Neurotrophic Keratitis

Etiology

Damage or dysfunction at any level of the trigeminal nerve, from the trigeminal nucleus to the corneal nerve endings, can lead to neurotrophic keratitis. The most common causes include herpetic keratitis, chemical burns, prolonged contact lens wear, corneal surgery, ablative procedures for trigeminal neuralgia, and surgical interventions for jaw fracture reduction. Less frequently, space-occupying intracranial lesions such as schwannomas, meningiomas, and aneurysms may compress the trigeminal nerve, impairing corneal sensitivity.

Systemic conditions that compromise trigeminal function, including diabetes, multiple sclerosis, and leprosy, also contribute to the development of neurotrophic keratitis. In rare cases, children may present with neurotrophic keratitis due to congenital syndromes, such as Riley-Day, Goldenhar-Gorlin, and Möbius syndromes, as well as familial corneal hypesthesia and congenital insensitivity to pain with anhidrosis.[12]

Neurotrophic keratitis results from impaired corneal innervation, disrupting corneal sensation, epithelial integrity, and ocular surface homeostasis. The corneal epithelium depends on trophic support from the trigeminal nerve, and loss of this innervation compromises wound healing and increases the risk of epithelial breakdown, ulceration, and stromal damage. The underlying etiology varies widely, encompassing infectious, inflammatory, traumatic, iatrogenic, metabolic, and neurological conditions. Recognizing these causes is essential for timely diagnosis and intervention to prevent disease progression.[13]

Infection

Several infections can directly damage the corneal nerves, leading to the development of neurotrophic keratitis. Among these conditions, herpetic keratitis caused by HSV or VZV is one of the most common etiologies (see Image. Ocular and Perioral Involvement in Herpes Simplex Virus Infection). HSV invades the trigeminal ganglion, causing permanent nerve damage and reducing corneal sensation. Similarly, VZV, the causative agent of herpes zoster ophthalmicus (HZO), affects the trigeminal nerve, leading to corneal anesthesia and epithelial dysfunction. Recurrent episodes of herpetic keratitis, even with antiviral treatment, result in progressive corneal sensory loss, increasing the risk of epithelial breakdown and ulceration.[14]

Leprosy, caused by Mycobacterium leprae, is another significant infectious cause of corneal anesthesia, particularly in endemic regions. The bacterium infiltrates the trigeminal nerve, leading to chronic inflammation, nerve atrophy, and eventual loss of corneal sensation. Patients with leprosy face a heightened risk of developing chronic corneal ulcers due to unnoticed trauma and impaired corneal healing.[15]

Traumatic and Iatrogenic Injury

Various surgical and traumatic events can directly or indirectly injure the corneal nerves, resulting in neurotrophic keratitis. Corneal surgery is a common cause, as procedures such as laser-assisted in situ keratomileusis (LASIK), photorefractive keratectomy (PRK), and small incision lenticule extraction (SMILE) disrupt corneal nerve integrity through flap creation or epithelial ablation, potentially leading to temporary or permanent neurotrophic changes. PKP (corneal transplantation) severs corneal nerve fibers during grafting, reducing sensitivity in the transplanted cornea. Patients undergoing keratoprosthesis (KPro), such as the Boston KPro, frequently develop corneal anesthesia, increasing the risk of recurrent epithelial defects and ulceration.[16]

Ocular trauma can also contribute to neurotrophic keratitis, particularly chemical burns from acid or alkali exposure, which can destroy corneal nerves and lead to irreversible neurotrophic damage. Thermal and mechanical injuries affecting the corneal epithelium and stroma may disrupt nerve function, impairing corneal healing. Additionally, penetrating injuries involving the trigeminal nerve can damage the ophthalmic division (cranial nerve V1), significantly reducing corneal sensation.[17]

Neurosurgical procedures involving the trigeminal nerve pose another risk. Surgeries for trigeminal neuralgia, including microvascular decompression and γ knife surgery, can impair corneal sensation by damaging the trigeminal nerve. Resection of cranial nerve tumors, such as acoustic neuromas, skull base tumors, or meningiomas, may inadvertently injure the trigeminal nerve, resulting in neurotrophic keratitis. Orbital decompression surgeries performed for thyroid eye disease can also lead to unintended corneal nerve injury, further predisposing patients to neurotrophic keratitis.[18]

Neurological Pathology

Conditions affecting the central and peripheral nervous systems can impair corneal innervation, contributing to neurotrophic keratitis. Stroke and other brainstem lesions can disrupt the trigeminal nerve nucleus, leading to corneal hypoesthesia or anesthesia. Ischemic or hemorrhagic strokes affecting the pons may impair corneal sensation, while brainstem tumors and demyelinating diseases, such as multiple sclerosis, can interfere with trigeminal nerve pathways, further compromising corneal innervation and sensation.[19]

Diabetic neuropathy is a significant risk factor for neurotrophic keratitis due to progressive trigeminal nerve dysfunction. Chronic diabetes mellitus leads to decreased corneal sensation, reduced tear secretion, and impaired corneal healing, increasing the risk of PEDs and ulceration.[20]

Congenital and genetic disorders that affect sensory nerve development can also lead to early-onset neurotrophic keratitis. Riley-Day syndrome (familial dysautonomia) and congenital insensitivity to pain (CIP) impair corneal nerve function, resulting in corneal anesthesia. Moebius syndrome, a congenital disorder involving multiple cranial nerves, including the trigeminal nerve, can similarly cause severe corneal hypoesthesia.[21]

Chronic Topical Medication and Ocular Surface Disease

Prolonged use of certain topical ophthalmic medications and extended contact lens wear can contribute to epithelial toxicity and corneal nerve damage, increasing the risk of neurotrophic keratitis.[22] Chronic use of preserved glaucoma medications, especially those containing benzalkonium chloride (BAK), is known to cause corneal epithelial and nerve toxicity. Long-term exposure to topical anesthetics, such as in proparacaine abuse cases, can result in severe neurotrophic corneal damage.[23]

Extended contact lens wear reduces corneal oxygenation, leading to progressive nerve degeneration and diminished corneal sensation. Patients who use extended-wear contact lenses face an increased risk of neurotrophic keratitis due to chronic hypoxia-induced nerve dysfunction.[24]

Autoimmune and Inflammatory Disorders

Certain immune-mediated diseases can lead to chronic ocular surface inflammation, resulting in progressive corneal nerve damage.[25] Sjögren syndrome, a chronic autoimmune disease affecting the lacrimal glands and ocular surface, causes severe dry eye disease (DED) and progressive corneal hypoesthesia. Persistent inflammation damages corneal nerves, contributing to neurotrophic keratitis.[26]

Severe mucocutaneous reactions in Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) lead to extensive corneal scarring and limbal stem cell deficiency, resulting in trigeminal nerve damage. Patients who survive these conditions often develop chronic ocular complications, including neurotrophic keratitis.[27] Granulomatous inflammation in diseases such as sarcoidosis, granulomatosis with polyangiitis (GPA), and systemic lupus erythematosus (SLE) can infiltrate the trigeminal nerve, disrupting corneal sensation and predisposing patients to neurotrophic keratitis.[28]

Neurotrophic keratitis arises from a complex interplay of infectious, traumatic, neurological, iatrogenic, autoimmune, and metabolic factors. The trigeminal nerve plays a critical role in preserving corneal health, and any disruption to its function can lead to corneal anesthesia, PEDs, and ulceration. Identifying the underlying cause is essential for effective management, as targeted treatment can help prevent disease progression and support corneal healing.

