[Innovative surgical treatment approaches for endothelial dysfunction : Descemet stripping only (DSO) and endothelial cell injection]. / Innovative chirurgische Therapieansätze der endothelialen Dysfunktion : "Descemet stripping only" (DSO) und Endothelzellinjektion.

Currently, due to a rising number of patients Germany and many other countries experience a large deficit of donor eyes for posterior lamellar keratoplasty procedures in the treatment of corneal endothelial diseases. To address this unmet need there is an ongoing investigation of treatment modalities which do not rely on donor tissue or enable clinicians to treat more patient eyes per donor eye. The authors introduce a promising approach for both treatment principles. First, the technique of Descemet stripping only (DSO) is detailed, in which a central part of the Descemet's membrane including the endothelium is surgically removed without replacement with donor tissue. This then allows endothelial cells from the periphery of the cornea to migrate into the central area and can reduce corneal opacification and swelling. As a representative technique of the second group, the authors introduce endothelial cell injection, in which human corneal endothelial cells are cultivated in vitro and then, after removal of the diseased endothelium, injected into the anterior chamber of the recipient's eye to form a new and healthy endothelium. This is supported by injection of Rho kinase inhibitors and a face-down positioning of the patient after surgery. It is postulated that endothelial cell injection could possibly enable clinicians to treat up to 300 patient eyes with the tissue generated from 1 donor eye. Whether and how these novel approaches will become established in Europe remains to be seen.

Evaluation of Medically Reversible Limbal Stem Cell Deficiency.

Objectives: To evaluate the clinical characteristics and treatment strategies of limbal stem cell deficiency (LSCD) patients managed with medical therapy. Materials and Methods: The study included 29 eyes of 21 patients with LSCD who were managed medically at Ege University Faculty of Medicine, Department of Ophthalmology between May 2013 and May 2023. LSCD stages before and after medical treatment were recorded according to the LSCD staging system published by the International LSCD Working Group. The medical records of patients showing improvement in LSCD stage with medical treatment without surgical intervention were evaluated. Results: The mean age was 35.5±23.8 years (range, 5-71 years) with a male-to-female ratio of 6:15. The primary etiology of LSCD was ocular rosacea in 12 patients (57.1%), marginal keratitis in the setting of blepharitis in 8 patients (38.1%), and topical medication toxicity in 1 patient (4.8%). The mean baseline best corrected visual acuity (BCVA) was 0.25±0.26 logarithm of the minimum angle of resolution (logMAR) (range, 0-1 logMAR). Pre-treatment LSCD stage was stage 1A in 5 eyes (17.2%), stage 1B in 12 eyes (41.4%), stage 1C in 4 eyes (13.8%), stage 2A in 4 eyes (13.8%), and stage 2B in 4 eyes (13.8%). Complete regression of LSCD was achieved in 6 eyes (20.7%) with medical treatment addressing the primary etiology. In the remaining eyes, after medical treatment, the severity of LSCD decreased below the surgical threshold, which is considered stage 2B. The mean final BCVA was 0.07±0.1 logMAR (range, 0-0.4 logMAR). Conclusion: This study highlights that LSCD can be completely or partially reversible with appropriate management, especially in cases with underlying limbal niche dysfunction, where inflammation plays a significant role. Although limbal stem cell transplantation is considered the main treatment approach for LSCD, localized and early-stage LSCD can be effectively managed medically without the need for surgical intervention.

Molecular and Cellular Mechanisms of the Therapeutic Effect of Mesenchymal Stem Cells and Extracellular Vesicles in Corneal Regeneration.

The cornea is a vital component of the visual system, and its integrity is crucial for optimal vision. Damage to the cornea resulting from trauma, infection, or disease can lead to blindness. Corneal regeneration using mesenchymal stem cells (MSCs) and MSC-derived extracellular vesicles (MSC-EVs) offers a promising alternative to corneal transplantation. MSCs are multipotent stromal cells that can differentiate into various cell types, including corneal cells. They can also secrete a variety of anti-inflammatory cytokines and several growth factors, promoting wound healing and tissue reconstruction. This review summarizes the current understanding of the molecular and cellular mechanisms by which MSCs and MSC-EVs contribute to corneal regeneration. It discusses the potential of MSCs and MSC-EV for treating various corneal diseases, including corneal epithelial defects, dry eye disease, and keratoconus. The review also highlights finalized human clinical trials investigating the safety and efficacy of MSC-based therapy in corneal regeneration. The therapeutic potential of MSCs and MSC-EVs for corneal regeneration is promising; however, further research is needed to optimize their clinical application.

