Management of Meibomian Glands
Number: 0797
Table Of Contents
PolicyApplicable CPT / HCPCS / ICD-10 Codes
Background
References
Policy
Aetna considers devices for evacuating meibomian glands by means of heat and intermittent pressure for the treatment of meibomian gland dysfunction (e.g., the LipiFlow System) experimental and investigational because of insufficient evidence of their effectiveness.
Aetna considers tear film imaging (e.g., LipiView Ocular Surface Interferometer) experimental and investigational because its clinical value has not been established.
Aetna considers in-vivo confocal microscopy experimental and investigational for evaluation of meibomian glands because its clinical value has not been established.
Aetna considers near-infrared dual imaging (e.g., LipiScan Dynamic Meibomian Imager) for evaluation of meibomian glands experimental and investigational because its clinical value has not been established.
Aetna considers the following (not an all-inlusive list) experimental and investigational for the treatment of dry eye because their effectiveness has not been established:
- Androgens
- Autologous platelet-rich plasma drops
- Intense pulsed light
- Intra-ductal probing
- Meibomian gland probing.
Background
Meibomian glands are large sebaceous glands that are located as separate gland strands in parallel arrangement within the tarsal plates of the eyelids. Their oily product, meibum, is secreted via a holocrine mechanism during which meibocytes are transformed into the meibum. Following production in the gland acini, meibum is transported through the ductal system via the connecting duct and the central duct towards the orifice at the free eyelid margin close to the inner eyelid border. Meibum is a complex mixture of various lipids and minor protein components as well as other components of the meibocytes, which form a clear liquid at body temperature. It is transported within the gland by the force of secretory pressure from continuous secretion and by muscular action of the orbicularis muscle and Riolans muscles during blinking. After it is delivered onto the posterior eyelid margin, meibum moves from the posterior eyelid margin reservoir onto the tear meniscus and is pulled as a thin layer onto the pre-ocular tear film every time the eyelid opens. During closure of the eyelid, it is compressed and a small part is continuously renewed. Meibum also has a barrier function against the spillage of tears over the inner border of the eyelid and against the entry of skin lipids (sebum) from the free eyelid margin (Knop and Knop, 2009a; Knop et al, 2009).
Obstructive meibomian gland dysfunction (MGD) is a common source of complaint among patients with dry eye (DE) syndrome and its prevalence increases with age. The principal clinical consequence of obstructive MGD is evaporative DE syndrome. Moreover, chronic obstruction of the meibomian glands may also result in degeneration of the secretory gland tissue that can lead to a secondary hypo-secretion even if the primary obstruction is later resolved by therapeutic approaches. Risk factors in the pathogenesis of obstructive MGD include age, hormonal disturbances and environmental influences (e.g., contact lenses). Furthermore, qualitative alterations in the composition of the meibum may lead to hyper-keratinization of the ductal epithelium and increased viscosity of the meibum. This can result in obstruction of the duct and orifice leading to a lack of meibum on the eyelid margin and tear film with downstream hyper-evaporative DE syndrome. At the same time, obstruction leads to a stasis of meibum inside the meibomian gland with increased pressure and resulting dilatation of the ducts and in atrophy of the acini with rarefaction of the secretory meibocytes and gland dropout. Stasis can also increase the growth of commensal bacteria, their production of oil degrading enzymes and release of toxic mediators. These factors can act as self-enforcing feedback loops that aggravate the primary hyper-keratinization and compositional disturbance of meibum and can hence lead to a progressive MGD (Knop and Knop, 2009b).
Conventional treatments of obstructive MGD entail eyelid hygiene (e.g., lid washing and use of preservative-free artificial tears), omega-3 dietary supplementation (e.g., eicosapentaenoic acid and docosahexaenoic acid), topical antibiotics (e.g., bacitracin and erythromycin), topical corticosteroids, topical cyclosporine, oral antibiotics (e.g., doxycycline, minocycline, and tetracycline), oral omega-6 fatty acids (e.g., linoleic acid and gamma-linolenic acid), as well as unclogging of glands that are blocked, which can be achieved by applying warm compresses to the eyelid or gentle lid massaging (Olson et al, 2003; Romero et al, 2004; Yoo et al, 2005; Perry et al, 2006; Pinna et al, 2007; Souchier et al, 2008; and Foster et al, 2009). Moreover, eyelid-warming devices have also been employed in the treatment of patients with MGD. However, the effectiveness of these devices has not been established.
Thermal Pulsation System (e.g., the LipiFlow System)
In a prospective, non-comparative, interventional case series, Goto et al (2002) assessed the short term safety and effectiveness of an infra-red warm compression device as treatment for non-inflamed MGD. In a total of 37 cases, subjective symptom scores and subjective face scores improved significantly, from 12.3 to 8.4, and from 7.0 to 5.3. The results for tear evaporation rates during forced blinking, fluorescein staining, rose bengal staining, tear film break up time (BUT), and meibomian gland orifice obstruction score had also improved significantly at the end of the 2-week period of infra-red thermotherapy. The authors concluded that the infra-red warm compression device was safe and effective for the treatment of MGD. Moreover, they noted that while the results were promising, the small sample size and lack of comparison group limit the generalizability of the findings.
In a prospective, controlled, observer masked, single intervention trial, Mitra et al (2005) measured changes in tear film lipid layer thickness (LLT) and ocular comfort in normal subjects after 10 mins use of a novel device, which delivers meibomian therapy with latent heat. A total of 24 normal subjects were randomized into three groups: Group I underwent 10 mins treatment with the activated device, Group II used the inactivated device for the same duration of time, and Group III had no intervention. The LLT of each subject was measured with a Keeler Tearscope prior and subsequent to the 10-min period. Subjective alteration in ocular comfort was also assessed. Seven of 8 subjects (87.5 %) in Group I exhibited an increase in LLT. The mean LLT in this group showed a statistically significant increase compared to Groups II and III. Six of 8 subjects (75 %) using the activated device experienced subjective improvement in ocular comfort.
In a prospective, interventional clinical trial, Matsumoto et al (2006) evaluated the safety and effectiveness of an original warm moist air device on tear functions and ocular surface of patients with simple MGD. A total of 15 patients with simple MGD and 20 healthy volunteers were enrolled in this study. The device was applied to the eyes of the subjects for 10 mins. Temperatures of the eyelids and corneas were measured with an infra-red thermometer. Symptoms of ocular fatigue were scored using visual analog scales (VAS). Schirmer test, tear film BUT, DR-1 tear film lipid layer interferometry, fluorescein staining, and rose bengal staining were also performed before and after the application of the eye steamer. After the initial study, another 2-week, prospective, clinical trial was carried out in 10 patients with MGD who received the warm moist air treatment. Ten other patients were also recruited and received warm compress treatment with hot towels for 2 weeks to evaluate the long-term effects of the warm moist air device and the warm compresses on tear film LLT and ocular surface health. The warm moist air device and the warm compresses were applied for 10 mins twice-daily. The changes in VAS scores for symptoms, tear film BUT values, fluorescein, and rose bengal staining scores were examined before and after each treatment during the second trial. VAS scores of ocular fatigue improved significantly with short- and long-term applications of the warm moist air device in both studies. The mean corneal surface and eyelid temperatures showed significant elevation within safe limits 10 mins after the moist air application. The mean tear film BUT prolonged significantly in patients receiving warm moist air applications but did not change significantly in those treated with warm compresses. DR-1 tear film lipid layer interference showed evidence of lipid expression in the patients and controls, with thickening of the tear film lipid layer after 10 mins of warm moist air device use. In the 2-week trial, tear film LLT increased in both warm moist air device and warm compress groups, with a greater extent of increase in the warm moist air device group. The authors concluded that the use of warm moist air device provided symptomatic relief of ocular fatigue and improvement of tear stability in patients with MGD. The new warm moist air device appears to be a safe and promising alternative in the treatment of MGD.
Korb and Blackie (2011) determined- the pressure needed to express the first non-liquid material from non-functional lower lid meibomian glands,
- the pressure required to evacuate all of the expressible material from the glands (simulating the authors' methodology for therapeutic meibomian gland expression), and
- the level of pain associated with these procedures.
All patients (n = 28) were recruited from those presenting for ocular examinations at a single practice. Custom instrumentation exerting pressures from 1.0 to 150.0 psi was developed to quantify the pressure applied during expression. The instrument was applied to the inner surface of the lower lid. The lid was then compressed between the thumb and the contact surface of the instrument. The applied pressure was displayed on a digital meter. The first procedure evaluated the pressure required to obtain the first non-liquid material from non-functional glands. The second evaluated the pressure needed for evacuating all expressible gland contents. The pain response was monitored throughout the procedure. The pressure to obtain the first non-liquid material ranged from 5 to 40 psi (mean of 16.1 +/- 8.2 psi) and for the evacuation of expressible contents, from 10 to 40 psi (mean of 25.6 +/- 11.4 psi). Only 7 % of the patients could tolerate the pressure necessary to administer complete therapeutic expression along the entire lower eyelid. The authors concluded that forces of significant magnitude are needed for therapeutic expression. Pain is the limiting factor for the conduct of this treatment.
