Symptoms
The most frequent clinical findings of dry eye can be meibomitis, telangiectasis, blepharitis, superficial punctate keratopathy, and hyperemia. Commonly, we describe typical symptoms of keratoconjunctivitis as dryness, burning[3] and a sandy or gritty eye irritation that becomes worse as the day progresses.[1] Symptoms may also be described as itchy,[3] scratchy,[4] stingy[3] or tired[3] eyes. Other symptoms are pain,[5] redness,[5] a pulling sensation,[3] and pressure behind the eye[3].
Many patients report a feeling that something,[3] such as a speck of dirt,[5] is in the eye. The resultant
damage to the eye's corneal surface increases discomfort and sensitivity to bright light.[3] Both eyes usually are affected.[6] There may also be a stringy discharge from the eyes.[5] Although it may seem counterintuitive, dry eye can induce the eyes to water.[5] This watering occurs because the eyes are irritated.[5] One may experience excessive tearing in the same way as one would if something became lodged in the eye.[5] These watery reflex tears will not reduce the dry eye
symptoms[5] because this type of tear is the watery type that are produced in response to injury, irritation, or emotion.[5] They do not have the lubricating and wound healing qualities necessary to prevent and heal dry eye.[5]
In those suffering from dry eye, blinking can have a negative impact as well as a positive. On the one hand, blinking causes the eyelid to induce shear forces on the cornea as the lid moves across the corneal surface. This force can be high and lead to abrasion of the corneal surface if the normal, protective tear film is not in place to absorb the shear forces. On the other hand, because in the normal eye blinking coats the corneal surface with tears,[5] symptoms can be worsened by activities in which the rate of blinking is reduced due to prolonged use of the eyes[3]. These activities include prolonged reading,[1] computer usage,[1][3][5] driving,[3] or watching television[3][5]. The severity of symptoms increase in windy,[5] dusty[3][5] or smoky (including cigarette smoke[5]) areas,[1][3] in dry environments[1][3], high altitudes including airplanes,[6] on days with low humidity,[3] and in areas where an
air conditioner[5] (especially in a car[3]), fan,[3] heater,[3] or even a hair dryer[5] is being used. The severity of symptoms are reduced during cool, rainy, or foggy weather and in humid places, such as in the shower.[3]
Many people experiencing dry eyes exhibit mild irritation with no long-term effects.[5] However, if the condition progresses, complications may result that cause eye damage,[5] resulting in impaired vision or infrequently in the loss of vision[3,5].
Symptom assessment is a key component of
dry eye diagnosis, and objective measurements often are unable to fully describe the disease. Several questionnaires have been developed to determine a score that would allow for dry eye diagnosis. The McMonnies & Ho dry eye questionnaire is frequently used in clinical studies of dry eyes. A version of the questionnaire can be accessed at:
http://www.dipolarhosting.net/agingeye/dryeye.asp.
Epidemiology and Etiology
Over time the condition of dry eye can lead to tiny abrasions on the surface of the eyes.[4] In advanced cases of dry eye, the epithelium undergoes pathologic changes, such as squamous metaplasia and loss of goblet cells.[1] Severe cases can also result in thickening of the corneal surface,[3] corneal erosion,[1] punctate keratopathy,[1] epithelial defects,[1] corneal ulceration (sterile and infected),[1] corneal neovascularization,[1] corneal scarring,[1][3] corneal thinning,[1] and even corneal perforation[1].
Keratoconjunctivitis sicca is relatively common within the United States, especially so in older patients.[1] Specifically, the persons most likely to be affected by dry eyes are those aged 40 or older.[6]
While persons with autoimmune diseases have a high likelihood of having dry eyes, most persons with dry eyes do not have an autoimmune disease.[6] Instances of Sjögren syndrome and keratoconjunctivitis sicca associated with it are present much more commonly in women, with a ratio of 9:1.[1] In addition, milder forms of keratoconjunctivitis sicca also are more common in women.[1] This is partly because hormonal changes,[6] such as those that occur in pregnancy, menstruation, and menopause,[6] can decrease tear production.[5] Dry eye is commom in areas of the world where malnutrition is common and the diet is deficient in vitamin A.[23] There are no racial correlates for this disease.[1]
An abnormality of any one of the three layers of tears produces an unstable or inadequate tear film composition, resulting in symptoms of keratitis sicca.[1] To help keep your eyes feeling comfortable and the optical components of your corneal surface in optimal condition, a normal, thin film of tears coats your eyes.