Evaluating the role of Demodex infestation and meibomian gland dysfunction in recurrent corneal erosion syndrome.

This investigation aims to observe the effects of demodex infection and meibomian gland function in recurrent corneal erosion syndrome (RCES), as well as the efficacy of intense pulsed light (IPL) in treating RCES. The study enrolled thirty patients diagnosed with RCES (30 eyes) alongside a control group of thirty-one individuals (31 eyes). Both cohorts underwent a series of diagnostic evaluations, including eyelash sampling, Demodex mite enumeration, infrared imaging of the meibomian glands, and blepharolipin scoring. The RCES subjects were further categorized into two subgroups upon stabilization for comparative analysis of treatment outcomes: the RCES-A subgroup received IPL therapy (16 patients), and the RCES-B subgroup was administered medication treatment (14 patients). Post-treatment, all participants were re-evaluated using the initial diagnostic procedures to monitor for recurrence. Preliminary findings indicated significant differences between the RCES and control groups in terms of meibomian gland scores (4 [3.0, 4.0] vs. 2 [1.0, 3.0]), blepharolipin scores (15.5 [11.0, 16.8] vs. 8.0 [5.5, 10.0]), and lid margin scores (3.0 [2.8, 3.0] vs. 2.0 [1.0, 3.0]), with P < 0.01 for all comparisons. Additionally, the Demodex count was significantly higher in the RCES group (8.0 [4.0,9.0]) compared to the control (0 [0, 2]) (Z = - 4.13, P = 0.00), with a Demodex positivity rate of 83.3% in the RCES group versus 38.7% in the control group (χ2 = 7.60, P < 0.01). Post-treatment, the RCES-A subgroup exhibited significant improvements in meibomian gland loss scores, blepharolipin scores, lid margin abnormality scores, and a reduction in Demodex counts (P < 0.01), with a post-treatment Demodex positivity rate of 56.3% (P = 0.11). During the follow-up, the RCES-A subgroup experienced a lower relapse rate compared to the RCES-B subgroup (1 vs. 6 patients). The findings suggest a correlation between meibomian gland dysfunction and Demodex infestation with the incidence of RCES. The application of IPL therapy in combination with meibomian gland massage demonstrates significant potential in enhancing meibomian gland functionality, reducing Demodex counts, and effectively mitigating the recurrence of RCES. Clinical trial registration: https://www.chictr.org.cn/ ChiCTR2000039494 (30/10/2020).

Infectious crystalline keratopathy-clinical-microbiological profile and outcome of management.

PURPOSE: To describe the clinical features, management, and long-term outcome of Infectious crystalline keratopathy (ICK). METHODS: The medical records of clinically diagnosed and microbiologically proven cases of ICK were reviewed from January 2011 to December 2022. Clinical characteristics include the presence of whitish needle-like projections with branching, limited to anterior-mid stroma. Keratoplasty being the most common risk factor, graft-related microbial keratitis during the same period was also studied. The demography, clinical profile, microbiology, treatment, and outcome were analyzed, and compared with secondary graft infiltrate(GI). RESULTS: Medical records of 24 cases with ICK were reviewed. The mean age was 49.3 ± 20.1 years, with 15(62.5%) males. Prior keratoplasty was done in 18 (75%) cases, with a mean graft size of 10.1 ± 1.5 mm, and mean interval between the last graft and presentation was 9.7 ± 6.2 (3-90) months. In comparison to GI (n = 24), ICK patients (n = 18,75%) were less symptomatic, presented late (7.3 ± 6.5 days vs 16.3 ± 19.4, p = 0.003), using frequent topical steroids (> 3 times/day, p = 0.006), smaller infiltrate size < 4 mm (p = 0.008), central (p = 0.02), less associated with epithelial defect (p = 0.0001), hypopyon (p = of 0.0002), corneal perforation (p = 0.0006), and surgical management (p = 0.03). On microbiology, 22 (91.6%) ICK cases were culture positive, 14 (63.6%) gram-positive, 3 (13.6%) gram-negative, 2 (9%) mixed bacteria, and 3 (13.6%) fungus, comparable with GI. CONCLUSION: ICK affects poor ocular surfaces usually following keratoplasty with larger graft size, the use of steroids being the most common association, and it responds to medical management as compared to GI.

Descemet's membrane detachment: An updated comprehensive review of etiopathogenesis, diagnosis, and management.

