Neurotrophic Keratopathy : Symptoms, Causes, Diagnosis and Management

Neurotrophic Keratopathy : Symptoms, Causes, Diagnosis and Management

Neurotrophic keratopathy (NK), Neurotrophic keratitis or Trigeminal neuropathic keratopathy is a rare degenerative corneal disease. It is characterised by lack of or decreased corneal sensation, corneal epithelial breakdown and impaired healing, resulting into increased susceptibility of the corneal surface to injury and compromised healing. In severe cases this can lead to stromal melting, corneal ulceration and even perforation.

Magendie (1824), first described this disease. Neurotrophic keratopathy was initially described as “neuroparalytic keratitis” and experimentally demonstrated by Magendie, who hypothesized the presence of trophic nerve fibers in the trigeminal nerve regulating tissue metabolism.

A decrease or absence of corneal sensation is the hallmark of neurotrophic keratopathy (Groos Jr EB,1997).

Corneal sensitivity is controlled by trigeminal nerve (fifth cranial nerve). Corneal nerves also provide trophic (nutritive) support and play a key role in maintaining anatomical integrity and function of the cornea, particularly of epithelium (Mϋller LJ 2003).

The cornea is supplied by the long ciliary nerve, derived via the nasociliary nerve from the ophthalmic branch of the trigeminal nerve. Any localised ocular or systemic condition which affects the nerve function along this course of the nerve (from trigeminal nucleus to the corneal nerve endings) can create corneal anaesthesia, resulting into neurotrophic keratopathy.

The cornea is one of the most richly innervated parts of the body. Corneal innervation not only provides sensations but is important in the maintenance of structure and function of the cornea. Normal innervation helps to regulate epithelial integrity, proliferation and wound healing of cornea.

The management of neurotrophic keratopathy is one of the most difficult and challenging task. Aim of therapy in neurotrophic keratopathy is prevention of disease progression, preservation of globe integrity and promotion of ocular surface repair. Prompt and aggressive treatment is important to prevent serious complications like infection, corneal ulceration, and perforation.


Patients commonly do not complain of ocular surface symptoms, since corneal sensory innervation is compromised in neurotrophic keratopathy. Therefore, patients may not seek medical advice for months or even years after the onset of the disease.

Sometimes patient may complain of blurred vision due to:

  • Irregular epithelium,
  • Scarring,
  • Corneal oedema or
  • Persistent epithelial corneal defects.

Corneal scarring may also lead to symptoms of ocular surface discomfort.


The causes of neurotrophic keratopathy are all those conditions that decrease sensitivity of cornea. The most common are herpes infections of the cornea, surgery for trigeminal neuralgia, and surgery for acoustic neuroma.

Various causes and associations of corneal anaesthesia are:

Fifth cranial nerve palsy:

  • Intracranial: Aneurysms, neoplasms, stroke.
  • Iatrogenic: Surgery for acoustic neuroma or trigeminal neuralgia.
  • Genetic: Familial dysautonomia (Riley-Day syndrome), Goldenhar-Gorlin syndrome, Möbius syndrome, familial corneal hypoaesthesia, or congenital insensitivity to pain with anhidrosis.
  • Facial trauma.


  • Viral infections: Herpes simplex and Herpes zoster.
  • Toxicity: Chemical injury, toxic keratopathy due to drugs, chronic topical anaesthesia abuse.
  • Iatrogenic: Refractive laser surgery e.g. laser in situ keratomileusis (LASIK), trauma to ciliary nerves via laser or surgery, corneal incisions.
  • Contact lens wear.
  • Chronic ocular surface injury.
  • Ocular inflammation.
  • Dark colour of eyes.
  • Increasing age.
  • Adie syndrome.
  • Thermal injury.
  • Orbital neoplasia.
  • Corneal dystrophies: Lattice, Granular.


  • Diabetes mellitus.
  • Vitamin A deficiency.
  • Leprosy.
  • Multiple sclerosis.


Corneal nerves are derived from the ophthalmic division of the trigeminal nerve, and to a lesser degree from the maxillary nerve. The limbus and peripheral cornea also receive autonomic sympathetic innervations from the superior cervical ganglion. Disruption of sensory and sympathetic pathways is thought to lead to decreased cell division.

