Neurotrophic keratopathy

Neurotrophic keratopathy is a rare degenerative disease of the cornea that can lead to vision loss if left untreated. The hallmark of this condition is reduced or absent sensation in the cornea, making it difficult for patients to feel damage until the disease has progressed significantly.

Table of contents

• What is neurotrophic keratopathy?
• Identification codes and synonyms
• How common is this condition?
• What causes neurotrophic keratopathy?
• Signs and symptoms
• How is it diagnosed?
• Disease stages
• Treatment approaches
• Potential complications
• Associated anatomy

What is neurotrophic keratopathy?

Neurotrophic keratopathy is a degenerative disease of the cornea (the clear front surface of the eye) caused by damage to the nerves that supply sensation to this area^[1]. When the corneal nerves are damaged, the eye loses its ability to sense touch and pain, which leads to problems with healing and maintaining a healthy corneal surface^[2].

The condition was first demonstrated experimentally in 1824 by a researcher named Magendie, who initially described it as “neuroparalytic keratitis”^[1]. The corneal nerves, which branch from the trigeminal nerve (the fifth cranial nerve responsible for facial sensation), provide both feeling and important growth factors that help keep the corneal surface healthy^[7].

Without proper nerve function, the cornea becomes vulnerable to damage, develops problems with the outer layer of cells, and may eventually develop ulcers or even perforation^[3]. This is a rare but potentially sight-threatening disease that requires prompt recognition and treatment^[1].

Identification codes and synonyms

Neurotrophic keratitis

10069732

H16.2

1F00.10

C0339296

How common is this condition?

Neurotrophic keratopathy is considered a rare disease. Studies suggest it affects fewer than 5 to 10 per 10,000 people^[2][6]. In Europe, the prevalence is estimated at around 1 in 2,380 people^[3].

The condition most commonly occurs in adults, though it can rarely present in children, particularly when caused by congenital conditions^[3]. Because patients often do not feel symptoms in the early stages due to reduced corneal sensitivity, the disease may be underdiagnosed^[6].

What causes neurotrophic keratopathy?

Neurotrophic keratopathy develops when the trigeminal nerve, which provides sensation to the cornea, becomes damaged or impaired^[3]. This nerve damage can happen in many different ways, through various diseases and injuries.

Viral infections are the most common cause of neurotrophic keratopathy. Herpes simplex virus and herpes zoster virus (the virus that causes shingles) can damage corneal nerves and lead to this condition^[2][3]. Nearly 6% of people with herpetic eye infections may develop neurotrophic keratopathy^[4].

Surgeries involving the eye or brain can also damage the nerves. Eye procedures such as laser vision correction (LASIK), corneal transplantation, and certain retinal surgeries have been associated with nerve damage^[1][3]. Brain surgeries, particularly those involving the trigeminal nerve for conditions like trigeminal neuralgia or acoustic neuroma, can result in corneal nerve impairment^[3].

Chronic use of certain eye medications can be harmful to corneal nerves. Topical medications including glaucoma drops, anesthetics, antiviral medications, antibiotics, and anti-inflammatory drugs may cause corneal toxicity with prolonged use^[3]. Even preservatives in eye drops, such as benzalkonium chloride found in some artificial tears, can damage nerves over time^[1].

Several systemic diseases can affect corneal sensation. Diabetes mellitus is an important cause, as high blood sugar levels can damage nerves throughout the body, including those in the cornea^[1][3]. Multiple sclerosis, leprosy, and vitamin A deficiency are other systemic conditions that can lead to neurotrophic keratopathy^[3].

Other causes include physical trauma to the eye, chemical burns, chronic contact lens wear, chronic dry eye syndrome, and intracranial masses such as tumors or aneurysms that compress the trigeminal nerve^[1][3]. Rare congenital conditions affecting nerve development can cause neurotrophic keratopathy in children^[3].

Signs and symptoms

One of the most challenging aspects of neurotrophic keratopathy is that many patients experience few or no symptoms, especially in the early stages, because the reduced corneal sensation prevents them from feeling damage to their eyes^[1][6]. This lack of symptoms can delay diagnosis until the disease has progressed^[6].

When symptoms do occur, patients may complain of eye dryness, sensitivity to light (photophobia), or redness^[2][3]. Some people notice blurred vision or have difficulty reading for extended periods^[2]. Despite the reduced sensitivity, some patients with more advanced disease may experience ocular discomfort^[8].

Visual impairment may be present and typically worsens as the disease progresses, particularly if the defects or ulcers develop in the central part of the cornea^[3]. Corneal scarring and irregular shape can further reduce visual function^[3].

In severe cases, the disease can progress to corneal melting (thinning), perforation, and ultimately vision loss^[1][3]. Without treatment, neurotrophic keratopathy can result in blindness^[6].

How is it diagnosed?

Diagnosing neurotrophic keratopathy requires a careful combination of reviewing the patient’s medical history and performing specific eye examinations^[1][6]. An accurate history is essential, as it may reveal conditions or events that could have damaged the corneal nerves, such as previous herpes virus infections, eye surgeries, brain surgeries, diabetes, or chronic dry eye^[6].

