From: Subject: eMedicine - Dry Eye Syndrome : Article by Anthony S Ekong, MD Date: Sat, 3 Aug 2002 17:04:52 -0500 MIME-Version: 1.0 Content-Type: multipart/related; boundary="----=_NextPart_000_005F_01C23B0F.E25B07C0"; type="text/html" X-MimeOLE: Produced By Microsoft MimeOLE V6.00.2600.0000 This is a multi-part message in MIME format. ------=_NextPart_000_005F_01C23B0F.E25B07C0 Content-Type: text/html; charset="Windows-1252" Content-Transfer-Encoding: quoted-printable Content-Location: http://www.emedicine.com/oph/topic597.htm eMedicine - Dry Eye Syndrome : Article by Anthony S = Ekong, MD
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Dry Eye Syndrome


Synonyms, Key=20 Words, and Related Terms: keratoconjunctivitis sicca, = KCS=20
Home | Search | Contents | A-Z=20 Index | Tools | Updates | Medline | Cover | Dictionary | GetCME | Rate this topic | Help
 eMedicine Journal = > Ophthalmology > Lacrimal System > Dry Eye = Syndrome=20
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AUTHOR INFORMATION = Section 1 of 10    <= IMG=20 height=3D10 alt=3D"Click here to go to the next section in this = topic"=20 src=3D"http://www.emedicine.com/images/next3.gif" width=3D31 = align=3Dmiddle=20 border=3D0>

Authored by = Anthony S Ekong, MD, Clinical Fellow, Department of=20 Ophthalmology, Division of Ocular Immunology and Uveitis, Massachusetts = Eye and=20 Ear Infirmary, Harvard Medical School

Coauthored by C Stephen Foster, MD, FACS, Director = of=20 Immunology and Uveitis Service, Professor, Department of Ophthalmology,=20 Massachusetts Eye and Ear Infirmary, Harvard Medical School

Anthony S Ekong, MD, is a member of the following medical societies: = American Academy of Ophthalmology, and = American Medical Association

Edited by Jack L Wilson, PhD, Distinguished = Professor,=20 Department of Anatomy and Neurobiology, University of Tennessee at = Memphis;=20 Donald S Fong, MD, MPH, Assistant Clinical Professor of = Ophthalmology, UCLA School of Medicine; Consulting Physician, Department = of=20 Ophthalmology, Southern California Permamente Medical Group; = Christopher=20 J Rapuano, MD, Co-Chairman of Refractive Surgery Department, = Associate=20 Professor, Cornea Service, Wills Eye Hospital, Jefferson Medical = College;=20 Lance L Brown, OD, MD, Ophthalmologist, Regional Eye = Center,=20 Affiliated With Freeman Hospital and St John's Hospital, Joplin, = Missouri; and=20 Hampton Roy, Sr, MD, Clinical Associate Professor, = Department=20 of Ophthalmology, University of Arkansas for Medical Sciences=20

Author's = Email: Anthony=20 S Ekong, MD 3D"Click
Editor's = Email: Jack=20 L Wilson, PhD

eMedicine Journal, August 27 2001, Volume 2, = Number=20 8
INTRODUCTION = Section 2 of 10    3D"Click

Background= :=20 Dry eye is a common disorder of the tear film that results from = decreased tear production, excessive tear evaporation, or abnormality in = mucin=20 or lipid components of the tear film. The tear layer covers the normal = ocular=20 surface. Generally, it is accepted that the tear film is made up of 3=20 intertwined layers, as follows:=20

  1. A superficial thin lipid layer is produced by the meibomian = glands, and=20 its principal function is to retard tear evaporation and to assist in = uniform=20 tear spreading.=20

  2. A middle thick aqueous layer is produced by the main lacrimal = glands=20 (reflex tearing), as well as the accessory lacrimal glands of Krause = and=20 Wolfring (basic tearing).=20

  3. An innermost hydrophilic mucin layer is produced by both the = conjunctiva=20 goblet cells and the ocular surface epithelium and associates itself = with the=20 ocular surface via its loose attachments to the glycocalyx of the = microplica=20 of the epithelium. It is the hydrophilic quality of the mucin that = allows the=20 aqueous to spread over the corneal epithelium.

