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Keratoconjunctivitis, Sicca

Last Updated: April 21, 2006
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Synonyms and related keywords: dry eye syndrome, sicca syndrome, keratitis sicca, KCS, xerophthalmia

  AUTHOR INFORMATION Section 1 of 10    Click here to go to the next section in this topic
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Author: Fernando H Murillo-Lopez, MD, Instructor, Department of Ophthalmology, Private Ophthalmology Unit at C.E.M.E.S.

Fernando H Murillo-Lopez, MD, is a member of the following medical societies: American Academy of Ophthalmology

Editor(s): Stephen D Plager, MD, FACS, Chief, Department of Ophthalmology, Dominican Hospital; Assistant Clinical Professor, Department of Ophthalmology, Stanford University Hospital; Simon K Law, MD, PharmD, Assistant Professor of Ophthalmology, Jules Stein Eye Institute, University of California at Los Angeles; Chief, Section of Ophthalmology Surgical Services, Veterans Affairs Healthcare Center of West Los Angeles; Christopher J Rapuano, MD, Professor, Department of Ophthalmology, Jefferson Medical College; Co-Chairman of the Cornea Service, Co-Chairman of Refractive Surgery Department, Wills Eye Hospital; Lance L Brown, OD, MD, Ophthalmologist, Regional Eye Center, Affiliated With Freeman Hospital and St John's Hospital, Joplin, Missouri; and Hampton Roy, Sr, MD, Associate Clinical Professor, Department of Ophthalmology, University of Arkansas for Medical Sciences

Disclosure


  INTRODUCTION Section 2 of 10   Click here to go to the previous section in this topic Click here to go to the top of this page Click here to go to the next section in this topic
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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 mm thick), produced by the Meibomian glands; (2) an aqueous layer (7.0 mm thick), produced by the main and accessory lacrimal glands of Krause and Wolfring; and (3) a hydrophilic mucin layer (0.02-0.05 mm 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:

    • In the US: 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   Click here to go to the previous section in this topic Click here to go to the top of this page Click here to go to the next section in this topic
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    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   Click here to go to the previous section in this topic Click here to go to the top of this page Click here to go to the next section in this topic
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    Chlamydia
    Conjunctivitis, Allergic
    Conjunctivitis, Bacterial
    Conjunctivitis, Giant Papillary
    Conjunctivitis, Viral
    Contact Lens Complications
    Corneal Abrasion
    Corneal Erosion, Recurrent
    Corneal Foreign Body
    Corneal Mucous Plaques
    Dermatitis, Atopic
    Dermatitis, Contact
    Dry Eye Syndrome
    Dystrophy, Map-dot-fingerprint
    Episcleritis
    Familial Dysautonomia
    Herpes Simplex
    Herpes Zoster
    Ichthyosis
    Keratitis, Herpes Simplex
    Keratitis, Interstitial
    Keratoconjunctivitis, Atopic
    Keratopathy, Neurotrophic
    Keratopathy, Pseudophakic Bullous
    Ocular Rosacea
    Psoriasis
    Scleritis


    Other Problems to be Considered:

    Filamentary keratitis

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      WORKUP Section 5 of 10   Click here to go to the previous section in this topic Click here to go to the top of this page Click here to go to the next section in this topic
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    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   Click here to go to the previous section in this topic Click here to go to the top of this page Click here to go to the next section in this topic
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    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.

