Vectored Thermal Pulsation, Intense Pulsed Light, and Eyelid Warm Compress Therapies for MGD

Vectored Thermal Pulsation, Intense Pulsed Light, and Eyelid Warm Compress (VIEW) Therapies for Meibomian Gland Dysfunction- A Randomized, Assessor-masked, Active-controlled Clinical Trial

Meibomian gland dysfunction (MGD), closely associated with Dry Eye Disease (DED), is a chronic condition where terminal ducts are obstructed and/or glandular secretion changes. The efficacy of traditional treatment options, e.g. eyelid warm compress therapy (EW) is limited with low compliance. This study aims to (1)compare the efficacy and safety of two emerging alternatives- vectored thermal pulsation(VTP) or intense pulsed light and meibomian gland expression(IPL + MGX) with EW therapy; (2)identify factors predicting outcome. This is a prospective, randomized, assessor-masked, active-controlled clinical study. 360 participants (360 study eyes) with mild-to-moderate MGD will be randomized by minimization into three arms equally, receiving either VTP by TearScience-LipiFlow® Thermal Pulsation System (month 0), IPL by Lumenis®️M22 with MGX (month 0, 1, 2, 3) or EW (twice daily). Lubricating eye drops (3% Hypromellose) will be provided for all subjects throughout the study period(15 months). Tear film breakup time will be assessed as primary outcome at month 6, 15. Serial measurements of MG, tear-film, DED-related parameters, intraocular pressure, compliance to EW, factors associated with outcomes and treatment-related complications will be conducted at baseline and each follow-up visit by masked observers at baseline and eight follow-up evaluation (month 0, 1, 2, 3, 4, 6, 9, 12, 15).

