CONCLUSION:Antiglaucoma eye drops affect the microstructure of corneal nerves.IVCM and ACCMetrics are useful tools that could be used to evaluate the corneal nerve changes.

Clinical features and in vivo confocal microscopy assessment in 12 patients with ocular cicatricial pemphigoid

AIM： To describe the clinical features and microstructural characteristics assessed by in vivo confocal microscopy（IVCM） in patients with ocular cicatricial pemphigoid（OCP）.· METHODS： A descriptive, uncontrolled case series study. Patients diagnosed with OCP were examined by clinical history, slit-lamp biomicroscopy features and IVCM images. The results of direct immunofluorescence（DIF） biopsies and indirect immunofluorescence（IIF） were also recorded. Local and systemic immunosuppressive therapy were administered and adjusted according to response.·RESULTS： A total of 12 consecutive OCP patients（7male, 5 female; mean age 60.42 ±10.39y） were recruited.All patients exhibited bilateral progressive conjunctival scarring and recurrent chronic conjunctivitis was the most frequent clinical pattern. The mean duration of symptoms prior to diagnosis of OCP was 2.95 ±2.85y（range： 5mo to 10y）. The Foster classification varied from stage I to IV and 20 eyes（83%） were within or greater than Foster stage Ⅲ on presentation. Two of the 12patients（17%） demonstrated positive DIF; 3 of the 12（25%） patients reported positive IIF. The mean duration of the follow-up period was 20.17 ±11.88mo（range： 6 to48mo）. IVCM showed variable degrees of abnormality in the conjuctiva-cornea and conjuctival scarring was detected in all the involved eyes. Corneal stromal cell activation and dendritic cell infiltration presented asocular surface inflammation, ocular surface keratinization along with the destroyed Vogt palisades was noted in eyes with potential limbal stem cell deficiency. After treatment, remission of ocular surface inflammation was achieved in all the patients, 18 eyes（75%） remained stable, 6 eyes（25%） had recurrent conjunctivitis and cicatrization in 2 eyes（8%） was progressing.· CONCLUSION： As an autoimmune disease, OCP manifests as variable degrees of clinical and laboratory abnormalities with both local and systemic immunosuppressive treatment playing important roles in disease therapy. IVCM can be as a valuable non-invasive technique to assess ocular surface changes in a cellular level with a potential value for providing diagnostic evidence and monitoring therapeutic effects during follow-up.

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 36age-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/mm2vs270 ±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/mm2vs18.1 ±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.

Clinical associations of corneal neuromas with ocular surface diseases

Corneal neuromas,also termed microneuromas,refer to microscopic,irregula rly-shaped enlargements of terminal subbasal nerve endings at sites of nerve damage or injury.The formation of corneal neuromas results from damage to corneal nerves,such as following corneal pathology or corneal or intraocular surge ries.Initially,denervated areas of sensory nerve fibers become invaded by sprouts of intact sensory nerve fibers,and later injured axons regenerate and new sprouts called neuromas develop.In recent years,analysis of corneal nerve abnormalities including corneal neuromas which can be identified using in vivo confocal microscopy,a non-invasive imaging technique with microscopic resolution,has been used to evaluate corneal neuropathy and ocular surface dysfunction.Corneal neuromas have been shown to be associated with clinical symptoms of discomfort and dryness of eyes,and are a promising surrogate biomarker for ocular surface diseases,such as neuropathic corneal pain,dry eye disease,diabetic corneal neuropathy,neurotrophic keratopathy,Sjogren's syndrome,bullous keratopathy,post-refra ctive surgery,and others.In this review,we have summarized the current literature on the association between these ocular surface diseases and the presentation of corneal microneuromas,as well as elaborated on their pathogenesis,visualization via in vivo confocal microscopy,and utility in monitoring treatment efficacy.As current quantitative analysis on neuromas mainly relies on manual annotation and quantification,which is user-dependent and labor-intensive,future direction includes the development of artificial intelligence software to identify and quantify these potential imaging biomarkers in a more automated and sensitive manner,allowing it to be applied in clinical settings more efficiently.Combining imaging and molecular biomarkers may also help elucidate the associations between corneal neuromas and ocular surface diseases.