In a prospective, cohort, observational, single-center study, Greiner (2016) examined the long-term (3 years) effects of a single (12 minutes) thermal pulsation system (TPS) treatment on symptomatic patients with evaporative DE disease (DED) secondary to MGD. Signs (meibomian gland secretion [MGS] scores and tear film break-up time [TBUT]) and symptoms (Ocular Surface Disease Index [OSDI] and Standard Patient Evaluation of Eye Dryness (SPEED) questionnaires) were determined in 20 patients (40 eyes) with MGD and dry eye symptoms at baseline (BL), 1 month, and 3 years post-TPS treatment using LipiFlow. Meibomian gland secretion scores increased from BL (4.5 ± 0.8) to 1 month (12.0 ± 1.1, p ≤ 0.001). Improvement persisted at 3 years (18.4 ± 1.4) relative to BL (p ≤ 0.001). Meibomian gland secretion scores in all regions of the lower eyelid were improved over BL at 1 month (nasal [p ≤ 0.001], central [p ≤ 0.001], temporal [p ≤ 0.01]) and 3 years (nasal [p ≤ 0.001], central [p ≤ 0.001], temporal [p ≤ 0.001]). Tear break-up time increased from BL (4.1 ± 0.4) to 1 month (7.9 ± 1.4, p ≤ 0.05) but was not significantly different than BL at 3 years (4.5 ± 0.6, p > 0.05). The OSDI scores decreased from BL (26.0 ± 4.6) to 1 month (14.7 ± 4.3, p ≤ 0.001) but returned to BL levels at 3 years (22.5 ± 5.4, p > 0.05). The SPEED scores decreased from BL (13.4 ± 1.0) to 1 month (6.5 ± 1.3, p ≤ 0.001), and this improvement persisted at 3 years (9.5 ± 1.6, p ≤ 0.001). The authors concluded that thermal pulsation may be an effective treatment option for DED secondary to MGD in that a single 12-min procedure is associated with significant improvement in MGS and SPEED scores for up to 3 years. The findings of this small study (n = 20) need to be validated by well-designed studies.
In a prospective, open-label, multi-center study, Blackie et al (2016) examined the sustained effect (up to 1 year) of a single, 12-min vectored thermal pulsation (VTP; LipiFlow) treatment in improving meibomian gland function and dry eye symptoms in patients with meibomian gland dysfunction and evaporative dry eye. This trial included 200 subjects (400 eyes) who were randomized to a single VTP treatment (treatment group) or twice-daily, 3-month, conventional warm compress and eyelid hygiene therapy (control group). Control group subjects received cross-over VTP treatment at 3 months (cross-over group). Effectiveness measures of meibomian gland secretion (MGS) and dry eye symptoms were evaluated at baseline and 1, 3, 6, 9, and 12 months. Subjects with inadequate symptom relief could receive additional meibomian gland dysfunction therapy after 3 (treatment group) and 6 months (cross-over group). At 3 months, the treatment group had greater mean improvement in MGS (p < 0.0001) and dry eye symptoms (p = 0.0068), compared to controls. At 12 months, 86 % of the treatment group had received only 1 VTP treatment, and sustained a mean improvement in MGS from 6.4 ± 3.7 (baseline) to 17.3 ± 9.1 (p < 0.0001) and dry eye symptoms from 44.1 ± 20.4 to 21.6 ± 21.3 (p < 0.0001); 89 % of the cross-over group had received only 1 VTP treatment with sustained mean improvement in MGS from 6.3 ± 3.6 to 18.4 ± 11.1 (p < 0.0001) and dry eye symptoms from 49.1 ± 21.0 to 24.0 ± 23.2 (p < 0.0001). Greater mean improvement in MGS was associated with less severe baseline MGS (p = 0.0017) and shorter duration of time between diagnosis and treatment (p = 0.0378). The authors concluded that a single VTP treatment could deliver a sustained mean improvement in meibomian gland function and mean reduction in dry eye symptoms, over 12 months. A single VTP treatment provided significantly greater mean improvement in meibomian gland function and dry eye symptoms as compared to a conventional, twice-daily, 3-month regimen. These results also suggested that early intervention for MGD would improve treatment outcomes. These researchers stated that while it was not possible to mask the patients to the therapy, a major drawback of this study was that the investigators were not masked.
In a retrospective, single-center study, Kim and co-workers (2017) examined the effect of thermal pulsation treatment (TPT) on tear film parameters, specifically osmolarity and MMP9, in patients with MGD and DED. These investigators reviewed 189 eyes that underwent TPT. Data were collected on pr-e and post-treatment osmolarity, MMP9, TBUT, and OSDI score. Statistical analyses were carried out to detect any significant differences following treatment. Thermal pulsation treatment led to significant improvements in TBUT (mean increase from 4.5 to 8.5 seconds [p < 0.001]), OSDI score (mean decrease from 50.5 to 41.6 [p = 0.024]), and MMP9 (50 % positive rate pre-treatment compared to 2 6% positive rate post-treatment [p < 0.0001]). In the subset of patients who had a baseline osmolarity of greater than 307 mOsm/L (i.e., diagnostic for DED), there was a significant improvement in the mean tear osmolarity from 317.1 to 306.6 mOsm/L after treatment (p = 0.002). The authors concluded that treating MGD was an important component of caring for the DED patient; TPT could improve MMP9 levels on the ocular surface of patients with MGD and DED, as well as improved osmolarity in those with abnormal initial values. These researchers stated that the findings of this study suggested that meibomian glands play an important role in tear film dynamics and, as such, effective therapy such as TPT aimed at improving meibomian gland health, could aid the restoration of normal tear film parameters and decrease patient symptoms of DED and MGD.
The authors stated that as consequence of the retrospective nature of the study, there were several drawbacks to this study. First, all patients included in the study represented those presenting to a tertiary care center. Many had tried and failed prior treatments, which may not be generalizable to all populations. Second, there were differential follow-up times, which could make the data susceptible to mean regression. Despite the range in follow-up times, these data points were included in the statistical analysis because they were still within the potential efficacy time frame of thermal pulsation. Third, there was no opportunity to measure patients serially to determine what exact time-points the treatment led to improved tear film inflammation and osmolarity. These investigators stated that future studies may examine more precisely when and by how much MMP9 levels and osmolarity levels change and at what time-point. Fourth, it was not possible to include a placebo group because of the retrospective nature. In the future, a randomized trial with a placebo group, which could include a sham treatment, may allow for more direct comparison to validate the findings of this study.
The American Academy of Ophthalmology (AAO)’s Preferred Practice Pattern on “Blepharitis” (2018) stated that “There are also several in-office procedural treatments available that may theoretically unclog the inspissated meibomian gland orifices using intense pulsed light (IPL) or mechanical means (e.g., microblepharoexfoliation of the eyelid margin, meibomian gland probing, and/or devices using thermal pulsation). Although there have been industry-sponsored studies, independent, randomized, masked clinical trials have yet to be performed to assess efficacy of these costly, primarily fee-for-service treatments”.
Pang and colleagues (2019) stated that MGD is the main cause of DED and is traditionally managed using warm compress treatment (WCT). Vectored TPT (VTPT) is a novel method for treating DED. In a systematic review and meta-analysis of RCTs, these researchers compared the efficacy of VTPT and WCT in the treatment of DED. The primary outcome was the gland function; the secondary outcomes were the TBUT, Schirmer test, tear osmolarity, lipid layer thickness, SPEED, and the improvement of subjective symptoms as evaluated by using the OSDI. PubMed, Embase, Cochrane Library, and ClinicalTrials.gov registries were searched for studies published before July 2018. This study consisted of 4 trials with 385 patients. Significantly greater improvement was observed in meibomian gland function (MD: 2.19; 95 % CI: 0.95 to 3.43), TBUT [MD: 1.08; 95 % CI: 0.06 to 2.10)], and SPEED [MD: -2.76; 95 % CI: -4.22 to -1.30)] at 2 to 4 weeks in the VTPT group than in the WCT group. A significantly greater decrease in OSDI was observed at 2 to 4 weeks [MD: -8.61; 95 % CI: -13.62 to -3.61) and 3 months [MD: -6.92; 95 % CI: -11.95 to -1.89) in the VTPT group than in the WCT group. The authors concluded that a single 12-min VTPT was more effective than traditional WCT in treating DED either in objective or subjective measurements. These researchers recommended choosing an appropriate treatment after shared decision-making.
Li et al (2020) examined the effect of meibomian thermal pulsation LipiFlow on obstructive and hyposecretory meibomian gland dysfunction (OMGD and HMGD). A total of 25 subjects diagnosed with OMGD and another 25 HMGD patients were collected receiving the unilateral treatment with LipiFlow. These researchers examined the parameters variables including Standard Patient Evaluation of Eye Dryness (SPEED), Ocular Surface Disease Index (OSDI), Schirmer I test (SIT), non-invasive keratographic breakup time (NIKBUT), tear meniscus height (TMH), and lipid layer thickness (LLT), partial blink rate (PBR), meibomian gland loss, meibomian gland morphology with LipiView. Meibomian gland expressibility and secretion quality were evaluated for OMGD subjects. All the results were recorded pre-therapy and 4 weeks, 8 weeks, 12 weeks post-therapy. SPEED, OSDI, and PB decreased, meanwhile, NIKBUT, TMH, SIT, and LLT increased compared with baseline in both groups after treatment (p < 0.001), whereas the magnitude of the improvement in the OMGD group was greater than that in the HMGD group (p < 0.001). There was no significant post-treatment structural meibomian gland change in both groups. The meibomian gland expressibility and secretion quality score increased after treatment in the OMGD group (p < 0.001). The authors concluded meibomian thermal pulsation LipiFlow was effective for both OMGD and HMGD and the therapeutic effect on OMGD was greater than that on HMGD.
