Chitosan-based thermosensitive hydrogel with long-term release of murine nerve growth factor for neurotrophic keratopathy

Neurotrophic keratopathy is a persistent defect of the corneal epithelium,with or without stromal ulceration,due to corneal nerve deficiency caused by a variety of etiologies.The treatment options for neurotrophic keratopathy are limited.In this study,an ophthalmic solution was constructed from a chitosan-based thermosensitive hydrogel with long-term release of murine nerve growth factor(CTH-mNGF).Its effectiveness was evaluated in corneal denervation(CD)mice and patients with neurotrophic keratopathy.In the preclinical setting,CTH-mNGF was assessed in a murine corneal denervation model.CTH-mNGF was transparent,thermosensitive,and ensured sustained release of mNGF for over 20 hours on the ocular surface,maintaining the local mNGF concentration around 1300 pg/mL in vivo.Corneal denervation mice treated with CTH-mNGF for 10 days showed a significant increase in corneal nerve area and total corneal nerve length compared with non-treated and CTH treated mice.A subsequent clinical trial of CTH-mNGF was conducted in patients with stage 2 or 3 neurotrophic keratopathy.Patients received topical CTH-mNGF twice daily for 8 weeks.Fluorescein sodium images,Schirmer’s test,intraocular pressure,Cochet-Bonnet corneal perception test,and best corrected visual acuity were evaluated.In total,six patients(total of seven eyes)diagnosed with neurotrophic keratopathy were enrolled.After 8 weeks of CTH-mNGF treatment,all participants showed a decreased area of corneal epithelial defect,as stained by fluorescence.Overall,six out of seven eyes had fluorescence staining scores<5.Moreover,best corrected visual acuity,intraocular pressure,Schirmer’s test and Cochet-Bonnet corneal perception test results showed no significant improvement.An increase in corneal nerve density was observed by in vivo confocal microscopy after 8 weeks of CTH-mNGF treatment in three out of seven eyes.This study demonstrates that CTH-mNGF is transparent,thermosensitive,and has sustained-release properties.Its effectiveness in healing corneal epithelial defects in all eyes with neurotrophic keratopathy suggests CTH-mNGF has promising application prospects in the treatment of neurotrophic keratopathy,being convenient and cost effective.

Bilateral malignant glaucoma with bullous keratopathy:A case report

BACKGROUND Malignant glaucoma,caused by aqueous misdirection,is a challenging postsurgical complication presented with normal/high intraocular pressure and shallowing of the central and peripheral anterior chambers.Its incidence is about 0.6%-4.0%.It can be secondary to filtering surgeries,laser iridotomy,and cataract surgery.Short axial length and a history of angle closure glaucoma are its main risk factors.Here,we report a bilateral malignant glaucoma with bullous keratopathy in the patient’s left eye.CASE SUMMARY We present a case of bilateral malignant glaucoma.The cause of malignant glaucoma for each eye of this patient was different.Hence,the management strategy and selection of surgical methods were also different.However,the normal anterior chamber was ultimately maintained,and maximum visual function was preserved.Even though the left eye received multiple surgeries and corneal endothelial decompensation occurred,the formation of a retroendothelial fibrous membrane partially compensated for the function of the corneal endothelium.CONCLUSION The formation of a retroendothelial fibrous membrane partially compensated for the function of the corneal endothelium.

Usage of topical insulin for the treatment of diabetic keratopathy,including corneal epithelial defects

BACKGROUND Diabetic keratopathy(DK)occurs in 46%-64%of patients with diabetes and requires serious attention.In patients with diabetes,the healing of corneal epithelial defects or ulcers takes longer than in patients without diabetes.Insulin is an effective factor in wound healing.The ability of systemic insulin to rapidly heal burn wounds has been reported for nearly a century,but only a few studies have been performed on the effects of topical insulin(TI)on the eye.Treatment with TI is effective in treating DK.AIM To review clinical and experimental animal studies providing evidence for the efficacy of TI to heal corneal wounds.METHODS National and international databases,including PubMed and Scopus,were searched using relevant keywords,and additional manual searches were conducted to assess the effectiveness of TI application on corneal wound healing.Journal articles published from January 1,2000 to December 1,2022 were examined.The relevancy of the identified citations was checked against predetermined eligibility standards,and relevant articles were extracted and reviewed.RESULTS A total of eight articles were found relevant to be discussed in this review,including four animal studies and four clinical studies.According to the studies conducted,TI is effective for corneal re-epithelialization in patients with diabetes based on corneal wound size and healing rate.CONCLUSION Available animal and clinical studies have shown that TI promotes corneal wound healing by several mechanisms.The use of TI was not associated with adverse effects in any of the published cases.Further studies are needed to enhance our knowledge and understanding of TI in the healing of DK.