Corneal alteration and pathogenesis in diabetes mellitus

The incidence of diabetes mellitus(DM) and its complications have increased considerably worldwide. Diabetic keratopathy is the major complication of the cornea characterized by delayed corneal wound healing, decreasing corneal epithelial sensitivity, and recurrent corneal ulcers. There is accumulating evidence that diabetic keratopathy is correlated with the hyperglycemic state. Different corneal components may produce different alterations under hyperglycemia. In addition, diabetic nerve alteration may become a novel biomarker of earlystage DM. Abnormalities of the corneal nerve plexus have been associated with diabetic inflammatory states. There is rapidly growing evidence based on investigations of diabetic corneal nerves through in vivo confocal microscopy. Understanding the molecular pathogenesis caused by hyperglycemia may assist in the identification of novel biomarkers, as well as therapeutic targets for early treatment. This review mainly summarizes recent findings on corneal alteration and pathogenesis in DM.

Diabetic corneal neuropathy as a surrogate marker for diabetic peripheral neuropathy

Diabetic neuropathy is a prevalent microvascular complication of diabetes mellitus,affecting nerves in all parts of the body including corneal nerves and peripheral nervous system,leading to diabetic corneal neuropathy and diabetic peripheral neuropathy,respectively.Diabetic peripheral neuropathy is diagnosed in clinical practice using electrophysiological nerve conduction studies,clinical scoring,and skin biopsies.However,these diagnostic methods have limited sensitivity in detecting small-fiber disease,hence they do not accurately reflect the status of diabetic neuropathy.More recently,analysis of alterations in the corneal nerves has emerged as a promising surrogate marker for diabetic peripheral neuropathy.In this review,we will discuss the relationship between diabetic corneal neuropathy and diabetic peripheral neuropathy,elaborating on the foundational aspects of each:pathogenesis,clinical presentation,evaluation,and management.We will further discuss the relevance of diabetic corneal neuropathy in detecting the presence of diabetic peripheral neuropathy,particularly early diabetic peripheral neuropathy;the correlation between the severity of diabetic corneal neuropathy and that of diabetic peripheral neuropathy;and the role of diabetic corneal neuropathy in the stratification of complications of diabetic peripheral neuropathy.

Factors influencing subjective symptoms in dry eye disease

AIM: To retrospectively investigate the association between dry eye symptoms and clinical or in vivo confocal microscopy parameters in patients with dry eye disease(DED), and to compare these parameters between eyes with DED and normal subjects.METHODS: This retrospective, cross-sectional, controlled study comprised 25 consecutive patients with non-Sj?gren dry eye disease and age-and sex-matched 25 healthy subjects. Each patient underwent a complete examination of the ocular surface in the following order: tear osmolarity measurements, InflammaDry test, tear break-up time, corneal fluorescein staining, Schirmer I test, subjective symptoms questionnaire using the dry eye-related qualityof-life score(DEQS), and in vivo confocal microscopy analysis of the central cornea. Beck depression inventory(BDI) as depressive scale and history of medications and smoking were also evaluated. Stepwise multiple regression analysis was used to assess the factors affecting the DEQS.RESULTS: In univariate analysis, DEQS was associated with tear break-up time(ρ=-0.48, P=0.01), oral medications, such as hypotensive drug(ρ=0.56, P=0.004) and antidepressant(ρ=0.57, P=0.003), and BDI(ρ=0.61, P=0.001) in patients with DED. In multiple regression analysis, explanatory variables relevant to the DEQS were the anti-depressant medications(P=0.04, partial regression coefficient B=21.04) and BDI(P=0.02, B=0.76, adjusted R2=0.54) in these patients. CONCLUSION: Our study shows a significant association between depression and dry eye symptoms. It suggests that dry eye symptoms associate with higher depressive symptoms and its medications, although our patients were not followed longitudinally.

