Neurotrophic keratitis: causes, stages, diagnosis and treatment

Neurotrophic keratitis, also known as neurotrophic keratopathy, is a rare degenerative corneal disorder caused by damage to sensory innervation, primarily branches of the trigeminal nerve. As the cornea loses normal sensitivity, blinking, trophic support of the epithelium, tear film stability, and the ocular surface's ability to heal are impaired. This results in persistent epithelial defects, ulcers, stromal thinning, and even perforation. [1]

The paradox of this disease is that the severity of corneal damage often doesn't correspond to the severity of symptoms. Due to decreased sensitivity, patients may not experience severe pain even with a serious epithelial defect or ulcer. Therefore, neurotrophic keratitis is often diagnosed late—at the stage of a persistent defect, scarring, tissue melting, or the threat of vision loss. [2]

The primary cause of the disease is any damage to the sensory innervation pathway from the cornea to the trigeminal nucleus. The most common causes include herpetic keratitis, diabetes mellitus, chemical burns, toxic effects of topical medications, corneal surgery, and neurosurgery. Recent literature also highlights the role of prolonged contact lens wear, overuse of local anesthetics, and central nervous system lesions. [3]

Clinically, neurotrophic keratitis is a vision-threatening condition that requires early recognition and step-by-step treatment. Today, treatment is no longer limited to artificial tears and corneal protection: autologous serum, amniotic membrane, recombinant nerve growth factor, scleral lenses, tarsorrhaphy, and corneal neurotization are also used. Therefore, a relevant article on this topic must be based on current disease stages and new treatment options. [4]

Key feature	What does this mean in practice?
Decreased or absent corneal sensitivity	The cornea is less protected and heals worse.
Few complaints with severe damage	The disease is easy to miss
Persistent epithelial defects	High risk of ulceration and scarring
Stromal melting	Risk of perforation
Association with trigeminal nerve damage	We need to look for the cause, not just treat the surface of the eye.

Source for the table. [5]

Code according to ICD-10 and ICD-11

There's an important nuance to the coding of neurotrophic keratitis. In the basic version of the International Classification of Diseases, 10th revision of the World Health Organization, the neurotrophic variant is included under the heading H16.2 - keratoconjunctivitis, which explicitly lists neurotrophic keratoconjunctivitis. In clinical practice, especially in systems based on clinical modification, the more precise code H16.239 - neurotrophic keratoconjunctivitis, eye unspecified - is more commonly used, as well as lateral codes for right, left, and both eyes. [6]

In the International Classification of Diseases, 11th revision, the disease is more clearly defined and coded as 9A74 – neurotrophic keratitis. The description of this category also includes clinical variants associated with herpetic and postoperative origin, as well as diabetic neurotrophic keratitis. This reflects the modern understanding of the disease as an independent clinical and pathogenetic condition, rather than simply a subtype of superficial corneal inflammation. [7]

In practice, physicians often code not only the neurotrophic keratitis itself but also its cause. For example, if the condition arose after a herpes infection, neurosurgery, diabetes, or a chemical burn, the documentation may include both the corneal lesion code and the underlying condition code. This approach better reflects the nature of the situation and aids in patient management. [8]

For the patient, this means something simple: different medical records may contain slightly different alphanumeric designations, but the clinical meaning remains the same – it's a corneal disease caused by a disruption of its neural trophism. Much more important than the formal code is the stage of the process, the depth of the corneal damage, and the cause of the decreased sensitivity. [9]

System	Code	Comment
International Classification of Diseases, 10th revision	H16.2	Includes neurotrophic keratoconjunctivitis
International Classification of Diseases, 10th revision, clinical coding	H16.239	Neurotrophic keratoconjunctivitis, eye not specified
International Classification of Diseases, 11th revision	9A74	Neurotrophic keratitis

Source for the table. [10]

