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 et.al. 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.
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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:
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:
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 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.
Impairment of corneal sensation due to damage of trigeminal nerve leads to NK, which is characterised by ocular surface disorders such as:
Based on the severity of corneal damage, Mackie (1995) classified neurotrophic keratopathy into three stages:
Stage 1: It is characterised by-
Stage 2: It is characterised by-
Stage 3: It is characterised by-
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.
Tear film evaluation:
Tear film may be quantitatively and qualitatively affected by the reduction of corneal sensitivity.
- 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.
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 in neurotrophic keratopathy may show:
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:
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:
Management should be carried out under medical supervision.
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.
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.
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.
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:
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:
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.