Neurotrophic keratitis is a degenerative eye condition caused by damage to the trigeminal nerve, the nerve responsible for corneal sensation. When that nerve stops working properly, the cornea loses its ability to feel pain, blink reflexively, and heal itself, leading to a cascade of surface breakdown that can progress from mild dryness all the way to corneal perforation and vision loss. The condition is rare, but the list of things that can trigger it is surprisingly long, and treatment has changed dramatically in recent years with the approval of the first drug specifically designed for it.
What Causes Neurotrophic Keratitis
The cornea is one of the most densely innervated tissues in the body. Those nerve fibers come from the ophthalmic branch of the trigeminal nerve (the fifth cranial nerve), and anything that damages this pathway, from the nerve’s origin in the brainstem all the way to its fine endings in the corneal surface, can set off neurotrophic keratitis. The underlying mechanism is always the same: partial or complete loss of corneal sensory innervation, which disrupts the signaling loop that tells the eye to produce tears, blink, and repair epithelial damage.1PubMed Central. New Pharmacological Approaches for the Treatment of Neurotrophic Keratitis
The most common causes fall into a few broad categories:
- Herpes virus infections: Herpes simplex keratitis and herpes zoster ophthalmicus (shingles affecting the eye) are leading causes. A prospective study using confocal microscopy showed that herpes zoster ophthalmicus significantly reduced corneal nerve branch density within two months of infection.2PubMed Central. Corneal nerve changes in herpes zoster ophthalmicus: a prospective longitudinal in vivo confocal microscopy study
- Diabetes: Diabetic neuropathy can affect the trigeminal nerve just as it affects peripheral nerves elsewhere. In some cases, a corneal ulcer from neurotrophic keratitis has been the first sign that a patient has diabetes at all.3PubMed. Neurotrophic keratopathy and diabetes mellitus
- Surgical and procedural damage: Neurosurgical procedures near the trigeminal nerve, ablation for trigeminal neuralgia, and even routine eye surgeries can sever or damage corneal nerves. LASIK, for instance, cuts through the corneal nerve plexus during flap creation, causing a form of neurotrophic disease that resolves in most patients but persists in some.4ScienceDirect / The Ocular Surface. Post-LASIK Tear Dysfunction and Dysesthesia
- Chemical burns: Alkali burns to the eye can completely destroy subbasal nerve fibers, with poor self-healing potential afterward.5PubMed Central. Chemical (Alkali) Burn-Induced Neurotrophic Keratitis Model in New Zealand Rabbit Investigated Using Medical Clinical Readouts and In Vivo Confocal Microscopy (IVCM)
- Other causes: Tumors compressing the trigeminal nerve, multiple sclerosis, congenital absence of the trigeminal nerve, long-term contact lens wear, and chronic use of certain topical eye medications (especially those with preservatives like benzalkonium chloride) can all contribute.
What makes neurotrophic keratitis particularly tricky is the paradox at its core: the cornea is breaking down, but the patient may not feel anything wrong. Pain is the usual alarm system that drives people to seek help for eye problems. When that alarm is silenced by nerve damage, the disease can progress quietly.
How It Progresses and What to Watch For
Neurotrophic keratitis is classified into three stages based on the severity of corneal damage, and recognizing which stage you are in matters because the treatment approach changes at each level.6PubMed Central. Diagnosis and management of neurotrophic keratitis
In stage 1, the corneal surface shows scattered irregularities. You might notice blurred vision, dryness, or redness, but the epithelium (the outermost layer of the cornea) is still intact. The eye may look hazy under a slit lamp, and tear film quality is often poor. This stage is easy to mistake for ordinary dry eye, and many patients spend months being treated for dry eye before the underlying nerve problem is identified.
Stage 2 is defined by a persistent epithelial defect, meaning the surface layer of the cornea has broken down and is not healing on its own. The defect is typically smooth-edged and oval, often located in the upper half of the cornea. At this point, the risk of infection rises because the cornea’s protective barrier has been compromised. Vision may be noticeably worse, and there may be a whitish ring of swollen cells around the defect.