Epidemiology

Neurotrophic keratitis is a rare corneal disease. Modern reviews typically describe it as an orphan condition with an estimated prevalence of 1 to 5 cases per 10,000 population, although the exact figures vary greatly depending on the method of calculation and inclusion criteria. More recent reviews indicate that the global prevalence is estimated at less than 1 to 5 per 10,000, and the European estimate from Orphanet reaches approximately 1 case per 2,380 people. [11]

Population data from the United States provide a more realistic figure for clinical practice. In an analysis of the IRIS registry, the average prevalence of neurotrophic keratopathy diagnoses was 21.34 cases per 100,000 patients. The authors also noted that the disease was more often associated with herpetic keratitis and diabetes mellitus, and vision after diagnosis was, on average, worse than at other observation periods. [12]

In a specialized cohort of 354 eyes of 322 patients, bilateral disease was present in 9.9% of eyes, 40% of patients were 75 years of age or older, and 55% were women. The distribution by Mackey stage was as follows: 37.3% stage I, 32.5% stage II, and 30.2% stage III. In the same cohort, herpetic causes accounted for 34.9%, diabetes for 12.4%, ocular surgery for 10.4%, and central nervous system involvement for 9.0%. [13]

The epidemiology of the disease is closely linked to the prevalence of its causes. The 2024 and 2025 reviews emphasize that herpes infections, diabetes mellitus, and postoperative corneal nerve damage pose the main burden on the healthcare system. With an aging population and rising diabetes rates, the number of patients with corneal neurotrophic lesions is likely to increase. [14]

Systematic underdiagnosis must also be taken into account. Due to the paucity of symptoms, especially pain, the disease is often diagnosed only at the stage of a persistent defect or ulcer. Therefore, the actual prevalence of neurotrophic keratitis may be higher than officially recorded figures. [15]

Epidemiological indicator	Data
Estimated prevalence of a rare disease	1-5 per 10,000
European Orphanet Assessment	about 1 in 2380
Prevalence in the IRIS registry	21.34 per 100,000
Bilateral involvement in a clinical cohort	9.9%
Patients 75 years and older in a clinical cohort	40%
Women in the clinical cohort	55%
Herpetic etiology in a clinical cohort	34.9%

Source for the table. [16]

Reasons

The primary pathogenetic cause of neurotrophic keratitis is damage to the sensory pathway of the trigeminal nerve, which innervates the cornea. This damage can occur at the level of the cornea itself, the corneal nerve endings, the ophthalmic branch of the trigeminal nerve, the ganglion, the nerve trunk, or even the central regions associated with the trigeminal system. In other words, the disease is not caused by a single microbe or a single operation, but by the loss of normal nerve support to the cornea. [17]

The most common ocular causes include herpetic keratitis, both herpes simplex and herpes zoster, topical anesthetic abuse, chemical and thermal burns, eye drop toxicity, contact lenses, and corneal surgery. EyeWiki specifically lists herpetic keratitis, topical anesthetic abuse, chemical burns, drug toxicity, and corneal surgery as the most common ocular factors.[18]

Systemic causes include diabetes mellitus, neurosurgical procedures and trauma, stroke, aneurysms, multiple sclerosis, intracranial masses, vitamin A deficiency, leprosy, and congenital trigeminal hypoplasia. These conditions have one thing in common: they disrupt the sensory innervation or metabolic support of the corneal nerves. Therefore, neurotrophic keratitis can be not only an ophthalmologic problem but also a neurologic or systemic one. [19]

In clinical practice, postoperative causes are particularly important. Laser-assisted keratomileusis, photorefractive keratectomy, corneal transplantation, and other anterior segment procedures damage the subbasal nerve plexuses and, in some patients, create conditions for persistent epithelial defects and neurotrophic damage. Reviews also indicate that neurosurgical treatment of trigeminal neuralgia and other procedures on the 5th cranial nerve can lead to this condition. [20]