Comprehensive diagnosis and treatment often require an interprofessional approach involving ophthalmologists, neurologists, rheumatologists, and infectious disease specialists. Advances in neurodegenerative therapies, corneal neurotization techniques, and NGF treatments hold promise for improving long-term outcomes in patients with neurotrophic keratitis.[29]

Epidemiology

Neurotrophic keratitis is a rare disease with an estimated prevalence of less than 5 per 10,000. The condition affects approximately 6% of herpetic keratitis cases, 12.8% of herpes zoster keratitis cases, and 2.8% of patients who have undergone surgical procedures for trigeminal neuralgia. Neurotrophic keratitis is rare but often underdiagnosed due to its insidious onset and lack of significant symptoms in the early stages. This potentially sight-threatening condition results from trigeminal nerve damage, leading to reduced or absent corneal sensation and impaired corneal healing. Epidemiologic patterns vary based on underlying etiology, geographic distribution, and access to diagnostic resources. A thorough understanding of these factors is essential for improving early detection, risk stratification, and therapeutic outcomes.

Prevalence and Incidence

Neurotrophic keratitis is a rare disease with an estimated prevalence of 5 per 10,000 individuals in the general population. However, this figure may underestimate the actual burden, as the condition is often undiagnosed or misdiagnosed, particularly in patients with chronic ocular surface disease or multiple comorbidities. The incidence of neurotrophic keratitis is closely linked to the prevalence of its primary causes, including herpetic keratitis, diabetes, and ocular surgeries.

Epidemiologic studies have provided insights into the condition's impact across different populations. A European multicenter study estimated the prevalence of moderate-to-severe neurotrophic keratitis at 0.02% of the general population. In the U.S., an epidemiological survey found that neurotrophic keratitis accounts for approximately 5% of corneal ulcers requiring ophthalmologic intervention. In tertiary eye care centers, the condition is identified in 3% to 4% of nonhealing corneal ulcer cases, underscoring its significance in corneal pathology. With the rising prevalence of diabetes, HZO, and iatrogenic corneal nerve damage from refractive and ocular surgeries, the burden of neurotrophic keratitis is expected to rise in the coming years.[30]

Distribution According to Age and Sex

Neurotrophic keratitis affects individuals across all age groups, but its incidence is higher in older adults, particularly those with underlying neurological disorders, diabetes, or a history of HZO. Adults older than 60 face an increased risk due to age-related decline in corneal nerve density and a higher prevalence of systemic diseases that impair trigeminal nerve function.

Pediatric cases of neurotrophic keratitis are rare but can occur in congenital trigeminal neuropathies, genetic dysautonomias, or birth-related cranial nerve injuries. Sex distribution varies based on the underlying cause. While neurotrophic keratitis associated with diabetes and herpetic infections is slightly more common in male patients, autoimmune conditions such as Sjögren syndrome and SLE-related neurotrophic keratitis are more frequently observed in female individuals.[31]

Geographic and Regional Variation

The prevalence of neurotrophic keratitis varies across regions due to differences in risk factors, healthcare access, and genetic predisposition. Herpetic keratitis remains the leading cause worldwide, with a higher prevalence in developed nations, where HSV and VZV are frequently encountered in ophthalmic practice.

Leprosy-related neurotrophic keratitis is a major public health concern in endemic regions such as South Asia, Africa, and parts of Latin America, where Mycobacterium leprae remains a leading cause of corneal nerve damage. Diabetes-related neurotrophic keratitis is more common in industrialized nations, where rising diabetes prevalence has increased the burden of trigeminal neuropathy and corneal complications.

Chemical burn-related neurotrophic keratitis occurs more frequently in regions with greater occupational exposure to industrial chemicals, particularly in developing countries with limited protective measures. Global disparities in healthcare infrastructure further influence diagnosis and management. In low-resource settings, a lack of early diagnostic tools and advanced treatments contributes to higher rates of corneal ulceration and vision loss due to undiagnosed neurotrophic keratitis.[32]

Etiology-Specific Epidemiology

The incidence of neurotrophic keratitis is closely tied to the prevalence of its underlying conditions. Herpetic infections, diabetes, ocular surgeries, and trauma account for most cases.[33]

HSV keratitis affects approximately 1.5 million individuals globally each year, with 10% to 20% of cases progressing to neurotrophic keratitis due to trigeminal nerve damage. HZO is a leading cause of postviral neurotrophic keratitis, affecting 20% to 25% of patients with ophthalmic shingles.[34]

Diabetes affects over 500 million people worldwide, and 20% to 30% of patients with diabetes exhibit corneal nerve abnormalities. Diabetes-related corneal neuropathy is a major risk factor for neurotrophic keratitis, particularly in individuals with diabetic retinopathy and autonomic neuropathy.[35]

Corneal surgeries, including LASIK, PRK, and corneal transplants, directly damage the corneal nerve plexus and contribute to up to 10% of neurotrophic keratitis cases. Trigeminal nerve injury following neurosurgical procedures, such as microvascular decompression for trigeminal neuralgia, has been implicated in the development of neurotrophic keratitis in approximately 5% to 8% of cases.[36]

Autoimmune diseases such as Sjögren syndrome, SLE, and sarcoidosis contribute to neurotrophic keratitis by causing chronic ocular surface inflammation and progressive nerve damage. Among patients with severe DED, neurotrophic keratitis occurs in approximately 3% to 5% of those with Sjögren syndrome.

Congenital disorders, including familial dysautonomia and Moebius syndrome, lead to early-onset neurotrophic keratitis, often detected in infancy. Stroke-related neurotrophic keratitis affects approximately 2% to 4% of patients with brainstem infarcts involving the trigeminal nerve pathways.[37]

Prevalence Across Disease Stages

The progression of neurotrophic keratitis follows a defined course, with an increasing risk of corneal ulceration, infection, and vision loss if left untreated. Stage 1 (mild disease) affects approximately 50% of diagnosed patients, with many cases remaining stable through lubricating therapy and regular monitoring. Stage 2 (moderate disease) accounts for 30% to 40% of cases, characterized by PEDs that require biological therapies such as autologous serum or NGF therapy. Stage 3 (severe disease) represents 10% to 20% of diagnosed cases. Due to stromal melting and perforation, management often requires surgical intervention, including tarsorrhaphy, AMT, or corneal neurotization.[9]

The prognosis of neurotrophic keratitis depends on early diagnosis and effective management. Patients diagnosed in Stage 1 or 2 typically achieve favorable visual outcomes, while those progressing to Stage 3 face an increased risk of blindness, secondary infections, and permanent corneal scarring.

Neurotrophic keratitis is rare but underdiagnosed, with significant clinical implications. The global burden of the disease is rising, driven by increasing cases of diabetes, herpetic infections, and postsurgical corneal nerve damage. While its overall prevalence remains low compared to other corneal diseases, delayed recognition and limited awareness contribute to severe complications and vision loss.

The epidemiology of neurotrophic keratitis varies by region and etiology, with herpetic keratitis, diabetes, and ocular trauma representing the most common causes. Understanding risk factors, geographic distribution, and disease progression is essential for early intervention and improved patient outcomes. Advances in emerging therapies, including cenegermin, corneal neurotization, and regenerative medicine, offer the potential to improve prognosis and long-term visual preservation in affected individuals.[38]

Pathophysiology

Corneal nerves are important in maintaining epithelial integrity, promoting proliferation, and facilitating wound healing. Corneal sensory nerve damage is believed to cause significant alterations in neuromodulator levels, leading to impaired epithelial cell vitality and metabolism. Disruptions in these processes can hinder epithelial cell mitosis, ultimately resulting in epithelial breakdown. Sensory nerve involvement also reduces the lacrimation reflex, further exacerbating corneal damage.[39]

Corneal epithelial thickness decreases in neurotrophic keratitis, with affected epithelial cells exhibiting intracellular swelling, microvilli loss, and abnormal basal lamina production. These morphological and metabolic disturbances contribute to persistent or recurrent epithelial defects, which may progress to corneal ulceration, stromal melting, and perforation. Various chemical mediators are implicated in the pathogenesis of neurotrophic keratitis, including NGF, substance P, neuropeptide Y, calcitonin gene-related peptide, galanin, and acetylcholine.[40]

Histopathology

Histopathological changes in neurotrophic keratitis involve progressive alterations in the corneal epithelium, stroma, and nerves, with variations based on disease severity and duration. Examining the microscopic and ultrastructural changes in neurotrophic keratitis provides valuable insight into its pathophysiology, progression, and response to treatment.

