Neurotrophic keratitis (NK) is a

degenerative disease Degenerative disease is the result of a continuous process based on degenerative cell changes, affecting tissues or organs, which will increasingly deteriorate over time. In neurodegenerative diseases, cells of the central nervous system stop wo ...

of the

cornea The cornea is the transparent front part of the eye that covers the iris, pupil, and anterior chamber. Along with the anterior chamber and lens, the cornea refracts light, accounting for approximately two-thirds of the eye's total optical ...

caused by damage of the

trigeminal nerve In neuroanatomy, the trigeminal nerve ( lit. ''triplet'' nerve), also known as the fifth cranial nerve, cranial nerve V, or simply CN V, is a cranial nerve responsible for sensation in the face and motor functions such as biting and chew ...

, which results in impairment of corneal sensitivity, spontaneous

corneal epithelium The corneal epithelium (epithelium corneæ anterior layer) is made up of epithelial tissue and covers the front of the cornea. It acts as a barrier to protect the cornea, resisting the free flow of fluids from the tears, and prevents bacteria fro ...

breakdown, poor corneal healing and development of corneal ulceration, melting and perforation. This is because, in addition to the primary sensory role, the nerve also plays a role maintaining the integrity of the cornea by supplying it with trophic factors and regulating tissue metabolism. Neurotrophic keratitis is classified as a

rare disease A rare disease is any disease that affects a small percentage of the population. In some parts of the world, an orphan disease is a rare disease whose rarity means there is a lack of a market large enough to gain support and resources for discov ...

, with an estimated prevalence of less than 5 in 10,000 people in Europe. It has been recorded that on average, 6% of herpetic keratitis cases may evolve to this disease, with a peak of 12.8% of cases of keratitis due to

varicella zoster virus Varicella-zoster virus (VZV), also known as human herpesvirus 3 (HHV-3, HHV3) or ''Human alphaherpesvirus 3'' (taxonomically), is one of nine known herpes viruses that can infect humans. It causes chickenpox (varicella) commonly affecting chil ...

. The diagnosis, and particularly the treatment of neurotrophic keratitis are the most complex and challenging aspects of this disease, as a satisfactory therapeutic approach is not yet available.

Causes

The

lacks blood vessels and is among the most densely innervated structures of the human body. Corneal nerves are responsible for maintaining the anatomical and functional integrity of the cornea, conveying tactile, temperature and pain sensations, playing a role in the

blink reflex The corneal reflex, also known as the blink reflex or eyelid reflex, is an involuntary blinking of the eyelids elicited by stimulation of the cornea (such as by touching or by a foreign body), though it could result from any peripheral stimulus. S ...

, in wound healing and in the production and secretion of

tears Tears are a clear liquid secreted by the lacrimal glands (tear gland) found in the eyes of all land mammals. Tears are made up of water, electrolytes, proteins, lipids, and mucins that form layers on the surface of eyes. The different types of ...

. Most corneal nerve fibres are sensory in origin and are derived from the ophthalmic branch of the

. Congenital or acquired ocular and systemic diseases can determine a lesion at different levels of the trigeminal nerve, which can lead to a reduction (hypoesthesia) or loss ( anesthesia) of sensitivity of the cornea. The most common causes of loss of corneal sensitivity are viral infections (

herpes simplex Herpes simplex is a viral infection caused by the herpes simplex virus. Infections are categorized based on the part of the body infected. Oral herpes involves the face or mouth. It may result in small blisters in groups often called col ...

and

herpes zoster ophthalmicus Herpes zoster ophthalmicus (HZO), also known as ophthalmic zoster, is shingles involving the eye or the surrounding area. Common signs include a rash of the forehead with swelling of the eyelid. There may also be eye pain and redness, inflamma ...

), chemical burns, physical injuries, corneal surgery, neurosurgery, chronic use of topical medications, or chronic use of contact lenses. Possible causes also include systemic diseases such as

diabetes mellitus Diabetes, also known as diabetes mellitus, is a group of metabolic disorders characterized by a high blood sugar level ( hyperglycemia) over a prolonged period of time. Symptoms often include frequent urination, increased thirst and increased ...

, multiple sclerosis or

leprosy Leprosy, also known as Hansen's disease (HD), is a long-term infection by the bacteria ''Mycobacterium leprae'' or ''Mycobacterium lepromatosis''. Infection can lead to damage of the nerves, respiratory tract, skin, and eyes. This nerve damag ...

. Other, albeit less frequent, potential causes of the disease are: intracranial space-occupying lesions such as neuroma, meningioma and

aneurysm An aneurysm is an outward bulging, likened to a bubble or balloon, caused by a localized, abnormal, weak spot on a blood vessel wall. Aneurysms may be a result of a hereditary condition or an acquired disease. Aneurysms can also be a nidus ( ...

s, which may compress the

and reduce corneal sensitivity. Conversely, congenital conditions that may lead to this disorder are very rare.