Mucin deficiency, as seen in Stevens-Johnson syndrome or after a = chemical=20 burn, leads to poor wetting of the corneal surface with subsequent = desiccation=20 and epithelial damage, even in the presence of adequate aqueous tear = production.=20

Keratoconjunctivitis sicca (KCS) is the name given to the ocular = surface=20 disorder that develops in patients with aqueous tear deficiency (ATD), = and it is=20 the most common cause of dry eye. KCS is subdivided into Sj=F6gren = syndrome (SS)=20 associated KCS and non-SS associated KCS. Evaporative loss is due = predominantly=20 to meibomian gland dysfunction (MGD). Patients with ATD have SS if they = have=20 associated xerostomia and/or connective tissue disease. Patients with = primary SS=20 have evidence of a systemic autoimmune disease as manifested by the = presence of=20 serum autoantibodies and very severe ATD and ocular surface disease. = These=20 patients, mostly women, do not have a separate, identifiable connective = tissue=20 disease. Subsets of patients with primary SS lack evidence of systemic = immune=20 dysfunction, but they have similar clinical ocular presentation. = Secondary SS is=20 defined as KCS associated with a diagnosable connective tissue disease, = most=20 commonly rheumatoid arthritis.

Pathophysiology: A genetic predisposition in SS = associated=20 KCS exists as evident by the high prevalence of human leukocyte antigen = B8=20 (HLA-B8) haplotype in these patients. This condition leads to production = of=20 autoantibodies, antinuclear antibody (ANA), rheumatic factor, or = SS-specific=20 antibodies (eg, anti-RO [SS-A], anti-LA [SS-B]), and lymphocytic = infiltration=20 (ie, CD4+ cells) of the lacrimal and salivary gland, with = glandular=20 degeneration and induction of apoptosis in the conjunctiva. Active T = lymphocytic=20 infiltrate in the conjunctiva also has been reported in non-SS = associated KCS.=20

Androgen receptors are located in lacrimal glands and in meibomian = glands. SS=20 is more common in postmenopausal women. At menopause, a decrease in = circulating=20 sex hormones (ie, estrogen, androgen) occurs, possibly affecting the = functional=20 and secretory aspect of the lacrimal gland. Forty years ago, initial = interest in=20 this area centered on estrogen and/or progesterone deficiency to explain = the=20 link between KCS and menopause. However, recent research has focused on=20 androgens, specifically testosterone, and/or metabolized androgens.=20

It has been postulated that in MGD a deficiency in androgens results = in loss=20 of the oil layer, exacerbating the evaporative tear loss.=20

Various proinflammatory cytokines that may cause cellular = destruction,=20 including interleukin 1 (IL-1), interleukin 6 (IL-6), and interleukin 8 = (IL-8),=20 are altered in patients with KCS. Additionally, adhesion molecules, such = as=20 intercellular adhesion molecule-1 (ICAM-1), important in cellular = diapedesis,=20 are up-regulated in the conjunctiva of patients with KCS.=20

Mucin synthesizing genes, designated MUC1-MUC8, have been = isolated,=20 and their role in hydration and stability of the tear film are being=20 investigated in patients with dry eye syndrome. Particularly significant = is=20 MUC5AC, expressed by stratified squamous cells of the = conjunctiva and=20 whose product is the predominant component of the mucous layer of tears. = A=20 defect in this gene may be a factor in dry eye syndrome development.=20

Normal production of tear proteins, such as lysozyme, lactoferrin, = lipocalin,=20 and phospholipase A2, is decreased in KCS. Decreased polar lipids, = phosphatidyl=20 ethanolamine (PE) and sphingomyelin (SM), are present in obstructive = MGD.

Frequency:

  • In the US: Dry eye is a very common disorder = affecting a=20 significant percentage of the population, especially those older than = 40=20 years. The estimated number of people affected ranges from 10-14 = million in=20 the US.
  • Internationally: The frequency of dry eye in = other=20 countries closely parallels that of the US. Prevalence of SS is = approximately=20 0.4% in Sweden.

Mortality/Morbidity: Dry eye may be complicated by = sterile=20 or infectious corneal ulceration, particularly in patients with SS. = Ulcers are=20 typically oval or circular, less than 3 mm in diameter, and located in = the=20 central or paracentral cornea. Occasionally, corneal perforation may = occur. In=20 rare cases, sterile or infectious corneal ulceration in dry eye syndrome = can=20 cause blindness.=20

Race: No known racial predilection exists.=20

Sex: Dry eye may be slightly more common in women. = KCS=20 associated with SS (a type of dry eye) is believed to affect 1-2% of the = population, and 90% of those affected are women.
CLINICAL Section 3 of 10   <= IMG=20 height=3D10 alt=3D"Click here to go to the previous section in = this topic"=20 src=3D"http://www.emedicine.com/images/back3.gif" width=3D31 = align=3Dmiddle=20 border=3D0> =