The Descemet membrane (DM) is the basement membrane of corneal endothelial cells, which are responsible for maintaining corneal transparency. DM detachment (DMD) can occur due to various reasons, with the most common etiology being post-surgical. Older age, blunt instruments, and faulty surgical technique predispose to the intraoperative or postoperative occurrence of DMD, and one should have a high index of suspicion for DMD in cases with unexplained or an atypical pattern of corneal edema after surgery. Prompt intervention for DMD management is imperative to effect early visual rehabilitation, decrease corneal morbidity, and avoid permanent damage leading to scarring of the cornea. Various classifications of DMD and management protocols have been described. Anterior-segment optical coherence tomography (AS-OCT) imaging is the most effective imaging to detect DMD and quantify its extent. Desmetopexy with air/gas is the initial treatment of choice and could be aided by suture fixation. Non-responsive cases might need endothelial keratoplasty.

The landscape of clinical trials in corneal regeneration: A systematic review of tissue engineering approaches in corneal disease.

The limited availability of a healthy donor cornea and the incidence of allograft failure led researchers to seek other corneal substitutes via tissue engineering. Exploring the trend of clinical trials of the cornea with the vision of tissue engineering provides an opportunity to reveal future potential corneal substitutes. The results of this clinical trial are beneficial for future study designs to overcome the limitations of current therapeutic approaches. In this study, registered clinical trials of bio-based approaches were reviewed for corneal regeneration on March 22, 2024. Among the 3955 registered trials for the cornea, 392 trials were included in this study, which categorized in three main bio-based scaffolds, stem cells, and bioactive macromolecules. In addition to the acellular cornea and human amniotic membrane, several bio-based materials have been introduced as corneal substrates such as collagen, fibrin, and agarose. However, some synthetic materials have been introduced in recent studies to improve the desired properties of bio-based scaffolds for corneal substitutes. Nevertheless, new insights into corneal regenerative medicine have recently emerged from cell sheets with autologous and allogeneic cell sources. In addition, the future perspective of corneal regeneration is described through a literature review of recent experimental models.

TGF-ß-Based Therapies for Treating Ocular Surface Disorders.

The cornea is continuously exposed to injuries, ranging from minor scratches to deep traumas. An effective healing mechanism is crucial for the cornea to restore its structure and function following major and minor insults. Transforming Growth Factor-Beta (TGF-ß), a versatile signaling molecule that coordinates various cell responses, has a central role in corneal wound healing. Upon corneal injury, TGF-ß is rapidly released into the extracellular environment, triggering cell migration and proliferation, the differentiation of keratocytes into myofibroblasts, and the initiation of the repair process. TGF-ß-mediated processes are essential for wound closure; however, excessive levels of TGF-ß can lead to fibrosis and scarring, causing impaired vision. Three primary isoforms of TGF-ß exist-TGF-ß1, TGF-ß2, and TGF-ß3. Although TGF-ß isoforms share many structural and functional similarities, they present distinct roles in corneal regeneration, which adds an additional layer of complexity to understand the role of TGF-ß in corneal wound healing. Further, aberrant TGF-ß activity has been linked to various corneal pathologies, such as scarring and Peter's Anomaly. Thus, understanding the molecular and cellular mechanisms by which TGF-ß1-3 regulate corneal wound healing will enable the development of potential therapeutic interventions targeting the key molecule in this process. Herein, we summarize the multifaceted roles of TGF-ß in corneal wound healing, dissecting its mechanisms of action and interactions with other molecules, and outline its role in corneal pathogenesis.

The 2023 Doyne Lecture-a cornea care system: evolution.

Blindness and visual impairment affect the quality of life of the individual and their family members. Corneal opacities are a key cause of vision loss around the world, especially in low-income and middle-income countries (LMIC). Corneal blindness and vision loss impacts every age group, and the risk factors and the causes are also varied. Socio-economic factors also play a significant role in its prevalence. Preventing, treating, and managing corneal conditions in LMIC contexts can therefore be quite complex and challenging. A model of eye care delivery developed and refined over the past four decades, the L V Prasad Eye Institute's cornea care system presents an example and a sense of hope. The model takes corneal care from world-class facilities in urban locations to rural locations, overcoming a variety of challenges. The initial breakthrough came with solving and ensuring a steady supply of corneal tissue. Then to training high-quality resources, building capacity, and investing in research that translates from the bench to the bedside. A variety of innovations, both in diagnosis and the operating theatre, have paved for improved outcomes that are tailored for the contexts in which this system operates. The institute envisions a future where its work further narrows the gap in eye care disparities and leads to life-changing impact in ophthalmic care of the cornea.