The hallmark of diagnosis is demonstrating reduced or absent corneal sensation^[1][7]. The simplest test involves gently touching the cornea with a wisp of cotton from a cotton-tipped applicator to see if the patient blinks or reports feeling the touch^[3]. A more precise method uses a Cochet-Bonnet aesthesiometer, a device with a nylon wire that tests how much pressure is needed before the patient can feel it touching the cornea^[3].

Examination using a slit lamp (a specialized microscope for examining the eye) allows doctors to see characteristic changes in the corneal surface^[6]. Special dyes such as fluorescein, rose Bengal, or lissamine green can be applied to highlight areas where the outer layer of the cornea is damaged or missing^[3].

Additional tests may include checking tear production with a Schirmer test and measuring tear film stability with tear film break-up time tests^[3]. A dilated eye examination should be performed to check the back of the eye^[3].

Advanced imaging with in vivo confocal microscopy can directly visualize and count the corneal nerves, providing objective evidence of nerve damage^[3][6]. This technology shows reduced nerve density and absence of nerves in affected corneas^[6].

Microbiological tests may be needed to rule out infections that could be causing or complicating the corneal problems^[3].

Disease stages

Neurotrophic keratopathy is classified into three stages based on the severity of corneal damage, using the Mackie classification system^[2][3][6].

Stage 1 represents the mildest form of the disease. In this stage, patients have subtle changes to the corneal surface including punctate keratopathy (small spots of damage to the outer layer), epithelial irregularities, possible stromal scarring, and superficial blood vessel growth into the cornea^[2][3]. The outer layer of the cornea may show some dryness and cloudiness^[7].

Stage 2 is characterized by a persistent epithelial defect, meaning an area where the outer layer of the cornea has broken down and does not heal properly^[2][3]. There may also be swelling in the deeper layers of the cornea^[3].

Stage 3 is the most severe stage and involves damage to the deeper corneal tissue (stroma). This stage is marked by corneal ulceration that can progress to corneal melting or thinning, and potentially perforation (a hole through the cornea)^[2][3]. This is the most dangerous stage with the highest risk of vision loss^[7].

Some experts have suggested modifications to this classification system that incorporate specific measurements of corneal sensation and provide more detail about prognosis^[6].

Treatment approaches

Treatment for neurotrophic keratopathy focuses on protecting the eye surface, promoting healing, and preventing progression of the disease^[1][7]. The approach varies depending on the stage of disease and must address any underlying conditions that may be contributing to the problem^[7].

Stage 1 treatment focuses on maintaining moisture and protecting the corneal surface. This includes frequent use of preservative-free artificial tears to keep the eye lubricated^[2][9]. Doctors may recommend taping the eyelid at night or using punctal plugs or cautery to help retain tears on the eye surface^[2][9].

Stage 2 treatment requires more aggressive intervention. Options include placing a therapeutic contact lens to protect the damaged cornea, using autologous serum eye drops (drops made from the patient’s own blood) or allogenic serum, which contain growth factors that promote healing^[1][2]. Partial eyelid closure through a procedure called tarsorrhaphy may be performed to protect the cornea^[1][2]. Botulinum toxin injections can be used to reduce eyelid movement and protect the healing cornea^[2]. Anti-inflammatory medications may be considered in some cases^[2].

Stage 3 treatment for severe disease may require human nerve growth factor therapy, a biological treatment that helps stimulate nerve regeneration and corneal healing^[1][2]. Surgical options include amniotic membrane transplantation (placing preserved tissue over the damaged cornea to promote healing), conjunctival flap (covering the cornea with tissue from the white part of the eye), or corneal neurotization (a procedure to restore nerve function to the cornea)^[1][2][9].

It is important to address any concurrent eye problems such as exposure keratopathy, dry eye disease, or limbal stem cell deficiency, as these can negatively affect treatment outcomes^[7]. Stopping any toxic eye medications and managing underlying conditions like diabetes are also crucial^[1].

Novel therapies being studied include matrix regenerating therapy, plasma rich in growth factors, Thymosin β4, Substance P combined with insulin-like growth factor-1, and nicergoline^[2][9]. These emerging treatments represent promising future options for managing neurotrophic keratopathy^[2].

Potential complications

Without proper treatment, neurotrophic keratopathy can lead to serious complications. The most concerning is progression from early epithelial changes to persistent epithelial defects that do not heal^[1].

As the disease advances, corneal ulceration can occur, which may deepen and involve the stroma (the middle layer of the cornea)^[1]. Stromal melting or thinning is a dangerous complication where the cornea begins to dissolve, potentially leading to perforation^[1][3].

Corneal perforation, where a hole develops through the full thickness of the cornea, is a medical emergency that can result in loss of the eye’s contents and permanent blindness if not treated immediately^[1].

Other complications include growth of new blood vessels into the normally clear cornea (corneal neovascularization), which can cloud vision^[1]. Bacterial or fungal infections can develop on the already compromised corneal surface, making treatment more difficult^[1].

Progressive corneal scarring can lead to permanent loss of clarity and irregular corneal shape, causing significant visual impairment even after the acute disease is controlled^[3]. The prognosis depends on how severe the nerve impairment is and how quickly treatment is started, with early intervention associated with better outcomes^[1].

Associated anatomy

• Cornea
• Trigeminal nerve (cranial nerve V)
• Ophthalmic branch of trigeminal nerve
• Corneal epithelium
• Corneal stroma