Neurotrophic keratitis: a narrative review

Introduction

Background

Neurotrophic keratitis (NK) is a neurodegenerative ocular condition characterized by reduced or absent corneal sensitivity, leading to progressive damage and impairment of corneal integrity, transparency, and vision (1). NK is caused by a dysfunction of the ophthalmic branch of the trigeminal nerve associated with the absence of normal sensory feedback (2). Common etiologies include herpes simplex virus (HSV) and varicella-zoster virus (VZV) infections, surgical or accidental trauma, prolonged use of contact lenses, systemic diseases, neurological conditions, chemical burns, and radiation exposure (3). As a result, the cornea becomes highly susceptible to trauma, infections, and ulcerations, all of which can cause severe complications such as perforation, loss of transparency, ocular discomfort or pain, and vision loss (2). Current management and treatment of NK focuses on preventing further corneal damage and promoting corneal and nerve healing.

Rationale and knowledge gap

Historically, the management of NK has been challenging due to several reasons, such as low prevalence, complex etiology, lack of awareness or delayed symptoms, insufficient screening, variable treatment responses, and the limited effectiveness of conventional treatments, which primarily address symptoms rather than addressing the underlying nerve impairment (1). Although several reviews on NK are available, many focus on older diagnostic tools (e.g., Cochet-Bonnet esthesiometer) and traditional treatments [e.g., lubricants, bandage contact lenses (BCLs)] without adequately covering the growing array of advanced therapies, such as recombinant human nerve growth factors (rhNGFs), regenerative matrix-based agents, and newer surgical techniques such as corneal neurotization. In addition, newly introduced diagnostic devices such as noncontact handheld esthesiometers are rarely discussed in depth. Furthermore, this review expands upon existing NK papers by incorporating not only the latest clinical and scientific insights but also key quantitative findings from relevant studies. Given these recent developments and the growing understanding of NK pathophysiology, a comprehensive review with updated information is essential. This review aims to fill that gap by examining both established and innovative strategies for NK management, while also presenting evidence-based medical data, thereby providing clinicians with an up-to-date framework on NK.

Objective

This review aims to provide an updated and comprehensive analysis of NK, from its pathophysiology and diagnostic criteria to the latest treatment modalities. The goal is to explore traditional management strategies, the mechanism and efficacy of emerging therapies, and the future directions of research and clinical practice in this field. We present this article in accordance with the Narrative Review reporting checklist (available at https://aes.amegroups.com/article/view/10.21037/aes-24-25/rc).

Methods

A systematic literature search was conducted from April 1, 2024, to August 1, 2024, using PubMed and Google Scholar. Search terms used included “neurotrophic keratitis”, “neurotrophic ulcer”, “corneal sensory innervation”, “ocular surface disease”, “cornea sensitivity”, and “cornea innervation”. Only articles published in English through August of 2024 were included. Studies were included if they were ophthalmology-related, regardless of study design, while non-English publications and papers with a primary focus outside ophthalmology were excluded. Selection was carried out by a single reviewer, and final inclusion decisions were reached by consensus based on each study’s relevance to the narrative review (Table 1).

NK overview

Pathophysiology of NK

Corneal nerves function

Corneal nerves are involved in several roles, including sensory, temperature, and tactile sensations. They also have autonomic functions, which help maintain the health and stability of the corneal surface by regulating tear secretion and other trophic factors (4).

Tactile sensations, such as mechanical, thermal, and chemical stimuli, may manifest as sensations of ocular dryness, discomfort, or pain (4). These stimuli are transmitted via sensory neurons that can also elicit the blink reflex. The blink reflex is an involuntary protective mechanism that helps protect the eye from potential harm. Blinking involves a neural circuit mediated by afferent nerves via the trigeminal nerve and efferent nerves via the facial nerve. When a stimulus, such as a threat to the eye or irritation, activates the sensory fibers, signals are sent to the spinal trigeminal nucleus in the brainstem. From there, efferent signals are transmitted via the facial nerve to the orbicularis oculi muscles, causing them to contract and initiate the blink response (5).

In addition to the blink reflex, afferent corneal nerves are also involved in eliciting the tear reflex, known as the lacrimation reflex. The lacrimation reflex involves the production and secretion of tears to help lubricate and cleanse the ocular surface in response to various stimuli such as irritation, emotion, or environmental factors. When the sensory nerves of the cornea detect a stimulus, they send a signal via the trigeminal nerve to the lacrimal nucleus in the brainstem. In response, efferent signals then travel along parasympathetic fibers of the facial nerve to the lacrimal gland, stimulating tear production and secretion (6).

Corneal nerves are also responsible for maintaining a healthy ocular surface through an intricate relationship between corneal nerves and epithelial cells. This involves neurotrophins and neuropeptides which aid in the growth, survival, regeneration, and development of neurons (7). Growth and survival factors are produced by corneal epithelial cells and include NGF, brain-derived neurotrophic factor (BDNF), glial cell-derived neurotrophic factor (GDNF), epidermal growth factor (EGF), ciliary neurotrophic factor (CNTF), neurotrophin-3 (NT-3), and neurotrophin-4 (NT-4) (8-10). Neurotrophins in the cornea are responsible for multiple activities for maintaining corneal health through specific receptor-mediated pathways. Neuromediators are chemical substances released by nerve cells to transmit signals to other cells, thereby facilitating communication within the nervous system. The main neuromediators produced by corneal nerves include substance P (SP), calcitonin gene-related peptide (CGRP), acetylcholine, cholecystokinin, noradrenaline, serotonin, neuropeptide Y (NPY), vasoactive intestinal peptide (VIP), met-enkephalin, brain natriuretic peptide, vasopressin and neurotensin (11-13). Neuromediators are released by corneal nerves to promote their cell growth, migration, adhesion, and development of the corneal epithelial cells (14). They bind to specific receptors on the surfaces of epithelial cells, triggering signaling pathways that modulate cellular behavior and tissue response. Additionally, corneal nerves have also been found to play a role in cornea-limbal epithelial stem cells. This was demonstrated in a mouse model study in which mice with absent trigeminal nerves had decreased levels of epithelial stem cell markers (15). The interaction between corneal nerves and epithelial cells, mediated by neuromediators and trophic factors, is crucial for maintaining corneal transparency and integrity. Disruption to this equilibrium, such as in NK, can lead to several complications because of the diminished function or absence of corneal nerves, which causes reduced corneal sensitivity, impaired healing, and increased vulnerability to injuries and infections. This highlights the importance of the corneal nerves not only in sensation and reflex arcs but also in the fundamental biological processes essential for corneal health. Understanding these biological pathways may provide a framework for developing future treatment options for NK.

Corneal inflammation

Inflammation is also believed to play a role in the development of NK (16). Under normal circumstances, the cornea is constantly exposed to foreign particles from the environment. However, there are several mechanisms in place to avoid a typical immune response such as reduced vascularization, the presence of anti-inflammatory molecules, and an immature state of immune cells that reside within it. This is known as immune privilege and is a key reason for a high success rate in corneal transplants (16). Alpha-melanocyte-stimulating hormone (α-MSH) is an important anti-inflammatory protein that is constitutively available in the ocular surface. It has many roles such as preventing activated T cells from releasing interferon (IFN)-γ, inhibiting B lymphocyte proliferation, promoting class switching of CD4⁺ T cell into regulatory T cells, reducing pro-inflammatory cytokine levels, and increasing anti-inflammatory molecules such as glutathione peroxidase levels, thereby reducing overall inflammation. In the cornea, α-MSH has shown promising potential in promoting corneal healing, promoting tear production, preventing corneal edema, leukocyte infiltration, and cell apoptosis, while promoting endothelial cell proliferation, suggesting its therapeutic potential in conditions like NK (17,18).