History:=20

  • In KCS, symptoms tend to be worse toward the end of the day, with=20 prolonged use of the eyes, or with exposure to extreme environmental=20 conditions. Patients with MGD may complain of redness of the eyelids = and=20 conjunctiva, but, in these patients, the symptoms are worse on = awakening in=20 the morning.
  • Paradoxically, some patients with dry eye syndrome complain of too = much=20 tearing. When evidence of dry eye syndrome exists, this symptom often = is=20 explained by excessive reflex tearing due to severe corneal surface = disease=20 from the dryness.
  • Certain systemic medications also decrease tear production, such = as=20 antihistamines, beta-blockers, and oral contraceptives.

Physical:

  • Signs of a dry eye include the following:
    • Bulbar conjunctival vascular dilation
    • Decreased tear meniscus
    • Irregular corneal surface
    • Decreased tear break-up time
    • Punctate epithelial keratopathy
    • Corneal filaments
    • Increased debris in the tear film
  • Symptoms often do not correlate with signs.
  • In severe cases, there may be an epithelial defect or a sterile = corneal=20 infiltrate or ulcer. Secondary infectious keratitis also can develop. = Both=20 sterile and infectious corneal perforations can occur.

Causes: A classification system formulated by the = National=20 Eye Institute distinguishes 2 main categories (or causes) of dry eye = states, an=20 aqueous deficiency state and an evaporative state.

  • Deficient aqueous production
  • Non-Sj=F6gren syndrome
    • Lacrimal disease (primary or secondary)=20

      • Systemic vitamin A deficiency (xerophthalmia)=20
      • Lacrimal ablation=20
      • Congenital alacrima (Riley-Day syndrome)=20
      • Primary lacrimal deficiency=20
      • Graft-versus-host disease
    • Infiltrative processes=20

      • Lymphoma=20
      • Amyloidosis=20
      • Hemachromatosis=20
      • Sarcoidosis
    • Infectious diseases=20

      • HIV diffuse infiltrative lymphadenopathy syndrome=20
      • Trachoma
    • Lacrimal obstructive disease=20

      • Trachoma=20
      • Ocular cicatricial pemphigoid=20
      • Erythema multiforme and Stevens-Johnson syndrome=20
      • Chemical burns=20
      • Endocrine imbalance
    • Anticholinergic medications
    • Decreased corneal sensation=20

      • Neurotrophic keratitis=20
      • Corneal surgery=20
      • Herpes simplex=20
      • Contact lens wear=20
      • Cranial nerve VII (CN VII) palsy=20
      • Diabetes=20
      • Aging
  • Sj=F6gren syndrome
    • Primary (no associated connective tissue disease = [CTD])
    • Secondary (associated CTD)=20

      • Rheumatoid arthritis=20
      • Systemic lupus erythematosus=20
      • Progressive systemic sclerosis (scleredema)=20
      • Primary biliary cirrhosis=20
      • Interstitial nephritis=20
      • Polymyositis and dermatomyositis
  • Evaporative loss
    • Blepharitis-associated - Obstructive meibomian gland = disease
    • Blink disorders
    • Disorders of eyelid aperture and eyelid/globe = congruity
DIFFERENTIALS = Section 4 of 10   3D"Click

Blepharitis, Adult =
Dry Eye Syndrome =
Floppy Eyelid = Syndrome=20
Keratoconjunctivitis, = Superior=20 Limbic
Keratopathy,=20 Neurotrophic
Ocular=20 Manifestations of HIV
Ocular Rosacea =


Other Problems to be Considered:

Anterior blepharitis
Exposure (Graves disease, Bell = palsy)
Contact lens=20 wear
Cranial nerve V trauma or corneal = surgery
Medicamentosa
Allergic=20 conjunctivitis
Nocturnal lagophthalmos
Superior limbic=20 keratoconjunctivitis
Thygeson superficial punctate keratopathy

WORKUP Section 5 of 10   =

Lab Studies:

  • Serology for circulating autoantibodies, including ANA or SS = antibodies=20 (ie, SS-A, SS-B), may be indicated.