Corneal Epithelium Changes

Neurotrophic keratitis initially presents with pathological changes in the corneal epithelium, which progressively worsen as the disease advances. One of the earliest histological findings is epithelial thinning, where the normal 5 to 7 cell layers of the corneal epithelium are reduced to just 1 to 2 layers. Loss of basal epithelial cell adhesion to the basement membrane leads to epithelial instability and delayed wound healing. Epithelial degeneration is characterized by cytoplasmic vacuolization, loss of cellular polarity, and nuclear pyknosis.[41]

Moderate-to-severe neurotrophic keratitis presents with epithelial erosions, denuded regions, and PEDs that fail to heal due to inadequate trophic support from corneal nerves. A hallmark histopathological feature of neurotrophic keratitis is the absence of mitotic activity in basal epithelial cells. Apoptotic cell death frequently affects both the superficial and basal epithelial layers, further compromising epithelial stability.[42]

Neurotrophic keratitis leads to an irregular, fragmented, and thickened corneal basement membrane. Defective hemidesmosome formation weakens epithelial adhesion, increasing the risk of recurrent epithelial breakdown and ulceration.[43]

Stromal Findings

The corneal stroma undergoes progressive degenerative changes, particularly in advanced stages.[44] A reduction in collagen fibril density leads to stromal thinning, while electron microscopy studies reveal fragmented and irregularly arranged collagen fibrils, contributing to corneal haze and opacification. Keratocyte density is significantly reduced, impairing stromal repair.[45]

Apoptosis and necrosis of keratocytes are prominent in moderate-to-severe neurotrophic keratitis. The absence of keratocyte proliferation results in poor stromal healing, progressive tissue loss, and corneal melting. In advanced cases, stromal liquefaction and necrosis may lead to corneal perforation. Chronic neurotrophic keratitis often leads to vascularization of the normally avascular corneal stroma, particularly in longstanding cases with chronic inflammation. Fibrotic tissue deposition, driven by increased fibroblast activity and disorganized extracellular matrix remodeling, contributes to corneal scarring.

Corneal Nerve Changes

Neurotrophic keratitis is fundamentally a disorder of nerve dysfunction, leading to profound morphological alterations in corneal nerves. One of the most striking histopathological findings is the loss of subbasal corneal nerves, with confocal microscopy studies demonstrating a 60% to 80% reduction in corneal nerve fiber density compared to healthy controls. Degeneration of the corneal nerve plexus results in a loss of trophic factors, further exacerbating epithelial and stromal damage.[46]

The remaining nerve fibers appear fragmented, swollen, and irregular, while electron microscopy reveals axonal degeneration, Schwann cell loss, and myelin breakdown. In viral infections such as HSV and VZV, inflammatory infiltrates may surround the remaining nerve fibers.[47] A key characteristic of neurotrophic keratitis is the decreased expression of crucial neurotrophic factors, including NGF, brain-derived neurotrophic factor, and substance P. The absence of neurotrophic signaling impairs epithelial proliferation, disrupts wound healing, and leads to corneal anesthesia.[48]

Tear Film and Ocular Surface Changes

The tear film composition and conjunctival epithelium are also affected in neurotrophic keratitis, contributing to ocular surface instability.[49] Histological analysis of the conjunctiva reveals a reduction in goblet cell density, leading to decreased mucin production. Altered mucin composition disrupts tear film stability, exacerbating corneal desiccation and epithelial damage.[50] Inflammatory changes in the tear film further contribute to disease progression, with increased levels of pro-inflammatory cytokines such as interleukin 1 (IL-1), tumor necrosis factor α (TNF-α), and matrix metalloproteinase 9 (MMP-9) promoting corneal nerve damage and delayed epithelial healing.[51] Dysfunction of the meibomian glands, often secondary to chronic ocular surface inflammation, leads to lipid layer abnormalities in the tear film, increasing evaporative stress on the cornea.[52]

Advanced Histopathological Findings in Severe Neurotrophic Keratitis

In late-stage neurotrophic keratitis, several histopathological alterations become prominent. Corneal melting and perforation occur due to the complete loss of epithelial and stromal layers, leaving only the Descemet membrane intact. Inflammatory cell infiltrates, including macrophages, lymphocytes, and neutrophils, are frequently observed in response to chronic corneal ulceration. Corneal neovascularization develops in cases with longstanding inflammation or trauma, further compromising corneal transparency. In some instances, secondary bacterial or fungal infections lead to corneal abscess formation.[53]

Diagnostic Correlation Using Confocal Microscopy

IVCM is a noninvasive imaging tool that visualizes histopathological changes in real time. In early-stage disease, IVCM reveals reduced nerve density, irregular nerve beading, and decreased epithelial cell reflectivity. Moderate-stage findings include significant nerve loss, keratocyte dropout, and increased stromal haze. In severe cases, IVCM detects complete loss of corneal nerves, stromal necrosis, inflammatory cell infiltration, and vascularization. These observations closely align with histopathological findings and assist in disease staging and management.

The histopathology of neurotrophic keratitis offers critical insights into disease progression, from early epithelial dysfunction to advanced corneal melting and perforation. Hallmark features include epithelial thinning, basement membrane disruption, keratocyte loss, stromal fibrosis, and profound corneal nerve degeneration. Recognizing these microscopic changes facilitates accurate diagnosis, staging, and targeted therapeutic strategies. Advances in neurotrophic therapies, corneal neurotization, and regenerative approaches hold the potential for reversing some of these alterations, improving long-term outcomes for affected individuals.[54]

Toxicokinetics

Toxicokinetics encompasses the absorption, distribution, metabolism, and excretion of toxic substances and their effects on biological tissues. In neurotrophic keratitis, toxicokinetic factors mainly involve topical ophthalmic medications, systemic drugs, environmental toxins, and metabolic disorders that contribute to corneal nerve damage, ocular surface toxicity, and impaired healing. Prolonged exposure to ocular irritants, preservatives, neurotoxic agents, and metabolic imbalances disrupts corneal homeostasis, increasing the risk of progressive corneal degeneration and epithelial breakdown.[55]

Absorption and Local Toxic Effects in Neurotrophic Keratitis

The cornea functions as a semipermeable barrier that absorbs topically applied medications and environmental toxins, which can directly contribute to corneal toxicity and neurotrophic damage. Ophthalmic drugs containing preservatives and some active ingredients can damage corneal epithelial cells, impair nerve function, and delay wound healing. BAK, a common preservative in eye drops, induces dose-dependent corneal epithelial cytotoxicity, mitochondrial dysfunction, and oxidative stress.

