Neurotrophic Keratitis

Evidence-based guide to neurotrophic keratitis (NK) — a degenerative corneal disease caused by impaired trigeminal nerve innervation leading to reduced or absent corneal sensation, epithelial breakdown, and risk of corneal perforation.

Covers the Mackie classification (Stages 1–3), corneal esthesiometry, differential diagnosis from other persistent epithelial defects, and optometric co-management with timely ophthalmology referral.

Includes referral pathways for cenegermin (recombinant nerve growth factor), amniotic membrane transplantation, and tarsorrhaphy — treatments beyond optometric scope but essential to understand for co-management.

Last updated: March 2026

Neurotrophic keratitis (NK) is a rare degenerative corneal disease caused by damage to the trigeminal nerve (cranial nerve V, ophthalmic division), resulting in impaired or absent corneal sensation. The loss of sensory innervation disrupts the trophic signalling essential for corneal epithelial integrity, tear production, and wound healing. Prevalence is estimated at fewer than 5 per 10,000 individuals globally (Bonini et al., 2003).

Common Causes of Trigeminal Damage

Herpes simplex keratitis (HSK): Most common infectious cause; direct neurotropic viral damage to corneal nerves
Herpes zoster ophthalmicus (HZO): Varicella-zoster reactivation in the ophthalmic division of CN V; NK develops in 20–50% of HZO cases (Hamrah et al., 2017)
Diabetes mellitus: Peripheral neuropathy including corneal nerve damage; corneal confocal microscopy shows reduced nerve fibre density in diabetic patients
Surgical damage: Post-LASIK, post-PRK, post-cataract surgery, post-vitreoretinal surgery; corneal nerve transection during refractive procedures
Acoustic neuroma / cerebellopontine angle tumours: Compression or surgical excision damaging the trigeminal nerve root
Chemical or thermal burns: Direct destruction of corneal nerve endings
Chronic topical medication toxicity: Long-term use of preserved eye drops (especially timolol, anesthetics, or NSAIDs) causing sub-basal nerve plexus damage
Congenital: Riley-Day syndrome (familial dysautonomia), Möbius syndrome, Goldenhar syndrome

Singapore Takeaway

Singapore has one of the highest diabetes prevalence rates globally at approximately 13% of adults aged 18–69 (MOH National Health Survey, 2022). Diabetic corneal neuropathy is an underdiagnosed contributor to NK. Additionally, Singapore's high volume of refractive surgery (LASIK/SMILE) and the ageing population with increasing herpes zoster incidence make post-surgical and post-herpetic NK clinically relevant. SNEC cornea service manages advanced NK cases, and optometrists play a crucial role in early detection through corneal sensation testing and referral for persistent epithelial defects.

The cornea is the most densely innervated tissue in the human body, with 300–600 times the nerve density of skin. The sub-basal nerve plexus, originating from the ophthalmic division of the trigeminal nerve (CN V1), provides critical sensory and trophic support to the corneal epithelium.

Mechanism of Disease

Loss of protective blink reflex: Reduced corneal sensation diminishes the afferent limb of the blink reflex, leading to inadequate lid closure and exposure
Tear film dysfunction: Trigeminal denervation reduces reflex tear secretion and alters tear composition (decreased substance P, CGRP, and nerve growth factor in tears)
Impaired epithelial trophism: Corneal nerves release neuropeptides (substance P, CGRP) and neurotrophins (NGF, BDNF) that directly stimulate epithelial cell proliferation, migration, and adhesion. Denervation halts this trophic support
Defective wound healing: Without neural signalling, the epithelium cannot mount an adequate healing response — epithelial stem cells at the limbus receive insufficient activation signals
Progressive stromal involvement: Persistent epithelial defects expose the stroma to enzymatic degradation (matrix metalloproteinases), leading to stromal thinning, melting, and ultimately perforation

The disease follows a predictable progression from punctate epitheliopathy (Stage 1) to persistent epithelial defect (Stage 2) to corneal ulcer with stromal involvement and risk of perforation (Stage 3). The hallmark clinical paradox is a "quiet eye" — significant corneal pathology with minimal or absent pain and inflammation, because the afferent sensory pathway is itself damaged.

