AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

This condition is characterized by inadequate tear film protection of the cornea because of either inadequate tear production or abnormal tear film constitution, which results in excessively fast evaporation or premature destruction of the tear film.

Pathophysiology

The tear film is constituted by 3 layers, as follows: (1) a lipid layer (0.11 µm thick), produced by the Meibomian glands; (2) an aqueous layer (7.0 µm thick), produced by the main and accessory lacrimal glands of Krause and Wolfring; and (3) a hydrophilic mucin layer (0.02-0.05 µm thick), produced by the conjunctival goblet cells. Any abnormality of 1 of the 3 layers produces an unstable tear film and symptoms of keratitis sicca.

The tear layer affected most frequently is the aqueous layer, resulting in aqueous tear deficiency (ATD) or lacrimal hyposecretion. The classification scheme proposed by the 2 workshops held in December 1993 and December 1994 at the National Eye Institute (NEI) stratified patients with dry eye into those with aqueous tear deficiency and those with increased evaporative loss.

Sjögren syndrome is characterized by the combination of aqueous tear deficiency and dry mouth (xerostomia). Women comprise 90-95% of patients with this syndrome that has been classified into 3 different subsets, as follows:

• Patients with systemic immune dysfunction but no defined connective tissue disease (primary Sjögren syndrome)
• Patients who lack evidence of systemic immune dysfunction or a defined connective tissue disease
• Patients who have a defined connective tissue disease, most commonly rheumatoid arthritis (secondary Sjögren syndrome). Dry eye is common in patients with rheumatoid arthritis, including those without Sjögren syndrome. Dry eye should always be taken into consideration regardless of the rheumatoid arthritis activity, because the severity of dry eye is independent of the rheumatoid arthritis activity.

All cases are characterized by progressive lymphocytic (predominantly B and CD4 lymphocytes) infiltration of the lacrimal and salivary glands that leads to disorganization of the normal gland architecture and consequent loss of function. At this time, the most comprehensive criteria for a diagnosis of Sjögren syndrome include the following:

• Abnormally low Schirmer test
• Objective evidence of low salivary flow
• Biopsy-proven lymphocytic infiltration of the labial salivary glands
• Dysfunction of the immune system as manifested by the presence of serum autoantibodies (eg, antinuclear antibodies, rheumatoid factor, anti-Ro [SS-A] and anti-La [SS-B] antibodies)

It has recently been shown that patients with keratoconjunctivitis sicca show elevated levels of tear nerve growth factor (NGF); these levels were decreased with 0.1% prednisolone. Data suggest that ocular surface NGF may play an important role in ocular surface inflammation processes associated with dry eyes.

Frequency

United States

Keratitis sicca is a relatively common condition, especially in older patients.

Mortality/Morbidity

Keratitis sicca can range from mild or barely symptomatic to moderate and severe cases, which can produce some of the following complications:

• Punctate keratopathy, epithelial defects, sterile corneal ulcer, and infectious corneal ulcer
• Corneal vascularization and corneal scarring
• Corneal perforation

Race

No racial predilection exists.

Sex

Sjögren syndrome and keratitis sicca associated with this condition are significantly greater in women (9:1). Milder forms of keratitis sicca also are more common in females than in males.

Age

Decreased tearing is associated with increased age.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

• The following are the most common complaints in patients who are experiencing keratitis sicca depending on the severity of this problem:
• • Foreign body sensation and ocular dryness and grittiness, typically worse toward the end of the day
  • Hyperemia
  • Mucoid discharge
  • Ocular irritation (exacerbated by smoky or dry environments, indoor heating systems, prolonged reading, or computer use)
  • Excessive tearing (secondary to reflex secretion)
• Documenting the history of exacerbating or alleviating factors and a systemic past medical history is important, including history of connective tissue disease, thyroid disease, and rheumatoid arthritis.
• A review of systems focused on rheumatological disease, history of neoplasias, and GI and ear, nose, and throat (ENT) symptoms should be documented.
• History of dry mouth should be requested.
• A list of systemic and topical medications is important.