Nerves enter middle third of corneal stroma and run forward anteriorly in a radial fashion towards the center, where they lose their myelin sheath approximately 1mm from the corneal limbus. Stromal nerves form the sub-epithelial nerve plexus between Bowman’s layer and the anterior stroma. They perforate Bowman’s layer and form the sub-basal epithelial nerve plexus, providing innervations to the basal epithelial cell layer and terminate within the superficial epithelial layers. Thin branches of sub-epithelial plexus ascend and penetrate Bowman’s layer, bending almost at a right angle to form the sub-basal nerve plexus at the basal epithelial cell layer.

The density of the sub-basal nerve plexus is reduced in NK and several predisposing disease states, including diabetes mellitus and viral keratitis. Reduced density of sub-basal nerves alters the concentration of several neuromediators and growth factors on the ocular surface. These neuromediators maintain a healthy ocular epithelial surface, in addition to altering rate of tear production. These include substance P, calcitonin gene-related peptide (CGRP), neuropeptide Y, vasoactive intestinal polypeptide, gelatine, methionine-enkephalin and acetylcholamine. Tear gland also helps in maintaining a healthy ocular surface epithelium by providing growth factors and other nutrients.

Deficiency in neuromediator reduces mitosis rates in epithelial cells, leading to epithelial thinning and surface breakdown. Limbal stem cells fail to replace central epithelium, resulting in a persistent epithelial defect. There is also a reduction in microvilli on the epithelial surface, causing poor adherence of tears to the cornea. Reduction of goblet cell density within conjunctival epithelium also alters tear composition.

Nerve growth factors (NGF) are mediators known to be essential for development and maintenance of both sympathetic and sensory nerves. NGF also produces acetylcholine and substance P. The cornea and conjunctiva have specific nerve fiber receptors that maintain normal corneal nerve density and help in preservation of the epithelium.

Normally a bidirectional interaction occurs between epithelial cells and nerve endings. Reduced corneal sensations render the corneal surface vulnerable to occult injury and decreased reflex tearing. It also appears to decrease healing rates of epithelial injury resulting in non healing epithelial defects.

Consequently, corneal sensory nerve damage impairs the neuromediator- epithelium interactions, which leads to impairment of epithelial maintenance and physiological renewal, and the development of recurrent or persistent epithelial defects.


Diagnosis of neurotrophic keratopathy is based on the clinical history, findings and evaluation of corneal sensitivity. Testing of corneal nerve sensitivity and imaging of corneal nerves aid in the management of NK patients who cannot have corneal transplantation.

Clinical history:

Clinical history should include causes that can cause local injury to corneal sensory nerves (chronic topical drug or anaesthetic abuse, previous ocular trauma or surgery, chemical injury or use of contact lenses), therapies that can cause impairment of trigeminal innervations (antihistamine, antipsychotic, and neuroleptic drugs), systemic diseases such as diabetes mellitus, and congenital diseases. Brain neoplasms and vascular accidents may damage the fifth cranial nerve or its nucleus.

Clinical presentation:

Impairment of corneal sensation due to damage of trigeminal nerve leads to NK, which is characterised by ocular surface disorders such as:

  • Superficial punctate keratopathy.
  • Dryness of cornea.
  • Cloudy corneal epithelium.
  • Corneal oedema.
  • Recurrent and/or persistent epithelial defects of cornea.
  • Stromal melting.
  • Corneal ulcers.
  • Corneal perforation.
  • Decreased blink rate.
  • Tear film instability with decreased tear film break up time (BUT).

Based on the severity of corneal damage, Mackie (1995) classified neurotrophic keratopathy into three stages:

Stage 1: It is characterised by-

  • Superficial punctate keratopathy.
  • Rose bengal staining of the inferior conjunctiva.
  • Increased viscosity of tear mucous.
  • Decrease in tear film break up time (BUT).
  • Epithelial hyperplasia and irregularity.
  • Superficial neovascularisation of cornea.
  • Stromal scarring.
  • Scattered small facets of dry epithelium (Gaule spots).
  • Dellen (saucer-shaped thinning in peripheral cornea) formation.