Chronic use of preserved glaucoma medications, such as prostaglandin analogs and β-blockers, can promote neurotrophic changes by destabilizing the tear film, increasing ocular surface inflammation, and triggering corneal nerve apoptosis. Topical anesthetic abuse (eg, proparacaine, tetracaine) leads to progressive neuroepithelial toxicity, corneal ulceration, and stromal necrosis.[56]

Systemic medications with toxicokinetic properties can also affect the corneal epithelium and nerves. Chemotherapeutic agents such as 5-fluorouracil, paclitaxel, and docetaxel contribute to corneal epithelial toxicity and reduced nerve density, increasing the risk of neurotrophic keratitis. Additionally, antidepressants, antipsychotics, and anticonvulsants that block sodium or calcium channels may impair corneal nerve function, leading to corneal anesthesia and delayed epithelial healing.[57]

Environmental and chemical exposures further contribute to corneal nerve damage. Prolonged exposure to industrial chemicals, air pollution, and UV radiation induces oxidative damage to corneal nerves. Chemical burns from acids or alkalis cause irreversible nerve injury, resulting in severe neurotrophic changes and corneal melting.[58]

Distribution of Toxic Agents in the Cornea and Tear Film

The distribution of toxic substances in the ocular microenvironment significantly influences the pathophysiology of neurotrophic keratitis. Lipophilic drugs and preservatives penetrate deeper into the corneal stroma, where they accumulate and induce chronic corneal nerve inflammation and toxicity. In contrast, hydrophilic agents, such as β-blockers and prostaglandin analogs, persist in the tear film, leading to prolonged ocular surface irritation and epithelial compromise.[59]

Chronic exposure to toxic ophthalmic agents disrupts tear film stability, altering tear osmolarity and increasing inflammatory cytokines (IL-1, TNF-α), which contribute to oxidative stress. Neuroinflammatory pathways involving reactive oxygen species (ROS) and matrix metalloproteinases (MMPs) further exacerbate corneal nerve apoptosis and delay healing.[60]

Metabolism and Biotransformation of Toxic Agents in Neurotrophic Keratitis

The corneal epithelium and stroma have limited metabolic capacity, making them susceptible to prolonged exposure to toxic substances. Unlike the liver, the cornea lacks robust enzymatic pathways for metabolizing toxic compounds, leading to prolonged retention and bioaccumulation of harmful agents. Chronic exposure to oxidative stressors overwhelms glutathione-dependent detoxification mechanisms in corneal cells, exacerbating damage to corneal nerves and epithelial cells.[61]

Systemic conditions further influence ocular metabolism. Diabetes mellitus increases oxidative stress, promotes the accumulation of glycation end products, and impairs nerve function, heightening the risk of neurotrophic keratitis. Vitamin A deficiency compromises corneal metabolism by reducing mucin production and epithelial integrity, further predisposing to corneal surface damage and neurotrophic changes.[62]

Excretion and Clearance of Toxic Agents

Tear turnover, blinking, and lacrimal drainage regulate the clearance of toxic agents from the ocular surface. Patients with neurotrophic keratitis exhibit reduced blink reflexes and impaired tear film dynamics, resulting in prolonged retention of toxic agents. Tear film stagnation extends corneal exposure to inflammatory mediators and oxidative stress, worsening corneal toxicity.[63]

Ocular surface diseases further delay drug clearance. Chronic use of ophthalmic medications in patients with DED increases drug retention, heightening the risk of toxicity. Lacrimal drainage impairment in conditions such as facial nerve palsy or Sjögren syndrome prolongs the contact time of toxic agents on the corneal surface, exacerbating corneal damage.[64]

Role of Toxicokinetics in Neurotrophic Keratitis Progression

The toxicokinetics of ophthalmic and systemic agents contribute to neurotrophic keratitis by directly damaging corneal nerves, impairing neurotrophic signaling, and inducing oxidative stress and inflammatory pathways. These mechanisms delay epithelial healing, promote stromal degradation, and disrupt tear film homeostasis, exacerbating corneal desiccation and ulcer formation. Bioaccumulation of toxic agents further leads to progressive neurodegeneration and corneal thinning.

The absorption, distribution, metabolism, and clearance of ophthalmic preservatives, systemic neurotoxic agents, metabolic disorders, and environmental toxins significantly impact corneal nerve function, epithelial healing, and ocular surface integrity. Chronic exposure to ophthalmic medications, such as BAK, anesthetics, and glaucoma drops, along with systemic neurotoxic agents and oxidative stressors, contributes to corneal neurodegeneration and impaired wound healing.

Addressing toxicokinetic factors through pharmacologic modifications, preservative-free formulations, antioxidant therapy, and neuroprotective strategies is essential for managing and preventing disease progression. Future research into ocular pharmacokinetics, neurotrophic factor modulation, and regenerative therapies may offer novel approaches to mitigating toxic effects on corneal nerves and improving outcomes in neurotrophic keratitis.

History and Physical

Neurotrophic keratitis is a rare but serious degenerative corneal disease characterized by corneal anesthesia, impaired healing, and progressive epithelial breakdown. Although clinical symptoms may be subtle or absent due to corneal sensory loss, a thorough patient history, comprehensive ocular examination, and targeted corneal sensitivity testing are essential for early detection and management.

History

The hallmark feature of neurotrophic keratitis is reduced or absent corneal sensation. A detailed patient history helps identify risk factors and underlying conditions contributing to trigeminal nerve dysfunction and corneal anesthesia.

Patients with neurotrophic keratitis rarely report symptoms and often present late in the disease course, likely due to diminished corneal sensation. However, some may initially develop redness and blurred vision. Visual impairment can result from PEDs, corneal edema, or scarring. A history of recurrent redness, eye pain, or cutaneous blistering and scarring may suggest prior herpetic infections. Additional risk factors include corneal trauma, surgery, chemical burns, prolonged use of topical medications, neurosurgical procedures, and diabetes.

Disease severity is classified into 3 stages based on the Mackie classification, with progression from stage 1 to stage 3 reflecting increasing corneal damage. Stage 1 presents with corneal epithelial changes, including a dry and cloudy epithelium, superficial punctate keratopathy, and corneal edema. Stage 2 is marked by persistent or recurrent epithelial defects, typically oval or circular in shape and most often localized to the superior half of the cornea. Stage 3 involves corneal ulceration with stromal involvement, which may lead to stromal melting and, in severe cases, corneal perforation.

The most common complaints include the following:

• Blurred vision due to PEDs, corneal edema, or scarring
• Mild redness, as inflammation is blunted by sensory loss
• Foreign body sensation, which is rare unless some sensation remains
• Increased tear film instability or DED symptoms

Severe cases may present with corneal ulceration or stromal thinning without preceding pain. Nonhealing PEDs or secondary infections may result from epithelial compromise.

Neurotrophic keratitis is often secondary to systemic or ocular conditions affecting the trigeminal nerve. The following must be carefully assessed:

• History of herpetic eye disease (HSV, HZO)
• Diabetes mellitus (peripheral neuropathy affecting corneal nerves)
• Ocular surgeries (LASIK, PRK, corneal transplantation, trigeminal nerve decompression)
• Neurological disorders (stroke, brainstem tumors, multiple sclerosis)
• Chemical or thermal burns (exposure to acids, alkalis, and temperature extremes)
• Chronic topical medication use (glaucoma drugs, anesthetic abuse, preservatives like BAK)
• Autoimmune diseases (Sjögren syndrome, sarcoidosis)
• Congenital conditions (Riley-Day syndrome, Moebius syndrome, familial dysautonomia)

Chronic use of preserved glaucoma medications, especially prostaglandin analogs, β-blockers, and carbonic anhydrase inhibitors, can lead to corneal toxicity and neurotrophic changes. Long-term corticosteroid use may suppress corneal healing. Abuse of topical anesthetics (proparacaine, tetracaine) can cause severe corneal damage and should always be ruled out.[65]

Physical Examination and Ocular Assessment

A detailed ocular examination is necessary to assess corneal structure, function, and nerve integrity. Visual acuity testing provides insight into disease severity. In early neurotrophic keratitis, visual acuity may remain relatively unaffected. As the disease progresses to a moderate stage, PEDs and mild corneal haze begin to impair vision. In severe cases, corneal ulceration, stromal scarring, and secondary infections can result in significant visual loss.[66]

Slit-lamp biomicroscopy is essential for staging the disease and identifying hallmark corneal changes. In stage 1, findings include punctate epithelial erosions, an irregular tear film, reduced corneal luster, and epithelial thinning without ulceration. Stage 2 is characterized by a PED with rolled edges, stromal involvement with mild haze or edema, and minimal inflammation despite evident epithelial damage. Stage 3 involves corneal ulceration, stromal melting, and thinning. In extreme cases, the Descemet membrane may bulge outward, forming a descemetocele. End-stage disease can progress to corneal perforation.[67]

Fluorescein dye application helps detect epithelial defects, ulcerations, and tear film abnormalities (see Image. Stage 1 Neurotrophic Keratitis). A delayed or absent corneal staining response suggests neurotrophic dysfunction. Additional staining techniques, such as Rose Bengal or Lissamine Green, can highlight conjunctival and epithelial irregularities.[68]

Loss or reduction of corneal sensation is the hallmark feature of neurotrophic keratitis that distinguishes it from other corneal diseases. The Cochet-Bonnet esthesiometer measures mechanical corneal sensitivity using a thin filament. This method is considered the gold standard for assessing corneal sensation. Normal corneal sensitivity corresponds to a response at a filament length of 5 to 6 cm. In early neurotrophic keratitis, sensitivity is reduced to 2 to 4 cm, while severe cases exhibit no response at 0 cm.

