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

OPHTHALMIC PEARLS

Diagnosing and Treating Neurotrophic Keratopathy

By Jill R. Wells, MD, and Marc A. Michelson, MD
Edited 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 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.)

Pathophysiology
The 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 Findings
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 Descemets 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.
Adies 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 scarsknown 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 workup should be considered.

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
Despite early and appropriate therapy, neurotrophic keratopathy may still progress to stage 3
disease.
Dr. Wells is an ophthalmology resident and Dr. Michelson is a clinical associate professor of
ophthalmology. Both are at the University of Alabama in Birmingham.
1
2
3
4

Lambiase, A. et al. Curr Opinion Ophthalmol 1999;10:270276.

Groos, E. Cornea 2004;94:11891196.
Bonini, S. et al. Eye 2003;17:989995.
Nishida, T. et al. Jpn J Ophthalmol 2007;51(6):442447.

Numerous Etiologies
INFECTION
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
Mbius 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
Adies pupil
Any chronic condition causing corneal epithelial
injury or inflammation

Source: Groos, E. Cornea 2004;94: 11891196.

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Discussed in this article:

mild chemical injury
trigeminal neuralgia
herpes
acoustic neuroma

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degenerative disease
diclofenac sodium
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