The authors stated that this study had 1 major drawback. These researchers had only 25 participants in each group and 12 weeks of follow-up. They stated that a large-scale case and longer follow-up are needed for future studies.
In a retrospective, single-blinded, cohort study, Hura and associates (2020) examined the effect of VTPT on visible meibomian gland structure (VMGS) in patients with MGD. Visible meibomian gland structure was examined at baseline and at 1-year in treatment (30 patients, 48 eyes) and control (13 patients, 22 eyes) groups. Meibography images were captured using dynamic meibomian imaging. Images were evaluated using a novel morphometric analysis technique and analyzed for change in area of VMGS (pixels). Additional outcomes measured include TBUT, corneal staining, tear osmolarity, MMP9, meibography grading, and meibomian gland evaluation. As high as 69 % of eyes in the treatment group showed an improvement in VMGS versus 27 % of eyes in the control group. As high as 31 % of eyes in the treatment group showed a decline in VMGS versus 73 % of eyes in the control group. TBUT (p = 0.0001), corneal staining (p = 0.0063), and meibomian gland evaluation scores (p = 0.0038) all significantly improved after VTPT; however, SPEED scores, MMP9, tear osmolarity, and meiboscale scores were not significantly improved 1-year post-treatment. The authors concluded that the findings of this study presented a compelling need for improved quantitative methods of analysis and grading MG structure. The results of this study also raised the possibility that absence of VMGS may not indicate absolute atrophy or loss of function; but may suggest loss of activity that improves with treatment, indicating gland re-activation. This was the 1st report presenting quantitative data that gland structure may increase after VTP therapy relative to untreated controls. These researchers stated that additional, prospective studies are needed to further validate these findings that may have significant implications regarding the benefits and timing of VTPT for MGD; the described protocol is currently more appropriate for research than for clinical practice.
Fallah and Loer (2021) examined the effect of VTPT for the treatment of MGD on objective measures of LLT and tear osmolarity. A total of 100 patients with MGD were recruited to participate. At their initial visit, baseline study parameters were recorded, and VTPT was administered. At the 2- to 3-month follow-up visit, the study parameters were reevaluated. Subjective symptoms were evaluated using the OSDI questionnaire; LLT was measured using an ocular surface interferometer. Tear osmolarity was calculated using impedance measurement of tear fluid collected from the eyelid margin. A total of 96 patients (192 eyes) completed the follow-up. Mean improvement in OSDI was 5.6 points (9 5% CI: -9.0 to -2.1, p = 0.002). There was no significant change in tear osmolarity (mean change -1.6 mOsm/L, 9 5% C: -4.7 to +1.3 mOsm/L, p = 0.3). There was no significant change in LLT (mean change -4.3 nm, 95 % CI: -9.1 to +0.5 nm, p = 0.08). The authors concluded that the hypothesis that VTPT would decrease tear osmolarity and increase LLT was not substantiated. Although these researchers detected significant improvement in subjective symptoms, the improvement was smaller than the improvements reported in previous studies. They stated that these findings suggested that the current understanding of the effects of VTPT is incomplete.
An UpToDate review on “Blepharitis” (Shtein, 2021a) states that “Nonpharmacologic modalities -- A variety of nonpharmacologic modalities for the management of blepharitis are available, including thermal pulsation devices and intense pulsed light therapy. Data on the efficacy of these therapies are limited. Given the cost of these modalities, until further data are available, we suggest not routinely using them in the management of patients with blepharitis”.
Furthermore, an UpToDate review on “Dry eye disease” (Shtein, 2021b) does not mention LipiFlow / vectored thermal pulsation as a management / therapeutic option.
In a systematic review and meta-analysis, Hu et al (2022) examined the safety and effectiveness of Lipiflow in the treatment of dry eye disease resulting from MGD. These investigators searched for RCTs in Embase, Medline, the Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, Web of Science, and ClinicalTrials.gov up to January 4, 2021. The subjective symptoms, objective tests of dry eye, meibomian gland function, and the incidence of AEs were evaluated. A total of 10 qualified RCTs incorporating 761 patients were analyzed. In the comparison of Lipiflow treatment and lid hygiene, the subgroup with inconsistent units of randomization and analysis showed that the Lipiflow treatment brought slight improvement in corneal fluorescein staining (MD of - 0.42; 95 % CI: - 0.75 to - 0.1), significant improvements in OSDI score (MD of - 7.4; 95 % CI: - 11.06 to - 3.74), SPEED score (MD of - 2.7; 95 % CI, - 3.95 to - 1.45), MGYLS (MD of 1.3; 95 % CI: 0.78 to 1.82), and meibomian glands yielding secretion score (MGYSS) (MD of 4.09; 95 % CI: 1.18 to 6.99). Meanwhile, significant improvements were detected in OSDI score, SPEED score, MGYLS, and MGYSS with patients who received Lipiflow treatment compared with those who received non-treatment. The AEs were comparable in the 2 control groups. The authors concluded that the Lipiflow treatment could improve the subjective and objective outcomes of MGD and did not increase the incidence of AEs. The improper choice of units of analysis may be the leading cause of heterogeneity, which should be noted in the design of future ophthalmology research. Moreover, these researchers stated that additional well-designed, well-designed, large-scale, non-sponsored RCTs are needed to reach a firmer conclusion.
In summary, there is currently insufficient evidence to support the use of devices for evacuating meibomian glands by means of heat and intermittent pressure for the treatment of MGD.
Tear Film Imaging (Ocular Surface Interferometry)
Interferometry is a non-invasive technique for recording tear film surface irregularities. While this technique has been used to diagnose DE, it is hindered by natural eye movements resulting in measurement noise. Currently, there is insufficient evidence to support the use of interferometry for the diagnosis of DE as a consequence of meibomian gland dysfunction or other cause such as hematopoietic stem cell transplantation (HSCT)
Savini et al (2008) noted that the currently available methods for the diagnosis of DE are still far from being perfect for a variety of reasons. These researchers highlighted the advantages and disadvantages of both traditional tests (e.g., Schirmer's test, break-up time, and ocular surface staining) and innovative non-invasive procedures, including tear meniscus height measurement, corneal topography, functional visual acuity, tear interferometry, tear evaporimetry, as well as tear osmolarity assessment.
Ban and colleagues (2009) examined the changes in the tear film lipid layer in HSCT patients with DE associated with chronic graft-versus-host disease (cGVHD) and compared with HSCT recipients without DE. These researchers performed a prospective study in 10 HSCT patients with DE associated with cGVHD and 11 HSCT recipients without DE. They performed Schirmer's test, tear film break-up time examinations, ocular surface dye staining and meibum expressibility test and DR-1 tear film lipid layer interferometry. DR-1 interferometry images of the tear film surface were assigned a “DR-1 grade” according to the Yokoi severity grading system. The DR-1 grades were analyzed according to the presence or absence of DE, conjunctival fibrosis, as well as systemic cGVHD. The mean DR-1 severity grade in patients with DE related to cGVHD (DE/cGVHD group; 3.9 +/- 0.9) was significantly higher than in patients without DE after HSCT (non-DE/non-cGVHD group; 1.3 +/- 0.6; p < 0.05). The DR-1 grade for HSCT recipients with conjunctival fibrosis was significantly higher than in patients without conjunctival fibrosis (p < 0.05). When DE severity was graded according to the recommendation of the 2007 Dry Eye Workshop Report, these findings showed a correlation between the severity of DE and DR-1 grades (r = 0.8812, p < 0.0001). The authors concluded that DR-1 interferometry may be applicable to diagnosing DE and evaluating its progression subsequent to HSCT.
Blackie and colleagues (2009) examined the relationship between DE symptoms and LLT in patients presenting for routine eye examination. Patients presenting consecutively for routine eye examinations were recruited (n = 137, age range of 18 to 60 years, mean of 41.7 +/- 15.5 years, 102 females and 35 males). Patients were required to complete the SPEED questionnaire after which their LLT was evaluated using a new interferometer (Ocular Surface Interferometer). Patients were assigned to 1 of 3 symptom categories:- no symptoms (SPEED = 0),
- mild-to-moderate symptoms (SPEED = 1 to 9), and
- severe symptoms (SPEED greater than or equal to 10).