Stage 3 is the most severe: the epithelial defect deepens into a true corneal ulcer, with loss of the stromal tissue beneath. Without intervention, this can progress to corneal melting and perforation, which threatens the entire eye. The fact that these patients often feel little or no pain at any stage is what makes neurotrophic keratitis so dangerous. By the time the condition is caught, it may already be at stage 2 or 3.
Getting the Diagnosis Right
Because the hallmark of neurotrophic keratitis is reduced or absent corneal sensation, the most important diagnostic step is testing how well the cornea can feel. The simplest method, still used in many clinics, is touching the cornea with a wisp of cotton or a dental floss filament and observing the blink response. This gives a rough yes-or-no answer but does not quantify sensation.
For a more precise measurement, clinicians use devices called aesthesiometers. The oldest and most widely known is the Cochet-Bonnet aesthesiometer, which presses a nylon filament against the cornea at varying lengths to gauge the threshold at which the patient feels it. Newer instruments use different stimuli: the Belmonte aesthesiometer delivers controlled air jets, and the Swiss liquid-jet aesthesiometer uses a tiny stream of saline. The most recently introduced device, the corneal Brill aesthesiometer, adds another option to the toolkit.7PubMed Central. Evaluation of Corneal Sensitivity: Tools We Have Reduced corneal sensation is an early indicator of the disease and can show up before visible damage appears on the surface.
Beyond sensation testing, in vivo confocal microscopy allows doctors to directly visualize the corneal nerve fibers at high magnification. In eyes with neurotrophic keratitis, this imaging reveals dramatically fewer nerve trunks and shorter total nerve length compared to healthy eyes. One study of surgically induced neurotrophic keratitis found that subbasal nerve length in affected eyes correlated directly with how much sensation remained.8JAMA Ophthalmology. Corneal Changes in Neurosurgically Induced Neurotrophic Keratitis While confocal microscopy is not available in every clinic, formal sensitivity testing with an aesthesiometer remains essential for assessing how well the corneal nerves are actually functioning.9PubMed Central. Corneal Nerve Assessment by Aesthesiometry: History, Advancements, and Future Directions
Conservative and Supportive Treatment
Treatment is staged to match the severity of the disease, and the first steps are always supportive. In stage 1, the goal is to protect the corneal surface and optimize the tear film. Preservative-free artificial tears are the starting point, because preserved drops can themselves damage corneal nerves over time. Any offending topical medications, particularly those containing benzalkonium chloride, should be stopped or switched.
If there is an underlying cause that can be treated, such as active herpes infection, addressing that cause is critical. But in many patients, the nerve damage has already occurred and is not reversible by treating the original disease alone. Supportive care in early-stage disease also includes moisture-chamber glasses, punctal plugs to keep tears on the eye longer, and therapeutic soft contact lenses that act as a bandage over the corneal surface.
A systematic review and meta-analysis comparing treatment outcomes paints a stark picture of why supportive care alone is often not enough for advanced disease. Among patients treated with lubricants and other non-specific measures, only about a quarter achieved complete corneal healing. By contrast, specific targeted treatments, including nerve growth factor drops, autologous serum, amniotic membrane transplantation, and corneal neurotization, all achieved complete healing rates well above 75%.10SpringerLink. Efficacy of treatments for neurotrophic keratopathy: a systematic review and meta-analysis That gap is large enough to suggest that once a persistent epithelial defect has set in, patients generally need more than lubricant drops.
Cenegermin and the Nerve Growth Factor Era
The most significant advance in neurotrophic keratitis treatment in recent years is cenegermin (sold under the brand name Oxervate), a topical eye drop containing a recombinant form of human nerve growth factor. Nerve growth factor is a protein the body naturally produces to support the survival and growth of nerve cells. Delivering it directly to the corneal surface addresses the root problem rather than just managing symptoms.