Modern clinical series confirm the prevalence of herpetic, diabetic, and surgical etiologies. This is important for the physician's work: with persistent epithelial defects, it is necessary not only to treat the cornea but also to actively search for the underlying cause—herpes, diabetes, previous surgery, burns, toxic effects of eye drops, or neurological disease. [21]

Cause	How it leads to illness
Herpetic keratitis	Damages the sensitive fibers of the cornea
Diabetes mellitus	Causes corneal neuropathy and impairs healing
Chemical and thermal burns	Destroy the epithelium and corneal nerves
Corneal surgery	Damages the subbasal nerve plexuses
Abuse of local anesthetics	Toxically damages the epithelium and nerves
Toxicity of topical preparations	Impairs sensitivity and epithelialization
Neurosurgical and neurological causes	They disrupt the trigeminal innervation pathway

Source for the table. [22]

Risk factors

Risk factors largely overlap with the underlying causes of the disease. The most significant are considered to be herpes simplex infection of the cornea, diabetes mellitus, corneal and ocular surface surgery, chemical burns, prolonged use of toxic topical medications, and neurosurgical interventions on the trigeminal nerve. Modern reviews emphasize that it is the combination of these factors that determines who falls into the highest-risk group. [23]

Age is also clinically important. In population studies and clinical series, the disease is more often detected in elderly patients, especially those over 75 years of age. This is likely due to the accumulation of risk factors and the higher prevalence of diabetes, herpes infections, surgery, and associated tear film disorders. [24]

A separate risk factor is decreased vigilance due to minimal symptoms. Patients who don't experience significant pain seek help late, and doctors sometimes interpret the changes as "simply dry eye" or "superficial keratitis." Therefore, diagnostic delays are also a factor in an unfavorable course of the disease. [25]

Additional factors include chronic contact lens wear, long-term use of preservative drops, ocular surface damage after multiple surgeries, and a combination of several damaging factors. The more factors disrupt neural and epithelial homeostasis, the higher the risk of progression from subclinical sensitivity to persistent epithelial defects and ulcers. [26]

Risk factor	Why is it important?
Herpes infection	The most common infectious cause of the disease
Diabetes mellitus	Disrupts corneal innervation and epithelialization
Corneal surgery	Damage nerve fibers
Chemical burn	May cause severe and persistent denervation
Toxic drops and preservatives	Support epithelial toxicity
Long-term lens wear	Increases surface damage
Old age	Associated with a large number of background factors
Late diagnosis	Increases the risk of ulcers and scarring

Source for the table. [27]

Pathogenesis

The pathogenesis of neurotrophic keratitis revolves around the loss of normal sensory innervation of the cornea. Corneal nerves not only perform sensory functions but also maintain epithelial integrity through neurotrophic factors, blink regulation, tear secretion, and local cellular homeostasis. When this system is disrupted, the cornea fails to regenerate normally, even after minor microtrauma. [28]

The next stage is disruption of the tear film and lacrimal functional unit. Reflex lacrimation decreases, blink rate decreases, and the epithelium becomes dry and unstable. This paves the way for superficial punctate keratopathy, and then for persistent epithelial defects. [29]

If the process continues, the epithelial defect ceases to close, its edges become smooth and raised, and the underlying stroma begins to become involved in the pathology. At this stage, an ulcer, stromal thinning, and the risk of tissue melting and perforation already develop. However, the inflammatory reaction can be surprisingly modest.
Moreover, the inflammatory reaction can be relatively weak, further masking the severity of the situation. [30]

A contemporary group studying neurotrophic keratopathy has proposed broadening the understanding of the disease and considering it a spectrum of disorders, ranging from altered sensitivity without visible slit changes to corneal perforation. This approach emphasizes that the pathological process begins before an ophthalmologist notices a gross ulcer. [31]

Pathogenetic link	What's happening
Damage to sensory innervation	The cornea loses trophic nerve support
Decreased blinking and lacrimation	The surface dryness increases
Impaired epithelial healing	Persistent defects occur
Stromal involvement	Ulcers and thinning develop
Melting and perforation	There is a risk of losing the eye and vision

