EyeNet Magazine / July/August 2008 / Diagnosing and Treating Neurotrophic Keratopathy

OPHTHALMIC PEARLS

Diagnosing and Treating Neurotrophic KeratopathyBy Jill R. Wells, MD, and Marc A. Michelson, MDEdited by Ingrid U. Scott, MD, MPH, Sharon Fekrat, MD, and Frederick W. Fraunfelder, MD

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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.

Clinical CausesAny 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.”)

PathophysiologyThe cornea has a high density of nerve endings from the long posterior ciliary nerves and is 100

times more sensitive than the conjunctiva. Studies have demonstrated that these sensory

neurons directly influence the integrity of the corneal epithelium. In the presence of neuronal

destruction, epithelial cells swell, lose microvilli and produce abnormal basal lamina. This can

slow or halt mitosis, which leads to epithelial breakdown.

Additional studies have defined the role of neurotransmitters in the cornea, including

acetylcholine, catecholamines, substance P, calcitonin gene-related peptide, neuropeptide Y,

intestinal peptide, galanin and methionine-enkephalin. Mitosis of epithelial cells is increased by

rising levels of intranuclear cyclic guanosine monophosphate (cGMP) and is decreased by

rising levels of intracellular cyclic adenosine monophosphate (cAMP). Acetylcholine increases

cGMP and therefore promotes epithelial growth. If this neurotransmitter is not released in the

cornea, epithelial breakdown will result. Substance P also induces the proliferation of corneal

epithelial cells.

A study in animals found that capsaicin (which depletes substance P) led to neurotrophic keratopathy, suggesting a trophic effect of substance P. In one clinical report, a patient with neurotrophic keratopathy demonstrated complete recovery after receiving a combination of substance P and insulin- like growth factor-1 eyedrops.1

Clinical FindingsNeurotrophic 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 DiagnosisThe 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.

TreatmentOnce 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). Completeepithelial 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 isneeded.2

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

Dr. Wells is an ophthalmology resident and Dr. Michelson is a clinical associate professor ofophthalmology. Both are at the University of Alabama in Birmingham.

1 Lambiase, A. et al. Curr Opinion Ophthalmol 1999;10:270–276.

2 Groos, E. Cornea 2004;94:1189–1196.

3 Bonini, S. et al. Eye 2003;17:989–995.

4 Nishida, T. et al. Jpn J Ophthalmol 2007;51(6):442–447.

Numerous EtiologiesINFECTION

Herpes simplex

Herpes zoster

Leprosy

TRIGEMINAL NERVE PALSY

Surgery (as for trigeminal neuralgia)

Neoplasia (such as acoustic neuroma)

Aneurysms

Facial trauma

CONGENITAL

Familial dysautonomia (Riley-Day syndrome)

Goldenhar-Gorlin syndrome

Möbius’ syndrome

Familial corneal hypesthesia

Congenital insensitivity to pain

with anhidrosis

SYSTEMIC DISEASE

Diabetes mellitus

Vitamin A deficiency

Multiple sclerosis

CORNEAL DYSTROPHIES

Lattice

Granular

IATROGENIC CAUSES

Contact lens wear

Trauma to the ciliary nerves

Corneal incisions

LASIK Panretinal laser photocoagulation

TOXIC CAUSES

Anesthetics

Timolol

Betaxolol

Sulfacetamide

Diclofenac sodium

Chemical burns

Carbon disulfide exposure

Hydrogen sulfide exposure

MISCELLANEOUS CAUSES

Increasing age

Adie’s pupil

Any chronic condition causing corneal epithelial

injury or inflammation

Source: Groos, E. Cornea 2004;94: 1189–1196.

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Discussed in this article:mild chemical injury

trigeminal neuralgia

herpes

acoustic neuroma

degenerative disease

diclofenac sodium

betaxololadenosine

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