Correlation of the retinopathy degree with the change of ocular surface and corneal nerve in patients with type 2 diabetes mellitus

AIM:To investigate the change of ocular surface and corneal nerve and their correlation in patients suffering from type 2 diabetes mellitus under different degrees of retinopathy.METHODS:Totally 129 type 2 diabetes mellitus patients(257 eyes)were included.They were divided into three groups:no diabetic retinopathy(NDR)group(33 cases,66 eyes),non-proliferative diabetic retinopathy(NPDR)group(32 cases,64 eyes),and proliferative diabetic retinopathy(PDR)group(34 cases,67 eyes).Healthy normal individuals were enrolled as controls(30 cases,60 eyes).Ocular Surface Disease Index(OSDI)questionnaire was completed by all subjects,and dry eye analyzer was applied to examine tear meniscus height(TMH),first tear break-up time(FTBUT),average tear break-up time(ATBUT),tear film lipid layer thickness classification,and meibomian gland loss(MGL)score.Corneal nerve fiber density(CNFD),corneal nerve branch density(CNBD),corneal nerve fiber length(CNFL),and corneal nerve fiber tortuosity(CNFT)were examined by in vivo confocal microscopy(IVCM).The differences and correlation among these parameters were analyzed.RESULTS:Total OSDI score,TMH,FTBUT,ATBUT,tear film lipid layer thickness,MGL score,CNFD,CNBD,CNFL,and CNFT were statistically different among the four groups(P<0.05).In NDR group,CNFL was positively correlated with TMH(r=0.493,both P<0.01)and ATBUT(r=0.437,P<0.05).CNFL in NPDR group was positively correlated with TMH(r=0.642,P<0.01)and ATBUT(r=0.6,P<0.01).CNFL in PDR group was positively correlated with TMH(r=0.364,P<0.05)and ATBUT(r=0.589,P<0.01),with low negative correlation with MGL score(r=-0.331,P<0.05).CONCLUSION:With the progression of diabetic retinopathy,TMH,BUT,lipid layer thickness,CNFL,CNFD,and CNBD gradually decreased,while total OSDI score,MGL score,and CNFT increased.CNFL is correlated with TMH and ATBUT in diabetic patients.

Deep learning-based analysis of macaque corneal sub-basal nerve fibers in confocal microscopy images

Background:To develop and validate a deep learning-based approach to the fully-automated analysis of macaque corneal sub-basal nerves using in vivo confocal microscopy(IVCM).Methods:IVCM was used to collect 108 images from 35 macaques.58 of the images from 22 macaques were used to evaluate different deep convolutional neural network(CNN)architectures for the automatic analysis of sub-basal nerves relative to manual tracings.The remaining images were used to independently assess correlations and interobserver performance relative to three readers.Results:Correlation scores using the coefficient of determination between readers and the best CNN averaged 0.80.For inter-observer comparison,inter-correlation coefficients(ICCs)between the three expert readers and the automated approach were 0.75,0.85 and 0.92.The ICC between all four observers was 0.84,the same as the average between the CNN and individual readers.Conclusions:Deep learning-based segmentation of sub-basal nerves in IVCM images shows high to very high correlation to manual segmentations in macaque data and is indistinguishable across readers.As quantitative measurements of corneal sub-basal nerves are important biomarkers for disease screening and management,the reported work offers utility to a variety of research and clinical studies using IVCM.

Bilateral retrocorneal hyaline scrolls secondary to asymptomatic congenital syphilis: A case report

BACKGROUND Retrocorneal hyaline scrolls are a rare phenomenon.We report a case of bilateral retrocorneal hyaline scrolls that were likely induced by asymptomatic congenital syphilis.CASE SUMMARY A 71-year-old woman presented with blurred vision due to cataracts.Slit-lamp microscopy revealed bilateral hyaline scrolls with a dichotomous branching pattern extending to the anterior chamber or rods attaching to the rough posterior surface of the cornea.The patient was positive for syphilis-specific antibodies,with no ocular or systemic evidence of congenital or acquired syphilis.Binocular cataract,retrocorneal scroll,and corneal endothelial gutta were considered.The scroll of the right eye was removed during cataract surgery and further observed using hematoxylin–eosin staining and scanning electron microscopy.The cornea of the right eye remained transparent,and the residual scroll seemed stable,however,the corneal endothelial density declined at 13 mo after surgery.In vivo confocal microscopy revealed coalescence of corneal guttae at the level of the corneal endothelium or adhesion to the posterior surface of the endothelium,with enlarged endothelial cells in both eyes.Activated keratocytes in the stroma and a highly reflective acellular structure at the level of the Descemet’s membrane were observed.The removed scroll had a cartilage-like hardness and a circularly arranged fiber-like acellular structure.CONCLUSION Occult congenital syphilis could induce corneal endothelial gutta and theformation of retrocorneal scrolls without other signs of ocular syphilis.