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Neurotrophic keratopathy – Treatment

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Neurotrophic keratopathy is a rare degenerative disease of the cornea that develops when nerve damage disrupts the eye’s natural protection and healing abilities. This condition can silently progress from mild surface changes to severe vision loss, making early recognition and treatment essential for preserving sight.

Understanding Treatment Goals in Neurotrophic Keratopathy

When someone develops neurotrophic keratopathy, the primary goal of treatment is to protect the corneal surface and promote healing while preventing further deterioration. The cornea, which is normally the most richly innervated structure in the human body, loses its sensation and ability to heal properly in this condition[1]. This means that treatment must focus on compensating for what the damaged nerves can no longer do naturally—maintaining moisture, encouraging cell regeneration, and defending against injury.

Treatment approaches are carefully selected based on how advanced the disease has become and what caused it in the first place. A patient in the early stages with only minor surface irregularities needs very different care than someone whose cornea has developed a deep ulcer[2]. Each person’s medical history, including past infections, surgeries, or underlying conditions like diabetes, also influences which treatments will work best. The earlier treatment begins, the better the chances of stopping the disease from progressing to more severe stages that could threaten vision permanently.

Medical authorities recognize that neurotrophic keratopathy requires a comprehensive strategy that addresses not just the visible damage to the cornea, but also the underlying nerve impairment[6]. Current medical care includes both established treatments that doctors have used for years and newer therapies being investigated in research settings. Some treatments aim to keep the eye lubricated and protected, while others work to stimulate the healing process directly by providing growth factors that the damaged nerves can no longer supply naturally.

Established Treatment Methods for Neurotrophic Keratopathy

Standard treatment begins with understanding that neurotrophic keratopathy progresses through distinct stages, each requiring specific interventions. Medical professionals commonly use the Mackie classification system, which divides the disease into three stages based on how much damage the cornea has sustained[2]. Stage 1 involves mild changes to the epithelium (the outermost layer of the cornea) such as punctate keratopathy, where small spots of damage appear on the surface. Stage 2 is characterized by a persistent epithelial defect that won’t heal on its own. Stage 3 represents the most severe form, where the deeper layers of the cornea become involved, potentially leading to ulceration, melting of corneal tissue, or even perforation.

For patients in Stage 1, treatment focuses on maintaining adequate lubrication and protecting the ocular surface from further damage. Artificial tears are used frequently throughout the day to keep the cornea moist, as damaged nerves cannot properly regulate tear production or stimulate normal blinking[2]. Some patients benefit from procedures to help retain natural tears, such as punctal plugs or punctal cautery, which block the drainage channels that normally carry tears away from the eye. For patients whose eyelids don’t close completely during sleep, taping the eyelid shut at night can prevent the cornea from drying out.

When the disease advances to Stage 2 with persistent epithelial defects, more intensive interventions become necessary. Therapeutic contact lenses act as a protective bandage over the damaged cornea, shielding it from the mechanical trauma of blinking while creating an environment that supports healing[2]. Another important treatment option involves autologous serum eye drops, which are prepared from a patient’s own blood. These drops contain natural growth factors and nutrients that can help stimulate corneal healing in ways that artificial tears cannot match. Some medical centers also use allogenic serum (from blood donors) when preparing a patient’s own serum isn’t feasible.

⚠️ Important
Many patients with neurotrophic keratopathy experience reduced or absent symptoms despite having significant corneal damage. The same nerve damage that prevents proper healing also reduces pain sensation, so people may not realize their condition is worsening. This makes regular monitoring by an eye care professional crucial, especially for anyone with risk factors like previous herpes eye infections or diabetes.

In some cases, doctors may consider using anti-inflammatory medications carefully, though this remains an area where treatment must be individualized[2]. Reducing inflammation can support healing, but certain anti-inflammatory drugs can themselves cause corneal toxicity if used long-term. Tarsorrhaphy, a surgical procedure that partially or completely sews the eyelids together temporarily, provides maximum protection for a severely damaged cornea by keeping it constantly covered and moist. Though this obviously affects vision temporarily, it can be lifesaving for the eye when other treatments haven’t worked. Similarly, botulinum toxin injections into the upper eyelid can create a temporary ptosis (drooping) that helps protect the cornea.

