Exposure Keratopathy

Original article
Juliet Hartford, Danielle Trief MD MsC
contributed by:
All contributors: Danielle Trief, MD MSc
Assigned editor:
Assigned status Up to Date by Juliet Hartford MS4, Danielle Trief
Review:
MD MsC on April 25, 2017.

Contents

 1 Disease Entity
o 1.1 Etiology, Pathophysiology
o 1.2 Risk Factors
 1.2.1 Lagophthalmos
 1.2.2 Proptosis
 1.2.3 Neurologic and neurotrophic disease
 1.2.4 Lid malposition
o 1.3 Primary prevention
 2 Diagnosis
o 2.1 History
o 2.2 Physical examination
o 2.3 Signs
o 2.4 Symptoms
 3 Management
o 3.1 Medical therapy
o 3.2 Surgery
o 3.3 Follow up
o 3.4 Complications
o 3.5 Prognosis
 4 References

Disease Entity

Exposure keratopathy (EK) is damage to the cornea that occurs primarily from prolonged
exposure of the ocular surface to the outside environment. EK can lead to ulceration, microbial
keratitis, and permanent vision loss from scarring.

Etiology, Pathophysiology
Figure 1: Tear film diagram. The tear film consists of three layers (although a contemporary
model proposes a gradient model rather than distinctly layered model).[1] The outermost layer
consists of lipids that are secreted by the meibomian glands. This layer is responsible for
lubrication and ensuring uniform spread of the tear film, prevention of evaporation, and
stabilization of a smooth ocular surface for refraction.[2] The aqueous layer comprises the middle
layer of the tear film and contains proteins, cytokines, growth factors, electrolytes, oxygen, and
glucose and is supplied by the main and accessory lacrimal glands.[3] The proteins in this layer
include lysozyme, lactoferrin, transferrin, ceruloplasmin, metalloproteinases, defensins, and
immunoglobulins.[4] This layer has many functions including but not limited to corneal
antimicrobial defense, lubrication, nutrition and supply of oxygen, mechanical clearance of
debris, and regulation of cellular functions.[5] Lastly, the mucinous layer, which is supplied by
both the conjunctiva and the cornea (conjunctival goblet and epithelial cells and corneal
epithelial cells) stabilizes the aqueous layer (by providing a viscous medium), maintains
attachment of the tear film to the corneal epithelium through the use of glycoproteins, and helps
uniformly distribute the tear film layer through the creation of a low surface tension
environment.[6]

Under normal circumstances, the eyelids and tear film protect the cornea, an avascular,
nonkeratinized epithelium, from trauma, desiccation, and microbial attack.[7][8] The tear film, a
composite fluid of three layers, has several important roles: it nourishes and lubricates the
cornea, aids in crisp visual acuity, and protects the cornea from bacterial invasion (Figure 1).[8]
Several factors help maintain an adequate distribution of the tear film; these include an intact
blink reflex, normal blink rate, and complete eyelid closure during sleep and blinking.[8]
Disruption to this system may lead to an epithelial defect. The corneal epithelium serves as a
barrier to the outside world through the use of tight junctions and damage to the integrity of this
structure can facilitate penetration of microbes and external debris.[8]

Risk Factors

Patients at risk for EK include those who suffer from conditions that interfere with the ability to
protect the cornea; be it via incomplete eyelid closure, inadequate blink reflex, inadequate blink
rate and/or decreased protective lubrication of the cornea. A summary of risk factors and
conditions is listed below.
Lagophthalmos

Lagophthalmos is the inability to close the eyelids completely. Because of this, a portion of the
eye remains open during a blink and during sleep, and is subject to damage from exposure. The
etiologies of lagophthalmos can be divided into the following subcategories:

• Facial nerve dysfunction (paralytic lagophthalmos)

• Eyelid dysfunction

• Excessive scar tissue or excessive eyelid removal during surgery (cicatricial lagophthalmos)

• Physiologic lagophthalmos (as in the case of nocturnal lagophthalmos).