Mackie Classification (1995) — Standard Staging System

The Mackie classification is the most widely used staging system for neurotrophic keratitis, guiding both assessment and management decisions.

Stage 1 (Epitheliopathy): Punctate epithelial erosions (fluorescein staining, typically inferior); irregular or dull corneal reflex; superficial corneal neovascularisation; rose bengal staining of conjunctiva; reduced tear break-up time. Corneal sensation is decreased. Vision may be mildly reduced.
Stage 2 (Persistent Epithelial Defect — PED): Non-healing epithelial defect, typically oval and in the upper half of the cornea; smooth, rolled (heaped) epithelial edges; surrounding stromal oedema and haze. Descemet folds may be present. No significant stromal thinning yet. Often located in the interpalpebral zone.
Stage 3 (Corneal Ulcer): Stromal involvement — ulceration with stromal thinning and melting; risk of perforation; may develop secondary infection (superinfection due to compromised epithelial barrier). Deep stromal opacification. Descemetocele formation possible. This is an ophthalmic emergency.

By Corneal Sensation Level

Mild hypoesthesia: Reduced but present corneal sensation; cotton wisp or Cochet-Bonnet esthesiometry ≤40 mm (normal ≥50 mm)
Moderate hypoesthesia: Markedly reduced sensation; Cochet-Bonnet 10–40 mm; blink reflex sluggish
Anaesthesia: Absent corneal sensation; Cochet-Bonnet 0 mm; no blink reflex to touch

Ocular Risk Factors

History of herpes simplex keratitis or herpes zoster ophthalmicus
Prior corneal or refractive surgery (LASIK, PRK, SMILE, corneal transplant)
Chronic topical medication use, especially preserved drops (timolol, anesthetics)
Chemical or thermal corneal burns
Long-term contact lens wear (may reduce corneal sensation over time)
Previous corneal or trigeminal surgery (e.g., ablation for trigeminal neuralgia)

Systemic Risk Factors

Diabetes mellitus: Peripheral neuropathy affecting corneal nerves; high prevalence in Singapore (~13% adults)
Stroke or cerebrovascular disease: Central trigeminal pathway damage
Multiple sclerosis: Demyelination of trigeminal pathways
Intracranial tumours: Acoustic neuroma, meningioma, trigeminal schwannoma compressing CN V
Leprosy: Though rare in Singapore, a recognized cause of corneal anaesthesia globally
Advanced age: Natural decline in corneal nerve density and sensation

Singapore-Specific Risk Factors

High diabetes prevalence: 13% of adults (MOH NHS 2022); diabetic corneal neuropathy is underdiagnosed
High volume of refractive surgery (LASIK/SMILE): post-surgical corneal denervation
Ageing population: increasing herpes zoster ophthalmicus incidence
Tropical climate: higher exposure to UV and environmental irritants may exacerbate surface disease

Stage 1 Signs (Epitheliopathy)

Dull, irregular corneal light reflex (loss of epithelial lustre)
Punctate epithelial erosions — scattered, often in inferior interpalpebral zone
Rose bengal or lissamine green staining of devitalised epithelial cells
Reduced tear break-up time (tear film instability)
Superficial corneal neovascularisation (early pannus)
Decreased or absent corneal sensation on esthesiometry

Stage 2 Signs (Persistent Epithelial Defect)

Oval or round epithelial defect: Typically located in the upper half or central cornea; stains brightly with fluorescein
Rolled (heaped) epithelial edges: Pathognomonic finding — loose, non-adherent epithelium piles up at defect margins
Surrounding stromal oedema: Haze and swelling around the defect
Descemet folds: Fine folds indicating stromal oedema
Characteristically "quiet" eye: Minimal conjunctival injection despite significant corneal pathology — key clinical clue

Stage 3 Signs (Corneal Ulcer)

