NORD gratefully acknowledges William B. Trattler, MD, Corneal and Cataract Eye Surgeon, Center For Excellence In Eye Care, Miami, FL for assistance in the preparation of this report.
Neurotrophic keratitis is a rare eye disorder that affects the cornea. The cornea is the clear (transparent) outer layer of the eye. It functions like a window that focuses the entry of light into the eye. The cornea bends light allowing it to pass through the pupil of the eye, eventually reaching the retina, where specialized cells called cones and rods convert light to nerve impulses. These impulses travel along the optic nerve to the brain to become images. Neurotrophic keratitis is caused when the nerves that serve (innervate) the cornea cannot function properly; these nerves carry impulses that help the cornea function. Neurotrophic keratitis causes reduced sensitivity of the cornea. When the cornea senses stimulation or pressure, the eyelids will close and tears will be produced to protect the cornea and the eye. Because these nerves do not function properly in neurotrophic keratitis, the outer layer of the cornea, called the epithelium, can break down, resulting in an epithelial defect. In more advanced neurotrophic keratitis, an interior layer called the cornea stroma can break down as well, resulting in thinning of the cornea. This is called stromal ‘melting’. In advanced stromal melting, the cornea can thin to a severe degree, which can result in a hole or opening to the inside of the eye, which can lead to infection and potentially loss of the eye. Neurotrophic keratitis can lead to a variety of complications, including poor wound healing of the cornea, scarring of the cornea, and loss of vision. There are many different conditions that can damage the nerves serving the cornea. A variety of therapies can be used to treat this disorder depending on how far the disorder has progressed in an individual.
Early on, affected individuals may not have any symptoms of the disorder (asymptomatic). Because the sensitivity of the cornea is reduced, affected individuals often do not complain of pain or discomfort in the eye. Blurred vision, red eyes, dry eyes, and decreased clarity (acuity) of vision can develop. Affected individuals may become extremely sensitive to light (photophobia). The affected cornea can be injured easily and it heals itself slower than an unaffected cornea does (poor wound healing). This leaves the cornea susceptible to damage. Affected individuals may experience frequent or recurrent corneal erosions, which is when an opening in the epithelial layer develops (epithelial defect). Since the epithelial layer is the protective layer of the cornea, an epithelial defect can leave the eye more susceptible to infection.
More serious complications can develop including irregular astigmatism, a condition causing blurred vision that results when the cornea becomes irregularly shaped or abnormally curved. Affected individuals may develop scarring of the cornea. As the inner layer called the stroma breaks down and becomes thinner, the cornea can become even more irregularly shaped, and more severe scarring can develop. In the most severe instances, the cornea can perforate, resulting in loss of the inner fluid of the eye. Neurotrophic keratitis can lead to permanent loss of vision if not properly treated.
Neurotrophic keratitis can be caused by any condition or disorder that affects the nerves that serve the cornea. The main nerve that serves the cornea is called the trigeminal nerve, which is also called the fifth cranial nerve. Damage to the ophthalmic division of the trigeminal nerve, which serves the cornea, can cause neurotrophic keratitis. When the nerves that serve the cornea are damaged this causes reduced sensitivity of the cornea and can lead to neurotrophic keratitis.
The cornea has no blood vessels. In order to remain wet and nourished, it must be regularly bathed with tears. Neurotrophic keratitis causes a decrease in reflex tears, which are the tears produced by the eye in response to foreign substances like dust. As corneal sensation decreases, less reflex tears are made in response to stimuli of the cornea, which can lead to the epithelium drying out and eventually breaking down.
Two common causes of neurotrophic keratitis are the herpes simplex virus I (the same virus that causes cold sores), or the herpes zoster virus (the virus that causes shingles). Surgery involving the cornea or that occurs near or around the eye can potentially damage the cornea, leading to neurotrophic keratitis. This can include surgery for cataracts, orbital surgery, laser eye surgery to correct vision problems, and corneal transplants. Surgery to treat trigeminal neuralgia can also damage the nerve and result in neurotrophic keratitis. Trigeminal neuralgia is a disorder in which affected individuals experience episodes of pain ranging from a mild, dull pain to intense, significant pain involving the trigeminal nerve. (For more information on this disorder, choose “trigeminal neuralgia” as your search term in the Rare Disease Database.)