Physical

The following are the most important findings that are present in the external and slit lamp examination of patients with keratitis sicca before placement of any drops in the eye:

• Perform a slit lamp examination to document some of the following:
• • Decreased tear meniscus
  • Increased debris in the tear film
  • Conjunctival pleating
  • Superficial punctate keratopathy (with positive fluorescein, lissamine green and/or rose bengal staining)
  • Conjunctival hyperemia
  • Mucous plaques and discharge
  • Xerostomia (in association with Sjögren syndrome)
  • Corneal filaments
  • Corneal epithelial defects or ulceration in more severe cases
• Determine tear breakup time after placing a drop of fluorescein in the cul-de-sac.
• Use rose bengal staining to look for conjunctival and corneal staining, particularly at the nasal and temporal limbus and/or inferior paracentral cornea.
• Perform the 5-minute Schirmer test with and without anesthesia using a Whatman #41 filter paper 5 mm in width and 35 mm in length. (Wetting <5 mm with anesthesia and <10 mm without anesthesia are considered abnormal.)
• Measure reflex secretion with a Schirmer II test if the initial Schirmer test is abnormal. The Schirmer II test is performed by irritating the nasal mucosa with a cotton-tipped applicator prior to measuring tear production with a Whatman #41 filter paper. (Wetting <15 mm after 5 min is considered abnormal.)

Causes

The causes for keratitis sicca are multiple and can be multifactorial. They can be classified into 3 categories by the element of the tear layer that is mostly affected, as follows: (1) those affecting the aqueous tear layer, (2) those affecting the lipid tear layer, and (3) those affecting the mucin tear layer.

• The following include the most common conditions associated with aqueous tear deficiency:
• • Idiopathic
  • Congenital alacrima
  • Systemic vitamin A deficiency (xerophthalmia)
• Lacrimal gland ablation
• Sensory denervation
• Collagen vascular diseases, including rheumatoid arthritis, Wegener granulomatosis, and systemic lupus erythematosus
• Sjögren syndrome
• Autoimmune disorders associated with Sjögren syndrome, as follows:
  • Rheumatoid arthritis
  • Scleroderma
  • Polymyositis
  • Polyarteritis nodosa
  • Hashimoto thyroiditis
  • Chronic hepatobiliary cirrhosis
  • Lymphocytic interstitial pneumonitis
  • Thrombocytopenic purpura
  • Hypergammaglobulinemia
  • Waldenström macroglobulinemia
  • Progressive systemic sclerosis
  • Dermatomyositis
  • Interstitial nephritis
• Conjunctival scarring secondary to the following:
  • Ocular pemphigoid
  • Stevens-Johnson syndrome
  • Trachoma
  • Chemical/thermal burns
  • Atopic disease
• Drugs, including the following:
  • Oral contraceptives
  • Antihistamines
  • Beta-blockers
  • Phenothiazines
  • Atropine
• Infiltration of the lacrimal glands by sarcoidosis or tumors
• Postradiation fibrosis of the lacrimal glands
• The most common disorders associated with abnormalities of the lipid tear layer are as follows:
• Blepharitis
• Rosacea
• The most common conditions resulting in abnormalities of the mucin tear layer are as follows:
• • Vitamin A deficiency
  • Trachoma
  • Diphtheric keratoconjunctivitis
  • Mucocutaneous disorders
  • Topical medications