Stage 2: It is characterised by-

  • Epithelial defects, usually in the superior half of cornea with smooth and rolled edges.
  • Surrounding rim of loose, poorly adherent opaque and oedematous epithelium around the epithelial defect.
  • Stromal oedema.
  • Descemet membrane folds.
  • Inflammatory reaction in anterior chamber.

Stage 3: It is characterised by-

  • Corneal ulcer.
  • Stromal melting.
  • Perforation of cornea.

Clinical findings:

Cranial nerve examination:

Examination of cranial nerves two to eight, including assessment of other divisions of the trigeminal (fifth cranial) nerve, may help in localising the site of underlying pathology causing corneal anaesthesia. Paresis of the third, fourth and sixth cranial nerves may indicate an aneurysm or cavernous sinus involvement that also affects the trigeminal nerve. Dysfunction of the seventh and eighth cranial nerve may indicate damage from acoustic neuroma or its surgical removal. Suspicion of cranial nerve diseases warrant blood tests for diabetes mellitus, hypervitaminosis A and imaging of brain and/ or orbit.

Orbital and adnexal examination:

Orbital and adnexal examination assesses the protection offered to the ocular surface by the eyelids.

  • Over exposure of cornea: Over exposure of cornea may lead to dry ocular surface that may accelerate breakdown of the corneal epithelium.
  • Thyroid eye disease: Previous thyroid eye disease may produce lid retraction and proptosis.
  • Blepharitis: Blepharitis may cause inflammation of ocular surface.
  • Trigeminal nerve: Previous surgery or trauma to trigeminal nerve.
  • Seventh cranial nerve palsy: Seventh cranial nerve palsy may produce lagophthalmos and corneal exposure.
  • Blink rate: Blink rate reduction may result in failure to distribute tears evenly over the ocular surface. This may lead to secondary dryness and exposure of cornea.

Tear film evaluation:

Tear film may be quantitatively and qualitatively affected by the reduction of corneal sensitivity.

  • Schirmer’s test: Schirmer’s test evaluates tear production.
  • Tear film break up time (BUT): Tear film break up time (BUT) evaluates tear film stability.

Ocular examination:

  • Conjunctiva: Conjunctiva may show Bitot spots, which are associated with hypovitaminosis A.
  • Anterior chamber: Anterior chamber activity may lead to corneal anaesthesia due to uveitis associated with chronic inflammatory disease.
  • Dilated ocular fundus examination: Dilated ocular fundus examination may reveal diabetic retinopathy, optic nerve pallor or oedema due to raised intracranial pressure produced by an intracranial tumour.
  • Cornea: Corneal examination under slit lamp (biomicroscopy) should be conducted for assessment. Vital stains such as fluorescein sodium, rose bengal or lissamine green may be used to visualise ocular surface. Corneal examination may reveal-

– Stromal scars from previous keratitis resulting in ocular anaesthesia.

– Evidence of previous LASIK.

– Corneal epithelial defects.

– Any asymptomatic corneal dystrophy.

– Secondary bacterial infection.

Corneal sensitivity evaluation:

Corneal sensitivity evaluation is vital test to confirm the diagnosis of NK. Assessment of corneal sensitivity may be useful to assess the severity of corneal nerve impairment. A difference in corneal sensitivity in different quadrants of the cornea may indicate a local cause for anaesthesia, such as viral keratitis. It can be measured:

Qualitatively: By touching the central and peripheral part of cornea with a wisp of sterile cotton swab.

Quantitatively: By a corneal aesthesiometer.

  • Cochet- Bonnet aesthesiometer: Cochet- Bonnet aesthesiometer quantifies corneal sensitivity by the length of a nylon filament required to initiate a blink reflex or a patient response.
  • Non-contact aesthesiometer: New non-contact aesthesiometer allow the evaluation of chemical, mechanical and thermal sensitivity of the ocular surface. Belmonte non-contact aesthesiometerstimulates central cornea with a series of pulses of warmed air at multiple pressures. The lowest airflow that is able to elicit a response is identified as the mechanical threshold. The chemical detection threshold is assessed by stimulating the central cornea with a mixture of air and various concentrations of carbon dioxide (CO2) with the flow restricted to below mechanical detection threshold. Thermal sensitivity threshold is assessed by changes in temperature of airflow.