Dry eye disease (DED) is an emerging, under-recognized and under-treated epidemic of the 21st century. It is one of the commonest reasons seeking eye consultation worldwide. Depending on the diagnostic criteria, geographic location and population concerned, prevalence of DED ranges from 30 to over 50% in the Asia Pacific regions compared to around 5-10% in the United States. Up to 90% of DED is closely associated with meibomian gland dysfunction (MGD), a chronic and progressive condition characterized by terminal duct obstruction, qualitative and/or quantitative changes in the glandular secretions (meibum) which causes tear instability by increasing tear evaporation and subsequently increased tear osmolarity, ocular surface inflammation, epithelial damage and ocular surface disease. Studies suggest that MGD affects between 5-20 % of Caucasians and over 60% of Asians populations. Conventional treatments for MGD including self-administered eyelid hygiene, eyelid warm compress therapy (EW), artificial tears, including lipid-containing lubricants are limited in their efficacies for moderate to advanced disease. Prescription medications (topical steroids, topical and oral antibiotics, topical immunomodulatory agents e.g. cyclosporine and oral omega-3 essential fatty acids) have demonstrated efficacies in improving symptoms and signs of MGD; however side-effects including preservative-related adverse events, development of antibiotic resistance, cost, accessibility, off-label use, and the need for ongoing treatments often limit their long-term use. Despite the described range of available options, management for MGDs is often considered unsatisfactory and frustrating by clinicians and patients. Compliance to long-term, home-based self-administered therapies is known to be suboptimal while practitioner-administered treatment including meibomian gland expression (MGX) provides transient relief. Intense pulsed light (IPL) therapy is widely used in cosmetic dermatology as well as therapeutically for a wide range of skin conditions with favourable efficacy and tolerability. Concurrent MGD improvements were observed serendipitously in patients undergoing IPL for rosacea. With growing interest in combining IPL+MGX as practitioner-administered physical therapy for MGD, recent review and meta-analysis showed its effectiveness and safety while calling to investigate its effect beyond 6 months after the last IPL treatment. Vectored thermal pulsation (VTP) is approved by FDA as another practitioner-administered physical therapy for MGD. The device covers both the cutaneous and mucosal surfaces of the eyelids; the rear portion of the device provides heat to the MG, and the front portion gives mechanical stimulation to the eyelid skin. It evacuates the MG of the upper and lower eyelids simultaneously with minimal discomfort while protecting the cornea, rendering the experience for patients generally favorable. Recent meta-analysis showed that a single 12-minute VTP was more efficacious than EW in treating MGD. Knowledge gaps: Level I evidence comparing efficacies between two promising practitioner-administered therapies VTP and multi-session IPL+MGX with standard self-administered twice-daily EW for MGD is currently lacking. The onset and offset of therapeutic effects, time course of multi-session IPL+MGX, single-session VTP or twice-daily EW on MGD up to 15-month post-treatment initiation or 12-month post last session of IPL have not been studied either in an RCT setting. These important gaps will be addressed in this application. Primary Objective: To compare the efficacy and safety of 1-session vectored thermal pulsation (VTP) or 4-session intense pulsed light and meibomian gland expression (IPL+MGX) with twice-daily eyelid warm compress (EW) therapy for meibomian gland dysfunction (MGD). Secondary Objectives: To compare the course of MGD among groups over 15 months (12-month after final IPL+MGX); To identify factors predicting responses and compliance to therapies. Hypotheses: Both 1-session VTP and 4-session IPL+MGX are more efficacious than twice-daily EW in improving MGD; MGD improves earlier after VTP; MGD improvement lasts longer after 4-session IPL+MGX. Study design: This is a prospective, randomized, assessor-masked, 3-arm (1:1:1), active-controlled trial of 360 subjects with meibomian gland dysfunction contributing one study eye. For subjects with both eyes eligible, the eye with the fewest quality of expressed meibum, thinnest lipid layer, or the lowest TFBUT values (in this order) will be selected as the study eye. A total of 360 patients with symptomatic MGD will be recruited from the participating hospitals coordinated by the Chinese University of Hong Kong (CUHK) Research Clinic, the CUHK Eye Centre (CUHKEC), Department of Ophthalmology and Visual Science, Faculty of Medicine, The CUHK. Randomization will be carried out by a computer-generated minimization program. Minimization is a dynamic process to reduce the imbalance between trial arms with respect to a range of predefined prognostic variables, and a randomization schedule is therefore not drawn up in advance. A form describing the baseline characteristics of each subject according to these minimization criteria: gender, age, and quality of expressed meibum from the study eye. Treatment allocation will be sent to the unmasked trial coordinator for arrangement at baseline (month 0). Enrolled patients will be randomized into one of the following groups, 1 month after recruitment during the 15-month study period receiving bilateral treatment of: Group A: 1-session VTP at month 0; Group B: 4-session IPL+MGX at month 0,1,2,3; Group C: twice daily EW for 15 months. All patients will be given one single topical lubricant (Hypromellose, 3mg/ml) to be used as frequently as needed from recruitment to study exit (total 16 months). IPL or VTP is given by unmasked treating investigators not involved in data collection. Follow-up investigators collecting the data are masked to participants' treatment assignment. This information can be disclosed upon request after the completion of the study. Unmasked trial coordinators will ensure masking by reminding and accompanying each patient before and during visit. Treatment-related complications will be evaluated by all participants in a standard datasheet regardless of group assignment. Follow-up investigators will be asked if they know each participant's group assignment at each visit and why. Tear film breakup time will be assessed as the primary outcome (month 6 and 15). Serial measurements of MG, tear-film, DED-related parameters, intraocular pressure, compliance to EW, factors associated with outcomes, and treatment-related complications will be conducted by masked investigators at baseline and eight follow-up evaluations (month 0, 1, 2, 3, 4, 6, 9, 12, 15).

Meibomian Gland Dysfunction, Dry Eye Disease, Vectored Thermal Pulsation therapy, Intense Pulsed Light therapy

This is a prospective, randomized, assessor-masked, 3-arm (1:1:1), active-controlled trial of 360 subjects with meibomian gland dysfunction contributing one study eye. For subjects with both eyes eligible, the eye with the most meibomian gland dropout (meiboscore), fewest expressible meibomian glands, thinnest lipid layer, or lowest TFBUT values (in this order) will be selected as the study eye. Enrolled patients will be randomized into one of the following groups, 1 month after recruitment during the 15-month study period receiving bilateral treatment of: Group A: 1-session VTP at month 0 Group B: 4-session IPL+MGX at month 0,1,2,3 Group C: twice daily EW for 15 months Topical lubricating eye drops (Hypromellose, 3mg/ml) will be the monotherapy for all subjects.

Unmasked trial coordinators will ensure masking by reminding and accompanying each patient before and during visits. Treatment related complications will be evaluated by all participants in a standard datasheet regardless of group assignment. Follow-up investigators will be asked if they know each participant's group assignment at each visit and why.