• Medication effect (particularly sedatives or neuromuscular blockers)

Paralytic lagophthalmos is most commonly due to facial nerve dysfunction. The facial nerve (CN
VII) controls most of the eyelid muscles, and facial nerve dysfunction will therefore lead to
weakened eyelid closure (Figure 2). It can be damaged by trauma, cerebrovascular accidents,
Bell’s palsy, tumors, infections, immune-mediated causes, and congenital cranial dysinnervation
syndromes.[9] Trauma, can be secondary to fractures to the skull base or mandible, or from
surgery (particularly neurosurgery). Additionally, the facial nerve is supplied by the anterior
inferior cerebellar artery and as such may be susceptible to cerebrovascular accidents. Bell’s
palsy is a type of facial paralysis that results in a weakness of facial muscles on one side of the
face. It holds its own host of possible causes, most notably, reactivation of herpes simplex virus.
Other infectious causes of Bell’s palsy include Lyme disease, varicella, mumps, poliomyelitis,
Guillaine-Barré syndrome, leprosy, diphtheria, and botulism.[9] Tumors that have the potential to
cause facial nerve dysfunction include acoustic neuromas in the cerebellopontine angle as well as
metastases.[9] Lastly, cranial dysinnervation syndromes, such as Mobius’ syndrome and
congenital facial palsy, are characterized by facial nerve dysfunction and subsequent
lagophthalmos.[9]
Figure 2: Right facial nerve palsy demonstrating Bell’s phenomenon. Forward gaze (A)
demonstrates asymmetrical eyelid position and a relatively elevated right upper lid as compared
to the left due to facial nerve dysfunction and lack of orbicularis oculi control. Eyelid closure
cannot be obtained in the right eye in (B) due to facial nerve palsy and the patient exhibits a
Bell’s phenomenon whereby the cornea rotates upward upon eyelid closure. Image courtesy of ©
2017 American Academy of Ophthalmology.

Post-operative lagophthalmos can commonly be seen following blepharoplasty, with one study
citing post-op lagophthalmos numbers as high as 47%.[10] Lagophthalmos in this setting may be
due to upper eyelid edema, orbital septal elevation, or excessive skin removal.[11] When due to
edema, the lagophthalmos usually resolves within seven days.[11] However, if lagophthalmos
persists, additional surgical treatment may be needed. In the case of upper-eyelid malposition,
scar tissue release with full-thickness interposition skin grafting may be needed.[11] Additionally,
trauma procedures and orbital tumor debulking and removal have the potential to be complicated
by post-operative lagophthalmos.

Nocturnal lagophthalmos, which is incomplete eyelid closure during sleep, is relatively common
in the general population, with one report citing up to 23% of individuals demonstrating some
degree of nocturnal lagophthalmos.[12] The presence of Bell’s phenomenon, whereby the eyeball
(and thus the cornea) rotates upward upon eyelid closure, particularly during sleep, may serve to
protect the cornea in cases of nocturnal lagophthalmos. However, not all sleeping patients exhibit
Bell’s phenomenon, with one study citing only 42% of 234 patients as having a positive Bell’s
during sleep.[13]

Certain medications may cause iatrogenic lagophthalmos, particularly medications used for
anesthesia, such as sedatives and neuromuscular blocking agents. Additionally, periocular
anesthesia used in aesthetic surgery may also lead to lagophthalmos given the potential muscle
toxicity associated with lidocaine, mepivacaine, procaine, and tetracaine.[14] Such toxicity,
although rare, can lead to damage of the orbicularis oculi muscle and lagophthalmos. Steps to
avoid orbicularis oculi toxicity include placement of the anesthetic injection high in the upper
eyelid and low in the lower eyelid, subcutaneous injection to avoid muscle tissue, and use of the
lowest volume and concentration of local anesthetic necessary.[14]

