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Background
Severe dry eyes (also known as dry eye syndrome, keratoconjunctivitis sicca, xerophthalmia, xerosis, or sicca syndrome) refers to chronic dryness and resultant inflammation of the cornea and conjunctiva. Dry eye syndrome can occur alone or in conjunction with immunologic disorders such as rheumatoid arthritis, systemic lupus erythematosus, or Sjogren's syndrome (SS).
There are 3 commonly used objective tests for documenting and assessing the severity of dry eyes: (i) the Schirmer test, (ii) the Rose Bengal test, and (iii) tear film break-up time (TFBUT). All are usually performed by ophthalmologists.
Tear production may be measured using the Schirmer test. A small piece of sterile filter paper, supplied in a standard kit, is placed in the lateral third of the lower eyelid. The extent of wetting in a given time is measured. Wetting of less than 5 mm in 5 mins is considered abnormal. Use of topical anesthesia and blotting of the tear reservoir prior to the test may improve accuracy as a measure of basal tear production. The findings are typically similar in both eyes.
End-organ damage to conjunctival and corneal epithelial cells may be assessed by ocular surface staining, which stains areas of devitalized tissue. Rose bengal, lissamine green, or fluorescein dyes may be used to assess the ocular surface. To perform the Rose Bengal test, 10 microliters of 1 % Rose Bengal are instilled into the inferior fornix of the unanesthetized eye. The patient is asked to blink twice to spread the stain over the conjunctiva and cornea. Staining can then be scored by the ophthalmologist using a slit lamp. A pattern of exposure zone (interpalpebral) corneal and bulbar conjunctival staining is typically seen with aqueous tear deficiency. Lissamine green dye has a staining profile similar to that of rose bengal and may cause less ocular irritation. It is not recommended for evaluating corneal epithelial disease.
Fluorescien dye stains areas of the corneal and conunctival epithelia where there is sufficient disruption of intercellular junctions to allow the dye to permeate into the tissue. Saline-moistened fluorescein strips or 1 % to 2 % sodium fluorescein solution is used to stain the tear film. One to 2 mins after instilling the eye, the ocular surface is examined through a biomicroscope using a cobalt blue filter. Staining is more intense when it is observed with a yellow filter. Mild fluoresceein staining can be observed in normal eyes and may be more prominent in the morning. Exposure-zone punctate or blotchy fluorescein staining is observed in dry eye, and staining is more easily visualized on the cornea than on the conjunctiva.
The TFBUT (or tear clearance) provides a global assessment of the function of the lacrimal functional unit and tear exchange on the ocular surface. The test is performed by measuring break-up time and tear osmolality after instillation of fluorescein. Break-up times less than 10 seconds are considered abnormal.
Tear osmolarity is considered a key point in dry eye disease (DED) and its measurement is the gold standard in the diagnosis of dry eye. In a prospective, multi-site clinical study, Sullivan et al (2010) evaluated the clinical utility of commonly used tests and tear osmolarity for evaluating the severity of DED. A total fo 314 consecutive subjects between the ages of 18 and 82 years were recruited from the general patient population, 299 of which qualified with complete datasets. Osmolarity testing, Schirmer test without anesthesia, TFBUT, corneal staining, meibomian dysfunction assessment, and conjunctival staining were performed bilaterally. A symptom questionnaire, the Ocular Surface Disease Index (OSDI), was also administered to each patient. Distributions of clinical signs and symptoms against a continuous composite severity index were evaluated. Osmolarity was found to have the highest correlation coefficient to disease severity (r(2) = 0.55), followed by conjunctival staining (r(2) = 0.47), corneal staining (r(2) = 0.43), OSDI (r(2) = 0.41), meibomian score (r(2) = 0.37), TFBUT (r(2) = 0.30), and Schirmer result (r(2) = 0.17). A comparison of standard threshold-based classification with the composite severity index revealed significant overlap between the disease severities of prospectively defined normal and dry eye groups. Fully 63 % of the subjects were found to be poorly classified by combinations of clinical thresholds. The authors concluded that tear film osmolarity was found to be the single best marker of disease severity across normal, mild/moderate, and severe categories. Other tests were found to be informative in the more severe forms of disease; thus, clinical judgment remains an important element in the clinical assessment of dry eye severity. The results also indicate that the initiation and progression of dry eye is multi-factorial and supports the rationale for re-defining severity on the basis of a continuum of clinical signs.