Source for the table. [32]

Symptoms

In the early stages, symptoms can be deceptively mild. Patients often complain of blurred vision, intermittent redness, dryness, unstable vision, and a feeling of poor ocular surface quality. However, the severe pain typical of many other keratitis types is often absent here, precisely because of decreased corneal sensitivity. [33]

As the condition progresses, epithelial changes, surface roughness, decreased corneal transparency, and persistent epithelial defects develop. Clinically, this may be accompanied by fluctuations in visual acuity, increased photophobia, and a feeling that the eye "doesn't heal" despite conventional treatment for dry eye or superficial keratitis.[34]

In severe stages, corneal ulceration, stromal opacification, edema, thinning, tissue melting, and perforation occur. Paradoxically, even in these cases, pain may be less than expected. This is what makes the disease particularly dangerous: the severity of symptoms does not guarantee safety, and the absence of pain does not mean an easy process. [35]

In children, the disease may present differently. EyeWiki notes that infants and young children with impaired corneal sensitivity may respond only to threatening gestures by blinking and may even cause secondary corneal damage to themselves. This emphasizes the need for vigilance in pediatric and neurological patients. [36]

Symptom	How often is it expected?
Blurred vision	Often
Redness	Maybe
Severe pain	Often absent or weak
Photophobia	Possible
Persistent epithelial defect	Typical for more severe stages
Ulcer, thinning, perforation	A sign of a severe course

Source for the table. [37]

Classification, forms and stages

The Mackey classification of three stages is still most widely used in clinical practice. Stage I corresponds to epithelial disorders without an obvious defect, most often in the form of punctate keratopathy, dry and dull epithelium, decreased tear film stability, and early epithelial dysfunction. Stage II is a persistent or recurrent epithelial defect, often oval in shape, with smooth and raised edges. Stage III is a corneal ulcer with stromal involvement, melting, and risk of perforation. [38]

In 2023, the Neurotrophic Keratopathy Study Group proposed a more detailed 6-stage system. It begins with altered sensitivity without overt keratopathy, then progresses through superficial epitheliopathy, persistent epithelial defects without stromal opacification, epitheliopathy or defect with stromal opacification, ulceration, and finally perforation. This system is useful because it allows for earlier detection and intervention. [39]

For everyday ophthalmological practice, the 3-stage Mackey system remains the most understandable and widely used, while the 6-stage system is more modern and pathogenetically accurate. Therefore, both systems can be found in articles and reports. The most reasonable approach is to use Mackey for everyday descriptions of severity and the new system for a more nuanced understanding of the early evolution of the disease. [40]

From a clinical perspective, the disease can also be described by its origin: post-herpetic, diabetic, post-operative, toxic, burn, neurosurgical, and congenital. This classification helps determine treatment tactics and prognosis, as, for example, burn and post-operative forms often have a more severe and prolonged course than mild superficial variants. [41]

System	Stages
Mackey's classification	I - epitheliopathy, II - persistent epithelial defect, III - ulcer, melting, perforation
New 6-speed system	From altered sensitivity without keratopathy to perforation
By etiology	Herpetic, diabetic, postoperative, toxic, burn, congenital

Source for the table. [42]

Complications and consequences

The most dangerous complications include persistent epithelial defects, corneal ulcers, stromal thinning, melting, and perforation. These conditions not only impair vision but also pose a direct threat to the anatomical integrity of the eye. This is why neurotrophic keratitis is considered a potentially blinding disease. [43]

Equally important are scarring, persistent opacities, vascularization, and a significant decrease in visual acuity. Even if the eye can be anatomically preserved, the late stage can leave irreversible damage to corneal transparency and visual function. In severe cases, the patient may later require a corneal transplant, and the prognosis after this also depends on the activity of the underlying process and corneal sensitivity. [44]