Of note, it’s been demonstrated that patients in intensive care units (ICU) and critical care
settings have an increased risk of developing EK.[15] The incidence of lagophthalmos in sedated
patients in the ICU is quite high (reports range between 21-75%), and has partly been attributed
to the sedative and neuromuscular blocking agents commonly used in this setting. [7][16][17] In
addition to their negative effects on eyelid closure, sedatives and neuromuscular blockers
interfere with the blink reflex that is responsible for adequate distribution of the tear film over
the cornea.[7] They also negatively affect Bell’s phenomenon.[7] Other factors that contribute to
EK in the ICU setting include positive pressure ventilation, which raises the patient’s venous
pressure and indirectly causes conjunctival edema and lagophthalmos, high flow oxygen rates
through nebulizers or face masks, which may desiccate the cornea, and fluid imbalances and
increased vascular permeability, which can lead to conjunctival edema and subsequent
lagophthamos.[18]
Proptosis

Figure 3: Thyroid orbitopathy. Patient demonstrating thyroid orbitopathy with marked proptosis.
Image courtesy of © 2017 American Academy of Ophthalmology.

Proptosis, a term commonly interchanged with exophthalmos, is anterior displacement of the

eyeball with respect to the orbit. This protrusion of the eyeball may be so great as to disrupt
normal eyelid closure. Conditions that are associated with proptosis include craniosynostosis
syndromes, thyroid disease, orbital tumors and Cushing’s syndrome. Patients with pulsatile
exophthalmos syndromes may also present with EK; such patients may include those with aortic
regurgitation, neurofibromatosis 1, carotid-cavernous sinus fistulae, arachnoid cysts, and trauma.

Thyroid eye disease warrants special mention as it is one of the leading causes of EK (Figure 3).
Thyroid eye disease can cause proptosis of the orbit, eyelid retraction, and chemosis. Proptosis
occurs secondary to increased volume behind the orbit due to cellular proliferation,
inflammation, and accumulation of glycosaminoglycans in the eye muscles and retroorbital
adipose and connective tissues.[19] Additionally, patients with thyroid disease may have eyelid
retraction as well as periorbital edema secondary to decreased venous drainage from the
congested orbital space.[19] Both of these factors contribute to incomplete eyelid closure and
increase the risk for EK.[19] Additionally, patients with thyroid dysfunction may suffer from
corneal nerve dysfunction and subsequent malfunctioning of the blink reflex, further increasing
the risk of EK.[20] Grave’s disease is an autoimmune disease that results in the overproduction of
thyroid hormones (hyperthyroidism). Although thyroid eye disease is traditionally associated
with Graves’ disease, it is also occasionally seen in euthyroid patients and in patients with
hypothyroid chronic autoimmune thyroiditis.[19]

Neurologic and neurotrophic disease

Figure 4: Neurotrophic keratopathy leading to decreased blink and concurrent exposure

keratopathy secondary to meningioma affecting the trigeminal nerve. Exposure keratopathy is
demonstrated by an uneven corneal surface with epithelial defect (left) and well-demarcated
fluorescein staining defect (right).
Patients with either neurologic or neurotrophic diseases may have an impaired blink reflex that
could predispose them to EK (Figure 4). Examples of neurologic disease include Parkinson
disease or neuromuscular disease. EK results from decreased blink rate and blink force.[21]

Neurotrophic diseases are the result of decreased corneal sensation. They are characterized by
corneal nerve dysfunction, which interferes with the normal blink reflex that is needed to
lubricate the eye and protect it from the external environment. Neurotrophic disease can be either
acquired or hereditary and infectious or non-infectious. Non-infectious non-hereditary forms of
neurotrophic keratitis can be secondary to a pathological change, due to autoimmune disease,
iatrogenic, substance - induced, or as part of a polyneuropathy syndrome. Examples of decreased
corneal nerve function secondary to the effect of ophthalmic pathological changes can be seen in
keratoconus, bullous keratopathy, and atopic keratoconjuctivitis.[20] Autoimmune causes of
decreased corneal nerve function include Graves’ disease and Sjogren’s syndrome.[20] Iatrogenic
corneal nerve dysfunction may occur in refractive vision corrective procedures. [20] Intranasal
cocaine abuse may also impair corneal nerve sensitivity and may predispose to EK.[22] Lastly,
systemic polyneuropathies may lead to impaired blink reflex secondary to decreased corneal
nerve sensitivity and include peripheral diabetic neuropathy, amyloidosis, sarcoidosis, vitamin
B12 deficiency, and alcoholism.[20]