Suzuki et al (2010) studied the association between tear osmolarity and dry eye severity grade, based on a modified Dry Eye Workshop (DEWS) scale, and between osmolarity and the signs and symptoms that determine dry eye disease severity. A total of 19 patients with DED were asked to complete an evaluation of dry eye signs and symptoms composed of the OSDI questionnaire, corneal staining with fluorescein, conjunctival staining with lissamine green, TFBUT, Schirmer's test with anesthesia, and tear sample collection. Tear samples were collected in 5-microL microcapillaries. Tear osmolarity was measured in the right eye with a tear osmometer. Tear osmolarity correlated significantly with dry eye severity grade (modified DEWS). Schirmer's test and tear osmolarity correlated significantly at r = -0.52, with Schirmer's test result, with adjustment for age, contributing significantly to the independent estimate of tear osmolarity. The authors concluded that tear osmolarity correlates with dry eye severity and therefore could provide a biomarker for disease severity.
Other evidence suggests that assessment of tear osmolarity provides the most objective, measurable test for determining improvement in patients with DED. Benelli et al (2010) assessed the effectiveness of 3 commercially available lubricant eye drops for the treatment of mild, dry, irritated eyes. This randomized investigator-masked study included 60 patients in which 20 subjects used carboxymethylcellulose sodium (CMC), 0.5 % (Cellufresh), Allergan Inc., Irvine, CA) (group 1); 20 subjects used a drop containing polyethylene glycol 400, 2.5 % and sodium hyaluronate (Blink Intensive Tears, Abbott Medical Optics Inc., Santa Ana, CA) (group 2); and 20 subjects used HP Guar 0.18 % (Systane, Alcon Laboratories Inc., Ft. Worth, TX) (group 3). Study visits were at baseline and 1 month. Tests performed at both visits included Schirmer, TFBUT, visual acuity, fluorescein staining, tear osmolarity and wavefront aberrometry. Osmolarity testing was performed prior to instillation of the lubricant eye drops and then a final time 5 mins after instillation of the drop at both day 1 and day 30. Tear osmolarity was performed only in the right eye and only one time before and after instillation of lubricant eye drops. At day 1, the mean reduction in osmolarity 5 mins after instillation of the lubricant eye drop was, -5.0 +/- 1.9 mOsm/L in group 1, -9.0 +/- 4.2 mOsm/L in group 2 and -5.0 +/- 2.2 mOsm/L in group 3. At day 30, the mean reduction in osmolarity 5 mins after instillation of the lubricant eye drop was, -5.6 +/- 2.3 mOsm/L in group 1; -9.9 +/- 2.8 mOsm/L in group 2 and -4.5 +/- 1.8 mOsm/L in group 3. The differences were statistically significant between groups 1 and 2, and 2 and 3. There was a reduction of osmolarity from day 1 to day 30, but the differences were not statistically significant. These researchers felt that after a 30-day treatment with the lubricant eye drops, the lower osmolarity values could indicate that the tear film is progressing towards a more normal osmolarity value. A future study could examine the tear osmolarity value after 60 or 90 days of usage. LogMAR BCVA results showed an improvement in group 2 compared with baseline with no change in BCVA in groups 1 and 3. There was no statistically significant change from day 1 to 1 month in TFBUT, while the Schirmer test showed an improvement in all groups at 1 month. The authors concluded that assessment of tear osmolarity provides the most objective, measurable test for determining improvement in patients with DED.