Alternative bedside methods include the cotton wisp test, which involves lightly touching the cornea to assess the blink response, and the dental floss test, a more standardized technique for evaluating corneal sensation. Contact lens wearers require separate corneal sensitivity assessments, as long-term lens use can diminish corneal nerve function.[69]

The Schirmer test evaluates tear production and often reveals reduced tear secretion in patients with neurotrophic keratitis. TBUT is typically shortened, reflecting tear film instability. Abnormalities in the mucin and lipid layers further contribute to corneal desiccation and impaired epithelial healing.[70]

Ancillary Diagnostic Tests

Several advanced imaging and diagnostic techniques help confirm neurotrophic keratitis and evaluate disease severity.[71] IVCM is a noninvasive imaging tool that provides real-time visualization of corneal nerves. In neurotrophic keratitis, IVCM findings include reduced subbasal nerve plexus density, nerve beading and fragmentation, and increased keratocyte apoptosis in severe cases.[72]

AS-OCT helps quantify corneal thinning and ulcer depth while also assessing stromal changes and tear film dynamics.[73] Impression cytology and biomarker analysis evaluate ocular surface inflammation and epithelial dysfunction. Patients with neurotrophic keratitis exhibit increased levels of pro-inflammatory cytokines, such as IL-1 and TNF-α, and decreased neurotrophic factors, including NGF and brain-derived neurotrophic factor.[74]

Corneal nerve imaging and analysis provide a comprehensive assessment of nerve integrity and regenerative potential. Combining corneal esthesiometry with confocal microscopy offers valuable insight into disease progression and response to treatment.[75]

Differential Diagnosis

While corneal anesthesia is pathognomonic for neurotrophic keratitis, similar clinical presentations occur in the following conditions:

• Exposure keratopathy (eg, lagophthalmos in facial nerve palsy)
• Severe DED (eg, Sjögren syndrome)
• Persistent corneal infections (eg, fungal keratitis, bacterial ulcers)
• Neurotrophic-related postsurgical complications (eg, post-LASIK dry eye vs. true neurotrophic keratitis)

A detailed history and physical examination are essential in the early detection and management of neurotrophic keratitis. Patients often lack pain perception, making clinical suspicion and objective tests, such as corneal sensitivity assessment, slit-lamp examination, and confocal microscopy, vital for accurate diagnosis. Identifying underlying risk factors, including diabetes, herpetic eye disease, prior ocular surgeries, and neurovascular conditions, enables targeted therapeutic interventions. Corneal sensitivity testing remains the cornerstone of diagnosing neurotrophic keratitis, while advanced imaging tools assist in disease staging and treatment monitoring. Early detection and an interprofessional approach are vital for preventing corneal ulceration, stromal melting, and vision-threatening complications.[76]

Evaluation

Neurotrophic keratitis is often suspected based on patient history, particularly in individuals with trigeminal impairment, PEDs or corneal ulcers, and decreased corneal sensitivity. Evaluating systemic diseases such as diabetes mellitus, medication use (eg, neuroleptics), and corneal risk factors (eg, contact lens misuse and chemical burns) is essential. A clinical assessment of cranial nerve function can help localize the site of the lesion. The presence of 7th or 8th nerve palsy may suggest an acoustic neuroma or surgical resection affecting the trigeminal nerve, while 3rd, 4th, and 6th cranial nerve involvement may indicate cavernous sinus pathology. Quantitative corneal sensitivity testing using a Cochet-Bonnet or no-contact gas esthesiometer provides an objective measure of sensory impairment.

A slit-lamp examination is crucial for identifying characteristic corneal lesions and sectoral iris atrophy, which is often associated with herpetic infections. If an ulcer is present, a microbiological evaluation is necessary to rule out an infection. A dilated fundus examination may reveal a pale or swollen optic disc in cases where intracranial tumors compress the trigeminal nerve. Assessing tear film function is also important, as reduced corneal sensitivity can alter the tear film and contribute to a cycle of worsening ocular surface health. Eyelid evaluation is necessary for both diagnostic and prognostic purposes, as conditions such as lagophthalmos can exacerbate neurotrophic keratitis.

The differential diagnosis of neurotrophic keratitis includes several other ocular conditions that may present with similar clinical features, such as the following:

• Bacterial keratitis
• Corneal mucus plaques
• DED
• HSV or VZV infection
• Keratoconjunctivitis
• Postoperative corneal melt
• Sjogren syndrome

A systematic clinical assessment, including history-taking, corneal sensitivity testing, slit-lamp examination, and advanced imaging, is essential for evaluating neurotrophic keratitis. Patients often lack significant symptoms due to corneal anesthesia. Therefore, early detection relies on a high index of suspicion and objective diagnostic testing to stage the disease and guide management.

Clinical Examination and Ocular Assessment

The cornerstone of neurotrophic keratitis evaluation is a detailed ocular examination focusing on corneal integrity, nerve function, and disease staging. Visual acuity testing helps assess disease severity. In stage 1, vision may remain normal or slightly reduced due to minor epithelial irregularities. Stage 2 presents with decreased vision caused by PEDs, mild corneal haze, or an irregular tear film. In stage 3, vision is markedly impaired due to corneal ulceration, stromal melting, scarring, or secondary infection.

Corneal sensation testing is an essential step for diagnosing neurotrophic keratitis, as loss or significant reduction in corneal sensation differentiates the condition from other causes of corneal ulceration. The Cochet-Bonnet esthesiometer measures corneal mechanical sensitivity using a nylon filament. A normal response occurs at 5 to 6 cm, while early neurotrophic keratitis shows reduced sensitivity (2–4 cm), and severe disease results in no response at 0 cm. Alternative bedside methods include the cotton wisp test, which assesses the blink reflex by lightly touching the cornea, and the dental floss test, which provides a standardized sensory evaluation for corneal anesthesia.

Slit-lamp biomicroscopy helps stage neurotrophic keratitis and identify structural damage. In stage 1, punctate epithelial erosions, tear film instability, and corneal haze are observed. Stage 2 is characterized by a PED with rolled edges, stromal involvement, and corneal thinning. Stage 3 presents with corneal ulceration, stromal melting, descemetocele formation, or perforation.[77]

Fluorescein staining and tear film analysis aid in detecting epithelial defects, delayed wound healing, and ulceration. A reduced or absent staining response suggests corneal anesthesia and neurotrophic dysfunction. Rose Bengal or Lissamine Green staining highlights conjunctival involvement.[78]

The Schirmer test and TBUT further assess tear function. The Schirmer test often reveals reduced tear production in neurotrophic keratitis patients, while a shortened TBUT indicates tear film instability, which can exacerbate ocular surface stress.[79]

Advanced Imaging and Diagnostic Modalities

Several imaging techniques aid in evaluating neurotrophic keratitis severity, nerve integrity, and disease progression.[80] IVCM provides real-time visualization of corneal nerve damage. Findings in neurotrophic keratitis include reduced subbasal nerve plexus density, fragmented and beaded nerve fibers, and keratocyte apoptosis in moderate-to-severe disease.[81] AS-OCT offers high-resolution corneal imaging to assess epithelial integrity, stromal thinning, and ulcer depth. This technique is valuable for quantifying disease progression and monitoring treatment response.