Hereditary forms of sensory and autonomic neuropathies that have the potential to compromise
corneal nerve integrity include Riley-Day syndrome, congenital aniridia, ocular-auriculo-
vertebral dysplasia, and multiple endocrine neoplasia 2A and 2B.[20] Lastly, infectious agents that
can affect the corneal nerves include herpesviridae (herpes-simplex virus type 1 and varicella-
zoster virus, the latter of which can present as Ramsay-Hunt syndrome), Mycobacterium leprae,
Acanthamoeba, and fungi.[20]

Lid malposition
Figure 5: Paralytic ectropion with resultant exposure. Paralytic ectropion exhibited in (A) with
resultant corneal exposure upon attempted eyelid closure and positive Bell’s phenomenon (B).
Image courtesy of © 2017 American Academy of Ophthalmology.

Lid malposition can prevent adequate closure of the eyelids, leading to EK. Causes of lid
malposition include cicatricial retraction, as previously mentioned, ectropion, entropion, and
eyelid coloboma.

Ectropion is an outward rotation of the eyelid margin whereas entropion is an inward rotation of
the eyelid margin. Ectropion can be either congenital, involutional, paralytic, cicatricial, or
mechanical.[23] Congenital ectropion of the upper lid may be associated with Down syndrome,
whereas congenital ectropion of lower lid may be associated with blepharophimosis
syndrome.[23] Involutional lower lid ectropion may be caused by disinsertion of the lower lid
retractors, laxity of the medial and lateral canthal tendons, and atrophy or degeneration of the
orbicularis oculi.[23] This can occur as part of the natural aging process. Paralytic ectropion may
be caused by facial nerve palsy leading to laxity of the orbicularis oculi (Figure 5).[23] Cicatricial
ectropion can be caused by shortening of the anterior lamella or skin of the orbicularis oculi
muscle from actinic skin changes, resection of skin lesions, trauma, burns, toxic reactions to
topical eye medications, skin diseases, and aggressive blepharoplasty.[23] A rare cause of
cicatricial ectropion is cutaneous anthrax infection, whereby the Bacillus anthracis organisms
proliferate at the site of inoculation and form a papule that progresses to form a vesicle, pustule,
and ultimately a necrotic black ulcer.[24] When the eyelid is the primary site of entry, progressive
lid edema may lead to cicatricial ectropion.[24] Lastly, mechanical pulling of the eyelid may cause
ectropion such as in the setting of a tumor.[23]
The causes of entropion may be congenital, acute spastic, involutional or cicatricial. Congenital
entropion can occur in the setting of retractor dysgenesis and shortened posterior lamella.[23]
Acute spastic entropion may be caused by ocular inflammation or irritation as can be seen with
trichiasis.[23] Involutional entropion is associated with medial and lateral canthal laxity or
dehiscence, disinsertion or stretching of the lower lid retractor complex, override of the preseptal
orbicularis, and extension of orbital fat anterior to the orbital rim.[23] Lastly, cicatricial entropion
may be caused by shortening of the posterior lamella from inflammation which may be caused
by trachoma, Stevens-Johnson syndrome, ocular cicatricial pemphigoid, herpes zoster, chemical
injuries, and toxic reactions to certain topical medications.[23]

Eyelid coloboma is another cause of eyelid malposition that may lead to EK. Eyelid coloboma
may be isolated or as part of a syndrome. Isolated eyelid colobomas may present with
corneopalpebral adhesions and may be complete, incomplete, or of the abortive type which has
variable size and a diverse range of corneopalpebral adhesions.[25] Syndromic variants of eyelid
coloboma include Fraser syndrome, Goldenhar syndrome, CHARGE syndrome (coloboma of the
eye, heart defects, atresia of the nasal choanae, retardation of growth and/or development, genital
and/or urinary abnormalities, ear abnormalities and deafness), or several other more rare
associated syndromes.[25]

Primary prevention

Primary prevention of EK involves the use of artificial tears and lubricating gel in at risk
populations.