Tear osmolarity can be measured in the clinical setting. Versura and colleagues (2010) evaluated tear osmolarity in patients with DED versus a control group to assess its diagnostic performance compared to clinical and laboratory tests performed in either clinical or research settings. Tear osmolarity was measured with the TearLab Osmolarity System (OcuSense) in 25 normal subjects and 105 DED patients (severity score 1 to 4, DEWS). The following tests were also performed: OSDI symptoms questionnaire, Schirmer I test, TFBUT, ferning test, lissamine green staining, tear clearance, corneal esthesiometry, and conjunctival cytology by scraping and imprint. Statistical evaluation was performed by un-paired Student's t and Mann-Whitney tests, the Spearman's rho and the Pearson's r correlation coefficients (significance p < 0.05); all variables were also analyzed for sensitivity, specificity, Receiver Operating Characteristics (ROC) curves, likelihood ratio LR+, and positive predictive value (PPV). Tear osmolarity normal values were 296.5 +/- 9.8 mOsm/L, increasing values were shown stepwise DED severity (mild to moderate to severe dry eye, respectively: 298.1 +/- 10.6 versus 306.7 +/- 9.5 versus 314.4 +/- 10.1, p < 0.05). A progressive worsening occurred in all the parameters with DED severity increase. Tear osmolarity exhibited the larger correlation strength versus tear clearance, TFBUT and clinical score, strength increased with DED severity, mainly to inflammatory score and corneal sensitivity. Tear osmolarity 305 mOsm/L was selected as cut-off value for dry eye, 309 mOsm/L for moderate dry eye, 318 mOsm/L for severe dry eye (Area-under-the-curve was 0.737, 0.759, and 0.711, respectively). The authors concluded that tear osmolarity can now be considered a test suitable to be performed in a clinical setting. It showed a good performance in the diagnosis of DED, higher than the other tests considered, mainly in severe dry eye. Tear osmolarity values should be interpreted as an indicator of DED evolutionary process to severity.
The American Academy of Ophthalmology (AAO) recommends the following conservative interventions for dry-eye syndrome: elimination of exacerbating medications where feasible; ocular environmental interventions; computer work site interventions; aqueous tear enhancement with topical agents or external means; and medications. In addition, any lid abnormalities should be corrected. Punctal occlusion or tarsorraphy are indicated in severe cases of dry eye syndrome that are refractory to conservative management.
Cyclosporine ophthalmic emulsion (Restasis) has been approved by the Food and Drug Administration (FDA) to increase tear production in patients whose tear production is presumed to be suppressed due to ocular inflammation associated with keratoconjunctivitis sicca. In patients whose tear production is presumed to be suppressed due to ocular inflammation associated with keratoconjunctivitis sicca, cyclosporine emulsion is thought to act as a partial immunomodulator.
Guidelines from the American Optometric Association (AOA, 2002) state that punctal occlusion may be necessary for persons with severe dry eyes. In its position statement on punctal occlusion for dry eye, the AAO affirmed that punctal occlusion is a surgical procedure, and that it is considered only in patients with moderately severe to severe dry eye when symptoms and signs of dry eye are not adequately controlled by artificial tears and adjustment of medications that may contribute to dry eye symptoms. The AAO position statement explained that patients with mild dry eye frequently do not respond to punctal occlusion, and that failure of response to artificial tears and punctal occlusion suggests other problems, such as blepharitis.
Punctal plugs provide a temporary or semi-permanent means of occluding the punctum (tear duct opening) in patients with severe dry eyes. Temporary occlusion can be performed using collagen plugs, which dissolve within 1 week, to determine if punctal occlusion results in epiphoria. If a trial of temporary punctual occlusion proves successful, patients may then be offered semi-permanent or permanent forms of occlusion. There is little chance that permanent occlusion would be helpful if the plugs did not decrease symptoms of dry eye syndrome.
The opening of the tear ducts (the puncta) can be permanently occluded to retain tears, although it occasionally leads to excess tearing (epiphoria). Semi-permanent (reversible) punctual occlusion can be achieved by non-dissolvable silicone punctual plugs. Less commonly, semi-permanent occlusion may be achieved by suturing the punctum. If the semi-permanent plugs help but do not remain in position, then permanent surgical punctal occlusion can be performed.
The most typical usage of plugs is in the lower two puncta, but some people have plugs in all 4 ducts (2 lower, 2 upper). Punctal plugs are generally made of silicone; silicone punctal plugs last for 6 or more months. More recentntly, plugs for long-term (6 or more month) punctal occlusion made of thermodynamic acrylic polymer (SmartPlug) and hydrogel (Oasis FormFit plug) have been developed.