Comprehensive review of the state-of-the-art in corneal 3D bioprinting, including regulatory aspects.

The global shortage of corneal transplants has spurred an urgency in the quest for efficient treatments. This systematic review not only provides a concise overview of the current landscape of corneal morphology, physiology, diseases, and conventional treatments but crucially delves into the forefront of tissue engineering for corneal regeneration. Emphasizing cellular and acellular components, bioprinting techniques, and pertinent biological assays, it explores optimization strategies for manufacturing and cost-effectiveness. To bridge the gap between research and industrial production, the review outlines the essential regulatory strategy required in Europe, encompassing relevant directives, frameworks, and governing bodies. This comprehensive regulatory framework spans the entire process, from procuring initial components to marketing and subsequent product surveillance. In a pivotal shift towards the future, the review culminates by highlighting the latest advancements in this sector, particularly the integration of tissue therapy with artificial intelligence. This synergy promises substantial optimization of the overall process, paving the way for unprecedented breakthroughs in corneal regeneration. In essence, this review not only elucidates the current state of corneal treatments and tissue engineering but also outlines regulatory pathways and anticipates the transformative impact of artificial intelligence, providing a comprehensive guide for researchers, practitioners, and policymakers in the field.

[Experimental evaluation of the efficacy of tissue-engineered constructs in the treatment of limbal stem cell deficiency]. / Eksperimental'naya otsenka effektivnosti primeneniya tkaneinzhenernoi konstruktsii v lechenii limbal'noi nedostatochnosti.

Limbal stem cell deficiency (LSCD) is one of the leading factors negatively affecting the success of keratoplasty, and its treatment remains an urgent problem in ophthalmology. With the development of regenerative medicine, one of the promising approaches is the transplantation of tissue-engineered constructs from cultured limbal stem cells (LSCs) in biopolymer carriers. PURPOSE: This study was conducted to develop an experimental model of LSCD and evaluate the effectiveness of transplantation of a tissue-engineered construct consisting of cultured cells containing a population of LSCs and a collagen carrier. MATERIAL AND METHODS: The study was performed on 12 rabbits and included several stages. At the first stage, the physiological effects of collagen matrix implantation into the limbal zone were studied. At the second stage, tissue-engineered constructs consisting of LSCs on a collagen matrix were formed and their effect on the regeneration processes in the experimental LSCD model was analyzed. The animals were divided into 2 groups: surgical treatment (transplantation of the tissue-engineered construct) was used in the experimental group, and conservative treatment was used in the control group. Slit-lamp biomicroscopy with photo-registration, fluorescein corneal staining, optical coherence tomography of the anterior segment of the eye, and impression cytology were used to assess the results. RESULTS: No side reactions were observed after implantation of the collagen matrix into the limbal zone. One month after surgical treatment of the LSCD model in the experimental group, complete epithelization with minor manifestations of epitheliopathy was observed. In the control group, erosion of the corneal epithelium was noted. The time of corneal epithelization in the experimental and control groups was 9.2±2.95 and 46.20±12.07 days, respectively (p=0.139). According to the data of impression cytology, in the experimental group there were no goblet cells in the central part of the cornea, which indicates the restoration of corneal type epithelial cells, in contrast to the control group. CONCLUSION: Transplantation of a tissue-engineered construct from cultured limbal cells on a collagen membrane should be considered as a promising method for the treatment of limbal stem cell deficiency.

Limbal stem cell therapy.

PURPOSE OF REVIEW: To highlight the progress and future direction of limbal stem cell (LSC) therapies for the treatment of limbal stem cell deficiency (LSCD). RECENT FINDINGS: Direct LSC transplantation have demonstrated good long-term outcomes. Cultivated limbal epithelial transplantation (CLET) has been an alternative to treat severe to total LSCD aiming to improve the safety and efficacy of the LSC transplant. A prospective early-stage uncontrolled clinical trial shows the feasibility and safety of CLET manufactured under xenobiotic free conditions. Other cell sources for repopulating of the corneal epithelium such as mesenchymal stem cells (MSCs) and induced pluripotent stem cells are being investigated. The first clinical trials of using MSCs showed short-term results, but long-term efficacy seems to be disappointing. A better understanding of the niche function and regulation of LSC survival and proliferation will lead to the development of medical therapies to rejuvenate the residual LSCs found in a majority of eyes with LSCD in vivo. Prior efforts have been largely focused on improving LSC transplantation. Additional effort should be placed on improving the accuracy of diagnosis and staging of LSCD, and implementing standardized outcome measures which enable comparison of efficacy of different LSCD treatments for different severity of LSCD. The choice of LSCD treatment will be customized based on the severity of LSCD in the future. SUMMARY: New approaches for managing different stages of LSCD are being developed. This concise review summarizes the progresses in LSC therapies for LSCD, underlying mechanisms, limitations, and future areas of development.