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Filamentary keratitis

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Keratitis sicca generally is diagnosed on slit lamp examination. Lab testing occasionally can be helpful.
• Tear protein analysis: This test allows the measurement of the lysozyme content of tears. Lysozyme accounts for approximately 20-40% of total tear protein content. The main disadvantages of this test include its lack of specificity in cases of the following:
• • Meibomitis
  • Herpes simplex keratitis
  • Bacterial conjunctivitis
• Lactoferrin analysis: This test is commercially available through colorimetric solid phase and enzyme-linked immunosorbent assay (ELISA) technique. It offers good correlation with other tests.
• Impression cytology: In advanced cases of keratitis sicca, the epithelium undergoes pathologic changes, resulting in squamous metaplasia and loss of goblet cells.
• • When the mucin layer of the tear is decreased (such as that associated with xerophthalmia or ocular cicatricial pemphigoid), squamous metaplasia and the following cytological characteristics occur:
    • Loss of goblet cells
    • Enlargement and increase of cytoplasmic/nuclear ratio of superficial epithelial cells
    • Keratinization
  • This method is highly sensitive; its main difficulty is the need for proper staining and expert microscopic evaluation of samples.

Histologic Findings

Pathologic examination of the lacrimal gland reveals age-related changes, including lobular and diffuse fibrosis and atrophy, as well as periductal fibrosis. An underlying autoimmune mechanism (represented by round cell infiltration) may be present. No circulating autoantibodies are present in patients who do not have Sjögren syndrome with keratitis sicca.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

Supplemental lubrication is the mainstay of treatment for mild and moderate keratitis sicca. Treatment of very severe keratitis sicca or keratitis sicca associated with a connective tissue disorder, including Sjögren syndrome, should be coordinated with an internist/rheumatologist.

Recently, the use of topical cyclosporine A (tCSA) 0.05% ophthalmic emulsion (Restasis) to treat keratoconjunctivitis sicca in a real-world setting has proven to be an effective treatment.

• Prescribe artificial tears, preferably preservative-free artificial tears, and a lubricating ointment. Mild cases can be treated with drops 4 times a day. More severe cases require more aggressive treatment, such as drops 10-12 times a day. Thick artificial tear drops or gels also can be used in more severe cases, although they tend to blur the vision. Tear ointments can be used during the day, but they generally are reserved to bedtime use because of the poor vision after placement.
• Treat any associated abnormalities, such as meibomian gland dysfunction, as these conditions can greatly exacerbate dry eye symptoms.
• Patch with lubrication at night.
• If mucous strands or filaments are present, remove with forceps, and add 10% acetylcysteine 4 times a day.
• Place an artificial tear insert (eg, Lacrisert) into the inferior cul-de-sac every morning.
• Insert temporary punctal occlusion with collagen (dissolvable) or silicone (permanent) plugs, and, if they are effective, perform electric cauterization of puncti.

Surgical Care

The surgical treatment of keratitis sicca is reserved for very severe cases where ulceration or impending perforation of the sterile corneal ulcer occurs. Surgical care includes the following:

• Sealing of the perforation or descemetocele with corneal cyanoacrylate tissue adhesive
• Corneal or corneoscleral patch for an impending or frank perforation
• Lateral tarsorrhaphy - Temporary tarsorrhaphy (50%) is indicated in patients with keratitis sicca secondary to exposure keratitis after facial nerve paralysis and after trigeminal nerve lesions that give rise to keratitis sicca secondary to loss of corneal sensation.
• Conjunctival flap

Consultations

• If a patient has a connective tissue component or symptoms suggestive of Sjögren syndrome, consultation with a rheumatologist or an internist is appropriate.
• Regular dental examinations are important because dry mouth significantly increases the risk of dental problems.
• Women should receive regular checkups from their gynecologists.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lubricating supplements are the most common medications used to treat this condition. If they are to be used more frequently than every 3 hours, preservative-free formulations are the treatment of choice. If a patient has Sjögren syndrome, the use of systemic immunosuppressants should be considered.

Drug Category: Lubricating drops

Used to reduce morbidity and to prevent complications.

Drug Category: Ocular inserts

Reduce symptoms resulting from moderate-to-severe dry eye syndromes.

Drug Category: Lubricating ointments

Used to prevent complications from dry eyes.