Short-term punctal plugs, composed of absorbable synthetic materials, have been developed that last less than 6 months have been developed for persons with seasonal symptoms or whose dry eyes are caused by a temporary condition. Examples of short-term punctal plugs include those composed of PCL (e.g., Duraplug Extended Temporary Canalicular Inserts), which last 3 to 6 months; absorbable copolymer of glycolic and trimethylene carbonate (ProLong long term absorbable plugs), which last 3 or more months; synthetic polydioxanone (Dissolvable VisiPlug Lacrimal Plugs), which last approximately 3 months; and synthetic collagen (Oasis extended duration absorbable, Oddesy Extend absorbable implants), which last up to 3 months.
Flow controller plugs that allow partial punctal plug occlusion may be used for persons with epiphoria from standard punctal plugs. Examples of these plugs include the FCI Perforated Plugs, and Eagle Vision Flow Controller Plugs.
Surgical punctal occlusion (occlusive punctoplasty) may be achieved by cautery, electrodessication, simple excision, or argon laser surgery. In its position statement, the AAO affirmed its earlier conclusion that the preferred surgical methods of permanent punctal occlusion are electrodessication or thermal cautery, and that laser punctal occlusion should be discouraged because it is less effective and more expensive than other methods.
In a randomized, controlled, double-masked, single-center clinical trial, Geldis and Nichols (2008) described the impact of punctal occlusion in symptomatic dry eye contact lens wearers and the relation between subjective and objective outcomes. A previously described dry-eye questionnaire was used to determine subject eligibility. Tear interferometry was performed to evaluate pre-lens tear film thickness, contact lens center thickness, and post-lens tear film thickness. Each subject was randomly assigned to receive the punctal plugs or a sham procedure. At the outcome examination, the subject completed the dry-eye questionnaire and answered 1 question rating the efficacy of the punctal plug treatment in addition to undergoing tear interferometry using an identical protocol as the first visit. A total of 19 subjects completed both visits of this study. There was a significant improvement in the dry-eye questionnaire scores from baseline to the outcome visit for both the plug (z = -2.52, p = 0.01) and sham groups (z = -2.93, p = 0.003). A significant increase in pre-lens tear film thickness occurred within the sham group from baseline to the outcome visit (z = -1.96, p = 0.05), but not for the punctal plug group. No other layers measured by interferometry were shown to change significantly for either group. The authors concluded that results comparing the sham and plug groups were not significantly different from each other with regards to the questionnaire score and treatment benefit assessment, indicating either the treatment effect was not detected, although present, or punctal occlusion had no treatment effect at all.
In a pilot study, Hadassah et al (2010) evaluated the effectiveness of succinylated collagen punctal plugs (SCPP) in the treatment of patients with dry eye syndrome (DES). Succinylated collagen punctal plugs were prepared from succinylated collagen with the exact dimensions of the punctum (length 1.5 to 2.5 mm, diameter 0.2 to 0.5 mm, water content between 50 and 55 %). Subjects were evaluated for best corrected visual acuity (BCVA), tear fluid levels (TFL), protein content (PC), tear fluid osmolarity (TFO), fluorescence staining of the cornea and TFBUT before and after punctal occlusion with SCPP. Tear fluid levels improved among all the patients after punctal occlusion with SCPP; BCVA showed improvement in case 4 (right eye/left eye), case 5 (left eye) and case 6 (right eye), who had developed dry eyes due to environmental conditions. Protein content increased on day 7 in all the patients and gradually decreased. Tear fluid levels decreased on days 3 and 5 in all patients after punctal occlusion with SCPP, and showed the same levels on day 14; TFL, PC, TFO and TFBUT showed significant improvement in all the patients after punctal occlusion with SCPP. The authors concluded that all patients experienced symptomatic relief after punctal occlusion with SCPP. There was no discomfort, foreign body sensation, plug extrusion, corneal aberration, infection, or formation of pyogenic granuloma with SCPP. They stated that SCPP is a promising alternative to other punctal plugs in the treatment of DES.