Diagnosis

Diagnosis is made based on classic history and symptoms as well as physical exam signs that are
outlined below.

History

Assess for a history of EK and the aforementioned risk factors above. Specific inquiry should be
made regarding any history of surgery, medical comorbidities (with particular emphasis on
thyroid disease and diabetes), current medication use (emphasis on sedatives or muscle
relaxants), and history of trauma.
Figure 6: Fluorescein staining showing typical EK affecting the inferior one-third of the cornea.
This patient was intubated and sedated in the ICU and had 1.5 mm lagophthalmos.

Physical examination

• Evaluate corneal sensation for possible neurotrophic keratopathy prior to instillation of any
topical anesthetic. Corneal sensation can be tested with either a cotton swab or with a graded
Cochet Bonnet esthesiometer (Figure 6).

• Slit lamp examination with and without fluorescein dye staining (Rose Bengal and Lissamine
green may also be used). Prior to staining assess for external signs as outlined below. Early EK is
characterized by corneal desiccation and upon administration of fluorescein dye superficial
punctate epithelial staining, most commonly localized to the inferior one third of the cornea
becomes apparent (Figure 6).[7] These microepithelial defects may coalesce into an abrasion or
progress to form an ulcer or infiltrate.[7] Assess for external signs as outlined below.

Signs

External signs to note include incomplete blink, lagophthalmos, exophthalmos, eyelid deformity
or malposition, and presence or absence of Bell’s phenomenon.[21] Assess for conjunctival
injection or chemosis.

Symptoms

Patients may complain of foreign body sensation, burning, increased tearing, and intermittent
blurry vision (from an unstable tear film).[21] Symptoms may be worse in the morning if they are
due to nocturnal lagophthalmos.[21] Other possible symptoms include pain and photophobia.[26]

Management

The cornerstone of treatment involves treating the underlying condition that led to exposure
keratopathy. In the interim, medical and surgical treatments can be applied.

Medical therapy
Figure 7: Punctal plug. A temporary silicone punctal plug can be seen here in the inferior
punctum.

Standard treatments include the use of frequent artificial tears with nightly lubricating
ointment.[21] Preservative free artificial tears can be used hourly. Ideally, the artificial tears and
lubricating drops should be preservative-free as frequent use of eye drops with preservatives can
promote inflammation and may disrupt the tear film.[27] Punctal plugs may also be considered
(Figure 7).[26]

Other treatment strategies promote eyelid closure when the primary cause of EK is
lagophthalmos. Methods of eyelid closure include passive closure, eyelid taping (MicroporeTM
[3M]), eye patching, Geliperm dressings, saline-soaked gauzes, paraffin gauze and suturing
(Frost sutures or temporary tarsorrhaphy).[7] Lastly, another strategy includes the use of a
moisture chamber or polyethylene film cover.[28][29]

A literature review indicated that the use of ocular lubrication was significantly more effective
than passive eyelid closure, basic eye toilet or Geliperm but equally effective to the use of lid
taping in the critical care setting.[7] The use of moisture chambers or polyethylene films provided
the greatest amount of protection.[7][29] Recent reports have documented the utility of using Glad
Press’n Seal as a simple method of creating a moisture chamber.[30]

Bandage and scleral contact lenses are another method of protecting the cornea.[26] However,
infection is always a risk with bandage contact lenses. Patients should be followed closely and
antibiotic prophylaxis should be considered, especially if the lens is worn overnight. Specialty
scleral contact lenses like the PROSE lens are especially helpful, but are not always covered by
insurance companies.[26]