    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   Click here to go to the previous section in this topic Click here to go to the top of this page Click here to go to the next section in this topic
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    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 Name
    Carboxymethylcellulose and similar lubricants (TheraTears, Bion Tears) -- Lubricates and relieves dry eyes and eye irritation associated with deficient tear production.
    Adult Dose1 gtt q1-4h prn
    Pediatric DoseAdminister as in adults
    ContraindicationsDocumented hypersensitivity
    InteractionsNone reported
    Pregnancy B - Usually safe but benefits must outweigh the risks.
    PrecautionsDo not use with contact lenses; discontinue use if eye pain, irritation, continued redness, or vision changes occur
    Drug Category: Ocular inserts -- Reduce symptoms resulting from moderate-to-severe dry eye syndromes.
    Drug Name
    Hydroxypropyl cellulose (Lacrisert) -- Acts to stabilize and thicken precorneal tear film and to prolong tear film breakup time, which occurs with dry eye states.
    Adult DoseInsert 5 mg qd into inferior cul-de-sac beneath the base of the tarsus; some patients may require bid frequency
    Pediatric DoseAdminister as in adults
    ContraindicationsDocumented hypersensitivity
    InteractionsNone reported
    Pregnancy A - Safe in pregnancy
    PrecautionsHyperemia, photophobia, stickiness of eyelashes, ocular discomfort, or irritation may occur
    Drug Category: Lubricating ointments -- Used to prevent complications from dry eyes.
    Drug Name
    White petrolatum, mineral oil, and similar lubricants (Duolube, HypoTears) -- Serves as lubricant and emollient.
    Adult DosePull down lid of affected eye, and apply small amount (0.25 in) of ointment to inside of the lid from every hour to just at bedtime depending on severity
    Pediatric DoseAdminister as in adults
    ContraindicationsDocumented hypersensitivity
    InteractionsNone reported
    Pregnancy B - Usually safe but benefits must outweigh the risks.
    PrecautionsDo not use with contact lenses; discontinue use if eye pain, irritation, continued redness, or vision changes occur
    Drug Category: Mucolytic agents -- Lower mucous viscosity by digesting mucoproteins. Use when mucous discharge or plaques are present.
    Drug Name
    10% N-acetylcysteine drops (Mucomyst) -- This mucolytic agent can be used successfully in patients with corneal filaments secondary to extreme keratitis sicca.
    Adult Dose1 gtt tid/qid
    Pediatric Dose1 gtt tid/qid
    ContraindicationsDo not use simultaneously with contact lenses
    InteractionsNone reported
    Pregnancy C - Safety for use during pregnancy has not been established.
    PrecautionsDo not use in patients with a possible infectious ulcer or concomitantly with topical antibiotics
    Drug Category: Immunomodulators -- Cyclosporine ophthalmic drops are thought to act as a partial immunomodulator. The exact mechanism of action is not known.
    Drug Name
    Cyclosporine ophthalmic (Restasis) -- Used to relieve dry eyes caused by suppressed tear production secondary to ocular inflammation.
    Adult DoseInstill 1 gtt in each eye q12h
    Pediatric Dose<16 years: Not established
    >16 years: Administer as in adults
    ContraindicationsDocumented hypersensitivity; ocular infection
    InteractionsNone reported
    Pregnancy C - Safety for use during pregnancy has not been established.
    PrecautionsHerpes keratitis; do not administer while wearing contact lenses; may cause ocular burning, conjunctival hyperemia, ocular discharge, excessive tearing, eye pain, foreign body sensation, pruritus, stinging, or blurred vision
      FOLLOW-UP Section 8 of 10   Click here to go to the previous section in this topic Click here to go to the top of this page Click here to go to the next section in this topic
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    Further Outpatient Care:

    Complications:

    Prognosis:

    Patient Education:

      MISCELLANEOUS Section 9 of 10   Click here to go to the previous section in this topic Click here to go to the top of this page Click here to go to the next section in this topic
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    Medical/Legal Pitfalls:

    • Early detection and aggressive treatment may help avoid corneal ulcers and scarring.
      BIBLIOGRAPHY Section 10 of 10   Click here to go to the previous section in this topic Click here to go to the top of this page
    Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Bibliography

    • 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 2005 Oct; 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 1984 Apr; 27(4): 459-61[Medline].
    • Fujita M, Igarashi T, Kurai T: Correlation between dry eye and rheumatoid arthritis activity. Am J Ophthalmol 2005 Nov; 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 1979 Jun; 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 2006 Feb; 113(2): 198-205[Medline].
    • Mathers WD: Ocular evaporation in meibomian gland dysfunction and dry eye. Ophthalmology 1993 Mar; 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 1994 Winter; 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 1987 Feb 27; 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 2005 Jul; 21(7): 1057-63[Medline].
    • Tsubota K, Toda I, Yagi Y: Three different types of dry eye syndrome. Cornea 1994 May; 13(3): 202-9[Medline].

    NOTE:
    Medicine is a constantly changing science and not all therapies are clearly established. New research changes drug and treatment therapies daily. The authors, editors, and publisher of this journal have used their best efforts to provide information that is up-to-date and accurate and is generally accepted within medical standards at the time of publication. However, as medical science is constantly changing and human error is always possible, the authors, editors, and publisher or any other party involved with the publication of this article do not warrant the information in this article is accurate or complete, nor are they responsible for omissions or errors in the article or for the results of using this information. The reader should confirm the information in this article from other sources prior to use. In particular, all drug doses, indications, and contraindications should be confirmed in the package insert. FULL DISCLAIMER

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