Other Tests:

  • Dry eye is essentially a clinical diagnosis, combining information = obtained from both the history and the examination and performing 1 or = more=20 tests to lend some objectivity to the diagnosis. No one test is = sufficiently=20 specific to permit an absolute diagnosis of dry eye.
  • Tear break-up test (TBUT) is determined by measuring the time = lapse=20 between instillation of fluorescein and appearance of the first dry = spots on=20 the cornea. Measure it prior to instillation of any anesthetic = eyedrops. A=20 fluorescein strip is moistened with saline and applied to the inferior = cul-de-sac. After several blinks, the tear film is examined using a = broad-beam=20 of slit lamp with a blue filter for the appearance of the first dry = spots on=20 the cornea. Decreased TBUT of less than 10 seconds is considered = abnormal,=20 indicative of tear instability.
  • Use rose bengal and fluorescein staining to evaluate = epitheliopathy. Rose=20 bengal stains not only dead and devitalized cells but also healthy = cells that=20 are protected inadequately by a mucin coating. Fluorescein pools in = epithelial=20 erosions and stains exposed basement membrane. Generally, it stains = the cornea=20 more than the conjunctiva. Lissamine green B and sulforhodamine also = have been=20 used as staining agents.
    • Early or mild cases of KCS are detected more easily with rose = bengal=20 than with fluorescein staining, and the conjunctiva usually is = stained more=20 intensely than the cornea. Interpalpebral staining of the nasal = and/or=20 inferior paracentral cornea is seen in KCS. A linear pattern of = inferior=20 conjunctiva and corneal staining by rose bengal is characteristic of = MGD.
    • Van Bijsterveld developed a scoring system for rose bengal that=20 evaluates the intensity of staining based on a scale of 0-3 in 3 = areas:=20 nasal conjunctiva, temporal conjunctiva, and cornea. With this = system, the=20 maximum possible score is 9. According to this system, a score of = 3.5 or=20 greater is considered positive for KCS.
  • Use the Schirmer test to test aqueous tear production. It is = performed by=20 placing a thin strip of filter paper in the inferior cul-de-sac; then, = the=20 eyes are closed for 5 minutes, and the amount of wetting of the paper = strip is=20 measured. Traditionally, the basic secretion test is performed = following the=20 instillation of topical anesthetic and the placement of a thin strip = of filter=20 paper in the inferior cul-de-sac. Measurement of less than 5 mm is = abnormal;=20 5-10 mm is equivocal.
    • The Schirmer I test, which measures both basic and reflex = tearing,=20 consists of the same test without the use of a topical anesthetic = agent.=20 Less than 10 mm of wetting after 5 minutes is diagnostic of ATD. The = test is=20 relatively specific, but it is poorly sensitive.
    • The Schirmer II test measures reflex tearing. It is performed = similar to=20 the basic secretion test, with the addition of nasal mucosal = irritation with=20 a cotton tip applicator. Wetting of less than 15 mm after 5 minutes = is=20 consistent with abnormalities of reflex secretion.
  • Absence of nasal lacrimal reflex tearing, presence of serum=20 autoantibodies, and severe ocular surface disease demonstrated by rose = bengal=20 or fluorescein staining argues strongly in favor of a diagnosis of SS=20 associated KCS.
  • Additional tests include tear film osmolarity, tear lysozyme, and = tear=20 lactoferrin. Tear film osmolarity has been shown to be elevated in = patients=20 with dry eyes. It is a very sensitive test for identifying a dry eye = but lacks=20 specificity. The test often is not used because of the lack of = commercially=20 available equipment for its measurement.

Procedures:

  • Lacrimal gland or minor (salivary) gland biopsy may be performed = to aid in=20 diagnosing SS.
Histologic Findings:=20 Histopathologically, squamous metaplasia with loss of goblet = cells,=20 cellular enlargement, and increase in cytoplasmic/nuclear ratio of the=20 superficial conjunctival epithelial cells are present in patients with = KCS.

TREATMENT Section 6 of 10   

Medical = Care:=20

    • Artificial tears with preservatives up to 4 times = daily
    • Lubricating ointment at bedtime
    • Hot compresses and eyelid massage, especially if associated with = MGD
  • Moderate=20

    • Artificial tears without preservatives 4 times daily to hourly=20

    • Lubricating ointment at bedtime=20

    • Doxycycline 100 mg qd/bid if indicated for MGD=20

    • Lower punctal occlusions
  • Severe=20

    • Perform all of the above treatments=20

    • Punctal occlusions (lower and upper)=20

    • Moist environment (humidifier, moisture shield)=20

    • Lateral tarsorrhaphy

  • Emerging therapy=20

    • Immunomodulatory agents (eg, topical cyclosporine A)=20

    • Topical androgens=20

    • Secretagogues (substance that increases acinar cell activity and = protein=20 synthesis, eg, oral pilocarpine)=20

    • Cytokine-blocking agents

Consultations: A rheumatologist can be consulted if = a=20 systemic collagen vascular disease is suspected.
MEDICATION = Section 7 of 10   

The goal = of=20 pharmacotherapy is to reduce morbidity and to prevent complications.