Stage 3 disease, with corneal ulceration or stromal involvement, requires aggressive intervention to preserve the structural integrity of the eye. Amniotic membrane transplantation involves placing a special membrane derived from the innermost layer of the placenta onto the corneal surface[2]. This biological material contains growth factors and anti-inflammatory substances that can help promote healing and reduce scarring. For corneas at risk of perforation, a conjunctival flap procedure moves tissue from the conjunctiva (the membrane covering the white of the eye) over the damaged cornea to provide structural support and bring blood vessels closer to the healing area. Though this procedure typically results in reduced vision through the covered cornea, it can save the eye from more catastrophic complications.

Throughout treatment at any stage, addressing any coexisting eye conditions is essential for success. Many patients with neurotrophic keratopathy also struggle with dry eye disease, exposure problems from eyelids that don’t close properly, or other ocular surface disorders that complicate healing[7]. Managing these concurrent issues improves the chances that treatments for the nerve damage itself will work effectively.

Innovative Therapies in Clinical Research

Research into neurotrophic keratopathy has accelerated significantly in recent years, driven by a deeper understanding of how nerves maintain corneal health and what happens when that innervation is lost. Scientists now know that corneal nerves don’t just transmit sensation—they actively release trophic factors (growth-promoting substances) that are essential for epithelial cell survival, regeneration, and wound healing[4]. When these factors are missing due to nerve damage, simply keeping the eye moist isn’t enough to restore normal healing.

One of the most significant advances in recent research has been the development of recombinant human nerve growth factor (rhNGF) eye drops. Nerve growth factor is a naturally occurring protein that plays a crucial role in the maintenance and survival of nerve cells. Clinical trials have investigated whether supplying this factor directly to the cornea through eye drops can compensate for what the damaged nerves can no longer provide[7]. Early results from these studies have shown promise, with some patients experiencing healing of persistent epithelial defects and corneal ulcers that hadn’t responded to conventional treatments. The trials have progressed through multiple phases, moving from initial safety testing in small groups to larger studies comparing the treatment to standard care.

Another innovative approach being explored involves corneal neurotization, a sophisticated surgical procedure that attempts to restore nerve function to the damaged cornea by connecting it to healthy nerves from other parts of the face[2]. During this procedure, surgeons identify functioning nerves—often from the opposite side of the face if one trigeminal nerve is damaged—and surgically transfer them or graft new nerve tissue to create a pathway for nerve fibers to grow into the affected cornea. This technique aims to restore not just sensation but also the release of trophic factors that promote long-term corneal health. The procedure is technically demanding and requires specialized expertise, but for appropriately selected patients, it offers the potential for restoring natural corneal function rather than just managing symptoms.

Matrix regenerating therapy represents another novel treatment approach being investigated[2]. This therapy involves applying a specially formulated substance to the corneal surface that mimics components of the eye’s natural extracellular matrix—the structural framework that supports cells. The goal is to create an environment that better supports epithelial cell migration and healing, particularly in cases where the underlying corneal structure has been damaged along with the nerves.

Plasma rich in growth factors (PRGF) offers a variation on the autologous serum approach but with higher concentrations of healing factors[2]. Researchers prepare PRGF by processing a patient’s blood in a specific way that concentrates platelets and the growth factors they contain. When applied to the cornea as eye drops, these concentrated growth factors may provide more powerful healing signals than standard autologous serum. Clinical trials are evaluating whether this enhanced preparation leads to better outcomes for patients with persistent epithelial defects.

Researchers have also investigated Thymosin β4, a naturally occurring peptide (a small protein) that appears to play multiple roles in wound healing[2]. Laboratory studies suggest it can promote cell migration, reduce inflammation, and support tissue repair. Clinical trials are exploring whether eye drops containing Thymosin β4 can help heal corneal defects in neurotrophic keratopathy by stimulating these beneficial effects directly at the ocular surface.

