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.

Interconnections between diabetic corneal neuropathy and diabetic retinopathy:diagnostic and therapeutic implications

Diabetic corneal neuropathy and diabetic retinopathy are ocular complications occurring in the context of diabetes mellitus.Diabetic corneal neuropathy refers to the progressive damage of corneal nerves.Diabetic retinopathy has traditionally been considered as damage to the retinal microvasculature.However,growing evidence suggests that diabetic retinopathy is a complex neurovascular disorder resulting from dysfunction of the neurovascular unit,which includes both the retinal vascular structures and neural tissues.Diabetic retinopathy is one of the leading causes of blindness and is frequently screened for as part of diabetic ocular screening.However,diabetic corneal neuropathy is commonly overlooked and underdiagnosed,leading to severe ocular surface impairment.Several studies have found that these two conditions tend to occur together,and they share similarities in their pathogenesis pathways,being triggered by a status of chronic hyperglycemia.This review aims to discuss the interconnection between diabetic corneal neuropathy and diabetic retinopathy,whether diabetic corneal neuropathy precedes diabetic retinopathy,as well as the relation between the stage of diabetic retinopathy and the severity of corneal neuropathy.We also endeavor to explore the relevance of a corneal screening in diabetic eyes and the possibility of using corneal nerve measurements to monitor the progression of diabetic retinopathy.

Corneal neuromediator profiles following laser refractive surgery

Laser refractive surgery is one of the most commonly performed procedures worldwide.In laser refractive surgery,Femtosecond Laser in Situ Keratomileusis and Refractive Lenticule Extraction have emerged as promising alternatives to microkeratome Laser in Situ Keratomileusis and Photorefractive Keratectomy.Following laser refractive surgery,the corneal nerves,epithelial and stromal cells release neuromediators,including neurotrophins,neuropeptides and neurotransmitters.Notably,nerve growth factor,substance P,calcitonin gene-related peptide and various cytokines are important mediators of neurogenic inflammation and corneal nerve regeneration.Alterations in neuromediator profiles and ocular surface parameters following laser refractive surgery are attributed to the surgical techniques and the severity of tissue insult induced.In this review,we will discuss the(1)Functions of neuromediators and their physiological and clinical significance;(2)Changes in the neuromediators following various laser refractive surgeries;(3)Correlation between neuromediators,ocular surface health and corneal nerve status;and(4)Future directions,including the use of neuromediators as potential biomarkers for ocular surface health following laser refractive surgery,and as adjuncts to aid in corneal regeneration after laser refractive surgery.

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.

Analysis of corneal nerve plexus in corneal confocal microscopy images

Small Aδand C nerve fibers of the sensory and autonomic nervous systems constitute 70–90%of peripheral nerve fibers including corneal nerves(Muller et al.,2003).Corneal nerves originate from the ophthalmic branch of the trigeminal nerve and enter the cornea at the limbus radially from all directions toward the central cornea at the level of anterior and middle stroma.The subepithelial nerve plexus lies at the interface between the Bowman layer and anterior stroma.They then divide into smaller branches and turn 90°toward Bowman’s layer(Muller et al.,2003),travelling between Bowman’s layer and the basal epithelial layer and forming the sub-basal nerve plexus(Muller et al.,2003).

Cosmetic outcome of femtosecond laserassisted pterygium surgery

Background:To examine the cosmetic outcome of femtosecond laser-assisted pterygium surgery(FLAPS)with conjunctival autograft(CAG)and its potential predictive factors.Methods:This Was a prospective interventional case series(NCT02866968).We included 29 patients(29 eyes)with primary pterygium who underwent FLAPS.Cosmetic outcome was graded by two graders(an ophthalmology resident and an experienced ophthalmologist)using Hirst classification system(1-4:excellent-poor).Weighted Cohen's kappa analysis was performed to examine the intra-and inter-rater reliability.The relationship between cosmetic outcome and various factors were determined by Spearman's correlation coefficients(r).Results:The preoperative severity of pterygium(Tan grading system)was mild/atrophic(7%),moderate/intermediate(62%),and severe/fleshy(31%).An ultrathin CAG(mean thickness of 74.5±9.8μm)was fashioned intraoperatively.An excellent cosmetic outcome of FLAPS(median±IQR)was observed at 3 months(1.0±1.0)and remained similar at 6 months(1.0±0.0)and 12 months(1.0±0.0)postoperatively.At final fllow-up,27(93%)patients achieved good-to-excellent cosmetic outcome,with 1(3%)patient having a poor outcome due to incomplete pterygium removal.Weighted kappa analysis of Hirst grading system showed excellent intra-rater(k:0.86-0.95)and inter-rater reliability(k:0.84-0.88).There was a weak and borderline significant correlation between good cosmetic outcome and reduced postoperative CAG thickness(r=0.38,P=0.06)but not with age,gender,preoperative pterygium severity,or intraoperative CAG thickness.Conclusions:FLAPS can result in an excellent cosmetic outcome,which may be attributed to the beneficial effect of an ultrathinCAG.Trial registration:ClinicalTrials.gov,NCT02866968.Registered in July 2016.

Cosmetic outcome of femtosecond laserassisted pterygium surgery

Background:To examine the cosmetic outcome of femtosecond laser-assisted pterygium surgery(FLAPS)with conjunctival autograft(CAG)and its potential predictive factors.Methods:This was a prospective interventional case series(NCT02866968).We included 29 patients(29 eyes)with primary pterygium who underwent FLAPS.Cosmetic outcome was graded by two graders(an ophthalmology resident and an experienced ophthalmologist)using Hirst classification system(1-4=excellent-poor).Weighted Cohen’s kappa analysis was performed to examine the intra-and inter-rater reliability.The relationship between cosmetic outcome and various factors were determined by Spearman’s correlation coefficients(r).Results:The preoperative severity of pterygium(Tan grading system)was mild/atrophic(7%),moderate/intermediate(62%),and severe/fleshy(31%).An ultrathin CAG(mean thickness of 74.5±9.8μm)was fashioned intraoperatively.An excellent cosmetic outcome of FLAPS(median±IQR)was observed at 3 months(1.0±1.0)and remained similar at 6months(1.0±0.0)and 12months(1.0±0.0)postoperatively.At final follow-up,27(93%)patients achieved good-to-excellent cosmetic outcome,with 1(3%)patient having a poor outcome due to incomplete pterygium removal.Weighted kappa analysis of Hirst grading system showed excellent intra-rater(κ=0.86-0.95)and inter-rater reliability(κ=0.84-0.88).There was a weak and borderline significant correlation between good cosmetic outcome and reduced postoperative CAG thickness(r=0.38,P=0.06)but not with age,gender,preoperative pterygium severity,or intraoperative CAG thickness.Conclusions:FLAPS can result in an excellent cosmetic outcome,which may be attributed to the beneficial effect of an ultrathin CAG.