Three main layers make up this tear film:
The innermost layer is the thinnest and is composed of mucin (or mucus). This thin layer of mucus is produced by the cells in the conjunctiva (the clear skin that lines the eye). The mucus has multiple functions and helps the overlying watery layer to spread evenly over the eye.
The middle layer is acqueous and is thickest. This layer is essentially a very dilute saltwater solution containing many important proteins for protection and healing. The lacrimal glands under the upper lids and the accessory tear glands produce this watery layer. This layer's function is to keep the eye moist and comfortable, flush out any dust, debris, or foreign objects that may enter into the eye, and provide wound healing and protection. Defects of the aqueous layer are the most common cause of dry eye syndrome.
The most superficial layer of the tear film is a very thin layer of lipids (fats or oils). These lipids contain omega-3 fatty acids and are produced by the meibomian glands and the glands of Zeis (oil glands in the eyelids). The main function of this lipid layer is to help decrease evaporation of the watery layer beneath it.
Deficient tear production
Keratoconjunctivitis sicca is usually due to inadequate tear production.[1][3] The aqueous tear layer is affected, resulting in aqueous tear deficiency (ATD) or lacrimal hyposecretion.[1] The lacrimal gland does not produce sufficient tears to keep the entire conjunctiva and cornea covered by a complete layer.[3] This usually occurs in people who are otherwise healthy. Increased age is associated with decreased tearing.[1] This is the most common type found in postmenopausal women.[3][7]
Causes include idiopathic, congenital alacrima, xerophthalmia, lacrimal gland ablation, and sensory denervation.[1] In rare cases, it may be a symptom of collagen vascular diseases, including rheumatoid arthritis[3], Wegener's granulomatosis, and systemic lupus erythematosus.[1] Sjögren's syndrome[3] and autoimmune diseases associated with Sjögren's syndrome are also conditions associated with aqueous tear deficiency.[1] Drugs such as isotretinoin,[3] sedatives,[3][6] diuretics,[3] tricyclic antidepressants,[6] antihypertensives,[3] oral contraceptives,[1][3] antihistamines,[1][3][5] nasal decongestants,[5] beta-blockers,[1] phenothiazines,[1] atropine,[1], and pain relieving opiates such as morphine[6] can cause or worsen this condition. Infiltration of the lacrimal glands by sarcoidosis or tumors, or postradiation fibrosis of the lacrimal glands can also cause this condition.[1]
Abnormal tear composition
Keratoconjunctivitis sicca can also be caused by abnormal tear composition resulting in rapid evaporation[3] or premature destruction of the tears.[1] When caused by rapid evaporation, it is termed evaporative dry eyes.[3] In this, although the tear gland produces a sufficient amount of tears, the rate of evaporation of the tears is too rapid.[3] There is a loss of water from the tears that results in tears that are too "salty" or hypertonic. As a result, the entire conjunctiva and cornea cannot be kept covered with a complete layer of tears during certain activities or in certain environments.[3] Dry-eye disease is accompanied by an increase in the proinflammatory forms of IL-1 (IL-1 alpha and mature IL-1 beta) and a decrease in the biologically inactive precursor IL-1 beta in tear fluid. Increased protease activity on the ocular surface may be one mechanism by which precursor IL-1 beta is cleaved to the mature, biologically active form. The conjunctival epithelium appears to be one source of the increased concentration of IL-1 in the tear fluid of patients with dry-eye disease. These results suggest that IL-1 may play a key role in the pathogenesis of keratoconjunctivitis sicca. Other identified factors in the tear film that may be altered in dry eye include epidermal growth factor (EGF), monocyte chemoattractant protein (MCP)-1, IL-8, tissue inhibitor of metalloproteinase (TIMP)-1 and -2, and numerous previously undetected tear components, such as angiogenin (ANG), VEGF, and the CXC and CC chemokines IFN-gamma inducible protein (IP)-10, growth-related oncogene (GRO), epithelial neutrophil-activating protein (ENA)-78, and macrophage inflammatory protein (MIP)-3alpha.