Stromal ulceration with thinning (stromal melting)
Deep stromal opacification
Descemetocele formation (bulging of Descemet membrane through thinned stroma)
Corneal perforation (Seidel test positive — streaming fluorescein)
Possible hypopyon if secondary infection supervenes
Anterior chamber reaction (may be mild due to denervation)

Reduced or absent ocular pain — the hallmark symptom paradox; patients may have severe corneal pathology yet report little to no discomfort because the sensory nerve is damaged
Blurred vision — from epithelial irregularity, stromal oedema, or scarring; may be the primary presenting complaint
Redness (mild) — often less than expected for the severity of the corneal defect
Tearing (reflex) — paradoxically, some patients report watering despite reduced basal tear secretion
Photophobia — may be present but is often mild compared to other causes of corneal defects
Foreign body sensation (mild or absent) — in contrast to other causes of epithelial defects where foreign body sensation is typically severe
History of herpetic eye disease, diabetes, or prior surgery — often elicited on careful history taking, providing the diagnostic clue

Clinical Clue

The discrepancy between the severity of corneal findings and the mildness of symptoms is the key diagnostic clue. A patient with a large corneal defect who reports "no pain" should prompt immediate corneal sensation testing. Ask specifically about prior herpes, diabetes, and eye surgery.

Vision-Threatening Complications

Corneal perforation: The most feared outcome; stromal melting progresses to full-thickness perforation; ophthalmic emergency requiring surgical repair
Secondary microbial keratitis: Loss of epithelial barrier allows bacterial, fungal, or amoebic superinfection; may progress rapidly
Permanent corneal scarring: Stromal opacification from chronic inflammation and ulceration; reduces best-corrected visual acuity
Corneal neovascularisation: Chronic inflammation drives new blood vessel growth into the cornea, reducing clarity
Descemetocele: Advanced stromal thinning leaves only Descemet membrane; imminent perforation

Functional Complications

Irregular astigmatism from corneal scarring
Chronic dry eye exacerbation (neurotrophic tear deficiency)
Contact lens intolerance (reduced sensation paradoxically may allow overwear, causing further damage)
Recurrent epithelial breakdown despite treatment
Need for corneal transplantation (penetrating or lamellar keratoplasty) in end-stage disease

Endocrine / Metabolic

Diabetes mellitus: Diabetic peripheral neuropathy extends to corneal nerves; corneal confocal microscopy studies show reduced sub-basal nerve fibre density, length, and branch density in diabetic patients (Petropoulos et al., 2013). Prevalence of subclinical corneal neuropathy in diabetes: 30–50%
Vitamin A deficiency: Can cause corneal epithelial dysfunction and reduced sensation; rare in Singapore but relevant in regional patients

Neurological

Stroke (brainstem): Lateral medullary syndrome (Wallenberg syndrome) damages the spinal trigeminal nucleus, causing ipsilateral facial anaesthesia including cornea
Multiple sclerosis: Demyelination of trigeminal pathways; corneal hypoesthesia present in up to 30% of MS patients
Acoustic neuroma / cerebellopontine angle tumours: Compression of CN V at the brainstem; post-surgical trigeminal damage after tumour excision
Trigeminal neuralgia: The disease itself or its treatment (radiofrequency ablation, microvascular decompression, gamma knife) may damage CN V

Infectious

Herpes simplex virus (HSV): Neurotropic virus that directly infects and damages corneal nerves and trigeminal ganglion
Herpes zoster virus (VZV): Reactivation in CN V1 (ophthalmic division) causes herpes zoster ophthalmicus; 20–50% develop NK
Leprosy (Hansen disease): Mycobacterium leprae has tropism for peripheral nerves including trigeminal

Congenital / Genetic

Familial dysautonomia (Riley-Day syndrome): Autosomal recessive; absent corneal sensation from birth; IKBKAP gene mutation
Möbius syndrome: Congenital CN VI and VII palsy; may have CN V involvement
Goldenhar syndrome: Oculo-auriculo-vertebral spectrum; may include corneal anaesthesia
Congenital corneal anaesthesia: Isolated absence of corneal sensation without other neurological findings