In a randomized, patient-assessor blinded, sham acupuncture controlled trial, Shin et al (2010) assessed the safety and effectiveness of acupuncture for ocular symptoms, tear film stability and tear secretion in dry eye patients. A total of 42 subjects with defined moderate to severe dry eye underwent acupuncture treatment 3 times a week for 3 weeks. Seventeen standard points (GV23; bilateral BL2, GB14, TE23, Ex1, ST1 and GB20; and unilateral SP3, LU9, LU10 and HT8 on the left for men and right for women) with "de qi" manipulation for the verum acupuncture group and 17 sham points of shallow penetration without other manipulation for the sham group were applied during the acupuncture treatment. Differences were measured using the ocular surface disease index (OSDI), the visual analog scale (VAS) of ocular discomfort, the TFBUT and the Schimer I test with anesthesia. In addition, adverse events were recorded. There were no statistically significant differences between results on the OSDI, VAS, TFBUT or Schimer I tests from baseline between the verum and sham acupuncture groups. However, results from the within-group analysis showed that the OSDI and VAS in both groups and the TFBUT in the verum acupuncture group were significantly improved after 3 weeks of treatment. No adverse events were reported during this trial. The authors concluded that both types of acupuncture improved signs and symptoms in dry-eye patients after a 4-week treatment. However, verum acupuncture did not result in better outcomes than sham acupuncture.
Lee and colleagues (2011) evaluated the effectiveness of acupuncture as a treatment option for treating the condition of dry eye. These investigators searched the literature using 14 databases from their inceptions to December 3, 2009, without language restrictions. They included randomized clinical trials (RCTs) comparing acupuncture with conventional treatment. Their risk of bias was assessed using Cochrane criteria. A total of 6 RCTs met all the inclusion criteria. Three RCTs compared the effects of acupuncture with artificial tears in patients with xerophthalmia or Sjögren syndrome. A meta-analysis of these data showed that acupuncture improved tear break-up times (p < 0.0001), Schirmer test scores (p < 0.00001), response rates (p = 0.002) and the region of cornea fluorescent staining (p = 0.0001) significantly more than artificial tears did. The other 3 RCTs compared the effects of acupuncture plus artificial tears with artificial tears alone -- 2 of these studies failed to show significant effects of acupuncture, while 1 reported significant effects. For Schirmer test scores and frequency of artificial tear usage, 2 RCTs reported superior effects of acupuncture plus artificial tears, while 1 RCT failed to do so. The authors concluded that these findings provide limited evidence for the effectiveness of acupuncture for treating dry eye. However, the total number of RCTs, the total sample size and the methodological quality were too low to draw firm conclusions.
Akpek and colleagues (2011) performed an outcomes-based review of reported treatment options for patients with dry eye secondary to SS. A search strategy was developed to identify prospective, interventional studies of treatments for SS-associated dry eye from electronic databases. Eligible references were restricted to English-language articles published after 1975. These sources were augmented by hand searches of reference lists from accessed articles. Study selection, data extraction, and grading of evidence were completed independently by 4 or more review authors. The searches identified 3,559 references as of August 10, 2010. After duplicate review of the titles and abstracts, 245 full-text papers were assessed, 62 of which were relevant for inclusion in the review. The authors concluded that in the current literature on SS-associated dry eye, there is a paucity of rigorous clinical trials to support therapy recommendations. Nonetheless, the recommended treatments include topical lubricants, topical anti-inflammatory therapy, and tear-conserving strategies. The effectiveness of oral secretagogues seems greater in the treatment of oral dryness than ocular dryness. Although oral hydroxychloroquine is commonly prescribed to patients with SS to alleviate fatigue and arthralgias, the literature lacks strong evidence for the efficacy of this treatment for dry eye. The authors also noted that "[s]everal studies demonstrate subjective symptom improvement after the use of serum tears, but there is a paucity of objective evidence that the treatment is beneficial in patients with SS".
The Tear Stability Analysis System (TSAS) is a computerized tear film imaging device that is designed to observe the tear film integrity and evaluate ocular surface deficiency. The instrument utilities an advanced laser to capture and analyze the tear quality of the eye. There is insufficient evidence that the TSAS is effective for the evaluation of patients with dry eyes.