Biologicals and Biomaterials for Corneal Regeneration and Vision Restoration in Limbal Stem Cell Deficiency.

The mammalian cornea is decorated with stem cells bestowed with the life-long task of renewing the epithelium, provided they remain healthy, functional, and in sufficient numbers. If not, a debilitating disease known as limbal stem cell deficiency (LSCD) can develop causing blindness. Decades after the first stem cell (SC) therapy is devised to treat this condition, patients continue to suffer unacceptable failures. During this time, improvements to therapeutics have included identifying better markers to isolate robust SC populations and nurturing them on crudely modified biological or biomaterial scaffolds including human amniotic membrane, fibrin, and contact lenses, prior to their delivery. Researchers are now gathering information about the biomolecular and biomechanical properties of the corneal SC niche to decipher what biological and/or synthetic materials can be incorporated into these carriers. Advances in biomedical engineering including electrospinning and 3D bioprinting with surface functionalization and micropatterning, and self-assembly models, have generated a wealth of biocompatible, biodegradable, integrating scaffolds to choose from, some of which are being tested for their SC delivery capacity in the hope of improving clinical outcomes for patients with LSCD.

Cell therapy in the cornea: The emerging role of microenvironment.

The cornea is an ideal testing field for cell therapies. Its highly ordered structure, where specific cell populations are sequestered in different layers, together with its accessibility, has allowed the development of the first stem cell-based therapy approved by the European Medicine Agency. Today, different techniques have been proposed for autologous and allogeneic limbal and non-limbal cell transplantation. Cell replacement has also been attempted in cases of endothelial cell decompensation as it occurs in Fuchs dystrophy: injection of cultivated allogeneic endothelial cells is now in advanced phases of clinical development. Recently, stromal substitutes have been developed with excellent integration capability and transparency. Finally, cell-derived products, such as exosomes obtained from different sources, have been investigated for the treatment of severe corneal diseases with encouraging results. Optimization of the success rate of cell therapies obviously requires high-quality cultured cells/products, but the role of the surrounding microenvironment is equally important to allow engraftment of transplanted cells, to preserve their functions and, ultimately, lead to restoration of tissue integrity and transparency of the cornea.

Evaluating the efficacy and safety of therapeutic interventions for corneal neuropathy: A systematic review.

Corneal neuropathy involves corneal nerve damage that disrupts ocular surface integrity, negatively impacting quality-of-life from pain and impaired vision. Any ocular or systemic condition that damages the trigeminal nerve can lead to corneal neuropathy. However, the condition currently does not have standardized diagnostic criteria or treatment protocols. The primary aim of this systematic review was to evaluate the efficacy and safety of interventions for treating corneal neuropathy. Randomized controlled trials (RCTs) that investigated corneal neuropathy treatments were eligible if the intervention(s) was compared to a placebo or active comparator. Comprehensive searches were conducted in Ovid MEDLINE, Ovid Embase and clinical trial registries from inception to July 2022. The Cochrane Risk-of-Bias 2 tool was used to assess study methodological quality. Certainty of the body of evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Overall, 20 RCTs were included. Evaluated interventions comprised regenerative therapies (n = 6 studies), dietary supplements (n = 4), anti-glycemic agents (n = 3), combination therapy (n = 3), supportive therapies (n = 2) and systemic pain pharmacotherapies (n = 2). Nine RCTs were judged at high risk of bias for most outcomes. Definitions for corneal neuropathy in the populations varied substantially across studies, consistent with lack of consensus on diagnostic criteria. A diverse range of outcomes were quantified, likely reflecting absence of an agreed core outcome set. There was insufficient evidence to draw definitive conclusions on the efficacy or safety of any intervention. There was low or very low certainty evidence for several neuroregenerative agents and dietary supplements for improving corneal nerve fiber length in corneal neuropathy due to dry eye disease and diabetes. Low or very low certainty evidence was found for neuroregenerative therapies and dietary supplements not altering corneal immune cell density. This review identifies a need to standardize the clinical definition of corneal neuropathy and define a minimum set of core outcome measures. Together, this will provide a foundation for improved phenotyping of clinical populations in studies, and improve the capacity to synthesize data to inform evidence-based care. Protocol registration: PROSPERO ID: CRD42022348475.