Optometric Assessment Protocol

Detailed history: Ask specifically about prior herpes simplex or zoster eye disease, diabetes, neurological conditions, prior eye surgery (LASIK, PRK, cataract), chronic topical medication use, and facial/trigeminal surgery
Corneal sensation testing (essential): Cotton wisp test (qualitative) — gently touch the central cornea with a fine wisp of cotton and compare response between eyes. Cochet-Bonnet esthesiometer (quantitative) — nylon filament of varying length; normal ≥50 mm, hypoesthesia <40 mm, anaesthesia = 0 mm
Slit-lamp biomicroscopy: Assess corneal surface (punctate staining, epithelial defect size and shape, rolled edges, stromal haze, neovascularisation, Descemet folds, thinning)
Fluorescein staining: Highlights epithelial defects; measure PED size for monitoring; note shape (typically oval) and location
Rose bengal / lissamine green staining: Stains devitalised and dead epithelial cells; useful for Stage 1 detection
Tear film assessment: TBUT (reduced), Schirmer test (may be reduced due to reflex tear loss), tear meniscus height
Blink rate observation: Reduced blink rate or incomplete blinks in the affected eye
Seidel test: If stromal thinning is advanced — apply fluorescein and look for streaming (aqueous leak) indicating perforation

Red Flags — Urgent Ophthalmology Referral

Persistent epithelial defect not healing after 2 weeks despite preservative-free lubrication
Any stromal thinning or melting (Stage 3)
Descemetocele or positive Seidel test (perforation)
Suspicion of secondary microbial infection (infiltrate, hypopyon, mucopurulent discharge)
Worsening defect size on serial measurement despite management
Complete corneal anaesthesia with any epithelial defect
New-onset corneal hypoesthesia with no obvious ocular cause (rule out intracranial pathology)

Diagnostic Criteria

Neurotrophic keratitis is diagnosed clinically by the combination of: (1) reduced or absent corneal sensation on esthesiometry, (2) corneal epithelial changes consistent with Mackie staging, (3) a known cause of trigeminal nerve damage. It is a diagnosis of exclusion for other causes of persistent epithelial defect — infection, autoimmune disease, and chemical injury must be ruled out. There is no single confirmatory laboratory test; in vivo confocal microscopy (IVCM) showing reduced sub-basal nerve density can support the diagnosis but is not required.

Management of neurotrophic keratitis is stage-dependent. The optometrist's primary role is early detection, corneal sensation testing, Stage 1 supportive care, and timely referral for Stage 2–3 disease. Treatment of the underlying cause (where possible) should be pursued in parallel.

Stage 1 — Optometric Management

Preservative-free artificial tears: Frequent instillation (every 1–2 hours while awake); preservative-free formulations are essential to avoid further epitheliotoxicity
Preservative-free gel/ointment at night: Provides extended ocular surface protection during sleep
Discontinue toxic topical medications: Review and advise cessation of preserved eye drops where possible (coordinate with prescribing doctor)
Environmental advice: Avoid air-conditioning drafts, use humidifier, wear moisture chamber spectacles or wraparound frames
Monitor: Serial corneal sensation testing, fluorescein staining, and PED size measurement at 2–4 week intervals

Stage 2 — Refer to Ophthalmologist (Co-manage)

Stage 2 disease requires ophthalmology management. The following treatments are beyond optometric scope but important to understand for co-management and patient education:

Bandage contact lens: Therapeutic soft lens to protect the epithelial defect and promote healing; requires close monitoring for infection (ophthalmology-directed)
Autologous serum tears: Patient's own serum provides neurotrophic factors (NGF, EGF, fibronectin) that promote epithelial healing
Cenegermin (Oxervate): Recombinant human nerve growth factor (rhNGF) — the first targeted pharmacotherapy for NK; FDA/EMA approved; promotes corneal nerve regeneration and epithelial healing (Bonini et al., 2018)
Tarsorrhaphy (partial): Surgical narrowing of the palpebral fissure to reduce corneal exposure
Amniotic membrane transplantation: Provides basement membrane scaffold, anti-inflammatory and neurotrophic factors