VTP purchased from TearScience®️ is an automated thermal pulsation system that is designed to heat and simultaneously evacuate the meibomian gland contents. It is performed by the unmasked treating investigators as described by the equipment manufacturer. In brief, one to two drops of topical anesthesia are applied prior to the bilateral application of the activators. The inner portion of the activator applies a constant temperature of 42.5°C to the tarsal conjunctiva of upper and lower eyelids. Simultaneously, the outer portion of the activator applies directional, pulsatile pressure to the external eyelid surfaces (maximum 6 psi) for the 12-minute treatment cycle. Participants will receive one session of VTP treatment only (month 0).

IPL is delivered using the proprietary "dry eye mode" setting of the Lumenis®️ M22TM system per the Toyos protocol. Pulse intensity (11-14 J/cm2) is inversely related to the Fitzpatrick skin phototype of each participant and will be used for the same patient throughout the study. IPL will be delivered to four overlapping zones inferior to each eye and a fifth pulse applied temporally adjacent to the lateral canthus four times. Both eyelids are closed and sealed with IPL-Aid disposable eye shields. MGX is immediately performed on both upper and lower eyelids of each eye and pain will be minimized by topical anesthetic. Participants will receive four-session IPL and MGX treatment (month 0, 1, 2 ,3).

EW using warm wet towel to each eye is performed twice daily for 10 mins. A treatment diary will be given for patients randomized to EW for daily recording which will be reviewed and recorded by the unmasked study coordinator at each study visit.

All patients will be given one single topical lubricant (Hypromellose, 3mg/ml) to be used as frequently as needed from recruitment to study exit (total 16 months).

Sodium fluorescein will be instilled in both eyes of the subject. A follow-up investigator will do the examination by slit lamp. Tear film breakup time (TFBUT) is the time to initial breakup of the tear film after a blink is measured three times and taken average.

Sodium fluorescein will be instilled in both eyes of the subject. A follow-up investigator will do the examination by slit lamp. Tear film breakup time (TFBUT) is the time to initial breakup of the tear film after a blink is measured three times and taken average.

The 12-item symptom frequency-based questionnaire Ocular Surface Disease Index (OSDI) is self-administered by patients at each study visit for assessment of dry eye disease (DED) related symptoms and its severity. Final OSDI score is calculated by dividing the product of the total sum of score and 25 by the total number of answered questions, with a range from 0 to 100 (normal: 0-12, mild dry eye disease: 13-22, moderate dry eye disease: 23-32, severe dry eye disease: >33).

The Standard Patient Evaluation of Eye Dryness (SPEED) questionnaire is self-administered by patients at each study visit for monitoring dry eye symptoms progression throughout the study. Final SPEED score is calculated by summating the score of all answered questions, with a range from 0 to 28 (mild dry eye symptoms: 0-4, moderate dry eye symptoms: 5-7, severe dry eye symptoms: >8).

The 2-item frequency- and severity-based visual analog scale Symptom Assessment iN Dry Eye (SANDE) questionnaire is self-administered by patients at each study visit to evaluate the frequency and severity of dry eye symptoms. Final SANDE score is calculated by obtaining the square root of the product of the frequency of symptoms score and the severity of symptoms score, with a range from 0 (minimal degree of dry eye symptoms) to 100 (maximal degree of dry eye symptoms)

The Ocular Comfort Index (OCI) questionnaire is self-administered by patients at each study visit to evaluate the topical treatment outcome of dry eye symptoms. The final OCI score will be linearly rescaled which ranges from 0 (minimal degree of dry eye symptoms) to 100 (maximal degree of dry eye symptoms).

The Dry Eye Questionnaire (DEQ-5) is self-administered by patients at each study visit for assessment of the frequency and intensity of dry eye symptoms. The final DEQ-5 score is calculated by summating the score of all answered questions, with a range from 0 to 22. A score greater or equal to 6 is considered positive for dry eye symptoms.

Sodium fluorescein will be instilled in both eyes of the subject. A follow-up investigator will do the examination by slit lamp. Tear film breakup time (TFBUT) is the time to initial breakup of the tear film after a blink is measured three times and taken average.

Non-invasive keratograph break-up time (NIKBUT) is measured using automated detection of the first break-up by Keratograph 5M (OCULUS, Wetzlar, Germany), while the subject maintains fixation and is requested to refrain from blinking. Three break-up time readings are averaged in each case for both eyes.

Bulbar conjunctival hyperaemia is evaluated by Keratograph 5M (OCULUS, Wetzlar, Germany) according to the proprietary JENVIS grading scale from 0 to 4.