Therapeutic effects of sericin on diabetic keratopathy in Otsuka Long-Evans Tokushima Fatty rats

An Otsuka Long-Evans Tokushima Fatty(OLETF)rat provides a useful model for studies to develop corneal wound healing drugs for use in diabetic keratopathy resulting from type 2 diabetes mellitus.We investigated the effects of sericin on corneal wound healing in OLETF rats.Corneal wounds were prepared by removal of the corneal epithelium and documented using a TRC-50X.Sericin was instilled into the eyes of rats five times a day following corneal abrasion.The plasma levels of glucose,triglycerides,cholesterol and insulin in 38 wk old OLETF rats were significantly higher than in normal control rats(LETO rats),and the rate of corneal wound healing in OLETF rats was slower than in normal rat,probably due to the suppression of cell migration and proliferation caused by high plasma glucose levels.The corneal wounds of OLETF rats instilled with saline showed almost complete healing 72h after corneal epithelial abrasion.On the other hand,the instillation of sericin has a potent effect in promoting wound healing and wound size reduction in OLETF rats and the wounds showed almost complete healing at 48 h after abrasion.The sericin may be an effective and safe drug to promote corneal wound healing in diabetic keratopathy.

Combined Descemet stripping automated endothelial keratoplasty and intravitreal dexamethasone implant for concomitant pseudophakic bullous keratopathy and cystoid macular edema

Dear Editor,Endothelial cell density decreases with age and in various ocular conditions,including corneal endotheliitis,uveitis,pseudoexfoliation syndrome,and birth injury(1)The reduction of endothelial cell density is exacerbated over time after intraocular surgery(1)Descemet stripping automated endothelial keratoplasty(DSAEK)is considered the primary procedure for patients with only endothelial dysfunction.

Dellen-like keratopathy associated with glaucoma drainage devices

To report the first case of dellen-like keratopathy with superior corneal thinning associated with implantation of glaucoma drainage devices. A 70-year-old male with a history of primary open angle glaucoma and dry eye disease underwent placement of glaucoma drainage devices with antimetabolite application in both eyes. Prior to placement, minimal refractive error was noted on manifest refraction. Several years later, the patient was referred for decreased vision and corneal irregularity. Examination showed pathologic corneal curvature, superior corneal thinning, and epithelial demarcation lines immediately anterior to the glaucoma drainage devices in both eyes. The epithelium remained intact with no evidence of limbal stem cell deficiency. Manifest refraction revealed a large change in both eyes. Topography was used to confirm the presence of irregular corneal curvature anterior to the glaucoma drainage devices. Dellen-like keratopathy with superior thinning is a rare sequela after implantation of a glaucoma drainage device that must be considered in elderly patients who undergo glaucoma surgery. It is likely related to a combination of tear film alteration related to previously large anterior blebs, antimetabolite application, and aqueous humor flow patterns around the drainage devices. Treatment should focus on lubrication.

Toxic keratopathy associated with abuse of topical anesthetics and amniotic membrane transplantation for treatment

AIMTo evaluate the clinical findings of toxic keratopathy associated with abuse of topical anesthetics and the treatment efficacy of amniotic membrane transplantation (AMT).METHODSFifteen eyes of 10 patients with abuse of topical anesthetics were included in this study. The data collected included patients' demographic information, initial best corrected visual acuity (BCVA), clinical findings, time to AMT, duration of epithelization, additional treatments, posttreatment BCVA, and the results of psychiatric examination.RESULTSAll patients were male, with the mean age of 37.9&#x000b1;5.4y. The patients had received 0.5% proparacaine hydrochloride due to pain resulting from foreign bodies, such as welding flash burns and car battery explosions, for a mean of 18.2&#x000b1;12.4d. The mean initial BCVA of the patients was 0.069&#x000b1;0.100. All patients had persistent epithelial defects, stromal infiltration, ring ulcer, and corneal edema. Initially, medical treatment was attempted in all cases. Because of severe pain, persistent epithelial defects and progressing stromal thinning did not improve with medical treatment, thus, the patients underwent AMT. The mean posttreatment BCVA of the patients was 0.33&#x000b1;0.27. All of them, except for two patients, showed improved visual acuity. One patient underwent evisceration for corneal melting and endophthalmitis in another center, and one patient underwent evisceration for severe pain of unknown origin. All 5 patients who consented to a psychiatric examination had depression, had personality disorder, and used tobacco.CONCLUSIONAMT appears to be an effective method for pain relief, rapid epithelial and stromal healing; however, visual prognosis is still poor despite medical and surgical interventions.