Impression cytology and biomarker analysis help detect ocular surface inflammation and epithelial abnormalities. Elevated levels of IL-1 and TNF-α, along with reduced NGF, suggest chronic neurotrophic disease.[82]

A systematic evaluation incorporating history, corneal sensitivity testing, slit-lamp examination, and advanced imaging is crucial for early detection, disease staging, and appropriate management. Neurotrophic keratitis should always be suspected in patients with nonhealing corneal defects and reduced corneal sensation. Prompt diagnosis and intervention can prevent severe complications such as corneal perforation and vision loss.

Treatment / Management

Overview

Early diagnosis, treatment, and careful monitoring of patients with neurotrophic keratitis are mandatory to achieve epithelial healing and prevent the progression of corneal damage. Preservative-free artificial tears may help improve the corneal surface at all stages of disease severity. In cases of stromal melting, topical collagenase inhibitors such as N-acetylcysteine, along with systemic administration of tetracycline or medroxyprogesterone, may be considered. The use of topical antibiotic eye drops is recommended in stages 2 and 3 to prevent infection. Topical NGF and autologous serum eye drops have emerged as promising treatments for neurotrophic keratopathy.[83]

Surgical treatments are reserved for refractory cases. Options include partial or total tarsorrhaphy, AMT, conjunctival flap procedures, and botulinum A toxin injection into the eyelid elevator muscle. Management strategies vary by disease stage. In stage 1, preservative-free artificial tears remain the primary treatment approach. Stage 2, characterized by PEDs, may require conjunctival flap procedures and partial tarsorrhaphy.

Stage 3, which involves corneal ulceration and risk of perforation, is managed with therapeutic contact lenses and AMT. Corneal perforations may necessitate cyanoacrylate glue application, conjunctival flap procedures, or lamellar or penetrating keratoplasty. Neurotization surgery, involving direct transfer of the supratrochlear or supraorbital nerves to the subconjunctival space, has shown promise in restoring corneal innervation.[84][85][86](B2)

The management of neurotrophic keratitis focuses on protecting the ocular surface, promoting corneal healing, preventing complications, and, when possible, restoring corneal nerve function. Treatment is stage-dependent, with mild cases managed conservatively and moderate-to-severe cases requiring advanced therapies and surgical interventions. To achieve optimal outcomes, an interprofessional approach involving ophthalmologists, neurologists, and corneal specialists is often necessary.[87]

The general principles of treatment for neurotrophic keratitis focus on reducing epithelial stress, optimizing corneal hydration, and protecting the ocular surface from trauma, desiccation, and infection. Depending on the severity of the disease, strategies to enhance epithelial healing involve both pharmacologic and surgical interventions. In select cases, efforts to restore corneal nerve function may be considered to improve long-term outcomes.[88]

Treatment for Mild Neurotrophic Keratitis

Treatment for mild neurotrophic keratitis focuses on improving ocular surface hydration, stabilizing the tear film, and promoting epithelial healing. Lubrication therapy is the cornerstone of treatment, with frequent use of preservative-free artificial tears, typically administered hourly. Gel-based or lipid-based tear substitutes may offer better retention and protection. Autologous serum eye drops (ASED) or PRP, rich in epithelial growth factors, cytokines, and vitamins, are often used 4 to 6 times daily to enhance corneal healing.[89](B3)

Tear film protection is crucial for management. Punctal occlusion, either temporary or permanent, helps improve tear retention and ocular surface hydration. Depending on individual needs, silicone punctal plugs or thermal cautery may be used. Moisture chamber goggles provide an additional protective measure by reducing tear evaporation and minimizing ocular surface stress.[90]

Toxic medications must be discontinued to prevent further corneal damage. Preserved eye drops, such as glaucoma medications containing BAK, should be avoided. Chronic topical anesthetics must be discontinued due to their highly toxic effects on corneal nerves. Long-term corticosteroids should be reduced or eliminated, as they impair epithelial healing.

NGF therapy with cenegermin, an FDA-approved recombinant human NGF, offers a targeted approach to stimulate corneal nerve regeneration. This therapy is particularly beneficial for stage 1 and stage 2 neurotrophic keratitis, helping prevent disease progression. Cenegermin is administered 6 times daily for 8 weeks to enhance corneal healing and nerve function recovery.[91]

Treatment for Moderate Neurotrophic Keratitis

Treatment for moderate neurotrophic keratitis focuses on promoting epithelial healing, preventing corneal ulceration, and protecting the ocular surface. Biological therapy is key to management, with AMT offering anti-inflammatory, anti-scarring, and epithelial growth-promoting effects. This treatment can be applied as a self-retaining cryopreserved amniotic membrane, such as ProKera, or as sutured or glued grafts for larger defects.[92] Cenegermin has proven effective in managing PEDs by stimulating nerve regeneration and epithelial healing. Serum eye drops, including autologous serum or PRP, provide additional support for nonhealing corneal epithelial defects.[93]

Protective strategies help maintain corneal integrity and reduce further damage. Soft therapeutic contact lenses, such as bandage or scleral lenses, shield the cornea from mechanical trauma while ensuring continuous hydration. Tarsorrhaphy, either temporary or permanent, serves as another protective measure by partially or completely closing the eyelids to minimize corneal exposure and desiccation. This procedure may be performed surgically or induced with botulinum toxin to achieve protective ptosis.

Treatment for Severe Neurotrophic Keratitis

Treatment for severe neurotrophic keratitis aims to prevent corneal perforation, restore structural integrity, and promote healing. Surgical interventions are often necessary for advanced disease. Tarsorrhaphy is essential in cases with severe epithelial defects and stromal thinning, providing protection and reducing desiccation. Amniotic membrane grafts serve as a critical measure in managing deep ulcers or corneal perforation risk. For larger defects, scleral or conjunctival flap surgery promotes healing by covering the damaged area.

Corneal neurotization, an emerging therapy, restores nerve function by rerouting healthy nerves such as the supraorbital, infraorbital, or great auricular nerve. This technique has demonstrated promising results in corneal reinnervation. Keratoplasty, either lamellar or penetrating, is considered in cases of deep corneal scarring or perforation, though graft survival remains poor due to persistent neurotrophic dysfunction. For end-stage neurotrophic keratitis, the Boston KPro provides an option when other treatments fail. However, this intervention requires lifelong monitoring due to the risk of complications, including infection and corneal melt.

Adjunctive treatments help stabilize corneal integrity and prevent further deterioration. Topical and systemic MMP inhibitors, such as doxycycline (50 mg BID) and medroxyprogesterone 1% eye drops, help reduce corneal melting and stromal degradation. Systemic immunosuppressive therapy, including cyclosporine, tacrolimus, and biologics, is considered in neurotrophic keratitis associated with autoimmune diseases such as Sjögren syndrome and SLE.[94](B3)

Emerging and future therapies hold promise for improving outcomes in severe neurotrophic keratitis. Gene therapy research focuses on NGF gene delivery to restore corneal innervation. Corneal stem cell therapy, including mesenchymal stem cells and limbal epithelial transplantation, is under investigation for its potential to enhance corneal regeneration. Bioengineered corneal replacements, such as artificial corneas incorporating neurotrophic factors, represent another avenue for advancing corneal healing and restoring visual function.[95]

An interprofessional approach is essential for managing neurotrophic keratitis, requiring collaboration among specialists. Ophthalmologists, including cornea specialists and refractive surgeons, lead the management by assessing corneal integrity and guiding treatment. Neurologists play a crucial role in evaluating trigeminal nerve pathology, which underlies the disease. Endocrinologists contribute by addressing diabetic-related neurotrophic keratitis, while rheumatologists assist in managing cases associated with autoimmune disorders.