One reason aging is associated with dry eye is because tear production decreases with age.[5] Dry eye may also be caused by thermal or chemical burns, or (in epidemic cases) by adenoviruses. Diabetics are at increased risk for the disease.[8][9]
An eye injury or other problem with the eyes or eyelids, such as bulging eyes or a drooping eyelid can cause keratoconjunctivitis sicca.[4] Disorders of the eyelid can impair the complex blinking motion required to spread tears.[6]
About half of all people who wear contact lenses complain of dry eyes.[5] This is because soft contact lenses, which float on the tear film that covers the cornea, absorb liquid from the tears.[5] Dry eye also occurs or becomes worse after LASIK and other refractive surgeries, in which the corneal nerves are cut during the creation of a corneal flap.[5] The corneal nerves stimulate tear secretion.[5] Dry eyes caused by these procedures often, but not always, resolve after several months.[6] Persons who are thinking about refractive surgery should consider this possible side-effect.[5]
Abnormalities of the lipid tear layer caused by blepharitis and rosacea, and abnormalities of the mucin tear layer caused by vitamin A deficiency, trachoma, diphtheric keratoconjunctivitis, mucocutaneous disorders and certain topical medications are causes of keratoconjunctivitis sicca.[1]
Persons with keratoconjunctivitis sicca have elevated levels of tear nerve growth factor (NGF).[1] It is possible that this ocular surface NGF plays an important role in ocular surface inflammation associated with dry eyes.[1]
Rosacea is a chronic skin disorder, affecting the face and chest, and develops mostly in the 3rd to 6th decades of life. It is characterized by erythema, telangiectasias, and recurrent flushings. During the time of this chronic inflammation, skin typically develops papules, pustules, and swelling. Ocular involvement occurs in 3 to 58% of patients with skin changes. Common ocular signs include blepharoconjunctivitis, meibomitis, and dry eyes. Rosacea keratitis, when present, however, has a poor prognosis and may lead to blindness. Among skin diseases, Helicobacter pylori infection has sometimes been related with rosacea. A higher prevalence of indigestion and Helicobacter pylori infection in rosacea patients than in healthy controls has been reported in limited studies. However, no causal relation has been identified. On the other hand, oral treatment with metronidazole is beneficial in all of three mentioned manifestations of rosacea (skin, eye, indigestion). More research is required to explore this possible link.
Diagnosis
Dry eyes can usually be diagnosed by the symptoms alone.[3] Tests can determine both the quantity and the quality of the tears.[6] A slit lamp examination can be performed to diagnose dry eye and to document any damage to the corneal surface.[1][3]
A Schirmer's test is used to measure the amount of moisture bathing the eye.[3] This test is useful for determining the severity of the condition.[5] A five-minute Schirmer's test with and without anesthesia using a Whatman #41 filter paper 5 mm wide by 35 mm long is performed.[1] For this test, wetting under 5 mm with or without anesthesia is considered diagnostic for dry eyes.[1]
If the results for the Schirmer's test are abnormal, a Schirmer II test can be performed to measure reflex secretion.[1] In this test, the nasal mucosa is irritated with a cotton-tipped applicator, after which tear production is measured with a Whatman #41 filter paper.[1] For this test, wetting under 15 mm after five minutes is considered abnormal.[1]
Tear breakup time (TBUT) tests measures the time it takes for tears to break up in the eye.[5] The tear breakup time is determined after placing a drop of fluorescein in the cul-de-sac (under the corner of the lower eyelid).[1]
A tear protein analysis test measures the lysozyme contained within tears.[1] In tears, lysozyme is part of the superficial immune system and accounts for more than 20 percent of total protein content.[1] A lactoferrin (an anti-microbial) analysis test provides good correlation with other tests.[1]
The presence of recently described molecules, the diadenosine polyphosphates, naturally occurring in tears, are abnormally high in different states of ocular dryness. One molecule, Ap4A, which is important in ocular healing (Mediero et al, 2006), can be quantified biochemically simply by acquiring a tear sample with a plain Schirmer test. Utilizing this technique it is possible to determine the concentrations of Ap4A in the tears of patients and in such a manner to diagnose objectively dry eye[10].