Infective crystalline keratopathy due to Citrobacter koseri

Rationale:Infectious keratopathy is an ocular emergency with the potential to cause irreversible blindness.Patient's concerns:A 63-year-old diabetic man presented with a 3-day history of painful red right eye.He had a history of multiple ocular surgeries in the affected eye without recent ocular trauma.Diagnosis:Infective crystalline keratopathy secondary to Citrobacter koseri.Interventions:Topical corticosteroids were discontinued,and dual topical antibiotic therapy of moxifloxacin 5%and gentamycin 0.3%were applied.Outcomes:Twelve hours after the start of treatment,the crystalline nature of the infiltrate disappeared,with enlargement of the epithelial defect.The antibiotic regime was continued and the lesion healed within a week of presentation with residual scarring.Lessons:Infective crystalline keratopathy classically presents with intrastromal branching fern-like opacities and minimal anterior segment inflammation in an immunosuppressed eye.The mainstay of management is corticosteroid discontinuation and the administration of empirical antibiotics until the results of the culture and sensitivity are available.In Citrobacter-related cases,treatment may result in a suppurative appearance before healing of the lesion.

Ethylenediaminetetraacetic Acid Chelation for Band Keratopathy before Ab Interno Glaucoma Surgery

An 87-year-old woman with primary open-angle glaucoma presented to our hospital. Although the combined cataract and minimally invasive glaucoma surgeries (MIGS) were an appropriate surgical option, the presence of band keratopathy made it difficult to perform ab interno glaucoma surgery in her right eye (OD);therefore, the corneal opacity was removed using ethylenediaminetetraacetic acid (EDTA) chelation procedure. One month after chelation, microhook ab interno trabeculotomy and cataract surgery were performed successfully. Clear intraoperative visualization of the angle structures is critical for the success of these MIGS procedures. In glaucomatous eyes that require MIGS, EDTA chelation is a good neoadjuvant therapy for coexisting band keratopathy.

Analysis of corneal morphologic and pathologic changes in early-stage congenital aniridic keratopathy

AIM：To determine typical corneal changes of congenital aniridic keratopathy（CAK）using corneal topography and confocal systems,and to identify characteristics that might assist in early diagnosis.METHODS：Patients with CAK and healthy control subjects underwent detailed ophthalmic examinations including axial length,corneal thickness,tear film condition,corneal topography,and laser-scanning in vivo confocal microscopy（IVCM）. RESULTS：In early stage aniridic keratopathy,Schirmer I test（SIT）,break-up time（BUT）,mean keratometry（mean K）and simulated keratometry（sim K）were reduced relative to controls（P〈0.05）,while simulation of corneal astigmatism（sim A）and corneal thickness were increased（P〈0.05）. In addition,significantly more eyes exhibited flat cornea compared with the control group. Inflammatory dendritic cells were present in the aniridic epithelium,with significantly increased density relative to controls（P〈0.05）. Palisade ridge-like features and abnormal cell morphology were observed in six out of sixteen CAK cases. In central cornea area,the aniridic corneas had the increased subbasal nerve density. CONCLUSION：These changes in corneal morphology in borderline situations can be useful to confirm the diagnosis of CAK.

Bee sting keratopathy with retained stinger

This case report aims to report an uncommon case of bee sting keratopathy with retained stinger.A 55-year-old man presented with left cornea bee sting while gardening two days prior to first visit.He complained of severe eye pain with redness,tearing and blurring of vision.On examination,his right eye visual acuity was 6/6 and in left eye was hand movement.There was generalized conjunctival hyperemia and cornea showing significant descemet striae.A bee stinger with surrounding infiltration noted at 2 o'clock was associated with striate keratitis.It was deeply seated at the posterior third of cornea stroma near to paracentral area.Pupil was mid-dilated with absence of relative afferent pupillary defect.There was neither hypopyon nor cataract.The posterior segment could not be visualized due to severe corneal edema.However,B-scan ultrasound was normal.Bee stinger was removed under local anaesthesia on the day of presentation.Post-operatively,patient was administered with topical moxifloxacin and topical non steroidal anti-inflammatory drugs.Three weeks later,there was resolution of cornea infiltrate with improvement of striate keratitis and his vision was improved to 1/60.However,cornea edema did not regress but ended up with bullous keratopathy.The patient has undergone descemet-stripping automated endothelial keratoplasty and his vision was improved to 6/9.We recommend early stinger removal to reduce the possible sequelae of bee sting toxicity for better visual outcome.

