Contemporary Diagnosis and Management of Dry Eye
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Introduction Dry eye (DE) disease is characterized by symptoms including, but not limited to, ocular stinging, burning, and tearing. The symptoms can range from being mildly irritating, to severely debilitating and negatively impacting quality of life. The impairment of the tear film, lacrimal functional unit, and meibomian glands (MGs) causes desiccation of the ocular surface, which in turn promotes and exacerbates inflammation. Dry eye is a multifactorial disease and the many causative factors can be completely exclusive from each other. This necessitates that the management of DE be multi-faceted. Dry eye disease affects millions of people around the world and this number will increase as the elderly population rise over the next few decades. However, emerging technologies are allowing clinicians and scientists to constantly discover new ways to diagnose and manage various aspects of DE. The global aim of this thesis was to evaluate some of the contemporary methods used in the diagnosis and management of DE disease. The specific aims of each chapter were as follows: • Chapter 3: To determine whether an experimental spectral domain ultra-long optical coherence tomographer (UL-OCT) can image MGs, and to compare its performance to the Heidelberg Retina Tomograph 3 (HRT3) with Rostock Cornea Module (RCM) in vivo laser scanning confocal microscope (Heidelberg Engineering GmbH, Heidelberg, Germany) and the Keratograph 5M (K5M) (OCULUS, Wetzlar, Germany). • Chapter 4: To determine the inter- and intra-observer repeatability in using the Keratograph 4 (K4) and K5M to grade MG dropout using meibography grading scales. • Chapter 5: To quantify the association of DE diagnostic tests to DE symptoms in an age-matched female cohort. • Chapter 6: To determine the effectiveness of an eyelid warming device in the management of MG dysfunction (MGD). • Chapter 7: To evaluate the effect of lid debridement-scaling (LDS) on DE signs and symptoms in individuals with Sjӧgren’s syndrome (SS). • Chapter 8: To determine the combined effect of a lubricant eye drop, lid hygiene, and omega 3 fatty acids on DE signs and symptoms. Methods • Chapter 3: The superior eyelids of 12 participants were everted and imaged using the UL-OCT. The inferior and superior eyelids were then everted and imaged using the K5M. Finally, the inferior eyelids were everted and imaged with the HRT3/RCM. • Chapter 4: The inferior and superior eyelids of 40 participants were imaged 3 times each on both the K4 and K5M. The images were split into one training and two study sets; the latter were graded (4-point meibography scale) by two observers on two separate occasions (24hrs apart) to examine repeatability. Semi-objective grading of MG dropout was conducted using ImageJ on K4 and K5M images. A 7-point meibography scale was used to grade a separate set of K5M images. • Chapter 5: Twenty females symptomatic of DE (Ocular Surface Disease Index, OSDI, ≥ 13) were age-matched to 20 asymptomatic females (OSDI < 13). Non-invasive tear breakup time (NIBUT), ocular staining, meibum quality, number of obstructed glands, lid wiper epitheliopathy (LWE), Line of Marx (LOM) placement, eyelid margin score, Schirmer’s test, meibography, and visual acuity were compared between the two groups. • Chapter 6: This was a prospective, randomized, controlled, single-masked, bilateral eye study that enrolled 29 participants. Participants were randomized into either the EyeBag group or the control group. Participants in the EyeBag group were instructed to use the EyeBag 10 minutes 2x/day, and the control group remained on their own DE treatment regimen (if applicable). All participants were seen at baseline, 2 weeks and 4 weeks. At 4 weeks, participants in the EyeBag group were asked to stop using the EyeBag. All participants were seen again at the 8 week mark. Primary outcomes were the OSDI, Current Symptoms Questionnaire (CSQ), MG score (MGS), and non-invasive tear break-up time (NIBUT). • Chapter 7: This prospective randomized controlled study enrolled 14 female participants with SS. Seven participants were randomized into the treatment group, where they were selected to receive LDS, the remainder did not receive LDS and served as controls. Lid debridement-scaling was conducted using a stainless steel golf club spud (Hilco Wilson Ophthalmics, Plainville, MA) on both the upper and lower eyelids of both eyes. Outcome variables were assessed prior to LDS and again 1 month later. The outcome variables were the OSDI, Symptoms iN Assessment of Dry Eye (SANDE) visual analogue scores, Sjӧgren’s International Collaborative Clinical Alliance Ocular Staining Score (SICCA OSS), fluorescein tear breakup time (FLBUT), MGS, MG yielding liquid secretions score (MGYLS), and LOM position. • Chapter 8: This prospective study enrolled 28 DE participants. Participants were instructed to use the TheraTears® Lubricant Eye Drops at least 2-4x a day, TheraTears® SteriLid 1-2x a day, and TheraTears® Nutrition 3 gel caps once a day. Participants were followed up at baseline, 1 month and 3 months. Outcome variables were the OSDI, SANDE, NIBUT, osmolarity, number of MGs blocked (#MG blocked), meibum quality, eyelid margin features, Schirmer’s test, tear film lipid layer thickness (LLT), meniscus height, corneal and conjunctival staining. Results • Chapter 3: All twelve