Alternative Therapies for Dry Eye Disease

Rhiya Mittal; Sneh Patel; Anat Galor

Disclosures

Curr Opin Ophthalmol. 2021;32(4):348-361. 

In This Article

Treating Meibomian Gland Dysfunction

Proper incorporation of meibum into the tear film is necessary for preventing evaporation of the inner muco-aqueous layer. Meibum secretion from MG can be impaired by MG hypofunction (MG dropout, injury, inflammation), MG duct obstruction (blepharitis, occlusion), and/or altered meibum quality,[14] all of which may manifest as ETD.[37] Current treatments for ETD aim to reduce some of these underlying abnormalities, including inhibiting inflammation, clearing obstructed ducts, and/or softening and physically expressing meibum.[14] Several emerging therapies have targeted these underlying causes in various ways.

Thermal and Massage Treatments

Inspissated meibum has a high viscosity, reducing its ability to pass through MG ducts. Studies have determined that the optimal temperature required to soften inspissated meibum is 41.5°C,[38] but in-home treatments with warm and moistened towels are not efficient at delivering or maintaining this temperature.[39] Solving this issue, multiple devices have been developed for in-office use.

For example, the LipiFlow Thermal Pulsation System (Johnson & Johnson Vision, Jacksonville, Florida) delivers a constant temperature of 42.5°C during a 12-min treatment session while simultaneously pulsating in order to physically express meibum.[40,41] In one study, 200 individuals with MGD (OSDI≥13, MG obstruction, lipid layer≤80 mm) were either treated with LipiFlow (n = 101, one treatment) or served as controls in a case-crossover design (n = 99, treated with warm compresses 2×/day for 3 months then LipiFlow).[42] Three months posttreatment, the treatment group showed greater symptom improvement (ΔOSDI: –24.0 ± 20.9 treatment vs –17.1 ± 18.6 control; P < 0.002) and MG expression (ΔMeibomian Gland Evaluator[43] score, examination of 15 glands, range 0–45, lower score indicates greater abnormality; +11.2 ± 9.3 treatment vs +4.5 ± 8.2 control; P < 0.0001) than the control group. At 12 months, after all individuals were treated with Lipiflow, the two groups improved from baseline in OSDI (treatment: 44.1 ± 20.4 to 21.6 ± 21.3; P < 0.0001 vs crossover: 51.8 ± 23.1 to 24.0 ± 23.2; P < 0.001; between groups: P = 0.9). MG expression scores were similarly improved between the groups (treatment: 6.40 ± 3.70 to 17.3 ± 9.1; P < 0.0001 vs crossover: 6.3 ± 3.6 to 18.4 ± 11.1; P < 0.001; between groups: P = 0.7) scores. Although no serious adverse events were reported with LipiFlow treatment, some subjects did experience transient eye/eyelid discomfort (1.5%) and eyelid skin dermatitis (1.5%). Overall, these data highlight the ability of a single LipiFlow treatment to improve symptoms and signs of MGD compared to hot compresses, with sustained effects for at least one year.[42]

Other devices have since entered the market with comparable results at lower price. The TearCare (Sight Sciences, Menlo Park, California) utilizes four adhesives that attach to each tarsal plate to deliver heat (41–45°C) to the MG s for 12 min. Following the thermal treatment, manual in-office meibum expression is performed.[44] The major difference from LipiFlow is that there is no massage component and patients are encouraged to blink during treatment to naturally stimulate meibum expression. A randomized clinical trial of 24 subjects with DED (symptoms, TBUT < 10 s, Schirmer≤10 mm) divided subjects into treatment (n = 12, one TearCare treatment) or control (n = 12, daily warm compress) for 4 weeks. Both groups had evidence of MGD at baseline with MG expression scores (via MG Evaluator) of 6.3 ± 3.6 in the treatment group and 9.0 ± 4.3 in the control group. After 4 weeks, symptoms (via Standardized Patient Evaluation of Eye Dryness (SPEED II, range 0–28): 15.7 ± 5.2 to 7.8 ± 3.5; P-value not given) and signs (TBUT: Δ11.7 ± 2.6 s; P < 0.0001, corneal staining: 3.5 ± 1.8 to 0.2 ± 0.4; P < 0.001) improved to a greater degree in the treatment vs control group, although between group p values were not presented. The treatment group also showed a greater improvement in MG expression scores (treatment: 6.3 ± 3.6 to 41.0 ± 2.1; P < 0.001 vs control group: 9.0 ± 4.3 to 8.2 ± 4.0; P-value not given; between groups: P < 0.0001). Along with these promising results, no adverse reactions were reported due to treatment.[44]