Surgery

Surgical treatments are often necessary to address the underlying pathophysiology. Usually
medical treatment is initially employed and surgical treatments are reserved for refractory cases
of EK. In the case of lagophthalmos temporary or permanent tarsorraphy has been used as well
as gold weight implantation (also for facial nerve palsy).[31][21] If the exposure is secondary to lid
malposition, canthoplasty, lid tightening procedures, and lid suspension may be considered.[31]
Eyelid reconstruction (for ectropion) and orbital decompression (for proptosis) can also be
considered when applicable.[21] Amniotic membrane has also been used in settings with
persistent epithelial defect. The membrane can be attached surgically via fibrin glue or sutures,
or through the use of a suspension ring/specialty lens, as in the case of the Prokera lens.[26]

Follow up

Figure 8: Corneal scar secondary to exposure keratopathy. Corneal scarring is apparent in the
inferior one-third of the cornea of this child who suffered from untreated exposure keratopathy in
the ICU setting.

Follow up depends on severity but is generally within 1-2 weeks for less severe cases and every
1-2 days for severe cases that are complicated by the presence of a corneal abrasion, ulceration
or infiltrate.[21]

Complications

Complications include corneal abrasion, ulceration, microbial keratitis, perforation and corneal
scar leading to vision loss (Figure 8).[32] Additionally, band keratopathy may present as a
complication of chronic EK.[33]

Of special consideration are patients with pre-existing dry-eye disease, which may make EK
more resistant to treatments and can worsen the prognosis.

Prognosis

Mild EK has an excellent prognosis, with most if not all patients making a full recovery if the
cornea remains intact without erosion, ulceration, or microbial infection.[18] Severe cases can
lead to scarring, perforation and permanent vision loss. Ultimate prognosis depends on the ability
to reverse the underlying etiology.
References

McCulley, J. P. & Shine, W. A compositional based model for the tear film lipid layer.
Trans Am Ophthalmol Soc 95, 79-88; discussion 88-93 (1997).
Holland, E. J., Mannis, M. J. & Lee, W. B. Ocular surface disease : cornea, conjunctiva
and tear film. (Elsevier/Saunders, 2013).
Holland, E. J., Mannis, M. J. & Lee, W. B. Ocular surface disease : cornea, conjunctiva
and tear film. (Elsevier/Saunders, 2013).
Krachmer, J., Mannis, M. J. & Holland, E. J. Cornea. Third edn, Vol. 1 (Mosby, 2011).
Krachmer, J., Mannis, M. J. & Holland, E. J. Cornea. Third edn, Vol. 1 (Mosby, 2011).
Krachmer, J., Mannis, M. J. & Holland, E. J. Cornea. Third edn, Vol. 1 (Mosby, 2011).
Grixti, A., Sadri, M., Edgar, J. & Datta, A. V. Common ocular surface disorders in patients
in intensive care units. Ocul Surf 10, 26-42, doi:10.1016/j.jtos.2011.10.001 (2012).
Krachmer, J., Mannis, M. J. & Holland, E. J. Cornea. Third edn, Vol. 1 (Mosby, 2011).
Lawrence, S. and C. Morris (2008). Lagophthalmos Evaluation and Treatment. EyeNet.
Accessed 2017.
Mokhtarzadeh, A. & Bradley, E. A. Safety and Long-term Outcomes of Congenital Ptosis
Surgery: A Population-Based Study. J Pediatr Ophthalmol Strabismus 53, 212-217,
doi:10.3928/01913913-20160511-02 (2016).
Trussler, A. P. & Rohrich, R. J. MOC-PSSM CME article: Blepharoplasty. Plast Reconstr
Surg 121, 1-10, doi:10.1097/01.prs.0000294667.93660.8b (2008)
Howitt, D. A. & Goldstein, J. H. Physiologic lagophthalmos. Am J Ophthalmol 68, 355
(1969).
Hall, A. J. Some Observations on the Acts of Closing and Opening the Eyes. Br J
Ophthalmol 20, 257-295 (1936).
Skibell, B. C., Soparkar, C.N., Tower, R. N. & Patrinely, J. R. Periocular anesthesia in
aesthetic surgery. Semin Plast Surg 21, 37-40, doi:10.1055/s-2007-967746 (2007