Neurotrophic Keratopathy

Overview

Neurotrophic keratopathy is a degenerative disease of the corneal epithelium resulting from impaired corneal innervation. A reduction in corneal sensitivity or complete corneal anesthesia is the hallmark of this disease and is responsible for producing epithelial keratopathy, ulceration and perforation. Although numerous ocular and systemic diseases may result in neurotrophic keratopathy, there is one common insult: a lesion of the trigeminal nerve (cranial nerve V) or its branches.

Patients with neurotrophic keratopathy should undergo a complete medical and surgical history, a review of medications and an ocular examination. Although the clinical diagnosis may be made without difficulty, the management of neurotrophic keratopathy can be quite challenging.

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Symptoms

• Rose bengal staining of the palpebral conjunctiva
• Increased viscosity of tear mucus
• Decreased tear break-up time
• Scattered small facets of dried epithelium
• Punctate epithelial staining with fluorescein
• Acute loss of epithelium, usually under the upper eyelid surrounding rim of loose epithelium
• Stromal edema
• Aqueous cell and flare
• edges of the defect becoming smooth and rolled with time 
• Corneal ulcer

 

Causes

Any condition affecting the trigeminal nerve or its branches can cause corneal anesthesia, resulting in neurotrophic keratopathy. The most common causes are herpes simplex and herpes zoster viral infections, followed by trigeminal neuralgia surgery and acoustic neuroma. During surgery, damage may occur to the trigeminal nucleus, root or ganglion, or to the ophthalmic branch of the nerve.

Toxicity from chronic use of topical ocular medications also may cause nerve damage and resultant corneal anesthesia. Indeed, topical anesthetics are a well-known cause of neurotrophic keratopathy. If a patient was recently diagnosed with a corneal abrasion and is a health care professional, the ophthalmologist must be suspicious for anesthetic abuse. Anesthetic abuse has also been linked to patients with psychiatric disease and/ or a history of drug abuse. Topical medications that may result in anesthesia include timolol, betaxolol, sulfacetamide and diclofenac sodium.

Another common etiology of neurotrophic keratopathy is diabetes mellitus. Diabetes either may be the primary cause of neurotrophic keratopathy or secondarily may predispose patients to this condition. Just as patients with long-standing diabetes may develop diabetic neuropathy in their hands and feet, a similar process can occur in the cornea, leading to sensory loss. Diabetic patients who undergo panretinal photocoagulation receive a secondary insult to the ciliary nerves. (For a complete list, see “Numerous Etiologies.”)

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Diagnosis

Neurotrophic keratopathy can be divided into three stages based on the Mackie classification.

Stage 1 is characterized by mild, nonspecific signs and symptoms, including rose bengal staining of the inferior palpebral conjunctiva (the earliest sign). The viscosity of the tear mucus increases. There is decreased tear break-up time, leading to dry spots on the epithelium, which then stain with fluorescein, with resultant vascularization and scarring if the progression of neurotrophic keratopathy is not halted.²

Stage 2 involves a nonhealing corneal epithelial defect. The surrounding epithelium becomes loose, and Descemet’s membrane develops folds as the stroma swells and becomes edematous. Characteristic of this stage, the defect forms a punched-out oval or circular shape. The edges of the defect may become smooth and rolled with time.

Stage 3 often ensues if stages 1 and 2 are not treated appropriately. It is characterized by stromal melting leading to perforation. The patient is often asymptomatic because of decreased corneal sensation.²

Examinations. Cranial nerve examination can help localize the cause of decreased corneal sensation. Dysfunction of cranial nerves VII and VIII may indicate an acoustic neuroma or damage from surgical resection of the lesion. Paresis of cranial nerves III, IV and VI may indicate an aneurysm or cavernous sinus pathology that also affects the trigeminal nerve. Adie’s pupil has been associated with neurotrophic keratopathy.²

The eyelids should be examined carefully for both diagnostic and prognostic information. Eyelids that do not close properly may indicate a cranial nerve VII palsy. In addition, lagophthalmos leads to epithelial exposure and accelerates progression to stage 3 disease.

Corneal sensitivity is a vital piece of information and may be measured qualitatively with a piece of twisted cotton or quantitatively with a Cochet-Bonnet esthesiometer. This device quantifies corneal sensitivity by the length of a nylon filament required to initiate a blink or patient response. The nylon filament may be extended to as long as 6 cm. One study reported that only those patients with values of 2 cm or less developed epithelial sloughing and ulceration.¹ It is important to remember that in some cases, such as herpes simplex and herpes zoster keratitis, the anesthesia of the cornea may be sectoral and therefore different quadrants of the cornea should be tested separately.

Slit-lamp and dilated funduscopic examinations must be performed in every patient and may give insight into the etiology. Corneal stromal scarring may indicate prior infection. Iris atrophy may be a sign of previous herpes infection. Dilated funduscopic examination may reveal diabetic retinopathy and/or extensive panretinal photocoagulation scars—known associations with neurotrophic keratopathy. There may be optic nerve pallor or swelling due to an intracranial tumor.

Differential Diagnosis: 

The diagnosis of neurotrophic keratopathy is generally made without difficulty based on history and examination findings. It is imperative to remember that the common finding in all cases is a decrease in corneal sensation. In stage 1 disease, punctate epithelial staining with fluorescein is a nonspecific sign and may be found in other conditions, including dry eye syndrome, blepharitis, chronic eye rubbing, exposure keratopathy, topical drug toxicity, ultraviolet keratopathy, mild chemical injury, contact lens– related disorders and corneal limbal stem cell deficiency. A careful medical and surgical history is important to sort through this differential diagnosis.

An ulcerated appearance of the cornea must raise suspicion for other causes, including infectious and immune etiologies. Appropriate cultures must be obtained and an immune work-up should be considered.

 

Prognosis

Despite early and appropriate therapy, neurotrophic keratopathy may still progress to stage 3 disease.

Treatment

Once the diagnosis of neurotrophic keratopathy is established, treatment needs to be initiated immediately to prevent progression.

Stage 1 disease is generally treated with preservative-free artificial tears and ointments as well as consideration of punctal occlusion. Any current topical medications should be discontinued if possible.

Stage 2 epithelial defect must be treated in order to prevent a corneal ulcer from developing and to promote healing. Prophylactic antibiotic drops are generally added to the preservative-free artificial tears. A lateral tarsorrhaphy may be recommended, which may be effective in closing the epithelial defect. However, if the tarsorrhaphy is released too soon, epithelial breakdown will follow.

Other treatment options include an injection of botulinum A toxin into the upper eyelid levator muscle or amniotic membrane transplantation over the epithelial defect.

Stage 3 disease demands immediate attention in order to stop the stromal lysis and prevent perforation. In cases of stromal melting, topical collagenase inhibitors such as N-acetylcysteine, tetracycline or medroxyprogesterone may be administered.³

An article in the Japanese Journal of Ophthalmology reported on patients with persistent epithelial defects due to neurotrophic keratopathy. Patients were treated for 28 days with a substance P-derived peptide (FGLM)-amide and insulin-like growth factor (IGF-1). Complete epithelial resurfacing was achieved in eight of nine patients with no adverse effects.⁴

Corneas that appear to be very thin despite lubrication and tarsorrhaphy often require cyanoacrylate glue and a bandage contact lens. If perforation has already occurred, glue may be applied if the defect is less than 2 mm; otherwise a lamellar or penetrating keratoplasty is needed.²