In a prospective case-control study, Gumus et al (2011) evaluated tear film stability in patients with tear dysfunction and an asymptomatic control group by using the novel, non-invasive Tear Stability Analysis System (TSAS). A total of 45 patients with dysfunctional tear syndrome (DTS) were stratified into 3 groups (1, 2, and 3/4) based on clinical severity, with higher scores indicating more severe symptoms; 25 asymptomatic control subjects were evaluated. Tear Stability Analysis System measurements were performed with the RT-7000 Auto Refractor-Keratometer (Tomey Corporation, Nagoya, Japan). Images of ring mires projected onto the cornea every second for 6 seconds were captured and analyzed. Focal changes in brightness were calculated as numerical ring break-up (RBU) values, and the elapsed time when the cumulative values (RBU sum) exceeded a threshold was defined as the ring break-up time (RBUT). RBUTs in the DTS groups were all significantly lower than those in the control subjects, with the lowest values found in DTS 3/4. RBUT was significantly shorter in DTS 3/4 than in DTS 1 (p < 0.001). The change in RBU sum over a 6-second period in the DTS groups combined or between the individual groups was statistically significant (p < 0.001), as was the difference between the 1- and 6-second values. For distinguishing between asymptomatic controls and DTS, the sensitivity and specificity of a 5.0-second RBUT cutoff were 82.0 % and 60.0 %, respectively. The authors concluded that the TSAS may be a useful, non-invasive instrument for evaluating tear stability and for classifying DTS severity. The findings from this small case-control study need to be validated by well-designed studies.
In a pilot study, Abelson et al (2012) examined (i) the use of an improved ocular tear film analysis protocol (OPI 2.0) in the Controlled Adverse Environment (CAE(SM)) model of dry eye disease, and (ii) the utility of new metrics in the identification of subpopulations of dry eye patients. A total of 33 dry eye subjects completed a single-center, single-visit, pilot CAE study. The primary end-point was mean break-up area (MBA) as assessed by the OPI 2.0 system. Secondary end-points included corneal fluorescein staining, tear film break-up time, and OPI 2.0 system measurements. Subjects were also asked to rate their ocular discomfort throughout the CAE. Dry eye end-points were measured at baseline, immediately following a 90-min CAE exposure, and again 30 mins after exposure. The post-CAE measurements of MBA showed a statistically significant decrease from the baseline measurements. The decrease was relatively specific to those patients with moderate-to-severe dry eye, as measured by baseline MBA. Secondary end-points including palpebral fissure size, corneal staining, and redness, also showed significant changes when pre- and post-CAE measurements were compared. A correlation analysis identified specific associations between MBA, blink rate, and palpebral fissure size. Comparison of MBA responses allowed clinicians to identify subpopulations of subjects who exhibited different compensatory mechanisms in response to CAE challenge. Of note, none of the measures of tear film break-up time showed statistically significant changes or correlations in pre-, versus post-CAE measures. The authors concluded that these findings confirmed that the tear film metric MBA can detect changes in the ocular surface induced by a CAE, and that these changes are correlated with other, established measures of dry eye disease. The observed decrease in MBA following CAE exposure demonstrated that compensatory mechanisms are initiated during the CAE exposure, and that this compensation may provide the means to identify and characterize clinically relevant subpopulations of dry eye patients. The findings from this small pilot study need to be validated by well-designed studies.
McGinnigle et al (2012) stated that dry eye is a common yet complex condition. Intrinsic and extrinsic factors can cause dysfunction of the lids, lacrimal glands, meibomian glands, ocular surface cells, or neural network. These problems would ultimately be expressed at the tear film-ocular surface interface. The manifestations of these problems are experienced as symptoms such as grittiness, discomfort, burning sensation, hyperemia, and secondary epiphora in some cases. Accurate investigation of dry eye is crucial to correct management of the condition. Techniques can be classed according to their investigation of tear production, tear stability, and surface damage (including histological tests). The application, validity, reliability, compatibility, protocols, and indications for these are important. The use of a diagnostic algorithm may lead to more accurate diagnosis and management. The lack of correlation between signs and symptoms seems to favor tear film osmolarity, an objective biomarker, as the best current clue to correct diagnosis.