In vivo corneal confocal microscopy (IVCM):

In vivo corneal confocal microscopy is a rapid and non-invasive imaging method, which provides understanding of corneal nerve morphology in health and in ocular and systemic diseases.

ICVM studies showed a significant decrease in number of sub-basal nerve fibers, and their density significantly correlates with reduced corneal sensation.

Histological findings:

Histological findings in neurotrophic keratopathy may show:

  • Decrease in epithelial thickness with loss of surface desquamating layer.
  • Reduction of surface cell microvilli.
  • Intracellular swelling of remaining surface epithelial cells.
  • Areas of abnormal basal lamina.
  • Decreased density of conjunctival goblet cells.
  • Increased length of surface microvilli.

Impression cytology:

Impression cytology may be necessary to rule out limbal deficiency of stem cells. Corneal epithelium is positive for cytokeratin 3 and negative for cytokeratin 19, while conjunctival epithelium is negative for cytokeratin 3 and positive for cytokeratin 19. If impression cytology from limbal area shows significant cytokeratin 19 (indicate conjunctival epithelium) and little cytokeratin 3 (indicate corneal epithelium), then the impression cytology would indicate limbal stem cell deficiency.

Neurotrophic keratopathy should be differentiated from other ocular conditions with similar manifestations, such as:

Neurotrophic keratopathy may have a similar clinical appearance to other ocular surface disorders at each clinical stage. History is often helpful in diagnosis towards NK and the presence of an anaesthetic cornea on clinical assessment is a critical sign.

Stage 1 NK: Features such as superficial punctate keratopathy and tear film abnormalities may be observed in diseases like:

  • Dry eye disease.
  • Exposure keratopathy.
  • Topical drug toxicity.
  • Contact lens related disorders.
  • Mild chemical injury.
  • Blepharitis.
  • Corneal limbal stem cell deficiency (LSCD).

Clinical history, clinical features and laboratory tests help in identifying the correct diagnosis, since all of these conditions may be associated with impairment of corneal sensation.

Later stages of NK: Presence of corneal ulcers warrants exclusion of other causes, including immune and infectious, which are always present with ocular inflammation and stromal infiltration. Aetiologies to be excluded are:

  • Infective corneal ulcer: A microbiological examination is performed to exclude viral, bacterial, or fungal infection.
  • Inflammatory corneal ulcer: Immune analysis for the presence of systemic autoimmune disease may be considered for an inflammatory ulcer.
  • Toxic-related corneal ulcer: History of topical therapy is necessary for a toxic-related corneal ulcer. Any local treatment should be discontinued to exclude drugs as the cause of toxic-related corneal ulcer.
  • Traumatic epithelial defect: A history of trauma, even a mild injury, would be suggestive of a traumatic epithelial defect.
  • Recurrent corneal erosion: Patients with recurrent corneal erosion may also give history of trauma.


Neurotrophic keratopathy is one of the most difficult and challenging ocular diseases that lacks specific treatment, since no medication can improve corneal sensitivity.

Till date, the treatment of NK is still conservative and any surgical procedure aimed at restoring corneal transparency should be discouraged because of the high risk of developing corneal epithelial defect, melting, ulcers, and perforation after surgery.

The primary aim of treatment is to protect the corneal surface and to promote epithelial re-growth. Treatment must begin early to prevent the progression of corneal damage and promote epithelial healing. Specific measures taken are based on the clinical stage of the disease at the time of presentation and severity of anaesthesia.

Stage 1 disease: Therapy in stage 1 disease aim at improving epithelial quality and transparency to avoid epithelial breakdown. A review of concurrent topical and systemic medications should be undertaken to minimise the use of therapies that might predispose to NK. Ideally, stage 1 disease requires discontinuation of all topical preparations. Other ocular surface associated diseases such as dry eye disease, exposure keratopathy and limbal stem cell deficiency disease, may require specific treatment.