Stage 3 — Emergency Ophthalmology Referral

Corneal gluing (cyanoacrylate) for imminent or small perforations
Emergency corneal transplantation (tectonic keratoplasty) for large perforations
Conjunctival flap for chronic non-healing ulcers
Treat secondary infection with appropriate antimicrobials (ophthalmology-directed)

Referral Triggers — When to Refer to Ophthalmology

Any Stage 2 disease (persistent epithelial defect >2 weeks)
All Stage 3 disease (corneal ulcer, stromal thinning, perforation) — URGENT/SAME-DAY
Stage 1 disease not improving after 4–6 weeks of preservative-free lubrication
Worsening epithelial defect despite compliant lubrication therapy
Suspected secondary microbial infection
Complete corneal anaesthesia (Cochet-Bonnet 0 mm) — refer regardless of stage for specialist monitoring
Unexplained unilateral corneal hypoesthesia — may indicate intracranial pathology; needs neuroimaging

Patient Education Scripts

Explaining the condition: "The nerves that supply feeling to your cornea have been damaged, which means your eye can't feel when something is wrong. Because your eye doesn't feel the damage, it can't heal itself properly. We need to protect the surface with frequent lubricating drops and monitor you closely."
Importance of compliance: "Even though your eye may not feel uncomfortable, it is very important to use your preservative-free drops regularly — at least every 1–2 hours during the day and ointment at bedtime. Missing doses can lead to worsening of the corneal surface."
Warning signs: "Please come back immediately or see your eye doctor if you notice increasing redness, discharge, or any sudden drop in vision. Because your cornea has reduced feeling, you may not feel pain even if something serious is happening — so watch for visual changes instead."

Follow-up Schedule

Stage 1 (mild): Review every 2–4 weeks; serial corneal sensation and fluorescein staining
Stage 1 (not improving): Refer at 4–6 weeks if no improvement
Stage 2: Co-manage with ophthalmologist; frequency as directed (typically weekly)
Stage 3: Ophthalmology-led; daily or every 2–3 days initially
Post-resolution: Long-term monitoring every 3–6 months; corneal sensation testing at each visit

Visual Outcome by Stage

Stage 1: Good prognosis with early detection and appropriate lubrication; epithelial surface can stabilise with preserved corneal clarity; many patients maintain useful vision with ongoing management
Stage 2: Variable; PED may heal with ophthalmology intervention (cenegermin, autologous serum, bandage CL), but risk of scarring increases with defect duration. The longer the PED persists, the worse the visual prognosis
Stage 3: Guarded to poor; corneal perforation requires emergency surgery; significant corneal scarring is common even with successful treatment; may ultimately require corneal transplantation

Factors Affecting Prognosis

Favorable: Early detection (Stage 1), identifiable and treatable underlying cause, preserved partial corneal sensation, good patient compliance with lubrication, access to cenegermin therapy
Unfavorable: Complete corneal anaesthesia, bilateral disease, underlying progressive neurological condition, concurrent exposure keratopathy (CN VII palsy), delayed presentation, poor compliance, recurrent disease

Long-term Outlook

Neurotrophic keratitis is typically a chronic, relapsing condition. Even after successful epithelial healing, the underlying nerve damage often persists, and recurrence risk remains high. Cenegermin (rhNGF) has improved outcomes significantly — the REPARO trial demonstrated complete corneal healing in 72% of patients with Stage 2–3 NK at 8 weeks (Bonini et al., 2018). Long-term monitoring and patient education are essential to prevent recurrence and detect early signs of relapse.