Categorical analysis (contingency table) and linear regression were performed on the data. For patients with severe DE symptoms, 74 % had an LLT less than or equal to 60 nm. Conversely, 72 % of patients with no DE symptoms had an LLT of greater than or equal to 75 nm (contingency table, Chi = 12.63, df = 2, p = 0.0018). Furthermore, a linear regression of LLT and SPEED score reveal a significant linear relationship (as LLT increases, SPEED score decreases; p = 0.0014). The authors concluded that these data indicated that approximately 3 of 4 patients reporting severe symptoms have relatively thin lipid layers of 60 nm or less, whereas approximately 3 of 4 patients without symptoms have relatively thick lipid layers of 75 nm or more. Thus, the presence of DE symptoms significantly increases the likelihood of a relatively thin lipid layer. Lipid layer thickness seems to correlate better to symptoms, especially severe symptoms, than other reported correlations with objective clinical tests for DE disease. Moreover, they stated that interferometry has the potential to be a practical and useful addition to clinical practice.
Lane et al (2012) evaluated the safety and effectiveness of the LipiFlow System compared to the iHeat WC for adults with MGD. This was a non-significant risk, prospective, open-label, randomized, cross-over, multi-center clinical trial. A total of 139 subjects were randomized between LipiFlow (n = 69) and WC control (n = 70). Subjects in the LipiFlow group received a 12-min LipiFlow treatment and were re-examined at 1 day, 2 weeks and 4 weeks. Control subjects received a 5-min iHeat treatment with instructions to perform the same treatment daily for 2 weeks. At 2 weeks, they crossed-over (LipiFlow Cross-over) and received the LipiFlow treatment. Effectiveness parameters included MG assessment, TBUT and dry eye symptoms. Safety parameters included adverse events, ocular health exam, ocular surface staining, intra-ocular pressure, visual acuity and discomfort. LipiFlow resulted in significant improvement (p < 0.05) in MG secretion at 2 and 4 weeks (mean ± standard deviation at baseline = 6.3 ± 3.5; 2 weeks = 14.3 ± 8.7; 4 weeks = 16.7 ± 8.7); and TBUT at 2 and 4 weeks: (at baseline = 5.5 ± 2.9; 2 weeks = 6.9 ± 5.0; 4 weeks = 7.4 ± 5.5). There was no significant change in MG secretion or TBUT in the control group. LipiFlow resulted in a greater significant reduction in dry eye symptoms than the iHeat WC. The cross-over group demonstrated similar significant improvement 2 weeks post-treatment with the LipiFlow. There was no significant difference between groups in the incidence of non-serious, device-related adverse events. The authors concluded that the LipiFlow System was significantly more effective than iHeat WC; they stated that these results supported its safety and effectiveness in the treatment of MGD and dry eye symptoms. This was an industry-sponsored, open-label, single cross-over study with a relatively small sample size and short-term follow-up. This study did not include a group receiving warm compresses only for 4 weeks. It should be noted that although the control group did not show significant increases in MG and tear film metrics at 2 weeks, the control group did have a significant reduction in self-reported dry eye symptom frequency and severity. Also, the control group was limited to 5 mins of warm compression therapy once-daily, while typical treatment for MGD consists of hot packs 3 to 4 times daily along with lid margin scrubs. The findings of this study need to be validated by well-designed studies.
In a prospective, randomized, cross-over, observer-masked clinical trial, Finis and colleagues (2014a) compared the effectiveness of a single LipiFlow(®) treatment with combined lid warming and massage in patients with MGD. Subjects were randomized to receive either a single 12-min LipiFlow-LipiFlow Thermal Pulsation (LTP) system treatment or to perform combined twice-daily lid warming and massage for 3 months. All subjects were examined before, and 1 and 3 months after initiation of treatments. Investigated parameters included subjective symptoms, lipid layer thickness, meibomian gland assessment, tear BUT, tear osmolarity, corneal and conjunctival staining, Schirmer test values, and tear meniscus height. A total of 31 subjects completed the 3-month follow-up. At 1 and 3 months, patients in the LipiFlow treatment group had a significant reduction in Ocular Surface Disease Index (OSDI) scores compared with those in the lid-margin hygiene group. Both treatments produced a significant improvement in expressible meibomian glands compared to the baseline parameters, but no significant difference was noted between the 2 groups. The other investigated objective parameters did not show a significant difference. The authors concluded that results of this study showed that a single LipiFlow treatment is as least as effective as a 3-month, twice-daily lid margin hygiene regimen for MGD. Moreover, they stated that the present study was observer-masked only, and therefore a placebo effect may have confounded any improvements in subjective symptoms and other parameters in both groups.
Finis and associates (2014b) stated that the quantitative measurement of the tear film lipid layer thickness is a relatively new and promising method. However, so far it has not been investigated whether there is a diurnal or a day-to-day variability and whether certain factors are confounding the measurement of the lipid layer thickness. In 3 different experimental settings, 10 subjects without known sicca syndrome were examined at 3 different time-points on one day, on 3 different days and before and after therapeutic expression of the Meibomian glands. As a comparison, the parameters tear film BUT, tear meniscus height, diagnostic expression of the Meibomian glands and subjective symptoms, determined using the OSDI questionnaire, were measured. The results of the study showed a smaller variation of the lipid layer thickness measurements during the day and from day to day compared to the tear film BUT. The expression of the Meibomian glands significantly increased the lipid layer thickness. There was a correlation between the baseline values of tear film BUT and the lipid layer thickness. The authors concluded that these findings data showed that the lipid layer thickness as measured with the Lipiview® interferometer appears to be a relatively constant parameter over time. In addition, the expression of the Meibomian glands could be identified as a potential confounding factor. In this study these investigators included only healthy subjects without known sicca syndrome; these findings need to be validated in dry eye patients.
Zhao et al (2015) noted that tear lipid morphology is important for normal tear function. Recently, there have been clinical studies using interferometry to assess LLT. These researchers examined the repeatability of a commercially available interferometer. Two observers measured LLT in 20 Asian subjects (20 eyes) using an interferometer (LipiView ocular surface interferometer, TearScience Inc., Morrisville, NC). Dry eye symptoms, TBUT and corneal fluorescein staining were also prospectively evaluated. Data for 20 participants were presented for either right or left eye (randomly selected). The mean LLT ± standard deviation of these participants was 53.53 ± 14.59 nm. When a single observer repeated the imaging on the same day, the coefficient of repeatability was 16 nm and the 95 % limits of agreement were between -11 nm and 18 nm. When a different observer repeated the scan, the coefficient of repeatability was 13 nm and limits of agreement were -9 nm and 16 nm. Lipid layer thickness was not significantly associated with TBUT, presence of any corneal staining in any corneal zones, or symptomatic status. The authors concluded that with the repeatability of measurements being known, the significance of LLT changes measured by this interferometer may be better interpreted. In this small Asian study, the LLT was lower than previously reported studies.
Satjawatcharaphong et al (2015) identified patient characteristics at a baseline ocular surface evaluation that correlated with improvement in DE symptoms at a follow-up visit after treatment with the LipiFlow Thermal Pulsation System. A total of 32 patients completed a comprehensive baseline ocular surface evaluation and were treated with the LipiFlow Thermal Pulsation System followed by maintenance home therapy. Lipid layer thickness and blink pattern were determined using the LipiView Interferometer. Non-invasive TBUT was measured using a Medmont E300 Corneal Topographer. Slit lamp biomicroscopy was used to evaluate invasive TBUT and corneal staining after instillation of fluorescein dye. Conjunctival staining, location of the line of Marx, and presence of lid wiper epitheliopathy were evaluated with lissamine green dye. Meibomian gland expressibility was scored using the TearScience Meibomian Gland Evaluator, and meibography was imaged using the Oculus Keratograph. A logistic regression model was used to estimate the odds ratios for having a decreased post-treatment score (reduced symptoms) of SPEED. Baseline SPEED score (p = 0.01) and sex (p = 0.03) had significant odds ratios at the α = 0.05 level. Baseline non-invasive TBUT (p = 0.07), number of grade 0 meibomian glands in the lower lid (p = 0.09), and conjunctival staining grade in the inferior region (p = 0.10) met an α = 0.10 criterion for significant odds ratios, but not the typical α = 0.05 criterion. Higher baseline SPEED score and male sex had greater odds for decreased post-treatment SPEED score. The authors concluded that they identified factors that better select candidates for LipiFlow Thermal Pulsation System.
Dohlman and colleagues (2016) noted that DED is a complex, multi-factorial condition that is challenging to diagnose and monitor clinically. To-date, diagnosis has consisted largely of self-reported symptom questionnaires and a collection of clinical tests including vital dye staining, estimation of TBUT and Schirmer's testing, as no gold standard exists. As the dry eye field has made progress in understanding disease pathogenesis, new methods for assessment of this condition have been developed. Dry eye disease is now known to be characterized by tear hyperosmolarity and ocular surface inflammation, and there are now commercially available devices that accurately and reliably measure tear osmolarity and matrix metalloproteinase 9 (MMP9), a marker of inflammation and tissue breakdown. In addition, there are a variety of imaging modalities that have shown promise in their ability to identify patients with DED by assessing tear film dimensions and tear film instability. The authors concluded that there is a significant need for the development of tear film assessments for accurate diagnosis and monitoring of dry eye. There are a number of new devices and techniques that have shown promise in their ability help clinicians manage patients with DED.