Secondary infection is another serious problem. A persistent epithelial defect and ulcer create an entry point for microbial keratitis, and in neurotrophic keratitis, this infection may be recognized later due to vague symptoms. This is why it is so important not to miss a secondary infectious component in differential diagnosis and treatment. [45]

The systemic consequences of the disease include chronic treatment, frequent visits to the ophthalmologist, the risk of recurrent exacerbations, and a significant reduction in quality of life. In some patients, the disease becomes protracted and requires combined treatment for months or even years. [46]

Complication	What is dangerous?
Persistent epithelial defect	It turns into an ulcer
Corneal ulcer	Threatens melting and scarring
Stromal melting	May result in perforation
Perforation	Emergency, eye threat
Scar and clouding	Persistent vision loss
Secondary infection	Worsens the prognosis and requires urgent treatment

Source for the table. [47]

When to see a doctor

An ophthalmologist should be consulted for any persistent decrease in vision, non-healing epithelial defect, eye redness following herpetic keratitis, corneal surgery, or diabetes, if standard treatments for dryness and superficial keratitis are ineffective. Neurotrophic keratitis is particularly common when objective changes are severe, but subjective complaints appear moderate. [48]

Urgent evaluation is necessary if there is a visible corneal defect, the appearance of a white spot, a sudden decrease in vision, increasing corneal opacity, or a suspected ulcer or perforation. In stages II and III, EyeWiki recommends more frequent monitoring, up to every 1-2 days, until the risk of perforation decreases. [49]

Patients following herpetic eye infections, chemical burns, laser vision correction, corneal transplants, and trigeminal nerve surgery should be especially vigilant. These groups are at increased risk of neurotrophic damage and often underestimate the severity of a "painless" defect. [50]

Situation	Urgency
Long-term blurred vision and persistent epitheliopathy	Make an appointment with an ophthalmologist quickly
Non-healing corneal defect	Urgently
White spot, ulcer, thinning	Urgently
Suspected perforation	Urgently
History of herpes, diabetes, recent corneal surgery	Low threshold for appeal

Source for the table. [51]

Diagnostics

Diagnosis is based on a combination of clinical presentation, medical history, and mandatory corneal sensitivity testing. Current consensus and EyeWiki emphasize that corneal sensitivity testing should be performed early, rather than later, because it distinguishes neurotrophic keratitis from many similar-looking conditions. [52]

The first step is a detailed medical history. It is important to identify herpes infections, diabetes, neurosurgical and ophthalmological procedures, chemical burns, toxic eye drops, chronic contact lens wear, and systemic diseases. Without this, the neurotrophic process can easily be mistaken for simple dry eye or infectious keratitis. [53]

The second stage is slit-lamp examination. This allows visualization of punctate epitheliopathy, dull epithelium, persistent defects with raised edges, stromal opacification, thinning, ulceration, melting, and signs of secondary infection. The slit lamp remains the primary tool for staging the disease according to Mackey. [54]

The third step is fluorescein staining. EyeWiki also recommends using lissamine green or rose bengal to evaluate the epithelium and conjunctiva. These tests help visualize even early surface abnormalities and clarify the extent of the defect. [55]

The fourth stage is quantitative or qualitative esthesiometer testing. Sensitivity should be checked before administering any drops, as anesthetics and other agents can distort the results. For this purpose, a cotton swab is used as a qualitative test or special esthesiometers, such as contact and non-contact models, are used. [56]

The fifth step is an assessment of the ocular surface: Schirmer's test, tear film stability, eyelid condition, blinking, and the presence of lagophthalmos. EyeWiki specifically notes that eyelid closure abnormalities, decreased blink rate, and other exposure factors should be sought, as they may exacerbate the disease. [57]

The sixth stage involves additional methods in complex cases. These include in vivo confocal microscopy to evaluate the subbasal nerves, photographic documentation, sometimes anterior segment optical coherence tomography, and an expanded search for a systemic cause. These methods do not replace a basic diagnosis, but they help clarify the severity and mechanism of the disease. [58]