A healthy cornea typically also contains dendritic cells, macrophages, and γδ T cells. During periods of inflammation, neutrophils are recruited and aid in corneal nerve regeneration through the release of growth factors (19,20). Disruptions to the stable immune environment in the cornea may induce damage to corneal nerves and lead to NK. This can be seen in diabetic keratopathy, which causes immune-mediated damage to the cornea through the accumulation of glycation end products (AGEs). Deposition of AGEs in the cornea leads to increased proinflammatory cytokines such as nuclear factor kappa beta (NF-kB), tumor necrosis factor (TNF-α) and IL-1β. In turn, myeloid cells begin accumulating near neurons and are thought to play a role in their damage. This was observed in a recent study demonstrating the role diabetes may have on corneal nerves in mice (21).

Incidence and prevalence

Determining the true incidence and prevalence of NK has been challenging due to the scarcity of data and the low frequency of the disease. NK is classified as an orphan disease (ORPHA137596) with estimates that suggest NK affects fewer than 5 per 10,000 individuals. This number is largely based on data related to its most common associated conditions such as herpetic keratitis and surgical interventions (1). For instance, the global incidence of herpetic keratitis is approximately 6.8 per 100,000 people annually, with the U.S. rate slightly higher at 11.8 per 100,000 people (22) possibly due to better reporting. One study suggests that 6% of patients who experienced herpetic keratitis subsequently develop NK (23). Meanwhile, another study observed a rate of 27% (24). Additionally, patients diagnosed with herpes zoster after the age of 60 years are thought to be at a higher risk of developing NK (25).

Another challenge in accurately determining the incidence and prevalence of NK is the difficulty in identifying it during its subclinical stages. NK prevalence is significantly underestimated due to lack of testing. The current prevalence numbers may correlate with cases of NK stages 2 and 3, but are less likely to correlate with NK stage 1. This is in part due to lack of corneal sensitivity testing and screening for subclinical NK (26).

Etiologies

A myriad of ocular conditions can cause NK. Almost any condition that can cause damage to any part of the trigeminal nerve can lead to NK. Common factors that impair corneal sensation include herpetic keratitis, brain tumors, and surgical interventions that may result in iatrogenic injury. Additional ocular factors such as chemical burns, physical trauma, corneal dystrophies, limbal stem cell deficiency, and prolonged use of topical medications (especially those with preservatives) can also contribute to decreased corneal sensitivity (27). Systemic conditions like diabetes, multiple sclerosis, congenital syndromes, and leprosy are similarly linked to decreased corneal sensation (14). Additionally, chronic ocular graft-versus-host disease (oGVHD) in patients who underwent allogeneic hematopoietic stem cell transplantation has been found to be a significant cause of NK (28,29).

Rarer causes have been reported in several case studies. For example, one case report describes the development of bilateral NK in a patient with Guillain Barre Syndrome (30). Other lesser-known causes include certain ocular surgeries/procedures. For example, a case series described the development of NK following ultrasound cycloplasty in refractory glaucoma (31). NK was also reported after slow-coagulation transscleral cyclophotocoagulation (32). The development of a neurotrophic ulcer has also been observed in a patient who underwent retrobulbar chlorpromazine injection for pain control (33). Thus, clinicians should maintain NK as a potential differential diagnosis even in cases with less common etiologies. Table 2 highlights both common and rare etiologies of NK, including systemic diseases, ocular surface disorders, and iatrogenic causes reported in recent literature (Table 2).

Symptoms

The presentation of NK can vary widely. No specific symptoms are characteristic for NK. Classically, patients complain of ocular symptoms due to impaired corneal sensation, which may lead to late presentations. Common symptoms include eye dryness, photophobia, reduced blinking rate, and impaired vision quality (3). As the disease progresses and becomes more severe, the level of discomfort and symptoms may paradoxically decrease or disappear altogether due to corneal hypoesthesia (1).

Physical examination

The evaluation of NK cases should involve a detailed neurological and ophthalmic examination to determine the severity and extent of the disease. A neurological examination should be performed to evaluate cranial nerve (CN) function, especially the ophthalmic division of the trigeminal nerve. Abnormalities in other CNs may indicate underlying etiologies such as cavernous sinus lesions or intracranial aneurysms (33). The physical examination should also include a thorough inspection of the face and ocular adnexa, examining for any skin abnormalities or vesicular rash that might indicate a herpetic infection (3).

Neurological examination

Patients suspected of NK should have a neurological examination to evaluate CNs II through VIII. The focus should be on the trigeminal nerve. However, involvement of other CNs can help identify the possible etiology of NK. CN VII and VIII palsies may indicate a possible neuroma. Oculomotor, trochlear, and abducent nerve palsies can localize cavernous sinus lesions (34).

Ophthalmic examination

The ophthalmic examination should begin with an external eye exam. The eyelids should be examined for lagophthalmos, ptosis, blink rate, and conjunctiva. Patients frequently exhibit no conjunctival injection in NK. Conversely, patients who do present with signs of inflammation may suggest an underlying infection, which can be evaluated with microbiological testing. Additionally, subconjunctival fibrosis might be observed, which can be linked to chronic autoimmune conditions or dry eye syndrome. Fluorescein and lissamine green dyes can be used to assess the health of the corneal and conjunctival epithelium (1).

NK can be classified into three clinical stages:

• Stage I: defined by punctuate epithelial erosions (PEEs) with intact epithelium;
• Stage II: recurrent or persistent epithelial defects (PEDs) that are usually oval with smooth and rolled edges without stromal involvement;
• Stage III: stromal involvement occurs that may lead to corneal ulcer, melting, and perforation (55).

Diagnosis

Corneal sensitivity

Decreased corneal sensitivity is the hallmark feature of NK. Corneal sensitivity tests range from simple qualitative assessments to more sophisticated quantitative methods. A common qualitative method involves lightly touching the central and peripheral cornea with a cotton thread. A normal response includes blinking and sensation recognition, whereas a diminished or absent response suggests impaired corneal sensitivity (56). For a more precise measurement, devices like the Cochet-Bonnet and Belmonte esthesiometer can be used to provide quantitative results of corneal sensitivity (56). In addition, a new noncontact handheld esthesiometer (Brill Engines esthesiometer) was recently approved by the U.S. Food and Drug Administration (FDA) for assessing corneal sensitivity. Since it is the only non-invasive and portable esthesiometer currently available, ophthalmologists may find it easier to identify NK in its subclinical stages and begin early interventions (19). A recent study investigated corneal sensitivity in patients with oGVHD using both a non-contact and Cochet-Bonnet esthesiometer. They found that decreased corneal sensitivity measured with a non-contact esthesiometer was significantly correlated with reduced subbasal nerve density [measured with in vivo confocal microscopy (IVCM)] and severity of epitheliopathy. However, a significant reduction in corneal sensitivity was not detected using the Cochet-Bonnet esthesiometer in the same patients (57). This suggests that non-contact esthesiometry may be more sensitive in detecting corneal nerve dysfunction and associated epitheliopathy in patients with oGVHD.