Overall, effective treatment hinges on stage-dependent therapy. Early intervention with NGF therapy, lubricants, and punctal occlusion helps prevent disease progression. In more advanced cases, biological and surgical options, such as AMT, tarsorrhaphy, and corneal neurotization, become necessary. Corneal neurotization offers a promising approach to restoring nerve function and improving long-term outcomes. Timely diagnosis and aggressive management of neurotrophic keratitis can significantly reduce the risk of corneal perforation and vision loss.[96]

Differential Diagnosis

Neurotrophic keratitis presents with persistent corneal epithelial defects, ulceration, and impaired healing, often without pain due to corneal sensory loss. However, several ocular surface diseases and corneal pathologies mimic this condition, leading to potential misdiagnosis and inappropriate treatment. A systematic approach to differentiating neurotrophic keratitis from similar conditions is essential for accurate diagnosis and management.

Exposure Keratopathy

Neurotrophic keratitis and exposure keratopathy share key clinical features, including epithelial defects, corneal ulceration, and ocular surface instability. Both conditions may arise in the context of facial nerve palsy, as seen in Bell palsy or acoustic neuroma, as well as eyelid malposition, such as lagophthalmos or ectropion. A reduced blink rate, commonly observed in conditions like Parkinson disease or stroke, can also contribute to their development. Key differences are summarized in Table 1 (see Table 1. Key Differences Between Neurotrophic Keratitis and Exposure Keratopathy).

Table 1. Key Differences Between Neurotrophic Keratitis and Exposure Keratopathy

Severe Dry Eye Disease

Severe DED or aqueous-deficient dry eye is often associated with Sjögren syndrome. Chronic ocular surface inflammation leads to punctate epithelial erosions and epithelial instability in both severe DED and neurotrophic keratitis. Patients with Sjögren syndrome or other autoimmune diseases may also develop PEDs. Key differences are summarized in Table 2 (see Table 2. Key Differences Between Neurotrophic Keratitis and Severe Dry Eye Disease).

Table 2. Key Differences Between Neurotrophic Keratitis and Severe Dry Eye Disease

Infectious Keratitis

Infectious keratitis, whether bacterial, viral, or fungal, shares key clinical features with neurotrophic keratitis. Both conditions can present with corneal ulceration and stromal involvement. In severe cases, patients may experience corneal thinning, melting, and an increased risk of perforation.[97][98] Key differences are summarized in Table 3 (see Table 3. Key Differences Between Neurotrophic Keratitis and Infectious Keratitis).

Table 3. Key Differences Between Neurotrophic Keratitis and Infectious Keratitis

Herpetic Keratitis

Both neurotrophic keratitis and herpetic keratitis involve trigeminal nerve impairment, leading to corneal epithelial defects and recurrent ulcers. Viral neuropathy in herpetic keratitis can result in corneal anesthesia, similar to neurotrophic keratitis. Key differences are summarized in Table 4 (see Table 4. Key Differences Between Neurotrophic Keratitis and Herpetic Keratitis).

Table 4. Key Differences Between Neurotrophic Keratitis and Herpetic Keratitis

Postsurgical Persistent Epithelial Defects

Persistent corneal epithelial defects following LASIK, PRK, and corneal transplantation may mimic those of neurotrophic keratitis. Each case involves impaired corneal healing and epithelial instability. Key differences are summarized in Table 5 (see Table 5. Key Differences Between Neurotrophic Keratitis and Postsurgical Persistent Epithelial Defects).

Table 5. Key Differences Between Neurotrophic Keratitis and Postsurgical Persistent Epithelial Defects

Neuropathic Pain Syndromes

Both neurotrophic keratitis and corneal neuropathy result from corneal nerve dysfunction. In both conditions, patients may report ocular discomfort despite minimal or absent clinical findings.[99] Key differences are summarized in Table 6 (see Table 6. Key Differences Between Neurotrophic Keratitis and Corneal Neuropathy).

Table 6. Key Differences Between Neurotrophic Keratitis and Corneal Neuropathy

Diagnosing neurotrophic keratitis requires a comprehensive patient history, corneal sensation testing, slit-lamp examination, and targeted imaging. To prevent misdiagnosis and inappropriate management, conditions such as exposure keratopathy, severe DED, herpetic keratitis, and microbial infections must be carefully excluded. Corneal sensitivity testing remains the primary differentiator in neurotrophic keratitis. Early intervention with neurotrophic support, AMT, or surgical options can prevent progression to corneal perforation.

Pertinent Studies and Ongoing Trials

Significant treatment advancements have been made for neurotrophic keratitis, particularly NGF therapy, AMT, and corneal neurotization. Several clinical trials and observational studies provide evidence supporting the efficacy of these novel interventions.

Nerve Growth Factor Therapy: The Cenegermin Trials

NGF therapy, specifically cenegermin (Oxervate™), has shown promising results in treating neurotrophic keratitis. The REPARO trial (Phase II/III, 2018) evaluated the efficacy of recombinant human NGF (cenegermin-bkbj). The results demonstrated that 72% of patients achieved complete corneal healing after 8 weeks of treatment. Additionally, long-term follow-up showed sustained corneal integrity in 80% of the responders. These findings support the conclusion that NGF therapy promotes corneal nerve regeneration and enhances epithelial healing.[100]

Meanwhile, the ongoing NGF-PATCH study is investigating the long-term benefits of NGF therapy and its role in preventing the recurrence of neurotrophic keratitis. Preliminary results indicate that NGF therapy improves corneal sensation and epithelial stability after treatment.[101]

Amniotic Membrane Transplantation Studies

The PROKERA® Clinical Trials evaluated the use of cryopreserved amniotic membrane (PROKERA) for treating moderate-to-severe neurotrophic keratitis. The results indicated that 65% to 80% of patients experienced complete healing of PEDs. In addition to promoting epithelial healing, PROKERA reduced inflammation and improved tear film stability. The study concluded that AMT may offer an effective alternative for epithelial healing in patients who do not respond to conventional therapies.[102]

The Sutureless AMT vs. Sutured AMT Trial (2022) compared the outcomes of self-retaining versus sutured amniotic membrane grafts. Findings revealed that sutureless AMT led to faster epithelial healing and improved patient comfort, highlighting its advantages over the traditional sutured method.[103]

Corneal Neurotization Trials

The Neurotrophic Keratopathy Surgical Neurotization Trial (2021) assessed the outcomes of direct nerve transfer techniques in neurotrophic keratitis. The trial demonstrated that 70% to 90% of patients experienced restoration of corneal sensation. Additionally, the procedure was shown to have significantly improved epithelial healing and reduced recurrent corneal ulcers. The study concluded that corneal neurotization is a promising approach for restoring functional corneal nerves and improving the management of neurotrophic keratitis.

Studies Involving Topical and Systemic Anti-Inflammatory Agents

The Doxycycline & Medroxyprogesterone for Corneal Melting Study (2020) explored the effects of systemic doxycycline (50 mg twice daily) and topical medroxyprogesterone 1% on stromal melting in severe neurotrophic keratitis cases. The study found that this combination significantly reduced stromal melting and recommended it for cases at high risk of corneal perforation.[104]

Future and Ongoing Research

Ongoing research into gene therapy aims to regenerate corneal nerves, with early trials conducted in animal models. Additionally, biological corneal replacements that incorporate neurotrophic factors show promise. Artificial intelligence-based monitoring systems are also being developed to detect early stages of neurotrophic keratitis using ocular surface imaging.