participants (7 female, 5 male) completed the study. The only instrument that was able to successfully image MGs was the K5M. • Chapter 4: When using the 4-point scale, inter-observer mean difference (MD) was 0.08±0.55 on day 1 and 0.13±0.50 on day 2, and the concordance correlation coefficient (CCC) was 0.79 and 0.81 on days 1 and 2 respectively. Intra-observer MD was 0.04±0.54, CCC=0.79 for observer 1, and -0.09±0.60, CCC=0.74 for observer 2. For the 7-point scale, inter-observer MD was 0.05±0.45, CCC=0.89 on day 1 and 0.01±0.41, CCC=0.91 on day 2. Intra-observer MD was -0.10±0.35, CCC=0.93 for observer 1 and -0.06±0.30, CCC=0.95 for observer 2. Percentage dropout measured between the K4 and K5M images showed lack of agreement, with only a 21.8% coefficient of repeatability. • Chapter 5: Twenty participant-pairs completed the study. The age (median/interquartile range(IQR)) of the symptomatic group was (60/15) and the asymptomatic group was (62/15). The diagnostic tests (median/IQR, p-value) that were significantly different between the symptomatic group vs. the asymptomatic group were OSDI (35.4/35.4 vs. 3.1/6.7, p < 0.01), NIBUT (2.1s/0.7s vs. 3.0s/3.0s, p = 0.01), meibum quality (3.0/0.0 grade units vs. 2.0/1.0 grade units, p < 0.01), number of obstructed glands (7.0/2.0 glands vs. 5.0/4.8 glands, p < 0.01), and ocular staining (5.5/3.8 grade units vs. 0.5/1.0 grade units, p < 0.01). The diagnostic tests (area under curve (AUC), odds ratio (OR)) that were most strongly associated with DE symptoms were ocular staining (0.93, 5.0), number of glands obstructed (0.79, 2.6), meibum quality (0.76, 2.4), and NIBUT (0.74, 3.2) (all p < 0.05). There was no significant difference between the two groups for the other DE diagnostic tests (all p > 0.05), and similarly, no significant association to DE symptoms (all p > 0.05). • Chapter 6: Twenty five participants completed the study (mean age 38±15 years, 7 male). There was a significant change in OSDI over time for the EyeBag group (mean values±SD, baseline: 39.1±12.5, week 2: 26.8±11.2, week 4: 26.6±26.6, week 8: 27.7±14.6; p<0.05), but no significant change in the control group. There was a significant improvement in symptoms immediately after conducting the EyeBag based on at-home CSQ scores (Δ=-5.0 points, p<0.05), but no significant change in the control group. There was no significant change in MGS and NIBUT over time for either group. • Chapter 7: There were 13 participants that completed the study. Data from the right eye only were analyzed. For the control group (n=6, mean age=62±12), the pre LDS, post LDS, and significance level (pre-mean±SD, post-mean±SD; p-value) were: OSDI (58.3±22.1, 48.3±29.0; p=0.051), SANDE (77.4±22.1, 89.6±32.6; p=0.20), SICCA OSS (7.0±4.5, 8.2±3.5; p=0.25), MGS (1.3±1.5, 1.0±0.9; p=0.75), MGYLS (0.3±0.5, 0.0±0.0; p=0.50), FLBUT (2.99 ±1.54, 2.85±1.79; p=0.63), LOM (2.0±0.0, 2.0±0.0, p=n/a). For the treatment group (n=7, mean age=58±8), the pre LDS, post LDS, and significance level were: OSDI (63.2±13.3, 46.9±19.4; p=0.04), SANDE (72.6±17.1, 77.0±28.0; p=0.54), SICCA OSS (6.6±2.9, 5.0±3.9; p=0.02), MGS (1.0±1.2, 3.1±1.7; p=0.01), MGYLS (0.0±0.0, 0.6±1.0; p=0.50), FLBUT (3.13±0.81, 3.45±1.03; p=0.53), LOM (0.9±0.9, 1.0±1.0, p=1.00). • Chapter 8: There were 20 participants (mean age = 43, from 23 to 66, 17F, 3M) that completed the study. On average, participants used the Lubricant Eye Drop 2.4x/day, the SteriLid 1.1x/day, and the Nutrition 3 gel caps 1x/day. There was a significant change over time (p<0.05) for OSDI (-21.2 points), SANDE (-32.4 points), NIBUT (+0.43s), eyelid margin features (-1.1 grade), meibum quality (-1.0 grade), and #MG blocked (-4.0 glands). Conclusions • Chapter 3: The UL-OCT was unable to image MGs. The HRT3/RCM imaged structures that resembled dermal rete pegs and papillae. Of the three methods used in this study, the only device that was able to successfully image MGs was the K5M. • Chapter 4: Observers graded from -1 to +1 grade units between and within themselves for a 4-point scale, 95% of the time. Although the inter- and intra-observer repeatability of the K4 and K5M were very similar, a low level of agreement in percentage dropout between K4 and K5M images suggests that the two instruments cannot be interchanged. Using a finer scale may be beneficial for detecting change over time. • Chapter 5: The diagnostic tests that were most strongly associated with DE symptoms in older women were ocular staining, meibum quality, number of glands obstructed, and tear film stability. • Chapter 6: The MGDRx® EyeBag was effective at relieving symptoms in participants with DE, but the effect on MG function and tear stability when used for only 4 weeks was modest. • Chapter 7: This pilot study showed that LDS improved symptoms, ocular staining and MG function for the group that received LDS. This indicates that LDS can aid in the management of SS DE. • Chapter 8: After using a combination of TheraTears® Lubricant Eye Drop, SteriLid, and Nutrition, participants experience significant relief in both DE symptoms and signs. This thesis was able to evaluate and suggest improvements to meibography techniques and grading. In addition, this thesis was also able to evaluate the effectiveness of various contemporary methods for DE treatment. The methods used in this study are clinically accessible and clinicians are free to use these findings and apply them directly to their clinical practice.