Diagnostic step	Why is it needed?
Anamnesis	Searches for herpes, diabetes, surgeries, burns, toxic factors
Slit lamp	Assesses the stage of the lesion
Fluorescein and other dyes	Highlight epithelial defects
Esthesiometry	Confirms decreased sensitivity
Schirmer test and tear film assessment	Show accompanying surface disturbance
Confocal microscopy	Visualizes corneal nerves

Source for the table. [59]

Differential diagnosis

Neurotrophic keratitis must often be differentiated from severe dry eye, exposure keratopathy, toxic eyedrop injury, contact lens complications, and chemical damage. These conditions can also cause significant corneal staining and persistent epithelial defects, but the key distinction remains assessment of corneal sensitivity and analysis of the underlying cause. [60]

Differentiation from infectious keratitis, especially herpetic and microbial, is especially important. Statistically, herpes remains one of the main causes of neurotrophic processes, so residual viral neuropathy and active infectious inflammation may coexist in one patient. Therefore, any epithelial defect in a neurotrophic background cannot automatically be considered "purely neurotrophic." [61]

Post-surgical persistent epithelial defects can also mimic neurotrophic keratitis. After laser and transplant procedures, careful analysis is needed to determine whether there is simply post-operative delayed healing or whether a true neurotrophic syndrome with sensory loss has already developed. Anamnesis, esthesiometry, and confocal microscopy are helpful in this regard. [62]

Limbal stem insufficiency is another important competing diagnosis because it is also accompanied by chronic epithelial defects and an unstable surface. In complex cases, the boundaries between these conditions may partially overlap, and the patient requires combined management. [63]

State	What helps to distinguish
Severe dry eye	Corneal anesthesia is usually less pronounced.
Exposure keratopathy	Obvious problems with eyelid closure
Toxic keratopathy	Relationship with local drugs
Infectious keratitis	More pronounced inflammation, infiltrates, infectious context
Post-surgical defect	Relationship with postoperative time and sensitivity level
Limbal brainstem insufficiency	Chronic epithelial instability with other pathogenesis

Source for the table. [64]

Treatment

Treatment of neurotrophic keratitis is always stepwise and depends on the stage of the disease, the depth of the defect, and the cause of the decreased sensitivity. The primary goal of therapy is not simply to make the eye "more hydrated," but to stop corneal destruction, close the epithelial defect, protect the stroma, prevent perforation, and, if possible, restore nerve trophism. Modern reviews emphasize that the approach should be individualized and combine indirect and direct interventions. [65]

The first step is almost always the elimination of toxic factors. StatPearls and EyeWiki recommend stopping or minimizing toxic preservative drops and local anesthetics, revising glaucoma therapy whenever possible, and avoiding topical nonsteroidal anti-inflammatory drugs, as they do not improve healing and can further reduce corneal sensitivity. At this stage, preservative-free artificial tears and ointment lubricants are used as actively as possible. [66]

In the early stages of Mackey's disease, the primary goal is to stabilize the epithelium and prevent the disease from developing into a permanent defect. Frequent use of preservative-free moisturizing drops, nighttime ointments, punctal occlusion, and ocular surface monitoring are considered the basis. In some cases, autologous serum or a therapeutic soft contact lens are considered even at this stage if epitheliopathy persists. [67]

Autologous serum and platelet-rich plasma are used as biological support for the ocular surface. These preparations contain growth factors, vitamins, and anti-inflammatory components that promote epithelialization. Recent reviews consider them an important option for non-healing defects, especially when regular hydration is insufficient. [68]

In stage II with persistent epithelial defects, protective methods are key. These include soft therapeutic lenses, scleral lenses, cryopreserved or sutured amniotic membrane, and, if necessary, partial tarsorrhaphy. The amniotic membrane provides mechanical protection, an anti-inflammatory effect, and a healing matrix. [69]