A combination approach using Substance P and insulin-like growth factor-1 (IGF-1) has also entered clinical investigation[2]. Substance P is a neuropeptide normally found in nerve fibers that innervate the cornea, and it plays a role in wound healing beyond its involvement in pain sensation. IGF-1 is a growth factor that promotes cell proliferation and survival. Together, these substances might work synergistically to compensate for multiple deficiencies created by nerve damage. Early-phase trials have examined the safety of this combination and are beginning to evaluate whether it improves healing rates in patients who haven’t responded to conventional treatments.

⚠️ Important
Participating in a clinical trial for neurotrophic keratopathy can provide access to cutting-edge treatments before they become widely available. However, trials have specific eligibility requirements based on disease stage, previous treatments, and other health factors. Not all experimental therapies will prove effective, and some may cause side effects not seen with standard treatments. Anyone considering trial participation should discuss the potential benefits and risks thoroughly with their eye care team.

An oral medication called nicergoline, which was originally developed for other purposes, has attracted interest for its potential effects on nerve function[2]. Some researchers theorize that by improving blood flow and potentially supporting nerve metabolism, this medication might help preserve remaining nerve function or support nerve regeneration in the cornea. Studies are ongoing to determine whether this systemic (whole-body) treatment approach could complement topical therapies applied directly to the eye.

Clinical trials for neurotrophic keratopathy treatments typically progress through well-defined phases. Phase I trials focus primarily on safety, usually involving small numbers of participants to determine what doses can be tolerated and what side effects might occur. Phase II trials expand to larger groups and begin evaluating whether the treatment actually works—whether it promotes healing, improves corneal sensitivity, or prevents progression of the disease. Phase III trials are large, often international studies that compare the new treatment directly against current standard care to determine if it offers meaningful advantages. These trials are conducted at specialized medical centers that have the expertise to properly diagnose and monitor patients with this rare condition. Locations for trials vary but often include major academic medical centers in the United States, Europe, and other regions with advanced ophthalmology research programs.

Most common treatment methods

  • Ocular surface protection and lubrication
    • Artificial tears applied frequently throughout the day to maintain corneal moisture
    • Punctal plugs or punctal cautery to prevent tear drainage and retain natural moisture
    • Eyelid taping at night for patients with incomplete eyelid closure
  • Therapeutic contact lenses
    • Bandage contact lenses that protect the corneal surface from mechanical trauma during blinking
    • Create a moist environment between the lens and cornea to support healing
  • Autologous and allogenic serum therapy
    • Eye drops prepared from patient’s own blood (autologous) or donor blood (allogenic)
    • Contain natural growth factors and nutrients not found in artificial tears
    • Support corneal epithelial healing through biological mechanisms
  • Surgical interventions for severe cases
    • Tarsorrhaphy: partial or complete temporary closure of eyelids to protect cornea
    • Amniotic membrane transplantation: application of placental membrane containing healing factors
    • Conjunctival flap: moving conjunctival tissue over damaged cornea for structural support
    • Corneal neurotization: surgical connection of healthy nerves to restore corneal innervation
  • Recombinant human nerve growth factor
    • Topical eye drops containing laboratory-produced nerve growth factor
    • Investigated in clinical trials for promoting healing of persistent defects and ulcers
  • Novel biological therapies under investigation
    • Matrix regenerating therapy: substances that mimic natural corneal structure
    • Plasma rich in growth factors: concentrated healing factors from patient’s blood
    • Thymosin β4: peptide that promotes cell migration and reduces inflammation
    • Substance P/IGF-1 combination: neuropeptide and growth factor working together
    • Nicergoline: oral medication potentially supporting nerve metabolism

Ongoing Clinical Trials on Neurotrophic keratopathy

  • Study on the Safety and Effectiveness of RGN-259 Eye Drops for Patients with Neurotrophic Keratopathy

    Not recruiting

    1 1
    Investigated diseases:
    Investigated drugs:
    Germany Italy Poland Spain

References

https://www.ncbi.nlm.nih.gov/books/NBK431106/

https://pmc.ncbi.nlm.nih.gov/articles/PMC8903790/

https://www.orpha.net/en/disease/detail/137596

https://www.nature.com/articles/6700616

https://www.ncbi.nlm.nih.gov/books/NBK431106/

https://bmcophthalmol.biomedcentral.com/articles/10.1186/s12886-021-02092-1

https://pmc.ncbi.nlm.nih.gov/articles/PMC3964170/

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FAQ

What causes neurotrophic keratopathy?