The evidence from clinical trials and ongoing studies underscores the effectiveness of NGF therapy, AMT, and surgical neurotization in managing neurotrophic keratitis. Future advancements in gene therapy and regenerative medicine bring optimism for restoring corneal innervation and halting the progression of this condition.

Treatment Planning

Treatment goals include the following:

• To prevent corneal complications, ie, ulceration, melting, and perforation
• To promote epithelial healing and nerve regeneration
• To restore corneal integrity and visual function

Stepwise Approach to Neurotrophic Keratitis Treatment

Patient with suspected neurotrophic keratitis

       ↓

Corneal sensation testing + Slit lamp examination

       ↓

STAGE 1: Mild neurotrophic keratitis (punctate epithelial defects)

       | → Lubrication (preservative-free tears, ointments)

       | → Autologous serum/PRP drops

       | → Punctal occlusion

       | → Discontinue toxic medications (preservatives, anesthetics)

       ↓

STAGE 2: Moderate neurotrophic keratitis  (PEDs)

       | → NGF therapy

       | → AMT (PROKERA®)

       | → Scleral/bandage contact lens

       | → Tarsorrhaphy (if severe)

       ↓

STAGE 3: Severe neurotrophic keratitis (Corneal ulceration, stromal melting)

       | → Urgent amniotic membrane graft

       | → Corneal neurotization surgery (if applicable)

       | → Boston KPro (end-stage) [105]

Table 7. Treatment Planning Based on Severity

Surgical Intervention Decision Pathway

Presence of PEDs?

   ↓

NO → Continue conservative therapy (NGF, lubrication)

   ↓

YES → Consider AMT or scleral lens

   ↓

Ulceration or stromal melting?

   ↓

NO → Monitor with NGF therapy

   ↓

YES → Consider corneal neurotization or keratoplasty

   ↓

End-stage corneal disease?

   ↓

YES → Consider Boston KPro [106]

Key Takeaways

Early intervention is critical in preventing the progression of neurotrophic keratitis to corneal perforation. NGF therapy and AMT serve as the foundation for treating moderate cases of neurotrophic keratitis. In severe cases, surgical interventions such as tarsorrhaphy, corneal neurotization, and keratoplasty should be considered. An interprofessional approach involving ophthalmologists, neurologists, and other specialists ensures improved patient outcomes by addressing all aspects of the condition. Structured treatment planning is essential for managing neurotrophic keratitis effectively and preventing vision-threatening complications.

Toxicity and Adverse Effect Management

Neurotrophic keratitis management involves various pharmacological and surgical interventions, some of which have associated toxicities and adverse effects. Recognizing and mitigating these effects are crucial to optimizing treatment outcomes.

Table 8. Adverse Effects of Pharmacologic Therapies

Table 9. Toxicities of Surgical and Biological Interventions

Strategies for Managing Toxicities and Adverse Effects

Monitoring for early signs of adverse effects is crucial during neurotrophic keratitis treatment. Regular corneal examinations and IOP monitoring help identify steroid-related complications. Additionally, frequent corneal sensitivity testing is important for patients undergoing long-term neurotrophic keratitis therapy to detect any changes in corneal nerve function.[107]

To reduce medication-related toxicity, preservative-free lubricants should be preferred to minimize irritation. The chronic use of nonsteroidal anti-inflammatory drugs (NSAIDs) or anesthetics should be avoided, as these agents can exacerbate epithelial damage.[108]

Optimizing surgical interventions is also key. Scleral contact lenses should be closely monitored for the risk of corneal hypoxia and infection. If amniotic membrane grafts show signs of nonadherence or infection, they should be replaced promptly to prevent further complications.[109]

Patient education plays an essential role in treatment adherence. Patients should be encouraged to comply with aseptic techniques when using serum eye drops. Before initiating aggressive therapies, the risks and benefits should be thoroughly discussed with the patient.[110]

Key Takeaways

Adverse effects of neurotrophic keratitis treatments must be anticipated and managed proactively. Regular follow-up is critical to detect complications early. A personalized approach that balances treatment efficacy with potential toxicities ensures the best outcomes. Addressing toxicity risks early improves treatment adherence, leading to better visual outcomes for patients with neurotrophic keratitis.

Staging

Staging neurotrophic keratitis is essential for guiding treatment and predicting disease progression. The most widely used classification system is the Mackie Classification, which divides the disorder into 3 stages based on corneal involvement and severity (see Table 10. Mackie Classification of Neurotrophic Keratitis).

Table 10. Mackie Classification of Neurotrophic Keratitis

Visual Representation of Neurotrophic Keratitis Staging

Mild neurotrophic keratitis is characterized by dry corneal epithelium, punctate erosions, and early loss of corneal sensitivity. Moderate neurotrophic keratitis demonstrates a PED accompanied by epithelial thinning and mild stromal involvement. Stage 3 represents severe neurotrophic keratitis, marked by ulceration, stromal melting, and a heightened risk of corneal perforation.

Table 11. Clinical and Management Implications Based on Staging

Key Takeaways

Early-stage neurotrophic keratitis should be managed with lubrication and neurotrophic support to maintain corneal integrity and prevent disease progression. In moderate cases, biological therapies, such as NGF and AMT, along with corneal protection strategies, become essential to promote healing. Severe neurotrophic keratitis requires urgent intervention to prevent corneal perforation and irreversible damage. Staging is vital in guiding personalized treatment, ensuring timely intervention, and reducing the risk of vision loss.

Prognosis

The prognosis of neurotrophic keratitis depends on early diagnosis, disease severity, and timely treatment. The condition progresses without intervention, resulting in epithelial breakdown, corneal ulceration, stromal melting, and eventual perforation, resulting in severe vision loss. Advances in treatment, including NGF therapy, AMT, and corneal neurotization, have significantly improved outcomes.

Table 12. Prognosis Based on Staging

Factors Influencing Prognosis

Timely diagnosis and treatment enhance corneal healing rates, reducing the risk of disease progression. NGF therapy improves corneal sensation and lowers the likelihood of worsening pathology. Corneal neurotization surgery offers long-term nerve restoration, supporting sustained epithelial healing. Adherence to treatment plays a critical role in preventing complications, as poor compliance can hinder recovery. Systemic conditions, including diabetes, HZO, and autoimmune diseases, negatively impact prognosis by further compromising corneal health.

With optimal management, many patients retain functional vision. However, untreated cases face a high risk of irreversible vision loss due to corneal scarring, perforation, or end-stage keratopathy. Emerging therapies, such as gene therapy and regenerative medicine, offer the potential for nerve restoration and visual recovery. Early diagnosis and a proactive, multimodal treatment strategy remain essential for preserving vision and preventing complications in neurotrophic keratitis.

Complications

Neurotrophic keratitis is a progressive degenerative corneal disease that, if left untreated, can lead to severe complications such as vision loss and corneal perforation. These complications result from corneal anesthesia, impaired wound healing, and PEDs.

Table 13. Major Complications of Neurotrophic Keratitis

Risk Factors for Developing Severe Complications

Delayed diagnosis allows the disease to advance, leading to irreversible damage. Poor adherence to treatment increases the likelihood of persistent corneal defects and secondary infections. Diabetes and herpetic disease heighten the risk of progressive stromal melting and ulceration. Chronic use of topical anesthetics or preservative-containing eye drops further exacerbates corneal toxicity.

Preventing Complications in Neurotrophic Keratitis

Early detection and aggressive lubrication therapy help prevent disease progression. NGF therapy enhances corneal healing and sensation. AMT supports the resolution of PEDs. In severe cases, surgical interventions, including tarsorrhaphy, neurotization, and keratoplasty, may be necessary.[111] Timely intervention and comprehensive management are essential to preventing vision-threatening complications and preserving corneal integrity in neurotrophic keratitis.