Another available device for heating the MG is iLux (Alcon, Fort Worth, Texas). iLux is a handheld battery-powered device that utilizes inner and outer pads to deliver heat (38–42°C) to the palpebral conjunctiva and external eyelids for eight minutes. Advantages over LipiFlow include focus-guided tips that provide customized eyelid warming and compression and a magnifying lens for visualization of MG ducts during treatment.[45] In an open-label study of 142 subjects with ETD (OSDI≥23, TBUT<10 s, MG obstruction), subjects were divided 1:1 to receive one bilateral treatment with either iLux or LipiFlow. Compared to baseline, at 4 weeks both groups showed comparable improvements in OSDI (iLux: 50.7 ± 18.6 to 19.5 ± 17.0; P < 0.0001 vs LipiFlow: 50.6 ± 18.7 to 22.6 ± 19.8; P < 0.0001; between groups: P = 0.3) and TBUT (OD values given; iLux: 3.9 ± 1.9 s to 6.7 ± 3.7 s; P < 0.0001 vs LipiFlow: 3.9 ± 2.0 s to 6.6 ± 3.2 s; P < 0.0001; between groups: P > 0.8). Similar degrees of improvement were also seen in MG scores (via MG Evaluator) after 4 weeks (OD values given; iLux: 6.0 ± 3.7 to 23.2 ± 12.1; P < 0.0001 vs LipiFlow: 6.2 ± 4.9 to 24.3 ± 11.2; P < 0.0001; between groups: P > 0.6). A few subjects in the iLux group experienced transient side effects posttreatment (burning sensations, pain, and petechial hemorrhage. Specific side effects in the LipiFlow group were not presented.[45]

Overall, these studies demonstrate that devices that heat and/or massage MGs can have a beneficial impact on symptoms and signs of ETD, in some cases to a greater degree than warm compresses alone.

Intense Pulsed Light

Intense pulsed light (IPL) has also been explored for the treatment of ETD. This therapy delivers short pulses of light (wavelengths 500–1200 nm) to the skin and is widely used by dermatologists to treat pigmented and vascular lesions.[46] Its application to DED was anecdotally noted in 2002, after individuals with rosacea (a dermatological disease often comorbid with DED[47]) had improvements in OSDI, TBUT, and staining after IPL treatment of facial telangiectasias.[48] IPL has been found to work synergistically with MG expression (MGX). In a prospective study, 100 subjects with MGD (Meibomian gland dropout <50%, <6 glands secreting liquid) were divided into 3 treatment groups consisting of MGX (n = 32), IPL (n = 33), or IPL+MGX (n = 35). Three months after last treatment, subjects in the IPL+MGX group had significantly improved OSDI (28.2 ± 16.8 to 15.9 ± 14.6; P = 0.002), TBUT (1.7 ± 1.3 s to 3.0 ± 0.7 s; P = 0.003), and MG dropout (21.0 ± 4.0% to 18.0 ± 5.0%; P = 0.001) whereas subjects who received IPL alone only showed significant improvement in TBUT (1.7 ± 0.7 s to 3.7 ± 1.0 s; P < 0.001) and subjects who received MGX alone only did not show significant improvement in any parameters. Although between groups comparisons were not provided for OSDI or TBUT, MG dropout decreased to a greater degree in the IPL+MGX vs MGX group (IPL+MGX: 21 ± 4% to 18 ± 5%; P = 0.1 vs MGX: 22 ± 10% to 24 ± 11%; P = 0.4; between groups: P < 0.01) and in the IPL vs MGX group (IPL: 33 ± 13% to 29 ± 12%; P = 0.3 vs MGX: 22 ± 10% to 24 ± 11%; P = 0.4; between groups: P < 0.01). However, baseline values did not significantly improve in any group, rendering the data less robust.[49] One open-label and one retrospective study similarly reported improvements in signs of MGD (e.g. MG plugging, TBUT) with combined IPL and MGX.[50,51] Side effects common to participants included mild pain and burning acutely but no long-term adverse effects.