In-Vivo Confocal Microscopy
In a prospective, case-controlled study, Liang and colleagues (2017) observed the morphology, fibrosis grade and inflammatory infiltration of meibomian glands using in-vivo confocal microscopy (IVCM) in MGD patients. According to the diagnostic criteria of MGD, a total of 20 MGD patients (20 eyes) were included in this study from August to October 2015; 15 normal subjects (15 eyes) were also studied. All subjects completed the questionnaire of the OSDI, lid margin and ocular surface examination by slit lamp microscropy, TBUT test, corneal and conjunctival staining (Oxford scale), Schirmer I test, infra-red meibomian photography and IVCM. Main outcomes in IVCM included meibomian gland acinar longest diameter (MGALD), meibomian gland acinar shortest diameter (MGASD), meibomian gland acinar unit density (MGAUD), meibomian gland acinar unit area (MGAUA), meibomian gland inflammatory cell density and fibrosis degree. The parameters between the MGD group and the control group were compared using the independent samples t-test. The OSDI score [(31.80 ± 22.97) points], 1id margin abnormality score [(3.10 ± 0.31) points], loss rate of meibomian glands (38.31 % ± 19.94 %)and corneal and conjunctival staining score [1.00 (2.75) points] in the MGD group were obviously higher than those in the control group [(7.93 ± 6.51) points, (0.33 ± 0.31) points, 21.31 % ± 7.70 %, and 0.00 (1.00 )points, p = 0.001, p < 0.001, p = 0.004, and p = 0.037, respectively]. The TBUT was significantly lower in the MGD group [(3.35 ± 2.28) s] than in the control group [(6.67 ± 2.51) s, p< 0.001]. According to Schirmer I test, there was no significant difference in the 2 groups (p = 0.139). The mean values of MGALD [(156.80 ± 46.10 )μm], MGASD [(38.75 ± 11 .72) μm], MGAUA [(10 113.84 ± 5 531.21) μm(2)], meibomian gland inflammatory cell density [(621.90 ± 405.63) cells/mm(2)] and fibrosis degree 1.50 (1.00) in the MGD patients were larger than those in the control group [(67.47 ± 9.117) μm,(22.00 ± 2.95) μm,(3,102.13 ± 1,111.97) μm(2), (188.80 ± 72.25) cells/mm(2), and 0.00 (0.00), all p < 0.001, respectively]. The mean MGAUD was lower in the MGD patients [(61.10 ± 34.97) glands/mm(2)] than in the control group [(105.07 ± 18.58) glands/mm(2), p < 0.001]. The authors concluded that IVCM was pertinent to examine the meibomian glands by detecting the irregularity of meibomian orifices, the diameter and area, and the inflammation and fibrosis levels in MGD patients. It may have a potential clinical value for the diagnosis of MGD.
Wu et al (2022) stated that confocal microscopy is a new technology that can aid in the in-vivo assessment of structural changes in several ocular surface diseases on a cellular level. The use of IVCM in DED will be a powerful method to evaluate morphological changes in the ocular surface globally in the future. In the dry eye field, IVCM has been employed in the examination of the cornea, bulbar and palpebral conjunctiva, meibomian glands, and lacrimal glands. The authors noted that confocal microscopy requires trained operators to acquire good quality scans but lacks built-in software to analyze nerves and inflammatory cells. As such, it is not used as often in clinical settings to diagnose dry eye.
Near-Infrared Dual Imaging (e.g., LipiScan Dynamic Meibomian Imager)
Near-infrared dual imaging (e.g., LipiScan Dynamic Meibomian Imaging (DMI) utilizes 2 novel imaging technologies -- adaptive trans-illumination and dynamic illumination. Each technology generates its own independent image of the glands, which is then processed, displayed and combined to provide a more accurate visualization of the structure of the meibomian glands. By means of these images, the optometrist or ophthalmologist can detect structural change in the meibomian glands. As MGD progresses, DMI reveals gland truncation and dilation in moderate disease followed by gland atrophy and drop-out in the most severe disease. However, there is a lack of evidence regarding the effectiveness of near-infrared dual imaging in the management of patients with MGD.
Nichols and colleagues (2005) evaluated the within- and between-reader reliability and the interrelation between 2 methods of grading meibography images. A video meibography sequence (1,200 frames) was captured from 290 patients using near-infrared light (650 to 700 nm) and a near-infrared CCD camera. One frame was selected for grading by 2 masked readers using 2 scales, where the 1st reader graded the image on 2 occasions and the 2nd reader graded the image on 1 occasion. The 1st grading scale was a gestalt assessment (categorically graded), which was an assessment of partial meibomian glands within the image. The 2nd was a count of individual whole glands. Within- and between-reader reliability and concurrent validity between the scales were examined. Within-reader reliability of the gestalt scale was moderate to high (simple kappa = 0.78, 95 % confidence interval [CI]: 0.71 to 0.85 and weighted kappa = 0.91, 95 % CI: 0.88 to 0.95). Within-reader reliability of individual gland counting was moderate via a 95 % limits of agreement analysis (-2.84-2.76 glands). Between-reader reliability of the gestalt scale was fair (simple kappa = 0.38, 95 % CI: 0.30 to 0.46 and weighted kappa = 0.57, 95 % CI: 0.47 to 0.68). Between-reader reliability of gland counting was fair via a 95 % limits of agreement analysis (-4.46-5.08 glands). There was a strong relation between the gestalt scale and gland counting indicating good concurrent validity (Z = -15.15, p < 0.0001). The authors concluded that these methods of grading meibography images demonstrated good within-reader reliability and fair between-reader reliability. Moreover, they stated that responsiveness to change will need to be addressed in future studies.
Furthermore, an UpToDate review on “Blepharitis” (Shtein, 2018) does not mention near-infrared dual imaging as a management tool.
Meibomian Gland Probing for the Treatment of Dry Eye
Maskin (2010) performed a retrospective evaluation of a new treatment for obstructive meibomian gland dysfunction (O-MGD) using invasive orifice penetration and intra-ductal probing. Medical charts of 25 consecutive patients with O-MGD (based on presence of lid margin or tarsal hyperemia, lid margin telangiectasia, thickening or irregularity, and meiboman gland orifice metaplasia) plus lid tenderness or symptoms of lid margin congestion were reviewed to evaluate the effect of probing on tenderness and congestion; 24 of 25 patients (96 %) had immediate post-probing relief, whereas all 25 patients (100 %) had relief of symptoms by 4 weeks after procedure; 20 patients (80 %) only required 1 treatment and had an average of 11.5-month follow-up; 5 patients (20 %) had re-treatment at an average of 4.6 months. All patients had symptom relief at time of last follow-up. Of 56 symptomatic and treated lids, 42 (75 %) were upper lids. Patients frequently reported improvement in newly recognized but previously sub-clinical symptoms. The author concluded that invasive orifice penetration and intra-ductal probing appeared to provide lasting rapid symptom relief for patients with O-MGD. Probing findings in this study frequently included- mild resistance upon orifice penetration,
- proximal duct gritty tactile and aural sensation suggestive of keratinized cellular debris, and
- focal variable resistance deeper within the duct, which may be relieved with the probe, suggestive of fibro-vascular tissue.
These researchers stated that these findings may offer probing characteristics that may allow for a grading system for duct obstruction. The post-probing improvement of symptoms not previously appreciated supported the notion that meibomian gland disease exists sub-clinically.
The report of the subcommittee on “Management and treatment of meibomian gland dysfunction” from the International Workshop on “Meibomian gland dysfunction” (Geerling et al, 2011) stated that “Intra-ductal probing has recently been introduced as a treatment for MGD. One report (clinical studies level III) on this management approach for MGD describes a modified surgical procedure as a primary treatment non-end stage MGD. This study of 25 patients demonstrated a high frequency of short-term symptomatic relief. Further study of this technique is in progress”.
Prozornaia and Brzhevskii (2013) reported the findings of 110 patients (aged from 3 to 42 years) who were examined to estimate the efficacy of chronic blepharitis treatment: 50 patients with chronic blepharitis and dry eye syndrome (DES), 28 with DES due to computer vision syndrome and 32 with isolated chronic blepharitis. All patients received eyelid massage. If the secretion was too thick and difficult to evacuate from meibomian glands then duct probing was performed. In addition a complex of hygienic procedures was performed using phyto-products ("Geltec-Medika", Russia): blepharoshampoo, blepharolotion, blepharogel 1 and 2. Moist warm pads (with blepharolotion and calendula extraction) were applied on the eyelids in 25 patients. Massage and probing of meibomian gland ducts and hygienic procedures were showed to be effective in management of clinical signs of chronic blepharitis including co-existing DES. Moist warm pads improved efficacy of background therapy in patients with meibomian gland hypofunction and had no effect in blepharitis with excessive meibomian gland secretion. Eyelid hygiene was showed to be effective in adults, children and infants.
Wladis (2013) stated that rosacea is a significant cause of ocular surface disease, and the current therapeutic armamentarium is often ineffective. Intra-ductal meibomian gland probing is a novel technique to address DES, although its use has not been described in the management of ocular surface disease from rosacea.