Medical therapy:

  • Topical artificial tears: To protect corneal epithelium and to minimise ocular surface irritation from long-term use, preservative-free topical preparations are considered for lubrication. Other topical preparations, if used for pre-existing ocular co-morbidity, may also be obtained preservative-free.
  • Eyelid hygiene: Eyelid hygiene and treatment of blepharitis improves meibomian gland function and reduces the risk of secondary infection.
  • Oral doxycycline: Oral doxycycline may be used to treat blepharitis and reduce tear concentrations of matrix metalloproteinases (MMPs). MMPs have been implicated as a contributing factor of the surface epithelium failing to heal in recurrent corneal erosion syndrome.
  • Bandage contact lens: Bandage contact lens was previously used as a temporary measure to protect the corneal surface. Bandage contact lens may introduce infection and be a risk factor for secondary infective keratitis.
  • Punctal plugs: Punctal plugs may be considered to block punctum, in order to increase tears on the ocular surface.

Surgical therapy:

  • Surgical correction: Any exposure of the corneal surface, secondary to either an eyelid defect or lid malposition, should be corrected by surgical means.
  • Limbal stem cell transplantation: Limbal stem cell transplantation may be considered in patients of NK with associated co-morbid condition of LSCD to improve the prognosis.

Stage 2 disease:  Epithelial defects should be treated to prevent the development of corneal ulcers, promote healing, and prevent the recurrence of corneal breakdown. All topical treatment for other ocular conditions should be discontinued, as there is significant risk of stromal lysis and perforation of ocular globe. While the mainstay of topical therapy is lubrication, there are several adjunctive topical therapies available to promote both corneal epithelial and nerve re-growth. Use of adjunctive therapy may be performed in combination with punctal plugging or a bandage contact lens.

Medical therapy:

  • Topical artificial tears: Like stage 1 disease, preservative-free topical artificial tears may be used to improve corneal surface.
  • Topical collagenase inhibitors: Topical collagenase inhibitors (e.g. N-acetylcysteine) may be considered to prevent stromal lysis and globe perforation.
  • Topical autologous serum eye drops: Treatment with topical autologous serum eye drops has been shown to promote epithelial regeneration and increase nerve density in the sub-basal plexus.
  • Umbilical cord serum eye drops: Umbilical cord serum eye drops have also been shown to promote healing like topical autologous serum eye drops in a similar manner. Both preparations have been found to have significantly higher concentrations of neuromediators that play a role in corneal epithelial healing than human tears.
  • Neuromediator preparations: Neuromediators and growth factors may represent a future therapeutic approach for the treatment and prevention of neurotrophic keratopathy. Preparations of individual neuromediators such as substance P in combination with insulin-like growth factor-1, epidermal growth factors, fibronectin and nerve growth factors, have been tried as a treatment of NK.
  • Injection of botulinum toxin A: Injection of botulinum toxin A into the levator muscle induces temporary ptosis, and may be considered as an alternative to lateral tarsorrhaphy.

Surgical therapy:

  • Lateral tarsorrhaphy: A lateral tarsorrhaphy may be performed to reduce the palpebral aperture, and thus the corneal exposure.
  • Palpebral spring: Palpebral spring may be used for the eyelid levator to reduce the palpebral aperture thereby preventing corneal exposure.
  • Amniotic membrane transplantation: Multilayered amniotic membrane transplantation may be utilised, more so in the management of refractory neurotrophic corneal ulcers. It is effective in promoting corneal epithelial healing and in reducing ocular surface vascularisation and inflammation.
  • Corneal neurotisation: In cases of unilateral NK, surgical replacement by corneal neurotisation of the dysfunctional nerve has been described. Branches of the contra-lateral supra-orbital and supratrochlear nerves may be attached at the limbus of the anaesthetic cornea.

Associated ocular surface conditions also require treatment. Intensive preservative-free antimicrobial therapy is used for secondary bacterial  keratitis. Topical corticosteroids reduce inflammation, but it requires close observation, as there is significant risk of precipitating stromal lysis and  ocular globe perforation.