Treatment
A variety of approaches can be taken to treatment. These can be summarized as: avoidance of exacerbating factors, tear stimulation and supplementation, wound healing and prevention, increasing tear retention, eyelid cleansing, and treatment of eye inflammation.[11]
General measures
Dry eyes can be exacerbated by smokey environments, dust and air conditioning and by our natural tendency to reduce our blink rate when concentrating. Purposefully blinking, especially during computer use and resting tired eyes are basic steps that can be taken to minimise discomfort.[11]
Rubbing one's eyes can irritate them further, so should be avoided [6]. Conditions such as blepharitis can often co-exist[11] and paying particular attention to cleaning the eyelids morning and night with mild shampoos and warm compresses can improve both conditions.
Environmental control
Dry, drafty environments and those with smoke and dust should be avoided.[3] This includes avoiding hair dryers, heaters, air conditioners or fans, especially when these devices are directed toward the eyes.[6] Wearing glasses or directing gaze downward, for example, by lowering computer screens can be helpful to protect the eyes when aggravating environmental factors cannot be avoided [6]. Using a humidifier,[3][4] especially in the winter,[4] can help by adding moisture to the dry indoor air[6].[11]. For mild and moderate cases, supplemental lubrication is an important part of treatment.[1] Application of artificial tears every few hours[3] can provide temporary relief.
Autologous serum eye drops
None of the commercially available artificial tear preparations include essential tear components such as epidermal growth factor, hepatocyte growth factor, fibronectin, neurotrophic growth factor, and vitamin A-all of which have been shown to play important roles in the maintenance of a healthy ocular surface epithelial milieu. Autologous serum eye drops contain these essential factors. However, there is some controversy regarding the efficacy of this treatment. At least one study (PubMed) has demonstrated that this modality is more effective than artificial tears in a randomized control study.
Additional options
Lubricating tear ointments can be used during the day, but they generally are used at bedtime due to poor vision after application.[1] They contain white petrolatum, mineral oil, and similar lubricants.[1] They serve as a lubricant and an emollient.[1] Application requires pulling down the eyelid and applying a small amount (0.25 in) inside.[1] Depending on the severity of the condition, it may be applied from every hour to just at bedtime.[1] It should not be used with contact lenses.[1] Specially designed glasses that form a moisture chamber around the eye may be used to create additional humidity.[6]
Medication
Inflammation occurring in response to tears film hypertonicity can be suppressed by mild topical steroids or with topical immunosuppressants such as cyclosporin.[12][13] For example, elevated levels of tear NGF have been shown to be decreased with 0.1% prednisolone.[1]
Fish consumption and omega-3 fatty acids
Consumption of dietary omega-3 fatty acids is associated with a decreased incidence of dry eye syndrome in women.[14] The underlying mechanism may be a reduction in pro-inflammatory proteins in the tear film.[14]. Early experimental work on omega-3 has shown promising results when used in a topical application [15] or given orally.[16]. We suggest using omega-3 fatty acids in both ways; orally and topically (alpha-linolenic acid was used in the study of topicals) .
Restasis
Topical cyclosporine A (tCSA) 0.05% ophthalmic emulsion is an immunosuppressant, marketed in the United States by Allergan under the trade name Restasis[1]. Approved as a prescription drug by the U.S. Food and Drug Administration[5] in 2002, the eye drop is reported to decrease surface inflammation[6]. Restasis is thought to work through inhibition[17] of transcription factors required for cytokine production and T-lymphocyte maturation.[18] A review of the summary basis of approval from the FDA website shows in a trial involving 1200 people, Restasis demonstrated a small positive effect: increased tear production in 15% of patients, compared to 5% with placebo[5]. Thus, only 10% of dry eye patients benefit from Restasis.
The typical prescription for Restasis is one drop instilled in each eye twice a day, 12 hours apart.[1] Restasis should not be used while wearing contact lenses,[1] during eye infections [5] or in people with a history of herpes virus infections[6]. Side effects include burning sensation (common)[5], redness, discharge, watery eyes, eye pain, foreign body sensation, itching, stinging, and blurred vision.[1][5] Long term use of cyclosporin at high doses is associated with an increased risk of cancer[19][20].