In a retrospective study, Maskin and Testa (2018) examined the impact of meibomian gland probing (MGP) on meibomian gland (MG) area from the upper lids of patients with O-MGD. This trial compared pre-MGP/post-MGP non-contact infrared meibography results in patients with O-MGD, viewing signs of MG growth within total measurement field. Post-MGP meibography of 34 lids (19 patients, greater than or equal to 4.5 to less than or equal to 12 months' follow-up) showed 41.2 % with MG growth; 10 lids had meibographies suitable for analysis, showing significant collective (116 glands) increase in mean individual glandular area (MIGA) of 4.87 % (p = 0.0145); 4 of 10 lids independently showed significant increase in MIGA, ranging from 10.70 % to 21.13 % (p < 0.0001, p = 0.0277, p = 0.0292, p = 0.0345), while 6 did not. At greater than 12 and less than 25 months' follow-up, 16 lids (9 additional patients) had follow-up showing 25 % with signs of MG growth. Analysis of 3 lids showed a significant collective (33 glands) increase in MIGA of 11.19 % (p = 0.0004); 2 of 3 lids independently showed significant increase in MIGA of 13.73 % and 20.00 % (p = 0.0097, p = 0.0001). Collectively, for all 13 analyzed lids (149 glands), there was a significant increase of 6.38 % in total glandular area (p = 0.0447) and a significant increase of 6.23 % in MIGA (p = 0.0003). The authors concluded that MGP was associated with increased MG tissue area and growth of atrophied MGs as viewed on meibography; MGP provided unequivocal physical proof of a patent meibum outflow tract through the natural orifice, and may promote glandular growth in part by direct mechanical establishment of a patent duct/orifice system. Moreover, these researchers stated that future research is needed to study these post-MGP meibography changes in a randomized controlled clinical trial (RCT).
Kheirkhah and colleagues (2020) stated that obstructive MGD can be refractory to medical therapy. Intra-ductal meibomian gland (MG) probing may offer a potential therapeutic approach for these patients, but no randomized trials have been conducted to-date. In a randomized, double-masked, single-center, sham-controlled clinical trial, these researchers examined clinical changes after intraductal MG probing for patients with refractory obstructive MGD. A total of 42 patients with refractory obstructive MGD associated with lid tenderness were included in this trial. Enrolled patients received one of the following treatments: MG probing plus post-procedural topical sulfacetamide/prednisolone ointment (Blephamide); MG probing plus post-procedural lubricating ointment (GenTeal); or sham probing plus GenTeal ointment. The probing was performed on the upper lids of both eyes. Primary outcome measures were symptoms as measured by OSDI and Symptom Assessment iN Dry Eye (SANDE), as well as TBUT; and secondary outcome measures were other clinical signs. Safety of the procedure was also assessed by examining the treatment-related AEs. At baseline and 4 weeks after the procedure a masked observer examined the following outcome measures: symptom questionnaires, including OSDI and SANDE, upper lid tenderness, lid margin telangiectasia, corneal fluorescein staining, conjunctival lissamine green staining, TBUT, Schirmer's test, and meibomian glands yielding liquid secretion (MGYLS). Compared to baseline, the MG probing/Blephamide group showed significant improvements in both OSDI and SANDE scores and the MG probing/GenTeal group demonstrated a significant improvement only in SANDE score. In contrast, the Sham/GenTeal group did not show any statistically significant changes in symptoms. There were no statistically significant changes in clinical signs in any group at the 4-week visit, except for improvement of lid tenderness in the sham probing group. The authors concluded that MG probing/Blephamide resulted in a significant improvement in symptoms in patients with refractory obstructive MGD without any significant effect on clinical signs. Moreover, these researchers stated that larger studies are needed to determine the effectiveness of MG probing.
Arita and Fukuoka (2020) examined currently available non-pharmaceutical treatment modalities for MGD. A detailed search of the PubMed and Medline databases was carried out to identify original articles in English that have examined such non-pharmaceutical therapies in patients with this condition. Conventional therapies such as application of a warming compress, the practice of lid hygiene, and manual expression of meibomian glands as well as more technologically advanced approaches such as intra-ductal probing, thermal pulsation, and IPL therapy were included in the review. The authors noted that neither subjects nor investigators were masked to treatment allocation in the studies of intra-ductal probing performed to-date indicating that caution should be exercised in drawing conclusions from their findings. The follow‐up periods of the studies were also relatively short, with the result that data on the long‐term safety and efficacy of this invasive technique are lacking. Furthermore, in most studies, probing was not compared with standard treatments in the clinical setting such as eyelid warming, lid hygiene, or meibomian gland expression; thus, further studies without potential bias are needed to confirm the safety and efficacy of this procedure. These researchers concluded that additional large-scale RCTs are also needed to provide more information such as the specific indications best suited to each treatment modality, the efficacy of such approaches in combination with pharmaceutical-based therapy, and the mechanisms of action of some of the more technologically advanced systems.
Arita and associates (2020) noted that selection of a treatment for MGD is currently based on the stage classification proposed at the 2011 workshop (Geerling et al, 2011). Such stage classification was itself based on a comprehensive evaluation of subjective symptoms, lid margin abnormalities (plugging, vascularity), meibum grade, and degree of ocular surface staining. However, it is often difficult to select a treatment method according to this complicated classification in the clinic. Moreover, it is unclear at what stage non-pharmaceutical therapeutic options, such as intra-ductal probing, TPT, and IPL should be performed.
Furthermore, UpToDate reviews on “Blepharitis” (Shtein, 2019a; 2021a), “Dry eyes” (Shtein, 2019b; 2021b), “Treatment of dry eye in Sjogren's syndrome: General principles and initial therapy” (Baer and Akpek , 2019a) and “Treatment of moderate to severe dry eye in Sjogren's syndrome” (Baer and Akpek , 2019b) do not mention meibomian gland probing as a therapeutic option.
Androgen for the Treatment of Dry Eye
Wang and Deng (2020) noted that androgen regulates the function of lacrimal and meibomian glands, and its deficiency is a pathological factor underlying DED. However, no androgen has been approved for treating DED due to lack of definite evidence regarding its safety and efficacy in clinics. In a systematic review, these researchers summarized the clinical studies on the safety and efficacy of androgen replacement therapy (ART) for DED. Medline (via PubMed), Embase, Clinicaltrials.gov, Wanfang and Chinese Clinical Trials Registry Database were searched for the relevant prospective studies, and 7 studies wherein androgen was applied topically via eye drops or systemically via oral or transdermal administration were included. The quality of these studies was assessed with the Cochrane Collaboration's tool for assessing risk of bias and methodological index for non-randomized studies. Most studies showed that androgen effectively improved dry eye-related symptoms and increased tear secretion. Furthermore, elderly men and peri-menopausal women with lower levels of circulating androgens responded better to ART. However, 1 study involving patients with Sjogren's syndrome showed no improvement in the ART group compared to the placebo control, or to the baseline level. Adverse effects were also common but limited to mild skin problems. The authors concluded that androgen is a potential treatment for DED, especially for people with primary androgen deficiency. Short-term application is relatively safe. Moreover, these researchers stated that further investigations with larger sample sizes are needed to ascertain the clinical value of androgen for the treatment of DED.
The authors stated that this analysis had several drawbacks. First, only 3 RCTs were included and all studies had small sample sizes. Furthermore, insufficient data prevented further meta-analysis to obtain conclusive results. Second, the study durations of most studies were 2 to 4 weeks, which was insufficient to observe the long-term adverse effects of androgen therapy. Finally, there was potential risk of bias from the selection of studies as all 4 non-RCTs were reported by the same researcher and only 7 useful studies were obtained.
Intense Pulsed Light for the Treatment of Dry Eye / Meibomian Gland Dysfunction
Liu and colleagues (2020) noted that MGD is frequently encountered by eye care practitioners. It is characterized by obstruction of the Meibomian glands and/or alterations in the consistency of glandular secretions. At present, no definitive treatment exists for this condition. In a systematic review and meta-analysis, these researchers examined the efficacy of intense pulsed light (IPL) therapy in the management of MGD. Data-bases including Embase, PubMed, Cochrane Central, Medline and Google Scholar were systematically searched to identify clinical trials that evaluated the efficacy of IPL in the treatment of MGD. Outcome measures were described as the standardized mean difference (SMD). The fixed- or random-effects model was selected for analysis based on the Cochrane I2 values representing heterogeneity. Publication bias was visually inspected using Begg's funnel plot. Data were synthesized from 4 RCTs comprising 122 subjects in the IPL group and 120 subjects in the control group. Pooled analysis indicated no statistically significant difference in the SPEED scores between the 2 groups [SMD -0.16 (95 % CI: -0.41 to 0.10)]; but a significant increase in Non-Invasive Tear Break-Up Time (NIBUT) scores in the IPL group (SMD, 0.90; 95 % CI: 0.40 to 1.40). The authors concluded that the findings of study did not provide any conclusive evidence for the efficacy of IPL therapy in the management of MGD. The analysis indicated that IPL therapy may result in an improvement of objective NIBUT scores but had no effect on subjective SPEED scores. These researchers stated that given the limited number of studies performed to-date, there is a need for more prospective, well-designed RCTs with a larger sample size to provide further evidence on the efficacy of IPL therapy.