Drug Category: Mucolytic agents

Lower mucous viscosity by digesting mucoproteins. Use when mucous discharge or plaques are present.

Drug Category: Immunomodulators

Cyclosporine ophthalmic drops are thought to act as a partial immunomodulator. The exact mechanism of action is not known.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Outpatient Care

• The frequency of follow-up care depends on the severity of the signs and symptoms.

Complications

• Significant punctate epitheliopathy can lead to corneal erosions, corneal ulceration (both sterile and infected), corneal neovascularization, corneal scarring, corneal thinning, and even corneal perforation.

Prognosis

• The prognosis with keratitis sicca varies considerably with the severity of these conditions. Most patients have mild-to-moderate cases, and they can be treated symptomatically with lubricants, providing good relief of symptoms.
• Patients with Sjögren syndrome represent a subgroup of patients with a worse prognosis, and, in some cases, they may require more extreme measures, including surgical treatment of perforated ulcers.

Patient Education

• Patients with Sjögren syndrome can obtain up-to-date information from the following organization: Sjögren Syndrome Foundation, Inc, 333 North Broadway, Jericho, New York 11753, (516) 933-6365 or (800) 4-SJOGREN.
• For excellent patient education resources, visit eMedicine's Eye and Vision Center. Also, see eMedicine's patient education article Dry Eye Syndrome.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Early detection and aggressive treatment may help avoid corneal ulcers and scarring.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

• Barber LD, Pflugfelder SC, Tauber J. Phase III safety evaluation of cyclosporine 0.1% ophthalmic emulsion administered twice daily to dry eye disease patients for up to 3 years. Ophthalmology. Oct 2005;112(10):1790-4. [Medline].
• Fox RI, Chan R, Michelson JB. Beneficial effect of artificial tears made with autologous serum in patients with keratoconjunctivitis sicca. Arthritis Rheum. Apr 1984;27(4):459-61. [Medline].
• Fujita M, Igarashi T, Kurai T. Correlation between dry eye and rheumatoid arthritis activity. Am J Ophthalmol. Nov 2005;140(5):808-13. [Medline].
• Lamberts DW, Foster CS, Perry HD. Schirmer test after topical anesthesia and the tear meniscus height in normal eyes. Arch Ophthalmol. Jun 1979;97(6):1082-5. [Medline].
• Lee HK, Ryu IH, Seo KY. Topical 0.1% prednisolone lowers nerve growth factor expression in keratoconjunctivitis sicca patients. Ophthalmology. Feb 2006;113(2):198-205. [Medline].
• Mathers WD. Ocular evaporation in meibomian gland dysfunction and dry eye. Ophthalmology. Mar 1993;100(3):347-51. [Medline].
• Murillo-Lopez F, Pflugfelder SC, eds. Cornea and External Disease: Clinical Diagnosis and Management, Vol II. 1997;663-686.
• Nelson JD. Diagnosis of keratoconjunctivitis sicca. Int Ophthalmol Clin. Winter 1994;34(1):37-56. [Medline].
• Pflugfelder SC, et al. Correlation of goblet cell density and mucosal epithelial mucin (MEM) expression in patients with ocular irritation. Invest Ophthalmol Vis Sci. 1995;36:S399.
• Pflugfelder SC, Roussel TJ, Culbertson WW. Primary Sjogren''s syndrome after infectious mononucleosis. JAMA. Feb 27 1987;257(8):1049-50. [Medline].
• Stonecipher K, Perry HD, Gross RH. The impact of topical cyclosporine A emulsion 0.05% on the outcomes of patients with keratoconjunctivitis sicca. Curr Med Res Opin. Jul 2005;21(7):1057-63. [Medline].
• Tsubota K, Toda I, Yagi Y. Three different types of dry eye syndrome. Cornea. May 1994;13(3):202-9. [Medline].

Article Last Updated: Apr 21, 2006