Generic alternatives
Less expensive generic alternatives to Restasis are available in some countries. In India, the generic is marketed as Cyclomune by Sun Pharma.[20]
Conserving tears
There are methods that allow both natural and artificial tears to stay longer, but have limited benefit[6]
Blocking tear drainage
In each eye, there are two puncta,[22] which are small openings that drain tears into the tear ducts[5]. There are methods to partially or completely close the tear ducts.[6] This blocks the flow of tears into the nose, and thus more tears are available to the eyes.[3]
Punctal plugs
Punctal plug
Punctal plugs are inserted into the puncta to block tear drainage.[5] For people who have not found dry eye relief with drugs, punctal plugs may provide limited benefit.[5] The plugs are reserved for people with moderate or severe dry eye when other medical treatment has not been adequate.[5]
Cauterization
If punctal plugs are effective, thermal[6] or electric[1] cauterization of puncti can be performed.
In thermal cauterization, a local anesthetic is used, and then a hot wire is applied.[6] This shrinks the drainage area tissues and causes scarring, which closes the tear duct.[6]
Customized contact lenses
Persons with severe dry eyes may benefit from the Boston Ocular Surface Prosthesis, which is a customized contact lens.[6] Resting on the sclera, the prosthesis creates a fluid filled layer over the cornea, thus preventing corneal drying.[6]
Surgery
In severe cases of keratoconjunctivitis sicca, tarsorrhaphy may be performed where the eyelids are partially sewn together. This reduces the palpebral fissure (eyelid separation), ideally leading to a reduction in tear evaporation.[3]
Experimental topical growth factors
Eye drops, containing the factors present in the normal, healthy corneal tissue, that are topically applied to the corneal surface are currently in clinical testing for moderate to severe dry eye. These eye drops are currently in development at A & G Therapeutics, Inc. of Irvine, CA in the USA.
Prognosis
Keratoconjunctivitis sicca usually is a chronic problem.[6] Prognosis of the disease shows considerable variance, depending upon the severity of the condition.[1] Many patients have mild-to-moderate cases, and can be treated symptomatically with lubricants[1] providing an adequate relief of symptoms.[1]
When dry eye symptoms are severe, vision and the quality of life is diminished.[5] People sometimes feel their vision blurs with use,[3] or severe irritation[3] to the point that they have trouble keeping their eyes open[5] or they may not be able to work or drive[5]. Those using a CRT or computer screen all day at work will likely experience extreme discomfort, sometimes to the point of being visually disabled.
Prevention
Experimental procedures to prevent dry eye are being studied. These methods include the topical application of stem cell derived proteins and other nutrients to revitalize the natural protein and nutrient content of the acqueous portion of the tear film.
References
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- A. Peral, G. Carracedo, M.C. Acosta, J. Gallar, J. Pintor."Increasing Levels of Diadenosine Polyphosphates in Dry Eye" (2006)Invest. Ophthalmol. Vis. Sci.47 (9):4053–4058 [1]
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- Tatlipinar S, Akpek E (2005). "Topical cyclosporine in the treatment of ocular surface disorders". Br J Ophthalmol 89 (10): 1363–7. doi:10.1136/bjo.2005.070888. PMID 16170133.
- Barber L, Pflugfelder S, Tauber J, Foulks G (2005). "Phase III safety evaluation of cyclosporine 0.1% ophthalmic emulsion administered twice daily to dry eye disease patients for up to 3 years". Ophthalmology 112 (10): 1790–4. doi:10.1016/j.ophtha.2005.05.013. PMID 16102833.
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- Rashid S, Jin Y, Ecoiffier T, Barabino S, Schaumberg M, Dana R D (2008). "Topical Omega-3 and Omega-6 Fatty Acids for Treatment of Dry Eye". Arch Ophthalmol 126 (2): 219–225. doi:10.1001/archophthalmol.2007.61. PMID 18268213.
- Creuzot C, Passemard M, Viau S, Joffre C, Pouliquen P, Elena PP, Bron A, Brignole F (2008). "Improvement of dry eye symptoms with polyunsaturated fatty acids". J Fr Ophtalmol 29 (8): 868–73. doi:JFO-10-2006-29-8-0181-5512-101019-200606358. PMID 17075501.
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- Barber LD, Pflugfelder SC, Tauber J, Foulks GN. 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.
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