Furthermore, he American Academy of Ophthalmology’s guideline on “Dry eye syndrome” (AAO, 2011) as well as the AAO’s “Dry eye syndrome summary benchmark” (AAO, 2012) did not mention the use of the Tear Stability Analysis System.
In a review on “Emerging drugs for the treatment of dry eye disease”, Gadaria-Rathod et al (2013) noted that recently discovered pathophysiology of DED has prompted investigators to explore new molecules that target the core mechanisms that drive DED. These include anti-inflammatory/immune-modulatory drugs, lubricant, hormones, secretagogues, and autologous serum.
In a Cochrane review, Pan and colleagues (2013) evaluated the safety and effectiveness of autologous serum eye drops (AS) compared to artificial tears for treating dry eye. These investigators searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (The Cochrane Library 2013, Issue 3), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE,(January 1950 to April 2013), EMBASE (January 1980 to April 2013), Latin American and Caribbean Literature on Health Sciences(LILACS) (January 1982 to April 2013), themetaRegister of Controlled Trials (mRCT) (www.controlled-trials.com), ClinicalTrials.gov(www.clinicaltrials.gov) and the WHO International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). They also searched the Science Citation Index Expanded database (September 2013) and reference lists of included studies. They did not use any date or language restrictions in the electronic searches for trials. They last searched the electronic databases on April 15, 2013. These researchers included RCTs in which AS was compared to artificial tears in the treatment of dry eye in adults. Two review authors independently screened all titles and abstracts and assessed full-text articles of potentially eligible trials. Two review authors extracted data and assessed the methodological quality and characteristics of the included trials. They contacted investigators for missing data. For both primary and secondary outcomes, they reported mean differences with corresponding 95 % confidence intervals (CIs) for continuous outcomes. These investigators identified 4 eligible RCTs in which AS was compared with artificial tear treatment or saline in individuals (n = 72 participants) with dry eye of various etiologies (Sjogren’s syndrome-related dry eye, non-Sjogren’s syndrome dry eye and post-operative dry eye induced by laser-assisted in situ keratomileusis (LASIK)). The quality of the evidence provided by these trials was variable. A majority of the risk of bias domains were judged to have an unclear risk of bias in 2 trials owing to insufficient reporting of trial characteristics. One trial was considered to have a low risk of bias for most domains while another was considered to have a high risk of bias for most domains. Incomplete outcome reporting and heterogeneity in the participant populations and follow-up periods prevented the inclusion of these trials in a summary meta-analysis. For the primary outcome, improvement in participant-reported symptoms at 1 month, 1 trial (12 participants) showed no difference in participant-reported symptoms between 20 % AS and artificial tears. Based on the results of 2 trials in 32 participants, 20 % AS may provide some improvement in participant-reported symptoms compared to traditional artificial tears after 2 weeks of treatment. One trial also showed positive results with a mean difference in TBUT of 2.00 seconds (95 % CI: 0.99 to 3.01 seconds) between 20 % AS and artificial tears after 2 weeks, which were not similar to findings from the other trials. Based on all other objective clinical assessments included in this review, AS was not associated with improvements in aqueous tear production measured by Schirmer's test (2 trials, 33 participants), ocular surface condition with fluorescein (4 trials, 72 participants) or Rose Bengal staining (3 trials, 60 participants), and epithelial metaplasia by impression cytology compared to artificial tears (1 trial, 12 participants). Data on adverse effects were not reported by 3 of the included studies. In one study, there were no serious adverse events reported with the collection of and treatment with AS. The authors concluded that overall there was inconsistency in the possible benefits of AS in improving participant-reported symptoms and TBUT and lack of effect based on other objective clinical measures. Moreover, they stated that well-planned, large, high-quality RCTs are warranted, in different severities of dry eye and using standardized questionnaires to measure participant-reported outcomes and objective clinical tests as well as objective biomarkers to assess the benefit of AS therapy for dry eye.
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