Chronic use (or overuse) of topical medications that can cause reduced corneal sensation can lead to the development of neurotrophic keratitis. Such medications can include timolol and betaxolol, which are used to treat glaucoma; sulfacetamide, which is a topical antibiotic; as well as diclofenac sodium and ketorolac, which are topical nonsteroidal anti-inflammatories drugs or NSAIDS.
Disorders that affect the cornea can lead to neurotrophic keratitis including corneal dystrophies, a group of rare disorders in which foreign material builds up within the cornea. Lattice and granular corneal dystrophy are most often associated with neurotrophic keratitis. NORD has a separate report on these disorders. For more information, choose “corneal dystrophies” as your search term in the Rare Disease Database.
There are a variety of other cause of neurotrophic keratitis. Long term use of contact lenses, as well as chemical or physical burns of the cornea can result in neurotrophic keratitis. Sometimes, the presence of a mass or tumor near the nerves that serve the cornea can cause neurotrophic keratitis. In these situations, the tumor pushes up against the trigeminal nerve causing compression of the nerve. An example of a tumor that can cause neurotrophic keratitis is an acoustic neuroma. An acoustic neuroma is a rare benign (non-cancerous) growth that develops on the eighth cranial nerve that can sometimes grow large enough to press up against nearby nerves including the trigeminal nerve.
Certain systemic diseases can be associated with neurotrophic keratitis including multiple sclerosis, diabetes, vitamin A deficiency, and leprosy.
Neurotrophic keratitis is rare in children. When children develop the disorder, it usually occurs in association with another disorder including familial dysautonomia, Golderhar-Gorlin syndrome, Mobius syndrome, and congenital sensitivity to pain with anhidrosis. These rare disorders are present at birth (congenital). NORD has information on these disorders. For more information, choose the specific disorder name as your search term in the Rare Disease Database.
Neurotrophic keratitis is a rare disorder. One estimate places the prevalence at below 5 people per every 10,000 in the general population. Prevalence is the number of people who have a disorder in a specific population at a given time; such as how many people have neurotrophic keratitis in the United States in a given year.
A diagnosis of neurotrophic keratitis is based upon identification of characteristic symptoms, a detailed patient and family history, a thorough clinical evaluation, and a variety of specialized tests. A diagnosis should be suspected in individuals with unexplained signs of reduced corneal sensitivity and damage to the cornea.
Clinical Testing and Workup
Doctors will use a device called an esthesiometer to measure corneal sensitivity. A handheld version called a Cochet-Bonnet may be used. The device resembles a large pen and has a thin, retractable strand of fiber. Pressure can be applied to the cornea by adjusting the length of the fiber. The fiber is fully extended and then is placed against the cornea. The length of the fiber is reduced until the patient feels pressure. Then, this is repeated with the other, unaffected cornea and the results are compared.
Eye doctors will look at the cornea under magnification. This can involve coating the cornea with a harmless dye that aids microscopic examination of living tissue (vital staining). Direct examination of the cornea can reveal decreased thickness of the epithelium and other characteristic defects affecting the cornea. An eye doctor may use a slit-lamp, a device that allows an eye doctor to examine the eyes under high magnification to detect corneal changes.
A specific method to evaluate the health and function of the cornea is called in vivo confocal microscopy or IVCM. This is a noninvasive technique that permits an eye doctor to obtain high resolution images of the cornea and other structures of the eye at a cellular level.
Additional tests can be conducted to test how well the eyes create tears (lacrimal function tests), or to evaluate the limbus, which is the border of the cornea and the whites of the eyes (sclera). If foreign material (infiltrates) is found in the cornea, the substance should be tested for bacterial infection. Viral cultures or immunofluorescence may be necessary to diagnose herpes zoster or herpes simplex infection. An immunofluorescence test uses antibodies chemically linked to fluorescent dyes to identify or quantify antigens to viruses in a tissue sample.