In the pivotal randomized trial, about 70% of patients treated with cenegermin achieved corneal healing by eight weeks, compared with roughly 29% of patients given the vehicle (placebo drops). The difference was both statistically and clinically significant, and cenegermin also reduced disease progression. Side effects were mostly mild and local, things like eye pain and increased tearing at the site of application.11PubMed. Topical Recombinant Human Nerve Growth Factor (Cenegermin) for Neurotrophic Keratopathy: A Multicenter Randomized Vehicle-Controlled Pivotal Trial
What makes cenegermin especially interesting is what happens after the treatment course ends. An eight-month follow-up study found that about three-quarters of patients maintained complete healing months after stopping the drops. More than that, confocal microscopy revealed actual nerve regrowth in the cornea, starting at the periphery and progressing inward. Corneal nerve fiber length increased, branching improved, and sensation recovered over the follow-up period, suggesting the drug’s effects outlast the treatment itself.12PubMed Central. Eight months follow-up of corneal nerves and sensitivity after treatment with cenegermin for neurotrophic keratopathy
Cenegermin is not cheap, and the treatment requires six daily instillations for eight weeks, which is a demanding schedule. The drops also need to be stored frozen and thawed before use each day. But for patients with stage 2 or stage 3 disease who have not responded to conservative measures, it represents the first treatment that goes after the underlying nerve biology rather than just protecting the surface.
Autologous Serum Drops
Before cenegermin was available, autologous serum drops were one of the go-to options for neurotrophic keratitis that did not respond to lubricants alone, and they remain widely used. These drops are made from the patient’s own blood: a sample is drawn, the serum is separated out and diluted (usually to 20%), and the resulting drops are used several times daily. Serum contains nerve growth factors, epithelial growth factors, and other proteins that support corneal healing.
The same meta-analysis that compared treatment categories found that autologous serum achieved complete healing in about 92% of treated patients, with a mean time to healing of roughly 28 days.10SpringerLink. Efficacy of treatments for neurotrophic keratopathy: a systematic review and meta-analysis These numbers look excellent, though it is worth noting that patient selection differs across studies, and the patients receiving autologous serum may not have been identical in severity to those receiving cenegermin. Still, autologous serum is a strong option, particularly for patients who cannot access or afford cenegermin. The main downsides are the need for repeated blood draws, the requirement for cold-chain storage, a small risk of contamination, and the fact that quality varies from patient to patient depending on their blood composition.
Surgical Approaches for Severe or Refractory Disease
When medical treatments are not enough, or when the cornea is actively melting, surgical options come into play. These divide broadly into procedures that protect and patch the corneal surface and a newer category that aims to restore nerve function directly.
Amniotic Membrane Transplantation
Amniotic membrane, the innermost layer of the placenta, has anti-inflammatory and growth-promoting properties that make it useful as a biological bandage for the cornea. In neurotrophic keratitis, a piece of cryopreserved amniotic membrane is placed over the corneal defect (sometimes in multiple layers for deeper ulcers) and secured in place. Studies support its safety and effectiveness in restoring epithelial health and improving visual acuity in eyes with neurotrophic keratitis.13PubMed Central. Amniotic membrane transplantation for managing dry eye and neurotrophic keratitis In one series of refractory neurotrophic ulcers, over half of patients achieved complete epithelial closure within the first month after surgery, and about two-thirds reported improvement in pain.14Arquivos Brasileiros de Oftalmologia. Amniotic membrane transplantation for neurotrophic corneal ulcers Other protective surgeries, such as tarsorrhaphy (partially sewing the eyelids together to shield the cornea), are sometimes used as a bridge or in combination with other treatments.
Corneal Neurotization
Corneal neurotization is a surgical technique that transplants a healthy sensory nerve graft to the cornea from a donor nerve elsewhere in the body, typically the supraorbital or supratrochlear nerve from the opposite side of the forehead, or the sural nerve from the leg. The idea is to reestablish direct nerve supply to the cornea, restoring both sensation and the trophic support that nerve fibers provide to the corneal surface.15PubMed Central. Corneal neurotization for the treatment of neurotrophic keratopathy
The meta-analysis found that neurotization achieved complete corneal healing in about 99% of cases, which was the highest rate among all treatments studied. The trade-off is time: healing after neurotization took an average of about 117 days, far longer than the roughly 16 to 28 days seen with amniotic membrane transplantation or nerve growth factor drops.10SpringerLink. Efficacy of treatments for neurotrophic keratopathy: a systematic review and meta-analysis That makes sense because the transplanted nerve fibers need months to grow into the corneal tissue and establish functional connections. Neurotization is generally considered for patients with moderate to severe disease who have either failed other treatments or whose nerve damage is so complete that topical approaches are unlikely to succeed long-term.