The lower tear meniscus height (TMH) is assessed using high magnification pre-calibrated digital imaging by Keratograph 5M (OCULUS, Wetzlar, Germany), and three measurement points (nasal and temporal limbus, pupil center) of the lower meniscus are averaged.

Lipid layer thickness (LLT) of the tear film as determined with LipiView II (TearScience, Morrisville, NC). Minimum, Maximum and Average thickness in nm will be measured.

Tear interferometric fringe pattern is graded according to the modified Guillon-Keeler system with LipiView II (TearScience, Morrisville, NC). It will be graded according to the modified Guillon-Keeler system: grade 1, open meshwork; grade 2, closed meshwork; grade 3, wave or flow; grade 4, amorphous; grade 5, colored fringes; grade 0, non-continuous layer (non-visible or abnormal colored fringes).

The meiboscore grading scale uses a 0 to 3 grading scale by LipiView II (TearScience, Morrisville, NC) infrared meibography on both superior and inferior eyelids, with a grade of 0 representing no meibomian gland atrophy, with grades of 1, 2, and 3 representing 1% to 33%, 34% to 66%, and ≥67% of glands lost, respectively.

Meibograde is evaluating gland distortion, gland shortening, and gland dropout by LipiView II (TearScience, Morrisville, NC) infrared meibography on both superior and inferior eyelids. Each of these characteristics is graded from 0-3, like the meiboscore, and then they are summed to give a total score of 0-9 per eyelid.

Partial blinking rate is reported as the percentage of incomplete blinks, which recorded by LipiView II (TearScience, Morrisville, NC).

Schirmer's test (ST) will be performed by standard filter paper strips without anesthesia for 5 mins in both eyes at the same time. The wetting length by tears in each strip is recorded. The strips will be collected in sterile centrifuge tubes respectively for laboratory tests.

Lid margin and eyelash abnormalities will be accessed by a slit lamp, including lid margin thickening, rounding, notching, foaming, telangiectasia, meibomian gland capping, staphylococcal lash crusting, seborrheic lash crusting, Demodex lash cylindrical collarettes, madarosis, poliosis, and trichiasis. All items will be graded based on a four-point scale: grade 0, absent; grade 1, mild; grade 2, moderate; grade 3, severe.

Corneal and conjunctival damage is evaluated by corneal and conjunctival staining scores according to the Oxford grading system (six-point scale). Fluorescein sodium will be Instilled in both eyes. The staining of the eyes will be examined by follow-up investigators with a slit lamp under cobalt blue light. Scores range from 0-5 ( absent to severe).

Lid wiper epitheliopathy (LWE) is evaluated relative to Korb's grading. Only the superior eyelid will be examined on the linear area of staining and severity of staining. The linear area of staining is graded on a three-point scale (grade 0, <2 mm; grade 1, 2-4 mm; grade 2, 5-9 mm; grade 3, ≥10 mm). The severity of staining is graded on a four-point scale (grade 0, none; grade 1, slight; grade 2, mild; grade 3, moderate; grade 4, severe). The total grade was the sum of the grading score of the linear area of staining and severity of staining.

Change in expressibility of meibomian glands in the meibomian glands yielding liquid secretion (MGYLS) (the inferior eyelid)

Expressibility of the inferior eyelid meibomian glands is assessed with the Meibomian Gland Evaluator (TearScience, North Carolina, USA) applied just inferior to the nasal, central, and temporal aspects of the inferior eyelid margin. The meibomian glands yielding liquid secretion (MGYLS) is the total number of glands which yielding lipid secretions at the nasal, central, and temporal aspects of the eyelid margin (5 glands each part).

Change in expressibility of meibomian glands in proportion of meibomian orifices yielding lipid secretions (the inferior eyelid))

Expressibility of the inferior eyelid meibomian glands is assessed with the Meibomian Gland Evaluator (TearScience, North Carolina, USA) applied just inferior to the nasal, central, and temporal aspects of the inferior eyelid margin. The proportion of meibomian orifices yielding lipid secretions is graded on a five-point scale: 0, more than 75% (4-5 glands); 1, 50% to 75% (3 glands); 2, 25% to 50% (2 glands); 3, less than 25% (1 gland); 4, none (0 gland).

Each gland in each area is assessed for expressibility and graded according to a 4-point scale (grade 0, no secretion; grade 1, inspissated/ toothpaste-like expression; grade 2, cloudy fluid secretion; and grade 3, clear fluid/normal secretion). The sum scores of 15 glands will be between 0 and 45.