Advances in Organoid Technology: A Focus on Corneal Limbal Organoids.

Organoid technology provides a versatile platform for simulating organogenesis, investigating disease pathogenesis, and exploring therapeutic interventions. Among various types of organoids that have been developed, corneal limbal organoids, the three-dimensional miniaturized corneas which are derived from either pluripotent stem cells or limbal epithelial stem cells, are particularly promising for clinical translation. This narrative review summarized the state-of-the-art in corneal limbal organoids research including the cultivation methods, clinical relevance and its limitations and challenges. The potential of corneal limbal organoids in mimicking corneal development, disease modelling, drug screening, and regenerative medicine was discussed. Technical improvements in cultivation techniques, imaging modalities, and gene editing tools are anticipated to overcome current limitations and further promote its clinical potential. Despite challenges and difficulties, the development of corneal limbal organoids opens a new era of regenerative medicine and provides a potential source of stem cell replacement therapies for challenging corneal diseases with the establishment of an in vitro corneal limbal organoid bank.

Exosomal microRNAs as potential biomarkers and therapeutic targets in corneal diseases.

Exosomes are a subtype of extracellular vesicle (EV) that are released and found in almost all body fluids. Exosomes consist of and carry a variety of bioactive molecules, including genetic information in the form of microRNAs (miRNAs). miRNA, a type of small non-coding RNA, plays a key role in regulating genes by suppressing their translation. miRNAs are often disrupted in the pathophysiology of different conditions, including eye disease. The stability and easy detectability of exosomal miRNAs in body fluids make them promising biomarkers for the diagnosis of different diseases. Additionally, due to the natural delivery capabilities of exosomes, they can be modified to transport therapeutic miRNAs to specific recipient cells. Most exosome research has primarily focused on cancer, so there is limited research highlighting the importance of exosomes in ocular biology, particularly in cornea-associated pathologies. This review provides an overview of the existing evidence regarding the primary functions of exosomal miRNAs and their potential role in diagnostic and therapeutic applications in the human cornea.

Neurotrophic keratopathy: General features and new therapies.

Neurotrophic keratopathy is an uncommon degenerative corneal disorder characterized by compromised corneal sensory innervation resulting in the formation of epithelial defects and nonhealing corneal ulcers. Various treatment modalities are available to stabilize disease progression, improve patient well-being, and prevent vision loss. For eligible patients, medical and surgical reinnervation have emerged as pioneering therapies, holding promise for better management. We present a comprehensive review of the disorder, providing an update relevant to ophthalmologists on pathogenesis, diagnosis, treatment options, and novel therapies targeting pathophysiological pathways.

Corneal neuropathic pain: a review to inform clinical practice.

Corneal neuropathic pain (CNP) is a poorly defined disease entity characterised by an aberrant pain response to normally non-painful stimuli and categorised into having peripheral and central mechanisms, with the former responding to instillation of topical anaesthetic. CNP is a challenging condition to diagnose due to numerous aetiologies, an absence of clinical signs and ancillary tests (in vivo confocal microscopy and esthesiometry), lacking the ability to confirm the diagnosis and having limited availability. Symptomatology maybe mirrored by severe and chronic forms of dry eye disease (DED), often leading to misdiagnosis and inadequate treatment. In practice, patients with suspected CNP can be assessed with questionnaires to elicit symptoms. A thorough ocular assessment is also performed to exclude any co-existent ocular conditions. A medical and mental health history should be sought due to associations with autoimmune disease, chronic pain syndromes, anxiety and depression. Management begins with communicating to the patient the nature of their condition. Ophthalmologists can prescribe topical therapies such as autologous serum eyedrops to optimise the ocular surface and promote neural regeneration. However, a multi-disciplinary treatment approach is often required, including mental health support, particularly when there are central mechanisms. General practitioners, pain specialists, neurologists and psychologists may be needed to assist with oral and behavioural therapies. Less data is available to support the safety and efficacy of adjuvant and surgical therapies and the long-term natural history remains to be determined. Hence clinical trials and registry studies are urgently needed to fill these data gaps with the aim to improve patient care.