Tear film

Evaluating the tear film is also important for diagnosing NK. Corneal anesthesia may lead to alterations in the tear film and potentially worsen NK. These alterations may include reduced tear production, decreased tear film thickness, altered tear composition, instability, inflammation, and increased osmolarity (1). Several diagnostic tests are commonly used to assess the tear film. These tests include tear breakup time for stability, Schirmer test for tear production, tear osmolarity test for tear composition, and tear meniscus height (58).

IVCM

IVCM is an advanced imaging tool that can be helpful for diagnosing NK, as it allows for direct visualization of corneal nerve fibers. In NK, IVCM typically shows a marked reduction in the density of sub-basal corneal nerve fibers, which is a key diagnostic feature reflecting the underlying nerve damage. Additionally, IVCM can reveal morphological abnormalities in these nerves, such as beading or fragmentation, which are indicative of neurodegeneration (32). However, it is worth mentioning that the interpretation of IVCM images is operator-dependent and can be affected by the image quality. One such solution that shows promise is using generative artificial intelligence (AI) to help quantify and analyze the IVCM scans (59).

Treatment

The treatment for NK is dependent on the stage and severity of disease. Identifying NK in its earliest stages and beginning treatment as soon as possible is important for good outcomes with this often-devastating disease. Early detection can maximize epithelial healing and slow disease progression. Notably, treatment should not be dependent solely on symptoms because patients are often asymptomatic, especially in the later stages of the disease with corneal hyposensitivity.

Iatrogenic toxicity

NK management includes discontinuing any inciting medications that may be causing corneal damage, especially preservatives in topical medications such as benzalkonium chloride, polyquaternium-1, and sodium perborate. In addition, systemic medications should also be assessed, such as neuroleptic, antipsychotic, and antihistamine drugs, for any other comorbidities, as these can worsen NK. Topical nonsteroidal anti-inflammatory drugs (NSAIDs) can be associated with toxic effects on the cornea and should be discontinued (60).

Infection

Managing NK involves treating current infections, bacterial or viral. Treatments involve infection-specific antibiotic eye drops or oral or topical antiviral medications. Clinicians should avoid the use of certain topical antibiotics, such as aminoglycosides and quinolones due to possible corneal toxicity side effects (12,61,62).

Inflammation

Treating NK involves treatment of any current ocular inflammation to prevent further damage. Topical immunomodulators and anti-inflammatory therapies such as cyclosporine, or lifitegrast can improve corneal healing (63,64). Steroids are generally used with extreme caution due to their potential to worsen the condition by inhibiting corneal healing and increasing the risk of corneal melting and perforation. While they can help manage inflammation, their use should be carefully considered and monitored due to this significant risk. Thus, low potency drops such as fluorometholone can be carefully used for a shorter duration to control inflammation (65). As mentioned before, NSAIDs should be avoided due to their corneal toxicity and increased risk of causing corneal ulcers.

Eyelid margin disease, such as meibomian gland dysfunction and blepharitis, can also cause inflammation and should be treated. Treatment includes warm compresses to the eyelids to soften the glandular secretions and improve oil flow, eyelid massages to express these oils, lid hygiene to help remove debris and prevent blockage of the meibomian glands, topical corticosteroids for marked inflammation, and topical or oral antibiotics, such as azithromycin or doxycycline, to help reduce inflammation and bacterial colonization of the glands (66-68).

Topical lubricants

Patients may require tear substitution or preservative-free lubricants to maintain optimal ocular conditions. The use of preservative-free artificial tears can supplement natural tear production, which is often impaired in NK patients. Artificial tears also help to stabilize the tear film, prevent corneal dryness, dilute pro-inflammatory mediators, and reduce the risk of further epithelial damage (2).

Bandage contact and scleral lenses

BCLs have multiple roles in protecting the corneal epithelium. They are commonly used in several conditions that cause PEDs (51,69). They work by shielding the cornea from mechanical abrasion caused by the eyelids and environmental irritants. BCLs also maintain a hydrating tear film over the cornea and have been found to better facilitate corneal erosion healing and reduction in pain compared to other methods (70). However, constant monitoring is important when using BCLs, as there can be an increased risk of infection (71).

Scleral lenses are a different type of lenses that can be beneficial in NK (72). They create a protective dome over the cornea, which is filled with a tear reservoir to continuously cleanse the eye. This not only protects the cornea but also provides it with the necessary oxygenation, hydration, and electrolytes to promote healing. Scleral lenses are especially beneficial in severe cases of NK where standard treatments fail to maintain a healthy corneal surface (50,73,74). By isolating the cornea from the external environment and maintaining a stable tear film, these expensive lenses can improve the quality of vision and reduce pain significantly.

Blood derived products

Autologous serum tears are made from the patient’s own blood, processed to remove red blood cells, and then diluted to mimic natural tears. These tears are rich in growth factors, vitamins, and nutrients, which aid in the healing of the corneal surface by promoting cell growth and reducing inflammation (75). One multicenter interventional case series assessed corneal staining outcomes in 102 patients with corneal epithelial defects who were treated with plasma rich in growth factors (PRGFs) for the first time. Overall, patients who initially had punctate epithelial erosions or epithelial defects were reduced from 76.5% to 47% and 23.5% to 7.8%, respectively, after 3 months of topical treatment (P<0.001). Among the patients with NK, 46.7% showed complete improvement, 20% showed partial improvement, 26.7% showed no change, and 6.7% showed worsening of disease. Amongst the patients with corneal ulcer, 58.3% showed complete improvement, 16.7% showed partial improvement, 16.7% showed no change, and 8.3% showed worsening of disease (76). Other studies have shown varying degrees of effectiveness in treating PEDs and NK (77-79).

On the other hand, platelet-rich plasma (PRP) involves concentrating platelets from the patient’s blood, which are then applied to the eye. PRP contains a high concentration of growth factors that accelerate the repair and regeneration of damaged corneal cells. PRP has also been effective in treating NK (80,81).

Both therapies leverage the body’s natural healing mechanisms, making them particularly useful for patients who do not respond well to conventional treatments.

Topical cenegermin

Cenegermin (Oxervate™, Dompé US Inc., Boston, MA, USA), a rhNGF, is the first drug specifically designed to target the underlying pathophysiology of NK. By stimulating nerve growth, cenegermin enhances corneal sensitivity, initiates natural tear production and blink reflexes while simultaneously promoting a healthier ocular surface (82). The treatment involves a course of eye drops, typically administered six times daily for eight weeks, which has been associated with high rates of complete corneal healing. Several double-blind, randomized controlled trials led to it being the first topical biological drug approved for the treatment of NK. A randomized controlled trial included 156 patients with stage 2 or stage 3 NK who were randomized in a 1:1:1 ratio of either rhNGF 10 µg/mL, 20 µg/mL, or vehicle eye drops. Corneal healing (defined as <0.5-mm maximum diameter of fluorescein staining in the lesion area) was assessed after four and eight weeks, with a 48- or 56-week follow-up period. At the end of four weeks, 19.6% of the vehicle group, 54.9% of the rhNGF 10 µg/mL group, and 58% of the rhNGF 20 µg/mL group showed corneal healing. At the end of 8 weeks, 43.1% of the vehicle group, 74.5% of the rhNGF 10 µg/mL group, and 70% of the rhNGF 20 µg/mL group showed corneal healing. Furthermore, over 96% of patients treated with rhNGF experienced no recurrence of disease during the follow-up period (83). Another randomized controlled trial was also conducted that included 48 patients with neurotrophic PEDs who were randomized in a 1:1 ratio to either cenegermin 20 µg/mL or vehicle eye drops for eight weeks. Their results showed corneal healing (defined as <0.5 mm of fluorescein staining in the greatest dimension of the lesion area) in only 29.2% of the vehicle group compared to 69.6% in the cenegermin group (84). Several other studies have shown similar efficacy in the use of cenegermin for NK (85-87).