Cenegermin, a recombinant human nerve growth factor, remains the most prominent direct pathogenetic agent for this disease. As of 2026, a systematic review highlighted that it is the first and only FDA-approved drug for neurotrophic keratopathy. It is administered six times daily for eight weeks and has been shown in clinical trials and reviews to improve epithelial healing, corneal sensitivity, and innervation. [70]

In the REPARO and subsequent studies, cenegermin demonstrated higher rates of complete corneal healing compared to vehicle, and a 2026 review reported a weighted mean improvement in corneal sensitivity of 116.5% and innervation of 64.5% after 8 weeks of treatment, although the authors specifically noted heterogeneity across studies and small sample sizes. This means that the drug has indeed changed the therapeutic landscape, but does not eliminate the need for careful monitoring and a comprehensive approach. [71]

In severe stage III, when an ulcer, stromal melting, or the threat of perforation already exists, treatment becomes urgent. Treatment options include amniotic membrane, tarsorrhaphy, cyanoacrylate-based glue for small perforations, protective lenses, and, for larger defects, lamellar or penetrating keratoplasty. The primary goal here is to preserve the integrity of the eye, not just improve epithelialization. [72]

Corneal neurotization is considered the most "root-level" surgical solution because it aims to restore the cornea's most sensitive innervation. A recent review from 2025 describes it as a promising long-term solution that addresses the root cause of the disease—corneal anesthesia. Results accumulated by 2025 show significant improvements in sensitivity, epithelialization, and surface stability, but the procedure remains technically challenging and is performed in specialized centers. [73]

Promising treatment options include topical insulin, matrix-regenerating agents, regenerative medicine, mesenchymal cell technologies, and new neurotrophic approaches. However, an important distinction between clinical practice and expectations remains: today, the standards with the greatest real-world support remain surface protection, biologic drops, amniotic membrane, cenegermin, and, in severe cases, tarsorrhaphy, keratoplasty, and neurotization. [74]

Stage or situation	Basic methods
Early epitheliopathy	Preservative-free tears, ointments, punctal occlusion
Persistent superficial disease	Autologous serum, therapeutic lenses
Persistent epithelial defect	Amniotic membrane, scleral lenses, cenegermin
Risk of progression	Tarsorrhaphy, biological methods, frequent monitoring
Ulcer, melting, perforation	Adhesive, membrane, tarsorrhaphy, keratoplasty
Severe refractory cases	Corneal neurotization

Source for the table. [75]

Prevention

Prevention of neurotrophic keratitis revolves around early identification of risk groups and careful ocular care. In patients with herpetic keratitis, diabetes mellitus, and those undergoing laser refractive surgery, corneal transplantation, and neurosurgical procedures, it is necessary to regularly assess not only visual acuity but also corneal sensitivity, epithelial stability, and signs of surface dryness. [76]

An important preventative measure is minimizing the toxic load of eye drops. The longer preservatives, local anesthetics, and certain anti-inflammatory agents are used, the higher the risk of chronic epithelial and nerve damage. For patients with high-risk ocular surfaces, preservative-free regimens and earlier correction of treatment toxicity are preferable. [77]

After corneal and anterior segment surgery, prevention includes careful monitoring of epithelialization, early detection of persistent defects, and timely implementation of biological and protective methods. The sooner a neurotrophic trend is detected, the greater the chance of stopping the process before ulceration and scarring occur. [78]

In patients with diabetes and systemic neurological diseases, prevention extends beyond ophthalmology. Good metabolic control, timely treatment of herpes infections, and coordination with a neurologist and endocrinologist can reduce the risk of severe corneal lesions. [79]

Preventive measure	Why is it needed?
Monitoring corneal sensitivity in risk groups	Allows you to notice the disease early
Using preservative-free drops	Reduces toxic load
Early treatment of herpes diseases	Reduces the risk of corneal neuropathy
Diabetes control	Reduces the risk of corneal denervation
Follow-up after corneal surgery	Helps to notice persistent defects in time

Source for the table. [80]