An advance imaging (x-ray) technique called magnetic resonance imaging (MRI) may be used to rule out other conditions or to try and determine the cause of neurotrophic keratitis. An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues. An MRI of the cranial nerves can sometimes show damage or compression of the trigeminal nerve. An MRI of the brain may be ordered to rule out other conditions.
Neurotrophic keratitis can be worse in individuals who have abnormalities affecting the eyelids. The eyelids are essential for the health and function of the eye, serving to help keep the eyes lubricated by promoting tears to form and by blinking to help dislodge foreign particles that build up in the eye. Individuals who have been diagnosed with neurotrophic keratitis should be evaluated for eyelid conditions including inflammation of the eyelids (blepharitis) and the inability to close the eyelids completely (lagophthalmos). Any eyelid conditions should be treated along with neurotrophic keratitis.
After a diagnosis is confirmed, neurotrophic keratitis will be classified into one of three distinct stages. This is known as the Mackie classification. Generally, Stage 1 refers to mild disease with alterations in the health or structure of the epithelium; stage 2 refers to persistent damage to the epithelium; and stage 3 refers to severe damage including corneal ulceration and degeneration of the stromal level of the cornea.
The treatment of neurotrophic keratitis is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, surgeons, physicians who specialize in diagnosing and treating eye disorders (ophthalmologists), eye doctors who specialize in diagnosing and treating disorders of the cornea (corneal specialists), physicians who specialize in diagnosing and treating neurological disorders (neurologists), and other healthcare professionals may need to systematically and comprehensively plan treatment.
Affected individuals should stop taking topical eye medications, especially those associated with the development of neurotrophic keratitis.
In 2018, the U.S. Food and Drug Administration (FDA) approved cenegermin (Oxervate®) for the treatment of individuals with neurotrophic keratitis. Oxervate is a topical eye drop. In clinical studies, as many as 70% of affected individuals demonstrated complete corneal healing within an eight-week period of time.
Other therapies that are used to treat neurotrophic keratitis include frequent lubrication and application of artificial tears in order to keep the cornea wet and clean. This treatment is recommended for all stages of neurotrophic keratitis.
Topical antibiotic eyedrops are used to treat bacterial infection or for preventive (prophylactic) treatment of infection.
When neurotrophic keratitis worsens despite treatment, surgery may become necessary. The most common surgery used is a partial or total tarsorrhaphy. Tarsorrhaphy is a surgical procedure in which the eyelids are partially sewn together to decrease the amount of space between the upper and lower eyelids. This helps to protect the cornea and allow corneal lesions to heal. In general, this is a safe and effective procedure and can be done for a short period of time or, sometimes, may be permanent.
For corneal ulcerations that do not heal, or for people with a severely affected cornea, amniotic membrane placement may be considered. The amniotic membrane is the innermost layer of the placenta. The least invasive way to utilize amniotic membrane is to place it on the eye in the office. The most common version, called Prokera, consists of a layer of amniotic membrane sandwiched between two rings of a flexible plastic that allow the amniotic membrane material to rest directly on the cornea surface. In more advanced neurotrophic keratitis, surgeons will surgically transplant a single layer or multiple layers of the amniotic membrane onto the surface of the cornea.
Neurotrophic keratitis can be treated with special contact lenses called scleral or corneal contact lenses. The scleral lens is dome-shaped and vaults over the cornea. The scleral lens is filled with a sterile saline solution in mild cases, while more advanced lubrication solutions can be used in later stages of neurotrophic keratitis. These solutions provide lubrication to the eye and assures that the cornea remains wet and that oxygen can reach cornea. The special contact lenses promote healing of the cornea, but can increase the risk of infection.
Information on current clinical trials is posted on the Internet at https://clinicaltrials.gov/. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.
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