Cenegermin has also shown promising results when treating pediatric patients with NK. A recent study of four pediatric patients with NK treated with cenegermin reported marked re-epithelialization and improved visual acuity in all patients with no adverse effects noted (88).

Cenegermin has also been demonstrated to be effective in treating neurotrophic corneal ulcer. One case study describes an 84-year-old female patient with refractory corneal ulcer. Despite multiple interventions, her condition persisted until the introduction of cenegermin, which led to significant improvement and restoration of corneal integrity within five weeks of initiation (89). Similar results were demonstrated in a retrospective study that included seven patients with corneal ulcer. All patients treated with an 8-week regimen of Cenegermin showed corneal healing with recurrence in only 1 patient at the three-year follow-up (90).

Up to two-thirds of the patient using cenegermin can experience eye pain, irritation, and erythema (91,92). Additionally, some reports suggested that cenegermin use could be associated with corneal epithelial plaque formation, that might lead to vision deterioration (93,94).

Matrix-based regenerating agents (RGTAs)

Another emerging therapy for NK in recent years consists of regenerating agents. These agents are complex polymers designed to mimic heparan sulfate, a key component of the extracellular matrix. These agents facilitate the regeneration of corneal tissue by promoting cell attachment, tissue healing, and regeneration (95). RGTA therapy has particularly showed promising results when treating neurotrophic corneal ulcer. A prospective clinical study of 25 patients with persistent corneal neurotrophic ulcers who were treated with RGTA demonstrated complete corneal healing in all patients. The average healing time was 4.13±2.32 weeks with a significant mean ulcer area reduction. Only two patients had recurrence of disease (96). A recent case report also describes a 73-year-old patient with neurotrophic corneal ulcer treated with RGTA and showed complete corneal healing with significant improvement in visual function (97). A separate case series study also describes eleven patients with refractory neurotrophic corneal ulcers despite conventional interventions. However, initiation of an RGTA regimen showed improvement and corneal healing in 9/11 cases (98). Several other case series and prospective studies have showed similar promising results with the use of these agents in neurotrophic ulcers (99-101).

Insulin

More recently, topical insulin has been found to play a role in treating NK. Insulin promotes corneal repair due to its role in facilitating epithelial cell migration and proliferation. Insulin’s potential role in corneal wound healing is suggested by the presence of insulin receptors on both the cornea and lacrimal gland (102). Insulin may be particularly useful in treating later stages of the disease and refractory NK. A retrospective analysis of 21 eyes with PEDs or corneal ulcers treated with topical insulin demonstrated a 90% rate of complete reepithelialization in patients (103). A similar study of 21 patients with PEDs treated with topical insulin and had a re-epithelialization rate of 81% (104). These results are supported by several other studies with similar treatment success rates (105,106). Insulin has also been found to be an effective and safe treatment option for NK in patients who underwent vitrectomy. A retrospective case-control study that included 37 eyes compared conventional non-invasive treatments (preservative-free lubricant eye drops and prophylactic topical antibiotics) alone versus in combination topical insulin. The insulin group had significantly faster epithelial healing than the control group with no reported adverse effects (107). Thus, the use of insulin therapy represents a new and innovative approach aimed at enhancing corneal healing, and while several studies have shown promising results, future studies are still needed to explore this treatment option.

Amniotic membrane transplant

The human amniotic membrane grafts are derived from the inner layer of the placenta. Amniotic membrane is rich in growth factors and cytokines. When applied to the cornea, these membranes act as a biological bandage, enhance healing by suppressing inflammation, prevent scar formation, and facilitate the growth of healthy epithelial cells. Amniotic membrane grafts can also be an effective approach for treating PEDs or active corneal melts with risk for perforation (108). One study demonstrated complete epithelialization and healing in 11/15 patients with neurotrophic corneal ulcers following amniotic membrane transplantation (109). Another study of 28 patients with persistent corneal epithelial defects refractory to medical management who underwent amniotic membrane transplantation showed successful treatment in 82.1% of the patients. In addition, the investigators found significantly increased corneal stromal thickness, and 4/5 patients with corneal perforation were successfully treated with multilayer amniotic membrane transplantation (110).

Tarsorrhaphy

Tarsorrhaphy is a surgical procedure that involves partial or complete closure of the eyelids to protect the corneal surface to minimize environmental exposure. It is typically used in refractory cases of NK and can be either temporary or permanent. Tarsorrhaphy has been shown to be highly effective in treating NK. Studies have reported high success rates with the use of tarsorrhaphy to treat corneal epithelial defects, including corneal ulcers and perforations (111-113).

Corneal neurotization

Corneal neurotization is a surgical procedure that involves rerouting nerves from a healthy donor site, such as the supraorbital nerve, to the affected cornea (114). This procedure is aimed at restoring corneal sensation and re-establishing the physiological mechanisms that protect the cornea. This technique is relatively new and often only considered in severe NK cases where there is significant or complete lack of corneal sensitivity. While the procedure may substantially enhance corneal health and sensitivity, specialized surgical expertise is required and has a variable success rate depending on the extent of nerve regeneration. One study describes six patients with corneal anesthesia who showed improved corneal sensitivity and visual acuity in all patients while preventing the progression of NK (115). In another retrospective study of 16 patients with NK who underwent corneal neurotization, nine patients showed improvement in visual acuity, 13 patients showed improvement in corneal sensitivity, and 11 patients showed improvement in corneal health (116).

Additionally, corneal neurotization has also shown promising results in pediatric patients. A review that included eight studies of pediatric patients with NK who underwent corneal neurotization found improved sensation in almost all cases. This shows the utility of corneal neurotization in pediatric patients, possibly due to their increased cortical plasticity and optimal sensory relearning given their young age (113).

While corneal neurotization can be an effective treatment option for NK, this surgical procedure is quite complex and requires expert techniques to avoid damage to the surrounding tissues (117).

Keratoplasty

Full-thickness keratoplasty is often used as a last resort for treating NK such as when perforation or ulcers occur (118). This procedure involves replacing the damaged or diseased cornea with healthy donor tissue. However, this procedure is not a first-line treatment choice for NK and is best indicated for cases of corneal perforations or impending perforations. The goal of a corneal transplant in NK patients is not only to improve visual acuity but also to restore the structural integrity of the eye, potentially re-establishing protection and improving the ocular surface environment. Thus, patients should still be treated with additional measures and treatment options as described above. Postoperative care is important, as these patients often require close monitoring for signs of corneal graft rejection.