Corneal neurotization: a narrative review of techniques, outcomes, and surgical considerations

Background and Objective:Corneal neurotization is a novel surgical technique used to restore corneal sensation in patients with neurotrophic keratopathy.Neurotrophic keratopathy is a disorder characterized by dysfunction of the ophthalmic division of the trigeminal nerve,which provides sensory innervation to the cornea.Without sensation,the cornea is at risk of infection,ulceration,perforation,and ultimately,vision loss.Corneal neurotization has emerged as an innovative technique to reinnervate anesthetized corneas by transferring a healthy donor nerve to the affected eye around the corneoscleral limbus.As the field of corneal neurotization rapidly grows,there is a need to synthesize the existing body of literature on corneal neurotization and identify important areas for further research.In this review,we will discuss neurotrophic keratopathy and its current management strategies,followed by an overview of corneal neurotization techniques,outcomes,surgical considerations,and future directions.Methods:PubMed and Google Scholar searches were conducted to retrieve and analyze relevant original papers and reviews on neurotrophic keratopathy and corneal neurotization up until April 2022.Key Content and Findings:Currently,numerous techniques for corneal neurotization exist,including direct nerve transfers,as well as indirect neurotization via interposition nerve grafts.So far,corneal neurotization has been shown to be highly successful in restoring corneal sensation,improving visual acuity,and improving corneal epithelial health.To date,there have been no significant differences in outcomes between direct versus indirect neurotization techniques,different donor nerves,or autologous versus allogeneic interposition grafts.However,there is some evidence that corneal neurotization procedures may be more successful in pediatric patients.Conclusions:Corneal neurotization shows great promise in treating neurotrophic corneas and represents the first management option to date that addresses the underlying pathophysiological mechanism of neurotrophic keratopathy by restoring corneal sensation.As the use of corneal neurotization continues to broaden,additional studies will become important to compare techniques in a systematic manner,with larger sample sizes,as well as standardized outcome measures and follow-up time.

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.

A comparative study of risk factors for corneal infection in diabetic and non-diabetic patients

AIM： To compare the clinical characteristics of infectious keratopathy in type 2 diabetes mellitus（T2DM） and nondiabetes mellitus（NDM） and to investigate risk factors for infectious keratopathy in T2DM patients. METHODS： Totally 230 patients with T2DM and 168 with NDM diagnosed as infectious keratopathy were hospitalized at Qingdao Eye Hospital from 2001 to 2015. Data including sex, age, occupation, season, smoking and alcohol consumption habits, duration between onset and treatments, duration of hospitalization were collected. Initially identified indicators were analyzed with a multivariate logistic regression. Glycosylated hemoglobin A1 c（Hb A1 c） in patients with T2DM was analyzed. The infectious keratopathies in the two groups were categorized and compared.RESULTS： The diabetic group consisted of 146（63.5%） males and 84（36.5%） females. The NDM group consisted of 111（66.1%） males and 57（33.9%） females. There was no signigicantly difference in sex distribution between the two groups（P〉0.05）. There were significant differences in age, occupation of patients, season of the onset of diseases, duration between onset and treatment, and durations of hospitalization between the two groups（P〈0.05）. In most of the patients in the diabetic group, the duration between onsetand treatment was ≤3 mo, and most was ≥3 mo in the NDM group. Multivariate logistic regression analysis revealed that age and season were related to the development of corneal infection in the T2DM group（OR=1.709, 1.706）. In the T2DM group, Hb A1 c was 9.09%±2.12%. There were statistically significant differences in the incidences of bacterial keratitis and herpes simplex keratitis in the two groups（P〈0.05）, but no significant statistical difference was found between fungal keratitis and amoebic keratitis（P〉0.05）. CONCLUSION： Advanced age and the summer and winter seasons are identified as risk factors for infectious keratopathy in T2DM patients, and T2DM patients are more prone to bacterial keratitis.

Management of corneal ulceration with a moisture chamber due to temporary lagophthalmos in a brain injury patient:A case report

BACKGROUND This study describes the use of a moisture chamber to treat corneal ulceration due to temporary lagophthalmos in a critically ill patient.CASE SUMMARY A 46-year-old woman was admitted to the intensive care unit after a car accident.She suffered multiple injuries that included brain injury and presented with moderately decreased consciousness and lagophthalmos in her right eye.Within 6 d,her consciousness improved considerably;at which time,exposure keratopathy occurred and worsened to corneal ulceration.Lubricating gel,antibiotic ointment,and bandage contact lens were all ineffective in preventing or treating the exposure keratopathy.Instead of tarsorrhaphy,a moisture chamber was applied which successfully controlled the corneal ulceration.The moisture chamber was discontinued when complete eyelid closure recovered a week later.CONCLUSION A moisture chamber may be an effective,noninvasive alternative to tarsorrhaphy for treating severe exposure keratopathy due to temporary lagophthalmos.

Corneal transplantation: Beyond the horizon

Evolving techniques in keratoplasty have undoubtedly led to thinner corneal grafts. These newer iterations of keratoplasty aim to reduce graft rejections, improve visual acuity and visual rehabilitation. Each technique poses its own advantages and disadvantages; the surgeon should select patients suitable for a particular technique while accounting for their surgical competency given the learning curve associated with these newer techniques. Alternatives to corneal transplant may have a role in addressing the shortages of corneal graft, these bioengineered material and medical treatment still need further studies to demonstrate its clinical applicability.