Cote and co-workers (2020) stated that MGD is the major cause of evaporative DED, which is the more prevalent form of dry eye disease; IPL therapy, involving treatment of the skin near the eyelids, has emerged as a potential treatment for MGD. In a Cochrane review, these researchers examined the safety and effectiveness of IPL for the management dry eye disease resulting from MGD. They searched CENTRAL, Medline (Ovid), Embase Ovid and 3 trial registers for eligible clinical trials on August 1, 2019. There were no restrictions on publication status, date or language. These investigators included RCTs studying the safety or effectiveness of IPL for treating MGD. Outcome measures included the change from baseline in subjective dry eye symptoms, adverse events (AEs), changes to lipid layer thickness, TBUT, tear osmolarity, eyelid irregularity, eyelid telangiectasia, meibomian gland orifice plugging, meibomian gland drop-out, corneal sodium fluorescein staining and conjunctival lissamine green staining. Two review authors independently screened abstracts and full-text articles, extracted data from eligible RCTs and judged the risk of bias using the Cochrane tool. They reached consensus on any disagreements by discussion; and summarized the overall certainty of the evidence using the GRADE Working Group approach. These investigators included 3 RCTs, 1 from New Zealand, 1 from Japan and 1 from China, published between 2015 and 2019. Together, these trials enrolled 114 adults (228 eyes). Two studies used a paired-eye (inter-eye comparison) design to evaluate the effects of a sham (control) IPL treatment relative to an actual IPL treatment. One study randomized individuals to either an IPL intervention combined with meibomian gland expression (MGX), or MGX alone (standard therapy) . The study follow-up periods ranged from 45 days to 9 months; none of the trials were at low risk of bias in all 7 domains. The first authors of 2 included studies were in receipt of funding from patents or the manufacturers of IPL devices. The funding sources and declaration of interests were not given in the report of the 3rd included trial. All 3 trials evaluated the effect of IPL on dry eye symptoms, quantified using the SPEED questionnaire. Pooling data from 2 trials that used a paired-eye design, the summary estimate for these studies indicated little to no reduction in dry eye symptoms with IPL relative to a sham intervention (mean difference [MD] -0.33 units, 95 % CI: -2.56 to 1.89; I² = 0 %; 2 studies, 144 eyes). The other study was not pooled as it had a unit-of-analysis error, but reported a reduction in symptoms in favor of IPL (MD -4.60, 95 % CI: -6.72 to -2.48; 84 eyes). The body of evidence for this outcome was of very low certainty, thus, these researchers were uncertain regarding the effect of IPL on dry eye symptoms. There were no relevant combinable data for any of the other secondary outcomes, thus the effect of IPL on clinical parameters relevant to dry eye disease were currently unclear. For sodium fluorescein TBUT, 2 studies indicated that there may be an improvement in favor of IPL (MD 2.02 seconds, 95 % CI: 0.87 to 3.17; MD 2.40 seconds, 95 % CI: 2.27 to 2.53; 172 eyes total; low-certainty evidence). These investigators were uncertain of the effect of IPL on non-invasive TBUT (MD 5.51 seconds, 95 % CI: 0.79 to 10.23; MD 3.20, 95 % CI: 3.09 to 3.31 seconds; 2 studies; 140 eyes total; very low-certainty evidence). For tear osmolarity, 1 study indicated that there may be an improvement in favor of IPL (MD -7.00 mOsmol/L, 95 % CI: -12.97 to -1.03; 56 eyes; low-certainty evidence). These researchers were uncertain of the effect of IPL on meibomian gland orifice plugging (MD -1.20 clinical units, 95 % CI: -1.24 to -1.16; 84 eyes; very low-certainty evidence). These investigators were uncertain of the effect of IPL on corneal sodium fluorescein staining. One study reported no evidence of a difference between the IPL and sham intervention arms at 3 months of follow-up (p = 0.409), and a second study reported data favoring IPL (MD -1.00 units, 95 % CI: -1.07 to -0.93 units; 172 eyes in total; very low-certainty evidence). These researchers considered the incidence of AEs at the study end-point, as a measure of safety. As most trials did not specifically report AEs, the safety of IPL as a treatment for MGD could also not be determined with any certainty. Very low-certainty results from individual studies suggested some adverse effects that may be experienced by participants, include mild pain and burning, and the potential for partially losing eyelashes (due to clinician error). The authors concluded that this systematic review found a scarcity of RCT evidence relating to the safety and effectiveness of IPL as a treatment for MGD. Whether IPL is of value for modifying the symptoms or signs of evaporative dry eye disease is currently uncertain. Due to a lack of comprehensive reporting of AEs, the safety profile of IPL in this patient population is also unclear. The current limitations in the evidence base should be considered by clinicians using this intervention to treat MGD, and outlined to individuals potentially undergoing this procedure with the intent of treating dry eye disease. The results of the 14 RCTs currently in progress will be of major importance for establishing a more definitive answer regarding the safety and effectiveness of IPL for treating MGD. These researchers intend to update this review when results from these trials become available.
In a systematic review and meta-analysis, Leng and associates (2021) examined the safety and efficacy of IPL for the treatment of MGD. PubMed, Embase, Web of Science, Cochrane Library, Google Scholar, China National Knowledge Infrastructure (CNKI), Wanfang, VIP, and SinoMed databases were searched through February 24, 2020. Randomized clinical trials and cohort studies comparing IPL+ meibomian gland expression (MGX) or IPL alone with control groups were included. The weighted MD (WMD) was calculated to analyze the OSDI score and SPEED score, and the SMD was calculated to analyze the TBUT. Heterogeneity was quantified by the I2 statistic ranging from 0 to 100 %, and a random effects model was used in this meta-analysis. All analyses were performed by RevMan 5.3. All p values were calculated by the t-test, and p values were regarded as statistically significant at p < 0.05. The Cochrane Collaboration's tool for assessing risk of bias was used to identify and evaluate bias in the literature. A total of 9 studies with a total of 539 patients were included; 8 studies examined TBUT, 6 examined OSDI scores, and 4 examined SPEED scores. IPL combined with MGX showed superiority regarding the TBUT (SMD 2.33, 95 % CI: 1.04 to 3.61), and OSDI scores (WMD 11.93, 95 % CI: - 17.10 to - 6.77), with high heterogeneity. The SPEED scores were not significantly different. The authors concluded that IPL combined with MGX may be a safe and effective treatment for MGD, however, it could not improve all symptoms; IPL alone was not superior to MGX. The efficacy was also affected by the number and average frequency of treatments. The efficacy of IPL may decrease within 6 months after the last treatment, so it should be considered a long-term adjuvant therapy combined with MGX. When patients received 3 or 4 treatments (once every 3 to 4 weeks), a return visit at 6 months after the last treatment was needed.
Trone et al (2022) stated that MGD is the most common etiology of DED worldwide and IPL appears to be a promising treatment with encouraging results. Lacrystim is a new IPL device (CE marking in 2019) and no studies have yet been published on it. In a retrospective study, these researchers carried out the 1st trial on this device with an objective assessment of its effectiveness and an extended follow-up over 6 months. Patients presenting with a DED with stable mild-to-moderate MGD and having received Lacrystim treatment between June 2019 and June 2020 were included. Subjects received 3 IPL sessions at day 0 (D0), D15 and D45 with 4 shots per side at a fluence of 8 mJ/cm2. DED clinical evaluation was carried out at D0, D15, D45, 3rd month and 6th month: Oxford scale and BUT, SIT and OSDI questionnaire. Lacrydiag imaging device carried out an objective examination of tear film: interferometry, meibography, tear meniscus height and non-invasive BUT (NIBUT). The primary endpoint was the evolution in NIBUT between the 1st visit D0 and 3rd month. Data collection was performed retrospectively. Statistical analysis was carried out using a linear mixed-effects model and a non-parametric linear mixed-effects model (R software). A total of 45 consecutive patients were included. NIBUT significantly increased between D0 and 3rd month (MD of 1.63 seconds, IC 95 %: 0.51 to 2.62; p = 0.002) with a prolonged effect at 6th month. OSDI and Oxford scores and interferometry were also significantly improved at 3rd month and 6th month. There was no significant change in BUT, SIT and tear meniscus height. No AE was noted. The authors concluded that IPL delivered by Lacrystim appeared safe and effective in the treatment of MGD although a RCT is needed to validate these preliminary findings.
The authors stated that this study had several drawbacks. Due to the retrospective design and the lack of a control group, the findings of this study were exploratory and preliminary. Nevertheless, this study presented the first indicative results of this new IPL device. To-date, there are very few prospective, controlled, RCT published on this topic. It is important but difficult to select an objective and robust clinical primary endpoint. These investigators choose NIBUT as a primary endpoint because it is a valid and objective evaluation criterion which is reproductible; and automatic measurement by Lacrydiag limited the placebo confounding factor in this trial. In the absence of a control group and double-masking, the placebo effect remains important in pathology such as DED. This is a common pitfall found in the literature. Similarly, considering the heterogeneity of patients with MGD, the study of the effect of IPL on specific subgroups of patients appeared interesting (e.g., severe MGD during graft-versus-host disease, contact lens wearers with MGD causing an excessive lens fouling or MGD during vernal keratoconjunctivitis). Furthermore, this type of treatment in the pediatric population should be examined in addition to palpebral massages, which are difficult to perform in practice in children.