Limitations

Several limitations should be acknowledged in this review paper. First, the review relies heavily on existing literature, which may include studies with varying methodologies and levels of evidence, potentially impacting the consistency and reliability of the conclusions drawn. Additionally, the scope of the paper may be limited by the availability of recent and comprehensive studies, as some newer treatments may lack extensive long-term data. The inclusion of various treatment modalities without a standardized comparison could lead to challenges in assessing their relative efficacy and safety. Despite these limitations, this review provides a wide range of inclusions from both established and emerging therapies, along with recent diagnostic advances, which offer clinicians a more complete overview of current management strategies for NK. Another primary strength of this review lies in its systematic inclusion of quantitative findings from the latest literature, offering a more detailed perspective on efficacy, safety, and outcomes of various NK treatments than many existing reviews. By synthesizing these data points, this paper provides a concrete reference for clinicians who seek evidence-based guidance and hopefully drive better outcomes for patients.

Conclusions

In conclusion, NK is a relatively rare yet debilitating corneal disease. The hallmark feature of NK is loss of corneal sensation, resulting in several complications, including decreased tear production, PEDs, a higher susceptibility to corneal ulcers, and loss of visual acuity. It is important for clinicians to have a low threshold of suspicion, as identifying and treating the disease in earlier stages is imperative to outcomes. The main diagnostic tests revolve around assessing corneal sensation. We would like to highlight the importance of corneal sensitivity testing/screening, especially in patients at risk of developing NK (as shown in Table 1). Once NK has been identified, many treatment options are available and range from simple lubricating eye drops to more complex and invasive surgical approaches. In addition, emerging medical and surgical therapies such as topical insulin, cenegermin, and corneal neurotization have shown promising results. Despite the progress made in NK management and treatment, future research is needed to improve outcomes and help prevent this sight threatening disease.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://aes.amegroups.com/article/view/10.21037/aes-24-25/rc

Peer Review File: Available at https://aes.amegroups.com/article/view/10.21037/aes-24-25/prf