Drug Category: Ophthalmic agents and = lubricants=20 -- Act as humectants in the eye.
Drug Name
 Artificial tears -- Used to = increase=20 lubrication of the eye.
Adult Dose 1-2 gtt qd/qid (may use more if = preservative-free)
Pediatric Dose Administer as in adults
Contraindications Documented hypersensitivity to=20 preservatives (eg, benzalkonium chloride)
Interactions None reported
Pregnancy A - Safe in pregnancy=20
Precautions Avoid frequent dosing of = preserved=20 tears
Drug Category: = Antibiotics=20 -- Empiric antimicrobial therapy must be comprehensive, covering = all=20 likely pathogens in the context of the clinical setting.
Drug Name
 Doxycycline (Bio-Tab, Doryx, = Vibramycin)=20 -- Inhibits protein synthesis and thus bacterial growth by binding = to 30S=20 and possibly 50S ribosomal subunits of susceptible bacteria.
Adult Dose 100 mg PO qd/bid if indicated = for MGD
Pediatric Dose <8 years: Not = recommended
>8=20 years: 2-5 mg/kg/d PO in 1-2 divided doses; not to exceed 200 mg/d
Contraindications Documented hypersensitivity; = severe=20 hepatic dysfunction
Interactions Bioavailability decreases with = antacids=20 containing aluminum, calcium, magnesium, iron, or bismuth = subsalicylate;=20 tetracyclines can increase hypoprothrombinemic effects of = anticoagulants;=20 tetracyclines can decrease effects of oral contraceptives, causing = breakthrough bleeding and increased risk of pregnancy
Pregnancy D - Unsafe in pregnancy=20
Precautions Photosensitivity may occur with = prolonged=20 exposure to sunlight or tanning equipment; reduce dose in renal=20 impairment; consider drug serum level determinations in prolonged = therapy;=20 tetracycline use during tooth development (last one half of = pregnancy=20 through age 8 y) can cause permanent discoloration of teeth; = Fanconilike=20 syndrome may occur with outdated = tetracyclines
FOLLOW-UP Section 8 of 10    =

Further Outpatient Care:

In/Out Patient Meds:

  • Artificial tears with and without preservatives depending on=20 severity
  • Doxycycline 100 mg qd/bid if indicated for MGD

Complications:

  • Decreased visual acuity
  • Blindness

Prognosis:

  • In general, prognosis for visual acuity in patients with dry eye = syndrome=20 is good.
MISCELLANEOUS = Section 9 of 10    <= IMG=20 height=3D10 alt=3D"Click here to go to the next section in this = topic"=20 src=3D"http://www.emedicine.com/images/next3.gif" width=3D31 = align=3Dmiddle=20 border=3D0>

Medical/Legal Pitfalls:

  • Early detection and aggressive therapy will reduce the incidence = of=20 corneal ulcer.
BIBLIOGRAPHY = Section 10 of 10   =

NOTE:
Medicine is a constantly = changing=20 science and not all therapies are clearly established. New = research=20 changes drug and treatment therapies daily. The authors, editors, = and=20 publisher of this journal have used their best efforts to provide=20 information that is up-to-date and accurate and is generally = accepted=20 within medical standards at the time of publication. However, as = medical=20 science is constantly changing and human error is always = possible,=20 the authors, editors, and publisher or any other party involved = with the=20 publication of this article do not warrant the information in this = article=20 is accurate or complete, nor are they responsible for omissions or = errors=20 in the article or for the results of using this information. The = reader=20 should confirm the information in this article from other sources = prior to=20 use. In particular, all drug doses, indications, and = contraindications=20 should be confirmed in the package insert. FULL = DISCLAIMER=20
eMedicine Journal,=20 August 27 2001, Volume 2, Number 8

Dry = Eye Syndrome=20 excerpt

=A9 Copyright 2002, eMedicine.com,=20 Inc.=20
 eMedicine Journal = > Ophthalmology > Lacrimal System > Dry Eye = Syndrome=20
Home | Search | Contents | A-Z=20 Index | Tools | Updates | Medline | Cover | Dictionary | GetCME | Rate this topic | Help
We are offering CME = for this=20 topic. Click on the GetCME button to take CME (Your first test = is=20 Free!)

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