Diagnosis

NK is diagnosed on the basis of the patient's medical history and a careful examination of the eye and surrounding area. With regard to the patient's medical history, special attention should be paid to any herpes virus infections and possible surgeries on the

, trauma, abuse of anaesthetics or chronic topical treatments, chemical burns or, use of contact lenses. It is also necessary to investigate the possible presence of

diabetes Diabetes, also known as diabetes mellitus, is a group of metabolic disorders characterized by a high blood sugar level ( hyperglycemia) over a prolonged period of time. Symptoms often include frequent urination, increased thirst and increased ...

or other systemic diseases such as multiple sclerosis. The clinical examination is usually performed through a series of assessments and tools: * General examination of cranial nerves, to determine the presence of nerve damage. * Eye examinations: # Complete eye examination: examination of the eyelids, blink rate, presence of inflammatory reactions and secretions, corneal epithelial alterations. # Corneal sensitivity test: performed by placing a cotton wad or cotton thread in contact with the corneal surface: this only allows to determine whether corneal sensitivity is normal, reduced or absent; or using an

esthesiometer An esthesiometer (British spelling aesthesiometer) is a device for measuring the tactile sensitivity of the skin (or mouth, or eye, etc.). The measure of the degree of tactile sensitivity is called aesthesiometry. The device was invented by Edward ...

that allows to assess corneal sensitivity. # Tear film function test, such as Schirmer's test, and tear film break-up time. # Fluorescein eye stain test, which shows any damage to the corneal and conjunctival epithelium

Classification

According to Mackie's classification, neurotrophic keratitis can be divided into three stages based on severity: # ''Stage I:'' characterized by alterations of the

, which is dry and opaque, with superficial punctate keratopathy and corneal oedema. Long-lasting neurotrophic keratitis may also cause hyperplasia of the epithelium, stromal scarring and neovascularization of the

. # ''Stage II:'' characterized by development of epithelial defects, often in the area near the centre of the

. # ''Stage III:'' characterized by ulcers of the

accompanied by stromal oedema and/or melting that may result in corneal perforation.

Treatment

Early diagnosis, targeted treatment according to the severity of the disease, and regular monitoring of patients with neurotrophic keratitis are critical to prevent damage progression and the occurrence of corneal ulcers, especially considering that the deterioration of the condition is often poorly symptomatic. The purpose of treatment is to prevent the progression of corneal damage and promote healing of the

. The treatment should always be personalized according to the severity of the disease. Conservative treatment is typically the best option. In stage I, the least serious, treatment consists of the administration of preservative-free artificial tears several times a day in order to lubricate and protect the ocular surface, improving the quality of the epithelium and preventing the possible loss of transparency of the

. In stage II, treatment should be aimed at preventing the development of corneal ulcers and promoting the healing of epithelial lesions. In addition to artificial tears, topical antibiotics may also be prescribed to prevent possible infections. Patients should be monitored very carefully since, being the disease poorly symptomatic, the corneal damage may progress without the patient noticing any worsening of the symptoms. Corneal contact lenses can also be used in this stage of the disease, for their protective action to improve corneal healing. In the most severe forms (stage III), it is necessary to stop the progression towards corneal perforation: in these cases, a possible surgical treatment option is

tarsorrhaphy Tarsorrhaphy is a surgical procedure in which the eyelids are partially sewn together to narrow the eyelid opening. It may be done to protect the cornea in cases of corneal exposure, as a treatment for Graves' ophthalmopathy, Möbius syndrome or ...

, i.e. the temporary or permanent closure of the eyelids by means of sutures or botulinum toxin injection. This protects the cornea, although the aesthetic result of these procedures may be difficult to accept for patients. Similarly, a procedure that entails the creation of a conjunctival flap has been shown to be effective in the treatment of chronic corneal ulcers with or without corneal perforation. In addition, another viable therapeutic option is amniotic membrane graft, which has recently been shown to play a role in stimulating

healing and in reducing vascularisation and inflammation of the ocular surface. Other approaches used in severe forms include the administration of autologous serum eye drops. Research studies have focused on developing novel treatments for neurotrophic keratitis, and several polypeptides, growth factors and neuromediators have been proposed. Studies were conducted on topical treatment with

Substance P Substance P (SP) is an undecapeptide (a peptide composed of a chain of 11 amino acid residues) and a member of the tachykinin neuropeptide family. It is a neuropeptide, acting as a neurotransmitter and as a neuromodulator. Substance P and its clo ...

and IGF-1 (insulin-like growth factor-1), demonstrating an effect on epithelial healing. Nerve Growth Factor (NGF) play a role in the epithelial proliferation and differentiation and in the survival of corneal sensory nerves. Topical treatment with murine NGF showed to promote recovery of epithelial integrity and corneal sensitivity in NK patients. Recently, a recombinant human nerve growth factor eye drop formulation has been developed for clinical use. Cenegermin, a recombinant form of human NGF, has recently been approved in

Europe Europe is a large peninsula conventionally considered a continent in its own right because of its great physical size and the weight of its history and traditions. Europe is also considered a subcontinent of Eurasia and it is located entirel ...

in an eye drop formulation for neurotrophic keratitis.
European Medicines Agency, New medicine for rare eye disease Cenegermin as an eye drop formulation for treatment of NK is approved by FDA in August 2018

References

External links