Funding: This study was supported by the Walter G. Ross Foundation (to R.K.L.) and partly supported by the Camiener Foundation Glaucoma Research Fund and the Gutierrez Family Research Fund.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://aes.amegroups.com/article/view/10.21037/aes-24-25/coif). R.K.L. serves as an unpaid editorial board member of Annals of Eye Science from May 2024 to December 2025. R.K.L. received grants from NIH Center Core Grant P30EY014801, a Research to Prevent Blindness Unrestricted Grant and Walter G. Ross Foundation. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Dua HS, Said DG, Messmer EM, et al. Neurotrophic keratopathy. Prog Retin Eye Res 2018;66:107-31. [Crossref] [PubMed]
2. Vera-Duarte GR, Jimenez-Collado D, Kahuam-López N, et al. Neurotrophic keratopathy: General features and new therapies. Surv Ophthalmol 2024;69:789-804. [Crossref] [PubMed]
3. Semeraro F, Forbice E, Romano V, et al. Neurotrophic keratitis. Ophthalmologica 2014;231:191-7. [Crossref] [PubMed]
4. Lele PP, Weddell G. Sensory nerves of the cornea and cutaneous sensibility. Exp Neurol 1959;1:334-59. [Crossref] [PubMed]
5. Penders CA, Delwaide PJ. Physiologic-approach to the human blink reflex. In: Desmedt JE. editor. New Developments in Electromyography and Clinical Neurophysiology. Basel: S.Karger AG; 1973:649-57.
6. Singh S, Shukla AK, Garkal P, et al. Study of tear function before and after laser-assisted in-situ keratomileusis. Indian J Ophthalmol 2023;71:1503-7. [Crossref] [PubMed]
7. Huang EJ, Reichardt LF. Neurotrophins: roles in neuronal development and function. Annu Rev Neurosci 2001;24:677-736. [Crossref] [PubMed]
8. Shaheen BS, Bakir M, Jain S. Corneal nerves in health and disease. Surv Ophthalmol 2014;59:263-85. [Crossref] [PubMed]
9. Emoto I, Beuerman RW. Stimulation of neurite growth by epithelial implants into corneal stroma. Neurosci Lett 1987;82:140-4. [Crossref] [PubMed]
10. You L, Kruse FE, Völcker HE. Neurotrophic factors in the human cornea. Invest Ophthalmol Vis Sci 2000;41:692-702. [PubMed]
11. Tervo T, Tervo K, Eränkö L. Ocular neuropeptides. Med Biol 1982;60:53-60. [PubMed]
12. Meng ID, Kurose M. The role of corneal afferent neurons in regulating tears under normal and dry eye conditions. Exp Eye Res 2013;117:79-87. [Crossref] [PubMed]
13. He J, Bazan HE. Neuroanatomy and Neurochemistry of Mouse Cornea. Invest Ophthalmol Vis Sci 2016;57:664-74. [Crossref] [PubMed]
14. Garcia-Hirschfeld J, Lopez-Briones LG, Belmonte C. Neurotrophic influences on corneal epithelial cells. Exp Eye Res 1994;59:597-605. [Crossref] [PubMed]
15. Ueno H, Ferrari G, Hattori T, et al. Dependence of corneal stem/progenitor cells on ocular surface innervation. Invest Ophthalmol Vis Sci 2012;53:867-72. [Crossref] [PubMed]
16. Hori J, Yamaguchi T, Keino H, et al. Immune privilege in corneal transplantation. Prog Retin Eye Res 2019;72:100758. [Crossref] [PubMed]
17. Chu C, Huang Y, Ru Y, et al. α-MSH ameliorates corneal surface dysfunction in scopolamine-induced dry eye rats and human corneal epithelial cells via enhancing EGFR expression. Exp Eye Res 2021;210:108685. [Crossref] [PubMed]
18. Wang S, Kahale F, Naderi A, et al. Therapeutic Effects of Stimulating the Melanocortin Pathway in Regulating Ocular Inflammation and Cell Death. Biomolecules 2024;14:169. [Crossref] [PubMed]
19. Wu M, Hill LJ, Downie LE, et al. Neuroimmune crosstalk in the cornea: The role of immune cells in corneal nerve maintenance during homeostasis and inflammation. Prog Retin Eye Res 2022;91:101105. [Crossref] [PubMed]
20. Hamrah P, Liu Y, Zhang Q, et al. The corneal stroma is endowed with a significant number of resident dendritic cells. Invest Ophthalmol Vis Sci 2003;44:581-9. [Crossref] [PubMed]
21. Surico PL, Narimatsu A, Forouzanfar K, et al. Effects of Diabetes Mellitus on Corneal Immune Cell Activation and the Development of Keratopathy. Cells 2024;13:532. [Crossref] [PubMed]
22. Young RC, Hodge DO, Liesegang TJ, et al. Incidence, recurrence, and outcomes of herpes simplex virus eye disease in Olmsted County, Minnesota, 1976-2007: the effect of oral antiviral prophylaxis. Arch Ophthalmol 2010;128:1178-83. [Crossref] [PubMed]
23. Labetoulle M, Auquier P, Conrad H, et al. Incidence of herpes simplex virus keratitis in France. Ophthalmology 2005;112:888-95. [Crossref] [PubMed]
24. Bonini S, Lambiase A, Rama P, et al. Topical treatment with nerve growth factor for neurotrophic keratitis. Ophthalmology 2000;107:1347-51; discussion 1351-2. [Crossref] [PubMed]
25. Ghaznawi N, Virdi A, Dayan A, et al. Herpes zoster ophthalmicus: comparison of disease in patients 60 years and older versus younger than 60 years. Ophthalmology 2011;118:2242-50. [Crossref] [PubMed]
26. Villalba M, Sabates V, Orgul S, et al. Detection of Subclinical Neurotrophic Keratopathy by Noncontact Esthesiometry. Ophthalmol Ther 2024;13:2393-404. [Crossref] [PubMed]
27. Chuephanich P, Supiyaphun C, Aravena C, et al. Characterization of the Corneal Subbasal Nerve Plexus in Limbal Stem Cell Deficiency. Cornea 2017;36:347-52. [Crossref] [PubMed]
28. Singh RB, Yuksel E, Sinha S, et al. Prevalence of neurotrophic keratopathy in patients with chronic ocular graft-versus-host disease. Ocul Surf 2022;26:13-8. [Crossref] [PubMed]
29. Surico PL, Luo ZK. Understanding Ocular Graft-versus-Host Disease to Facilitate an Integrated Multidisciplinary Approach. Transplant Cell Ther 2024;30:S570-84. [Crossref] [PubMed]
30. Qin D, Wang L, Peng X, et al. Guillain-Barré Syndrome With Associated Bilateral Neurotrophic Keratopathy. J Neuroophthalmol 2024;44:e213-5. [Crossref] [PubMed]
31. Chen Z, Wu Y, Yu M. Iris neovascularization and neurotrophic keratopathy following ultrasound cycloplasty in refractory glaucoma: case series. BMC Ophthalmol 2024;24:188. [Crossref] [PubMed]
32. Sayed MS, Khodeiry MM, Elhusseiny AM, et al. Neurotrophic Keratopathy After Slow Coagulation Transscleral Cyclophotocoagulation. Cornea 2023;42:1582-5. [Crossref] [PubMed]
33. Hauck MJ, Lee HH, Timoney PJ, et al. Neurotrophic corneal ulcer after retrobulbar injection of chlorpromazine. Ophthalmic Plast Reconstr Surg 2012;28:e74-6. [Crossref] [PubMed]
34. Bonini S, Rama P, Olzi D, et al. Neurotrophic keratitis. Eye (Lond) 2003;17:989-95. [Crossref] [PubMed]
35. Mantelli F, Nardella C, Tiberi E, et al. Congenital Corneal Anesthesia and Neurotrophic Keratitis: Diagnosis and Management. Biomed Res Int 2015;2015:805876. [Crossref] [PubMed]
36. Gelzinis A, Simonaviciute D, Krucaite A, et al. Neurotrophic Keratitis Due to Congenital Corneal Anesthesia with Deafness, Hypotonia, Intellectual Disability, Face Abnormality and Metabolic Disorder: A New Syndrome? Medicina (Kaunas) 2022;58:657. [Crossref] [PubMed]
37. Lomi N, Rani D. Neurotrophic keratitis in hereditary sensory autonomic neuropathy. Natl Med J India 2021;34:316. [Crossref] [PubMed]
38. Morishige N, Morita Y, Yamada N, et al. Congenital hypoplastic trigeminal nerve revealed by manifestation of corneal disorders likely caused by neural factor deficiency. Case Rep Ophthalmol 2014;5:181-5. [Crossref] [PubMed]
39. Murphy PJ, Patel S, Kong N, et al. Noninvasive assessment of corneal sensitivity in young and elderly diabetic and nondiabetic subjects. Invest Ophthalmol Vis Sci 2004;45:1737-42. [Crossref] [PubMed]
40. Rosenberg ME, Tervo TM, Immonen IJ, et al. Corneal structure and sensitivity in type 1 diabetes mellitus. Invest Ophthalmol Vis Sci 2000;41:2915-21. [PubMed]