Condition	Key Distinguishing Feature
Dry Eye Disease (Aqueous Deficient)	Normal corneal sensation; bilateral; responds to lubrication; no persistent epithelial defect; Schirmer test markedly reduced; no rolled epithelial edges
Exposure Keratopathy (CN VII palsy)	Normal corneal sensation; lagophthalmos visible; inferior corneal staining predominates; Bell phenomenon present; history of facial nerve palsy
Recurrent Corneal Erosion Syndrome	Normal corneal sensation; history of trauma or EBMD; episodic acute pain (typically on waking); cornea heals between episodes
Infectious Keratitis (Bacterial/Fungal)	Painful red eye (unless neurotrophic); purulent discharge; dense stromal infiltrate; hypopyon common; corneal sensation usually normal unless herpetic
Limbal Stem Cell Deficiency	Corneal conjunctivalisation; vascularisation from limbus; whorl-like staining pattern; may have normal sensation; history of chemical burn, Stevens-Johnson, or aniridia

The single most important differentiating test is corneal sensation testing — reduced or absent sensation in the setting of a non-healing epithelial defect with a "quiet" eye is highly suggestive of neurotrophic keratitis. Always compare sensation between eyes.

Test corneal sensation in every patient with a non-healing epithelial defect. The cotton wisp test takes seconds and is the single most important diagnostic step. A "quiet eye" with a significant defect should trigger immediate sensation testing.
Always compare sensation between both eyes. Unilateral reduction is more clinically significant than bilateral mild reduction (which may be age-related). Document the result quantitatively where possible (Cochet-Bonnet reading).
Ask the "three Hs" in history: Herpes (simplex or zoster), Hyperglycemia (diabetes), and (surgical) History. These three categories account for the vast majority of NK cases.
Preservative-free formulations are non-negotiable. Preserved drops (especially benzalkonium chloride) are directly toxic to the already compromised corneal epithelium and nerves. Switching a patient from preserved to preservative-free tears can itself improve Stage 1 disease.
A painless corneal ulcer is not benign — it is more dangerous. The absence of pain does not mean the absence of pathology. Educate patients that vision changes, not pain, are their warning signal.
Unexplained unilateral corneal hypoesthesia without ocular cause warrants neuroimaging. It may be the first sign of an intracranial tumour (acoustic neuroma, meningioma) or demyelinating disease. Refer urgently.

Bonini S, Rama P, Olzi D, Lambiase A. Neurotrophic keratitis. Eye (Lond). 2003;17(8):989-995. doi:10.1038/sj.eye.6700616
Bonini S, Lambiase A, Rama P, et al. Phase II randomized, double-masked, vehicle-controlled trial of recombinant human nerve growth factor for neurotrophic keratitis. Ophthalmology. 2018;125(9):1332-1343. doi:10.1016/j.ophtha.2018.02.022
Mackie IA. Neuroparalytic keratitis. In: Fraunfelder FT, Roy FH, eds. Current Ocular Therapy. Philadelphia: WB Saunders; 1995:452-454.
Hamrah P, Cruzat A, Dastjerdi MH, et al. Corneal sensation and subbasal nerve alterations in patients with herpes simplex keratitis: an in vivo confocal microscopy study. Ophthalmology. 2010;117(10):1930-1936. doi:10.1016/j.ophtha.2010.07.010
Petropoulos IN, Alam U, Fadavi H, et al. Rapid automated diagnosis of diabetic peripheral neuropathy with in vivo corneal confocal microscopy. Invest Ophthalmol Vis Sci. 2014;55(4):2071-2078. doi:10.1167/iovs.13-13787
Dua HS, Said DG, Messmer EM, et al. Neurotrophic keratopathy. Prog Retin Eye Res. 2018;66:107-131. doi:10.1016/j.preteyeres.2018.04.003
Sacchetti M, Lambiase A. Diagnosis and management of neurotrophic keratitis. Clin Ophthalmol. 2014;8:571-579. doi:10.2147/OPTH.S45921
Ministry of Health Singapore. National Health Survey 2022 — Report. Singapore: MOH; 2023. Available at: www.moh.gov.sg

Related Resources

Herpes Simplex Keratitis

Most common infectious cause of neurotrophic keratitis

Dry Eye Syndrome

Key differential diagnosis — normal corneal sensation distinguishes from NK

Dry Eye Severity Calculator

Assess tear film parameters — useful for baseline NK Stage 1 assessment

Evidence Snapshots — Dry Eye

TFOS DEWS III and landmark dry eye trial summaries

Clinical Illustration

Etiology