Forecast

The prognosis directly depends on the stage at which the disease is diagnosed. At stages I and II, with timely treatment, the chances of stabilizing the ocular surface and preserving vision are much higher. At stage III, the risk of irreversible scarring, secondary infection, perforation, and severe vision loss increases dramatically. [81]

The cause of the disease is also important. Herpetic, diabetic, and postoperative forms may require longer observation and are more likely to recur. Systemic diseases and ongoing nerve damage impair recovery even with good local treatment. [82]

Modern methods have improved the prognosis compared to previous decades. Cenegermin, amniotic membrane, scleral lenses, and corneal neurotization can help patients who previously quickly progressed to scarring and perforation. However, this disease cannot be called completely "safe": even with treatment, it requires frequent monitoring and caution. [83]

Overall, the best prognosis is for patients who have had early corneal sensitivity testing, promptly treated with toxic factors, and timely initiation of stage-specific therapy. The worst prognosis is for patients with a late diagnosis, advanced stromal stage, and severe systemic disease. [84]

Prognostic factor	Influence
Early stage	Best forecast
Persistent epithelial defect	Requires active treatment
Ulcer and melting	Significantly worsen the prognosis
Diabetes and herpes background	Increase the risk of chronic disease
Early pathogenetic therapy	Improves the chances of preserving the surface and vision

Source for the table. [85]

FAQ

Can neurotrophic keratitis be almost painless?
Yes. This is one of the most insidious symptoms of the disease: due to decreased corneal sensitivity, severe damage can be accompanied by minimal pain. [86]

Are neurotrophic keratitis and dry eye syndrome the same thing?
No. Dry eye syndrome can accompany and worsen neurotrophic keratitis, but in neurotrophic keratitis, the key mechanism is damage to the corneal innervation. [87]

Is cenegermin always necessary?
Not always. The choice depends on the stage, depth of the lesion, drug availability, and overall treatment plan. However, for moderate to severe disease, cenegermin is considered an important pathogenetic treatment option. [88]

Can artificial tears alone cure the disease?
In the earliest stages, hydration sometimes helps stabilize the surface, but with persistent epithelial defects, ulcers, or severe denervation, artificial tears alone are usually insufficient. [89]

When is surgery necessary?
Surgical options are considered for severe, refractory, or ocular-threatening cases. These may include tarsorrhaphy, amniotic membrane grafting, keratoplasty, or corneal neurotization. [90]

Can the disease return after treatment?
Yes, relapse is possible, especially if the underlying cause of the decreased sensitivity persists. EyeWiki specifically notes that relapse is possible in some patients after discontinuing cenegermin treatment. [91]

Key points from experts

Alessandro Lambiase, MD, Professor of Ophthalmology, Director of the Department of Senses, and Director of the Ophthalmology Residency at Sapienza University in Rome, is a professor of ophthalmology. His long-standing work on neurotrophic keratitis and nerve growth factor underscores a key modern shift in this field: addressing not only the epithelial defect but also the disrupted corneal nerve trophism itself. This approach has led to the development of nerve growth factor therapy and interest in the early stages of the disease. [92]

Stephen S. Pflugfelder, MD, professor and holder of the James and Margaret Elkins Chair, is director of the Ocular Surface Center in the Department of Ophthalmology at Baylor College of Medicine. His clinical and research focus on ocular surface diseases emphasizes that neurotrophic keratitis cannot be managed as a "regular corneal ulcer." It requires a unique strategy to protect the surface, control inflammation, promote healing, and restore nerve function. [93]

Mina Massaro-Giordano, MD, ophthalmologist, director of the dry eye service in the Division of Ophthalmology at NYU Langone Health, and former professor of ophthalmology at the University of Pennsylvania, is a professor of ophthalmology. Her clinical work on ocular surface diseases and her contributions to educational materials on neurotrophic keratitis underscore a particularly important point: in this disease, the absence of pain should not reassure either
the physician or the patient, because a superficial defect can quickly progress to a vision-threatening stage. [94]