41. Rocha EM, Gutierrez DR. Hypovitaminosis A: a hidden cause of neurotrophic keratitis. Arq Bras Oftalmol 2024;87:e2023. [Crossref] [PubMed]
42. Nguyen VT, Hwang TN, Shamie N, et al. Amyloidosis-associated neurotrophic keratopathy precipitated by overcorrected blepharoptosis. Cornea 2009;28:575-6. [Crossref] [PubMed]
43. Versura P, Giannaccare G, Pellegrini M, et al. Neurotrophic keratitis: current challenges and future prospects. Eye Brain 2018;10:37-45. [Crossref] [PubMed]
44. Wajnsztajn D, Faraj LA, Sanchez-Tabernero S, et al. Neurotrophic keratitis: inflammatory pathogenesis and novel therapies. Curr Opin Allergy Clin Immunol 2023;23:520-8. [Crossref] [PubMed]
45. Chen LP, Li D, Li XJ, et al. Postoperative trigeminal neuropathy outcomes following surgery for tumors involving the trigeminal nerve. Acta Neurochir (Wien) 2023;165:2885-93. [Crossref] [PubMed]
46. Xie C, Liu B, Zhao X, et al. Characteristics of the ocular surface in neurotrophic keratitis induced by trigeminal nerve injury following neurosurgery. Int Ophthalmol 2023;43:1229-40. [Crossref] [PubMed]
47. Mastropasqua L, Massaro-Giordano G, Nubile M, et al. Understanding the Pathogenesis of Neurotrophic Keratitis: The Role of Corneal Nerves. J Cell Physiol 2017;232:717-24. [Crossref] [PubMed]
48. Raj N, Panigrahi A, Alam M, et al. Bromfenac-induced neurotrophic keratitis in a corneal graft. BMJ Case Rep 2022;15:e249400. [Crossref] [PubMed]
49. Vohra M, Gour A, Rajput J, et al. Chemical (Alkali) Burn-Induced Neurotrophic Keratitis Model in New Zealand Rabbit Investigated Using Medical Clinical Readouts and In Vivo Confocal Microscopy (IVCM). Cells 2024;13:379. [Crossref] [PubMed]
50. Calvillo MP, McLaren JW, Hodge DO, et al. Corneal reinnervation after LASIK: prospective 3-year longitudinal study. Invest Ophthalmol Vis Sci 2004;45:3991-6. [Crossref] [PubMed]
51. Darwish T, Brahma A, O’Donnell C, et al. Subbasal nerve fiber regeneration after LASIK and LASEK assessed by noncontact esthesiometry and in vivo confocal microscopy: prospective study. J Cataract Refract Surg 2007;33:1515-21. [Crossref] [PubMed]
52. Gouvea L, Penatti R, Rocha KM. Neurotrophic keratitis after penetrating keratoplasty for lattice dystrophy. Am J Ophthalmol Case Rep 2021;22:101058. [Crossref] [PubMed]
53. Wasilewski D, Mello GH, Moreira H. Impact of collagen crosslinking on corneal sensitivity in keratoconus patients. Cornea 2013;32:899-902. [Crossref] [PubMed]
54. Israilevich RN, Syed ZA, Xu D, et al. Neurotrophic keratopathy following rhegmatogenous retinal detachment surgery. Can J Ophthalmol 2024;59:e321-6. [Crossref] [PubMed]
55. Mackie IA. Neuroparalytic keratitis. In: Fraunfelder F, Roy FH, Meyer SM. editors. Current Ocular Therapy. Philadelphia, PA, USA: WB Saunders; 1995.
56. Crabtree JR, Tannir S, Tran K, et al. Corneal Nerve Assessment by Aesthesiometry: History, Advancements, and Future Directions. Vision (Basel) 2024;8:34. [Crossref] [PubMed]
57. Surico PL, Yavuz Saricay L, Singh RB, et al. Corneal Sensitivity and Neuropathy in Patients With Ocular Graft-Versus-Host Disease. Cornea 2024;44:838-44. [Crossref] [PubMed]
58. Dohlman TH, Ciralsky JB, Lai EC. Tear film assessments for the diagnosis of dry eye. Curr Opin Allergy Clin Immunol 2016;16:487-91. [Crossref] [PubMed]
59. Stoddard-Bennett T, Bonnet C, Deng SX. Three-Dimensional Reconstruction of Subbasal Nerve Density in Eyes With Limbal Stem Cell Deficiency: A Pilot Study. Cornea 2024;43:1278-84. [Crossref] [PubMed]
60. Gaynes BI, Fiscella R. Topical nonsteroidal anti-inflammatory drugs for ophthalmic use: a safety review. Drug Saf 2002;25:233-50. [Crossref] [PubMed]
61. Walter K, Tyler ME. Severe corneal toxicity after topical fluoroquinolone therapy: report of two cases. Cornea 2006;25:855-7. [Crossref] [PubMed]
62. Pollock GA, McKelvie PA, McCarty DJ, et al. In vivo effects of fluoroquinolones on rabbit corneas. Clin Exp Ophthalmol 2003;31:517-21. [Crossref] [PubMed]
63. Reynolds SA, Kabat AG. Therapeutic options for the management of early neurotrophic keratopathy: a case report and review. Optometry 2006;77:503-7. [Crossref] [PubMed]
64. Sun CC, Lee SY, Chen LH, et al. Targeting Ca(2+)-dependent pathways to promote corneal epithelial wound healing induced by CISD2 deficiency. Cell Signal 2023;109:110755. [Crossref] [PubMed]
65. Dang DH, Riaz KM, Karamichos D. Treatment of Non-Infectious Corneal Injury: Review of Diagnostic Agents, Therapeutic Medications, and Future Targets. Drugs 2022;82:145-67. [Crossref] [PubMed]
66. Geerling G, Tauber J, Baudouin C, et al. The international workshop on meibomian gland dysfunction: report of the subcommittee on management and treatment of meibomian gland dysfunction. Invest Ophthalmol Vis Sci 2011;52:2050-64. [Crossref] [PubMed]
67. Rocha KM, Farid M, Raju L, et al. Eyelid margin disease (blepharitis and meibomian gland dysfunction): clinical review of evidence-based and emerging treatments. J Cataract Refract Surg 2024;50:876-82. [Crossref] [PubMed]
68. Jackson WB. Blepharitis: current strategies for diagnosis and management. Can J Ophthalmol 2008;43:170-9. [Crossref] [PubMed]
69. Blackmore SJ. The use of contact lenses in the treatment of persistent epithelial defects. Cont Lens Anterior Eye 2010;33:239-44. [Crossref] [PubMed]
70. Triharpini NN, Gede Jayanegara IW, Handayani AT, et al. Comparison Between Bandage Contact Lenses and Pressure Patching on the Erosion Area and Pain Scale in Patients With Corneal Erosion. Asia Pac J Ophthalmol (Phila) 2015;4:97-100. [Crossref] [PubMed]
71. Kent HD, Cohen EJ, Laibson PR, et al. Microbial keratitis and corneal ulceration associated with therapeutic soft contact lenses. CLAO J 1990;16:49-52. [PubMed]
72. Witsberger E, Schornack M. Scleral Lens Use in Neurotrophic Keratopathy: A Review of Current Concepts and Practice. Eye Contact Lens 2021;47:144-8. [Crossref] [PubMed]
73. Rosenthal P, Cotter JM, Baum J. Treatment of persistent corneal epithelial defect with extended wear of a fluid-ventilated gas-permeable scleral contact lens. Am J Ophthalmol 2000;130:33-41. [Crossref] [PubMed]
74. Alshami S, Bradley E, Nau C, et al. Outcomes of scleral lens therapy in patients with neurotrophic keratopathy at a tertiary referral center. Invest Ophthalmol Vis Sci Conf 2018;59:1795.
75. Matsumoto Y, Dogru M, Goto E, et al. Autologous serum application in the treatment of neurotrophic keratopathy. Ophthalmology 2004;111:1115-20. [Crossref] [PubMed]
76. Ghalibafan S, Osei KA, Amescua G, et al. Efficacy of plasma rich in growth factors (PRGF) in stage 1 neurotrophic keratitis. Eye (Lond) 2024;38:1390-1. [Crossref] [PubMed]
77. Guadilla AM, Balado P, Baeza A, et al. Effectiveness of topical autologous serum treatment in neurotrophic keratopathy. Arch Soc Esp Oftalmol 2013;88:302-6. [Crossref] [PubMed]
78. Tsubota K, Goto E, Shimmura S, et al. Treatment of persistent corneal epithelial defect by autologous serum application. Ophthalmology 1999;106:1984-9. [Crossref] [PubMed]
79. Sanchez-Avila RM, Merayo-Lloves J, Riestra AC, et al. Treatment of patients with neurotrophic keratitis stages 2 and 3 with plasma rich in growth factors (PRGF-Endoret) eye-drops. Int Ophthalmol 2018;38:1193-204. [Crossref] [PubMed]
80. Wróbel-Dudzińska D, Alio J, Rodriguez A, et al. Clinical Efficacy of Platelet-Rich Plasma in the Treatment of Neurotrophic Corneal Ulcer. J Ophthalmol 2018;2018:3538764. [Crossref] [PubMed]