Non-steroidal anti-inflammatory drugs (NSAIDs) are contraindicated due to their potential of causing corneal melting as a side effect from their anaesthetic properties.

Stage 3 disease: In stage 3 disease, the cornea is at significant risk of perforation. This requires immediate intervention to stop stromal lysis and prevent the perforation. In such cases, preservation of the globe integrity rather than preservation of vision takes precedence. Like stage 1 and stage 2, avoid toxic effects of topical preparations and only preservative-free topical artificial tears and prophylactic topical antibiotics may be used.

Medical therapy:

  • Topical artificial tears: Like stage 1 and stage 2 diseases, preservative-free topical artificial tears may be used to improve corneal surface.
  • Topical collagenase inhibitors: In cases of corneal melting, topical collagenase inhibitors, such as N-acetylcysteine or medroxyprogesterone may be used.
  • Corneal cyanoacrylate glue: Corneal cyanoacrylate glue application followed by insertion of a bandage contact lens may be used in the presence of small corneal perforations.

Surgical therapy:

  • Conjunctival flap: Conjunctival flap may restore ocular surface integrity and provide metabolic and mechanical support for corneal healing. This is effective for the treatment of chronic corneal ulceration with or without corneal perforation.
  • Amniotic membrane transplantation: In addition to other measures, multilayered amniotic membrane transplantation may be done to protect corneal surface.
  • Lateral Tarsorrhaphy: Lateral tarsorrhaphy is also effective in promoting corneal healing, but it provides a poor cosmetic outcome and visual function is sacrificed.
  • Lamellar and penetrating keratoplasty: Both lamellar and penetrating keratoplasty may be used for larger corneal perforations. As cases of NK are characterised by altered innervations and there is invariably limbal neovascularisation, perfoming keratoplasty is associated with a high failure rate and recurrence of an epithelial defect.
  • Boston keratoprosthesis (Kpro): Boston keratoprosthesis (Kpro) may be an alternative to keratoplasty in the treatment of an anaesthetic cornea, but the risk of device extrusion from keratolysis and inflammation must be considered prior to Kpro surgery.


It is important to stress to the patient to have frequent eye examination, since the disease often lacks signs and symptoms, and protection with preservative-free artificial tears to prevent epithelial breakdown is necessary.

Prognosis of neurotrophic keratopathy depends upon:

  • Specific cause behind impairment of corneal sensitivity.
  • The duration of the condition.
  • Degree of corneal anaesthesia or hypoesthesia.
  • Association with other ocular surface disorders such as dry eye disease, exposure keratopathy and limbal stem cell deficiency.

Prognosis of congenital NK is usually poor since no effective medical therapy is available. Most of the patients are likely to end up developing alterations in ocular surface or disease complications.

Usually more severe the corneal sensory impairment, higher is the rapidity of disease progression towards stromal lysis/ melting, perforation and loss of sight due to anatomical loss of the eye or permanent loss of corneal transparency.

Presence of associated ocular surface disease may affect the prognosis.

Even in patients that do not have complete corneal anaesthesia or associated disease, sometimes even with timely appropriate therapy, neurotrophic keratopathy may may still progress to stage 3 (e.g. corneal ulcer). Neurotrophic corneal ulcer requires prompt treatment to stop stromal lysis and corneal perforation. Corneal ulcer may develop permanent diminution of vision from ensuing corneal scarring and astigmatism, even if there is no perforation.


Anaesthetic cornea due to neurotrophic keratopathy may develop complications such as:

  • Blurred vision due to epithelial irregularity, corneal neovascularisation or corneal scarring.
  • Secondary infections leading to bacterial keratitis.
  • Corneal perforation following stromal melting or corneal ulceration.


Since there is wide range of underlying pathologies observed in neurotrophic keratopathy, there is no consistent approach possible to prevent the disease.

The most important preventive approach is the prompt identification of patients with stage 1who can be addressed with intense and continuous ocular lubrication with preservative-free artificial tears. The prevention of disease progression with the use of therapeutic bandage contact lenses is also a valid approach for small persistent epithelial defects.