Many hypotheses exist regarding how IPL improves facets of DED, including improved meibum quality due to increased periocular skin temperature, destruction of periocular telangiectasias rich in pro-inflammatory mediators, killing of bacteria, inhibition of inflammatory cytokines (IL-6, tumor necrosis factor (TNF)-α), and reduction of reactive oxidative species.[52] One study nicely demonstrated that IPL reduced inflammatory mediators in tears. In a randomized study, 44 subjects with MGD (SPEED II≥6, MG obstruction) received either active IPL (n = 44 eyes, 14–16J/cm2) or sham treatment (n = 44 eyes, 0J/cm2) 3 times over 12 weeks. At 12 weeks, decreased concentrations of inflammatory mediators were noted in tears of individuals who received active vs sham treatment [Interleukin (IL)-17a (Δactive: −211.7 ± 33.8pg/mL; P < 0.001 vs Δsham: -89.6 ± 22.2pg/mL; P = 0.1; between groups: P < 0.001), IL-6 (Δactive: −405.6 ± 65.6pg/mL; P < 0.01 vs Δsham: −143.5 ± 26.0pg/mL; P-value not given; between groups: P < 0.001), and prostaglandin (PG) E2 (Δactive: −1.6 ± 0.1ng/mL; P-value not given vs Δsham: -0.7 ± 0.1ng/mL; P-value not given; between groups: P < 0.001)]. Interestingly, and similar to what has been noted clinically,[53] no significant correlations were noted between inflammatory mediators and DED parameters (SPEED II, TBUT). Negative correlations were noted between inflammatory markers and number of MG yielding clear secretions (IL-17a: r = −0.7; P < 0.001, IL-6: r = -0.8; P < 0.001), indicating a potential relationship between inflammation and altered meibum quality.[54] Overall, IPL improved symptoms and signs of MGD, as well as inflammation, either alone or in combination with MGX. Missing from the literature are comparisons with other therapies, such as LipiFlow. Such studies are needed to understand the patient population best served by IPL.

Manuka Honey

Antibacterial therapies have previously been used in MGD and ETD, most commonly azithromycin and doxycycline.[55,56] A naturally derived antibacterial agent, Leptospermum spp honey, or Manuka honey, has been incorporated into Optimel eye drops (Melcare Biomedical Pty Ltd, Queensland, Australia). The antibacterial effects of this honey are attributed to its low pH, high osmolarity, and H2O2 content, which inhibits bacterial cell division.[57] A randomized control study of 114 subjects with moderate to severe MGD (MGD grades 1–4,[58] TBUT<10 s) divided subjects into treatment (98% Manuka gel (n = 37) or 16% Manuka drops (n = 37), 2×/day) and control (n = 40; warm compress) groups. At 8 weeks, improvements were seen within all groups at similar degrees in OSDI (98% Optimel: 45.4 ± 17.3 to 29.1 ± 18.7 vs 16% Optimel: 38.2 ± 15.6 to 24.6 ± 13.6 vs control: 36.2 ± 23.3 to 25.3 ± 16.8; P < 0.05 for all; between groups: P = 0.5) and TBUT (98% Optimel: 1.8 ± 1.8 s to 3.0 ± 1.7 s vs 16% Optimel: 1.8 ± 1.8 s to 3.9 ± 2.6 s vs control: 1.5 ± 1.2 s to 3.2 ± 3.8 s; P < 0.05 for all; between groups: P = 0.5). The treatment vs control group did, however, have a more significant improvement in MG expressibility (examination of 5 glands, range 0–3; 98% Optimel: 1.7 ± 3.9 to 0.4 ± 0.6; P < 0.05 vs 16% Optimel: 1.1 ± 1.0 to 0.7 ± 1.4; P < 0.05 vs control: 0.8 ± 0.8 to 0.6 ± 0.8; P = 0.1; between groups: P < 0.05) and meibum quality (sum of values from 8 glands, range 0–3 each gland, total range 0–24), 98% Optimel: 15.6 ± 5.2 to 8.1 ± 4.4 vs 16% Optimel: 15.2 ± 5.7 to 9.5 ± 6.7 vs control: 14.6 ± 5.2 to 11.2 ± 6.0; P < 0.05 for all; between groups: P < 0.01). The potential antibacterial effects of Manuka honey were noted as colony counts of Staphylococcus epidermidis (present in 42% of participants at baseline) decreased after 8 weeks to a greater degree in the treatment groups vs control group (98% Optimel: 696.0 ± 911.0 to 226.0 ± 442.0; P = 0.03 vs 16% Optimel: 421.0 ± 763.0 to 288.0 ± 817.0; P = 0.04 vs control: 248.0 ± 391.0 to 155.0 ± 123.0; P = 0.1; between groups: P = 0.05). However, a confounding factor is that colony counts were higher in the treatment vs control groups at baseline.[59] Unfortunately, another randomized study of 59 subjects with MGD (altered meibum quality and expressibility) found that Manuka honey (n = 32; 16% Optimel drops 2×/day) had similar effects to subjects treated with lubricant eye drops and warm compresses (n = 27) after 21 days follow-up, including various MG parameters.[60] Noted side effects associated with Optimel drops were redness and stinging.[59,60]

In summary, these studies suggest that in-office strategies that warm and massage the eyelids, IPL therapy, and novel antimicrobial agents, may all have a role as alternative therapies for individuals with MGD and ETD.

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