81. Kim KM, Shin YT, Kim HK. Effect of autologous platelet-rich plasma on persistent corneal epithelial defect after infectious keratitis. Jpn J Ophthalmol 2012;56:544-50. [Crossref] [PubMed]
82. Adams BS, Patel AR. Cenegermin. In: StatPearls. Treasure Island (FL): StatPearls Publishing; 2023.
83. Bonini S, Lambiase A, Rama P, et al. Phase II Randomized, Double-Masked, Vehicle-Controlled Trial of Recombinant Human Nerve Growth Factor for Neurotrophic Keratitis. Ophthalmology 2018;125:1332-43. [Crossref] [PubMed]
84. Pflugfelder SC, Massaro-Giordano M, Perez VL, et al. Topical Recombinant Human Nerve Growth Factor (Cenegermin) for Neurotrophic Keratopathy: A Multicenter Randomized Vehicle-Controlled Pivotal Trial. Ophthalmology 2020;127:14-26. [Crossref] [PubMed]
85. Dai X, Tunc U, Zhu X, et al. Effect of Topical Recombinant Human Nerve Growth Factor on Corneal Epithelial Regeneration in Refractory Epithelial Keratopathy. Ocul Immunol Inflamm 2024;32:2074-80. [Crossref] [PubMed]
86. García-Delpech S, Udaondo P, Fernández-Santodomingo AS, et al. Neurotrophic Keratopathy Treated with Topical Recombinant Human Nerve Growth Factor (Cenegermin): Case Series Study with Long-Term Follow-Up. Case Rep Ophthalmol 2022;13:663-70. [Crossref] [PubMed]
87. Epitropoulos AT, Weiss JL. Topical human recombinant nerve growth factor for stage 1 Neurotrophic Keratitis: Retrospective case series of cenegermin treatment. Am J Ophthalmol Case Rep 2022;27:101649. [Crossref] [PubMed]
88. Elhusseiny AM, Traish AS, Saeed HN, et al. Topical cenegermin 0.002% for pediatric neurotrophic keratopathy. Eur J Ophthalmol 2022;32:3420-4. [Crossref] [PubMed]
89. Ahuja AS, Bowden FW 3rd, Robben JL. A Novel Treatment for Neurotrophic Corneal Ulcer Using Topical Cenegermin (OXERVATE™) Containing Recombinant Human Nerve Growth Factor. Cureus 2020;12:e11724. [Crossref] [PubMed]
90. Bruscolini A, Marenco M, Albanese GM, et al. Long-term clinical efficacy of topical treatment with recombinant human nerve growth factor in neurotrophic keratopathy: a novel cure for a rare degenerative corneal disease? Orphanet J Rare Dis 2022;17:57. [Crossref] [PubMed]
91. Bonini S, Lambiase A, Rama P, et al. Phase I Trial of Recombinant Human Nerve Growth Factor for Neurotrophic Keratitis. Ophthalmology 2018;125:1468-71. [Crossref] [PubMed]
92. Ferrari MP, Mantelli F, Sacchetti M, et al. Safety and pharmacokinetics of escalating doses of human recombinant nerve growth factor eye drops in a double-masked, randomized clinical trial. BioDrugs 2014;28:275-83. [Crossref] [PubMed]
93. Surico PL, Kaufman AR, Lin J, et al. Corneal Superficial Plaque Formation After Recombinant Human Nerve Growth Factor Use in a Patient With Neurotrophic Keratopathy and Limbal Stem Cell Deficiency From Mucous Membrane Pemphigoid. Cornea 2024;43:899-902. [Crossref] [PubMed]
94. Weinlander E, Ling J, Reddy A, et al. Epithelial Plaque Formation Secondary to Recombinant Human Nerve Growth Factor. Cornea 2020;39:1174-6. [Crossref] [PubMed]
95. Brignole-Baudouin F, Warnet JM, Barritault D, et al. RGTA-based matrix therapy in severe experimental corneal lesions: safety and efficacy studies. J Fr Ophtalmol 2013;36:740-7. [Crossref] [PubMed]
96. Guerra M, Marques S, Gil JQ, et al. Neurotrophic Keratopathy: Therapeutic Approach Using a Novel Matrix Regenerating Agent. J Ocul Pharmacol Ther 2017;33:662-9. [Crossref] [PubMed]
97. Pereira S, Resende R, Coelho P, et al. Matrix Regenerating Agent (RGTA) in a Neurotrophic Corneal Ulcer. Cureus 2020;12:e11167. [Crossref] [PubMed]
98. Salazar-Quiñones L, Molero-Senosiáin M, Aguilar-Munoa S, et al. Management of corneal neurotrophic ulcers with Cacicol®-RGTA (ReGeneraTing Agent): a case series. Arch Soc Esp Oftalmol (Engl Ed) 2020;95:421-8. [Crossref] [PubMed]
99. Arvola RP, Robciuc A, Holopainen JM. Matrix Regeneration Therapy: A Case Series of Corneal Neurotrophic Ulcers. Cornea 2016;35:451-5. [Crossref] [PubMed]
100. Aifa A, Gueudry J, Portmann A, et al. Topical treatment with a new matrix therapy agent (RGTA) for the treatment of corneal neurotrophic ulcers. Invest Ophthalmol Vis Sci 2012;53:8181-5. [Crossref] [PubMed]
101. Cochener B, Zagnoli C, Hugny-Larroque C, et al. Healing of resistant corneal neurotrophic ulcers using a matrix regenerating agent. J Fr Ophtalmol 2019;42:159-65. [Crossref] [PubMed]
102. Rocha EM, Cunha DA, Carneiro EM, et al. Insulin, insulin receptor and insulin-like growth factor-I receptor on the human ocular surface. Adv Exp Med Biol 2002;506:607-10. [Crossref] [PubMed]
103. Soares RJDSM, Arêde C, Sousa Neves F, et al. Topical Insulin-Utility and Results in Refractory Neurotrophic Keratopathy in Stages 2 and 3. Cornea 2022;41:990-4. [Crossref] [PubMed]
104. Diaz-Valle D, Burgos-Blasco B, Gegundez-Fernandez JA, et al. Topical insulin for refractory persistent corneal epithelial defects. Eur J Ophthalmol 2021;31:2280-6. [Crossref] [PubMed]
105. Fai S, Ahem A, Mustapha M, et al. Randomized Controlled Trial of Topical Insulin for Healing Corneal Epithelial Defects Induced During Vitreoretinal Surgery in Diabetics. Asia Pac J Ophthalmol (Phila) 2017;6:418-24. [PubMed]
106. Wang AL, Weinlander E, Metcalf BM, et al. Use of Topical Insulin to Treat Refractory Neurotrophic Corneal Ulcers. Cornea 2017;36:1426-8. [Crossref] [PubMed]
107. Eleiwa TK, Khater AA, Elhusseiny AM. Topical insulin in neurotrophic keratopathy after diabetic vitrectomy. Sci Rep 2024;14:10986. [Crossref] [PubMed]
108. Mead OG, Tighe S, Tseng SCG. Amniotic membrane transplantation for managing dry eye and neurotrophic keratitis. Taiwan J Ophthalmol 2020;10:13-21. [Crossref] [PubMed]
109. Khokhar S, Natung T, Sony P, et al. Amniotic membrane transplantation in refractory neurotrophic corneal ulcers: a randomized, controlled clinical trial. Cornea 2005;24:654-60. [Crossref] [PubMed]
110. Prabhasawat P, Tesavibul N, Komolsuradej W. Single and multilayer amniotic membrane transplantation for persistent corneal epithelial defect with and without stromal thinning and perforation. Br J Ophthalmol 2001;85:1455-63. [Crossref] [PubMed]
111. Donnenfeld ED, Perry HD, Nelson DB. Cyanoacrylate temporary tarsorrhaphy in the management of corneal epithelial defects. Ophthalmic Surg 1991;22:591-3. [Crossref] [PubMed]
112. Rapoza PA, Harrison DA, Bussa JJ, et al. Temporary sutured tube-tarsorrhaphy: reversible eyelid closure technique. Ophthalmic Surg 1993;24:328-30. [Crossref] [PubMed]
113. Pakarinen M, Tervo T, Tarkkanen A. Tarsorraphy in the treatment of persistent corneal lesions. Acta Ophthalmol Suppl (1985) 1987;182:69-73. [Crossref] [PubMed]
114. Solyman O, Elhusseiny AM, Ali SF, et al. A Review of Pediatric Corneal Neurotization. Int Ophthalmol Clin 2022;62:83-94. [Crossref] [PubMed]
115. Terzis JK, Dryer MM, Bodner BI. Corneal neurotization: a novel solution to neurotrophic keratopathy. Plast Reconstr Surg 2009;123:112-20. [Crossref] [PubMed]
116. Aujla J, Tong JY, Curragh D, et al. Corneal Neurotization for Neurotrophic Keratopathy: A Multicenter Experience. Ophthalmic Plast Reconstr Surg 2024;40:655-60. [Crossref] [PubMed]
117. Saini M, Kalia A, Jain AK, et al. Clinical outcomes of corneal neurotization using sural nerve graft in neurotrophic keratopathy. PLoS One 2023;18:e0294756. [Crossref] [PubMed]
118. Jonas JB, Rank RM, Budde WM. Tectonic sclerokeratoplasty and tectonic penetrating keratoplasty as treatment for perforated or predescemetal corneal ulcers. Am J Ophthalmol 2001;132:14-8. [Crossref] [PubMed]