Emerging Therapies and Other Approaches
Beyond cenegermin and autologous serum, researchers are exploring other ways to treat or prevent corneal nerve damage. One approach involves a matrix-regenerating agent called Cacicol (also known as RGTA, or ReGeneraTing Agent), a synthetic polymer designed to mimic components of the extracellular matrix and help restore the microenvironment that corneal nerves need to survive and regrow. Early clinical work suggests it is effective and safe for treating neurotrophic keratitis.16PubMed. Neurotrophic Keratopathy: Therapeutic Approach Using a Novel Matrix Regenerating Agent
Other investigational strategies include platelet-rich plasma drops (similar in concept to autologous serum but more concentrated in growth factors), thymosin beta-4 (a peptide involved in wound healing), and gene therapy approaches aimed at boosting nerve growth factor production directly in the cornea. None of these have reached the level of evidence or regulatory approval that cenegermin has, but the landscape is moving quickly compared to even a decade ago, when lubricants and tarsorrhaphy were essentially all that was available.
When Children Are Affected
Neurotrophic keratitis is overwhelmingly a condition of adults, but it does occur in children, sometimes from birth. Congenital absence or underdevelopment of the trigeminal nerve is one cause, and it presents a unique set of challenges because young children cannot articulate what they are feeling (or not feeling). In one reported case, a three-year-old was diagnosed after her parents noticed she did not react when poked in the eye. She was treated with cenegermin, which did not fully resolve her epithelial defect, but subsequent fitting with a PROSE device (a specialized large-diameter scleral lens) healed the defect within nine days and improved her vision substantially.17PubMed Central. Unilateral pediatric neurotrophic keratitis due to congenital left trigeminal nerve aplasia with PROSE (prosthetic replacement of the ocular surface ecosystem) treatment
Pediatric cases underscore an important general principle: treatment often works best as a combination tailored to the individual. A single intervention may not be enough, and stepping through options, sometimes layering them, is a common reality in managing this disease at any age.
Living With Neurotrophic Keratitis
One aspect that often gets overlooked in clinical discussions is the toll the disease takes on daily life. Because the cornea does not feel pain normally, patients may not realize how severely their eye is affected until vision has already declined. And even in cases where the cornea is stabilized, the chronic nature of the disease, the demanding treatment schedules, and the ongoing anxiety about recurrence weigh heavily.
A utility analysis measuring quality of life in patients with neurotrophic keratitis found a significant impact that existed independently of vision loss. Patients reported particular difficulty with everyday tasks requiring reliable vision and described feelings of dependence and role limitation that went beyond what their visual acuity alone would predict.18PubMed. Impact of neurotrophic keratopathy on quality of life: a utility analysis This finding matters because it argues for treating neurotrophic keratitis aggressively even in cases where the measured vision loss seems modest. The functional and emotional burden is real and underappreciated.
Why Early Detection Changes Everything
The single most useful thing a person at risk for neurotrophic keratitis can take away from the medical literature is this: catching it at stage 1, before the epithelium breaks down, dramatically simplifies treatment and improves outcomes. Stage 1 can often be managed with preservative-free lubricants, protective lenses, and close monitoring. Stage 2 and 3 frequently require expensive biologics, surgical intervention, or both. The problem is that stage 1 feels a lot like ordinary dry eye, and the defining feature of the disease, reduced sensation, works against early self-detection.
Anyone with a known risk factor, a history of herpes keratitis or shingles near the eye, diabetes with neuropathy, previous eye or brain surgery involving the trigeminal pathway, or a chemical eye injury, should have corneal sensation tested periodically. It takes seconds with a cotton wisp and can flag a problem long before the surface starts to break down. The gap between what lubricants alone can accomplish (roughly a quarter of patients healed) and what targeted treatments achieve (three-quarters or more) is reason enough to push for a specific diagnosis rather than treating vaguely for dry eye when the risk factors are there.