In a retrospective study, Fukuoka and Arita (2022) compared the effectiveness of IPL therapy for MGD using the new AQUA CEL (AC, Jeisys) device and the traditional M22 (Lumenis) device. A total of 59 eyes of 59 patients with MGD (12 men and 47 women, mean age of 49 ± 12 years) were enrolled. They randomly received 4 sessions of IPL therapy every 3 weeks either with AC (30 eyes) or M22 (29 eyes). SPEED questionnaire score, NIBUT, lid margin abnormalities, corneal and conjunctival fluorescein staining, fluorescein BUT (FBUT), SIT, meiboscore and meibum grade were evaluated before treatment and 1 month after treatment. Before IPL, no significant differences were observed in age, gender, or measured parameters between the AC and M22 groups (p > 0.05, respectively). SPEED score, NIBUT, lid margin abnormalities, fluorescein staining, FBUT, and meibum grade improved significantly in both groups after IPL compared to before IPL (p < 0.001, respectively). There were no significant differences in measured parameters between the 2 groups after IPL (p > 0.05, respectively). The authors concluded that the findings of this study suggested IPL therapy with AC and M22 devices has been shown to be equally effective for the treatment of MGD. Moreover, these researchers stated that further investigation is needed to validate these findings. They noted that larger, prospective, randomized clinical studies with a longer follow-up period are needed to compare the effectiveness of the IPL devices and to develop standard treatment protocols for the use of IPL therapy.
The authors stated that this study had several drawbacks. First, this trial was retrospective. Second, the mechanisms underlying the improvement in subjective and objective parameters of the 2 IPL devices were not elucidated in this study. Third, the follow-up period was relatively short. Furthermore, subjects were only Japanese. Most Japanese are classified as Fitzpatrick skin type III. The reactivity of the skin to light or to ultraviolet light may differ between the study patients and individuals of other ethnicities. These researchers did not compare various protocols for the best treatment efficacy with each IPL device. Further investigation is required to validate these findings. Larger prospective randomized clinical studies with a longer follow-up period will be needed to compare the efficacy of the IPL devices and to develop standard treatment protocols for the use of IPL therapy.
BlephEx (Blepharo Exfoliation)
In a prospective, observational, single-center study, Nattis et al (2019) examined bacterial burden on the eyelid margin and within meibomian glands for influence on specific ocular surface disease (OSD) markers across the meibomian gland dysfunction (MGD) spectrum. A total of 40 patients were divided into 4 equal groups of 10 that encompassed increasingly worse MGD/OSD categories. All patients answered the standard Ocular Surface Disease Index questionnaire, and underwent tear osmolarity testing (TOT), Schirmer 1, matrix metalloproteinase 9 (MMP-9) testing, meibography, and lissamine green staining. Cultures of eyelid margins and meibomian gland secretions were directly plated on blood, chocolate, and Sabouraud agar; smears were sent for gram and Papinicolau evaluation. Mean patient age was 55.25 ± 17.22 years; there were 10 men and 30 women. TOT and MMP-9 testing were similar across groups. Culture positivity was 62.5 % for right eyes, 70 % for left eyes, and was not statistically different across groups (for both eyelid margin and meibomian glands). The majority of cultures were positive for coagulase-negative staphylococcus (CNS). The authors concluded that the findings of this study were in concordance with others, citing the predominance of CNS within the biofilm of both "normal" and clinically significant MGD/OSD patients. They stated that this study exemplified that symptoms of OSD do not necessarily correlate with degree of clinical examination findings, nor culture positivity. These researchers stated that these findings argued that bacterial burden should be reconsidered as a direct risk factor and treatment target for MGD/OSD patients.
The authors stated that their findings pose a challenge for development of a “universal” treatment algorithm for dry eye/MGD in terms of targeting the microbial milieu. One may argue MDG/OSD should be treated via eradication of the bacterial biofilm -- this may be accomplished by mechanical debridement (e.g., BlephEx [Franklin, TN]), meibomian gland expression, Lipiflow [TearScience, Morrisville, NC]) and/or antibiotic use (topical or oral).
Furthermore, an UpToDate review on “Dry eye disease” (Shtein, 2021b) does not mention blepharo exfoliation as a management / therapeutic option.
Zhu et al (2022) stated that chalazia are benign eyelid lesions caused by the obstruction and inflammatory reaction of the meibomian glands. Demodex mites are one potential cause of chalazia resulting in mechanical obstruction of the meibomian gland. In a prospective, randomized study, these researchers examined a novel approach in the treatment of chalazia by means of micro-blepharo-exfoliation (MBE), an in-office lid hygiene technique that exfoliates the eyelid margins. A total of 50 patients with clinical evidence of acute chalazion were enrolled in this trial. Subjects were randomly assigned to a MBE plus lid hygiene group (n = 23, mean age of 66.6 ± 16.6 years) or a lid hygiene alone group (n = 27, mean age of 62.1 ± 14.4 years). The MBE plus lid hygiene group received MBE treatment and were evaluated 1 month after the baseline visit. The main outcome measured was the resolution of the chalazion at the 1-month follow-up visit. The lid hygiene plus MBE treatment group demonstrated a statistically significant resolution of the chalazion compared with the lid hygiene group alone (p = 0.007; Chi-square test). Among the MBE plus hygiene group, 87 % of the patients had resolution of their chalazion as opposed to the lid hygiene alone group, which had 44 % resolution. The authors concluded that this was the 1st prospective, randomized clinical trial that showed the effectiveness of MBE as a non-invasive adjunctive treatment method for chalazion resolution. Moreover, these investigators stated that larger studies with a true control group and a longer follow-up are needed to validate these findings.
These researchers stated that although this study was prospective in nature, there were still several drawbacks. First, this trial had a relatively small sample size of 50 patients with abbreviated follow-up (1 month). Second, this was a single-center study; thus, limiting the diversity of the participants. Third, although previous studies using MBE with various scrubs for the treatment of Demodex blepharitis showed no significant difference in effectiveness between the scrubs, further research should look into the use of different scrubs with MBE to examine if they could lead to further improvement of chalazia treatment.
Autologous Platelet-Rich Plasma Drops for the Treatment of Dry Eye Disease from Meibomian Gland Dysfunction
In a retrospective, consecutive, case-series, pilot study, Murtaza et al (2022) examined the effects of autologous platelet-rich plasma (PRP) drops for evaporative dry eye (EDE) disease from MGD. This trial included 20 eyes of 10 patients with EDE from MGD treated with PRP drops from November 2020 to November 2021 at a single outpatient clinic in Ontario, Canada. PRP drops were prepared from whole blood using a 2-step centrifugation method. Patients were instructed to instill these drops 6 times daily for 4 weeks. The Canadian Dry Eye Assessment (CDEA) questionnaire score, patient subjective assessment (PSA) score, 1st and average NIBUT (f/a NIBUT), TMH, bulbar redness (BR), and meibograph grade (were measured before and after the treatment course. Significant improvements in dry eye symptoms and tear film parameters were observed. Dry eye symptoms significantly improved as per the CDEA (MD = -5.45, 95 % CI: -7.9 to -3.1, p < 0.001) and PSA (MD = -2.6, 95 % CI: -3.9 to -1.2, p < 0.001). There were significant improvements in tear film parameters including fNIBUT (MD = 3.85s, 95 % CI: 1.2 to 6.8, p = 0.006), aNIBUT (MD = -6.81s, 95 % CI: 5.7 to 11.1, p < 0.001) and TMH (MD = 0.08, 95 % CI: 0.003 to 0.2, p = 0.045). There was an improvement in conjunctival injection as measured by BR (MD = -0.36, 95 % CI: -0.4 to -0.15, p = 0.373); 5 eyes experienced a 1-grade improvement in meibograph grade (p = 0.453), and none experienced worsening in meibograph grade with treatment. No temporary or permanent adverse effects were noted. The authors concluded that 4 weeks of PRP therapy resulted in significant functional improvements in dry eye symptoms and tear film quality and quantity. Improvements in conjunctival injection and microstructural improvements in meibomian glands were also observed in some eyes. These researchers stated that overall, PRP is a promising treatment option for patients with EDE from MGD refractory to conventional treatments. Moreover, these researchers stated that future research should examine optimizing PRP preparation parameters and determining the long-term effects of PRP therapy.
The authors stated that the small sample size of this trial limited the applicability of these findings. The treatment duration was only 4 weeks, and the average follow-up duration was 1 month, making it difficult to ascertain the long-term, sustained effects of PRP. Given the short follow-up, it was also difficult to determine the change in the number and types of oral and topical dry eye medications and therapies after PRP treatment. Patients were encouraged to continue their pre-treatment dry eye regimens after PRP treatment. Finally, investigating other clinical parameters such as tear film osmolarity and lipid layer thickness may have been useful in understanding the effects of PRP therapy on EDE and MGD.
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