Neurotrophic keratopathy develops when the trigeminal nerve—which provides sensation and trophic support to the cornea—becomes damaged. The most common cause is viral infections, particularly herpes simplex virus or herpes zoster (shingles), which can damage corneal nerves. Other causes include diabetes mellitus, ocular surgeries like LASIK or corneal transplantation, neurosurgical procedures, chronic use of certain eye drops (especially anesthetics), physical or chemical burns to the eye, prolonged contact lens wear, and rarely, congenital syndromes affecting nerve development.

Can you feel pain if you have neurotrophic keratopathy?

Paradoxically, many patients with neurotrophic keratopathy experience reduced or absent pain sensation in the affected eye, even when significant corneal damage is present. This is because the same nerve damage that causes the disease also impairs the ability to sense pain. However, some patients do report symptoms like dryness, photosensitivity (light sensitivity), or a feeling that something is in the eye. The reduced pain can be dangerous because it means patients might not realize their condition is worsening until vision is already affected.

How is neurotrophic keratopathy diagnosed?

Diagnosis relies on a combination of medical history review, physical examination, and specific testing for corneal sensitivity. An eye doctor will ask about previous eye infections (especially herpes), surgeries, diabetes, and other risk factors. The examination includes slit-lamp evaluation to look for characteristic corneal changes. The most important test is assessing corneal sensation, which can be done simply with a cotton swab wisp or more precisely with an instrument called a Cochet-Bonnet esthesiometer. Advanced imaging with in vivo confocal microscopy can directly visualize and count corneal nerves, providing objective evidence of nerve loss.

What happens if neurotrophic keratopathy is left untreated?

Untreated neurotrophic keratopathy typically progresses through increasingly severe stages. It begins with subtle surface irregularities and dry spots on the cornea, then advances to persistent epithelial defects that won’t heal. Without treatment, these can deepen into corneal ulcers that involve the deeper stromal layers. The most severe complications include corneal melting (where the tissue actually breaks down), perforation (a hole through the cornea), bacterial superinfection, and potentially irreversible vision loss or even loss of the eye itself. Early treatment significantly improves outcomes.

Are there new treatments being developed for neurotrophic keratopathy?

Yes, research into neurotrophic keratopathy has expanded considerably. Recombinant human nerve growth factor eye drops have been studied in clinical trials and show promise for healing persistent corneal defects. Corneal neurotization surgery, which reconnects healthy nerves to the damaged cornea, offers hope for long-term restoration of nerve function. Other therapies under investigation include plasma rich in growth factors, Thymosin β4 peptide, combination Substance P and IGF-1 treatments, matrix regenerating therapy, and oral medications like nicergoline. These trials are ongoing at specialized centers, and some treatments may eventually become more widely available as research progresses.

🎯 Key takeaways

  • • Neurotrophic keratopathy is caused by damage to corneal nerves, making the eye unable to sense injury or heal properly—a hidden danger that can progress silently.
  • • Treatment success depends heavily on early detection and matching the intervention to disease stage, from simple lubrication for mild cases to surgical procedures for severe complications.
  • • Anyone who has had herpes eye infections, undergoes corneal surgery, or lives with diabetes should be monitored regularly for signs of this condition.
  • • Autologous serum eye drops—made from a patient’s own blood—contain natural growth factors that can help heal damaged corneas in ways artificial tears cannot.
  • • Corneal neurotization surgery represents a paradigm shift from managing symptoms to actually restoring nerve function, potentially offering long-term solutions for severe cases.
  • • Recombinant human nerve growth factor has shown promise in clinical trials for healing persistent corneal defects that haven’t responded to conventional treatments.
  • • The absence of pain doesn’t mean your eye is healthy—reduced sensation is actually the hallmark of this disease and requires vigilant professional monitoring.
  • • Multiple innovative therapies are currently being investigated in clinical trials, offering hope that future treatment options will be more effective at restoring corneal health and preventing vision loss.

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