Procedure-related pain (VAS) is graded on a ten-point score (from no pain, moderate pain, to worst pain) as safety outcome measures.

The intraocular pressure, the fluid pressure of the eye, is assessed by a non-contact tonometer as the safety outcome measure.

Lens opacity is graded by the slip lamp according to the Lens Opacities Classification System (LOCS II) as a safety outcome measure. There are 4 standards for nuclear grading (grade 0/1/2/3), 5 standards for cortical grading (0/TR/1/2/3/4/5), and 4 standards for posterior grading (0/1/2/3/4).

Anterior chamber activities are graded by the Standardization of Uveitis Nomenclature (SUN) grading system: 1) cells (0/0.5+/1+/2+/3+/4+); 2) flare (0/1+/2+/3+/4+).

Iris defect and transillumination are assessed by 2-point scale as safety outcome measure. (0: no; 1: absent).

Both of the subject's eyes will be dilated. The fundus examination is performed by a follow-up investigator, and abnormalities of fundus will be recorded. The number of participants with the situation will be counted.

Loss of lashes and eyebrows are assessed by 2-point scale as safety outcome measure. (0: no; 1: absent). The number of participants with the situation will be counted.

Facial redness is assessed by 2-point scale as safety outcome measure. (0: no; 1: absent). The number of participants with the situation will be counted.

Facial swelling is graded by 2-point scale as safety outcome measure. (0: no; 1: absent). The number of participants with the situation will be counted.

Facial bruises are graded by 2-point scale as safety outcome measure. (0: no; 1: absent). The number of participants with the situation will be counted.

Facial pigmentation is graded by 2-point scale as safety outcome measure. (0: no; 1: absent). The number of participants with the situation will be counted.

Each eye will be sampled by a sterile, polyester swab on the inferior fornix of the conjunctiva. The swabs will be placed in 2 mL microcentrifuge tubes at 4 °C. Extraction will be performed by laboratory staff, then the sample will be transferred to -80 °C laboratory freezer for long-term storage before further gene expression tests. After genomic DNA extraction from conjunctival swab samples for 16S rRNA sequencing, the resulting amplicons will be filtered, clustered into operational taxonomic units (OTUs) and taxonomically classified using reference databases. The α-diversity will be calculated and reported as ordination plots.

Each eye will be sampled by a sterile, polyester swab on the inferior fornix of the conjunctiva. The swabs will be placed in 2 mL microcentrifuge tubes at 4 °C. Extraction will be performed by laboratory staff, then the sample will be transferred to -80 °C laboratory freezer for long-term storage before further gene expression tests. After genomic DNA extraction from conjunctival swab samples for 16S rRNA sequencing, the resulting amplicons will be filtered, clustered into operational taxonomic units (OTUs) and taxonomically classified using reference databases. The β-diversity will be calculated and reported as ordination plots.

Subjects' blood specimens will be collected at the baseline visit and pre-treated for further laboratory tests. After genomic DNA extraction from venous blood, Single-nucleotide polymorphism (SNP) will be selected, sequenced and compared between treatment groups for pharmacogenomic analyses.

Inclusion Criteria: ≥18 years of age with no upper age limit; Agree to attend follow-up visits and comply to treatment regimen; Symptomatic dry eye TFBUT (average of 3 times) ≤ 5 seconds and OSDI ≥ 13; Mild to moderate (level 3-4) MGD on at least one eye; Fitzpatrick skin type 1-4. Exclusion Criteria: Contact lens wear 3 months before or during the study period; Use of topical (including anti-glaucomatous, cyclosporin, antibiotics) or systemic medication known to affect (worsen or improve) MGD 3 months before or during the study period; Major systemic (e.g. Sjogren's syndrome), dermatologic (e.g. Rosacea) known to affect MGD or ocular conditions (including thyroid eye disease, recurrent conjunctivitis, ocular allergies); Ocular procedures (excluding uncomplicated cataract operation) 3 months before and any ocular procedure during the study period; Dermatological treatment (including chemical peeling, laser, IPL or energy device in the periocular and facial region) 6 months before or during the study period; Contraindications to IPL therapy (including recent sun-burn, photosensitivity, active or pigmented skin lesions, cancer, implants, tattoos, semi-permanent makeup in the periocular area); Contraindications to VTP therapy (ocular surgery, ocular injury, ocular herpes of eye or eyelid, and ocular inflammation 3 months before the study; active ocular infection, etc.) Women who are pregnant, nursing, planning pregnancy, or of childbearing potential not using a reliable method of contraception.

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