This randomized controlled, assessor blind study was conducted between July 1, 2018 and December 30, 2018.
2.1 Patient Selection and Study Design
45 patients clinically diagnosed with refractory o-MGD enrolled in this study. The inclusion criteria included: (1) older than 18 years, (2) Standard Patient Evaluation of Eye Dryness (SPEED) questionnaire≥6, (3) more than half of the 15 evaluated meibomian gland orifices in each eyelid were obstructed and had no lipid secretion with extrusion, (4) meibum grade≤24, (5) breakup time of tear film (TBUT)≤5s, (6) Schirmer test＞5s, (7) Meibo-Scan (OCULUS) revealed less than 1/3 atrophy area of the meibomian gland in both the upper and lower eyelids, (8) refractory was defined as lack of symptom relief with conservative treatment (eyelid warming, massage, and artificial tears) for at least 1 year prior to study treatment. All patients were informed of possible treatment-related complications and the possibility of being assigned to an invasive treatment group. All agreed to receive the possible therapeutic regimen and signed an informed consent form. Patients with a history of corneal contact lens, mite blepharitis, acute eye inflammation, or infection and apparent eyelid margin scarring as well as patients using a lacrimal plug or receiving LASIK (Laser Assisted In-situ Keratomi) were excluded from the study.
The multiple rate comparison method performed with PASS version 15 was used to estimate sample size. The pilot study, which involved 5 patients per group, showed that 20%, 20%, and 80% of patients in IPL, MGP and MGP-IPL groups experienced effective symptom improvement following treatment (with a decrease in SPEED score before treatment and half a year after final treatment＞5). Power calculations with a type I error of 0.05 and type II error of 0.9 were executed. The results showed a sample size of 38 achieves 90% power in detecting an effect size (W) of 0.5774 using a 2 degrees of freedom Chi-Square Test with a significance level (alpha) of 0.05. So, each group needed at least 13 patients.
Participants were randomly divided into 3 groups (15 patients per group) via block randomization, and allocation concealment was implemented using a closed envelop method. Patients in group I received an IPL treatment course (treated with IPL 3 times at 3-week intervals). Patients in group II received an MGP treatment course (treated with MGP one time). In group III, 3 weeks after initial MGP treatment, patients also received IPL 3 times at 3-week intervals. The clinical effects were assessed at baseline, 3 and 12 weeks following MGP treatment for group II and 3 weeks after final treatment for groups I and III. Furthermore, six months following final treatment for all 3 groups, all patients completed SPEED and answered a question in terms of requiring to receive any treatment once more. Patient enrollment, random allocation sequence generation, and intervention assignment were performed by the first author (HXD).
2.2 Treatment Procedure
2.2.1 Intraductal meibomian canal probing
With the help of SuZhou LiuLiu Medical Equipment co. LTD, we designed a private probe based on the original Maskin probe and a rinse hollow tube (Fig.1). The probe was 4.5mm in length with a blunt end 0.12 mm in diameter. The hollow tube was 2.0 mm in length and 0.16 mm in diameter. The process of intraductal MGP proceeded as follows: (1) to ease the pain of probing, 4% lidocaine was injected into the upper and lower eyelids parallel to the palpebral margin, resulting in a local bulgy of the skin. (2) the eyelids were flipped outward with a cotton swab and an operating microscope was positioned over the target eyelid to more clearly show the orifices. Then, the operator inserted the probe into the glands vertically to the orifices. Impact force was required when resistance from the orifices or intraductal was encountered. After probing, chalazion forceps were used to squeeze out remnant meibum. Self-limited hemorrhage was the most common complication, for which a blood point and blood trickle could be observed and no particular treatment was needed. (3) then, a hollow tube was used to swash the meibomian gland by injecting 0.1% Dexamethasone (Guangzhou Baiyun Mountain Pharmaceutical co. LTD, China) and 0.25% Amikacin (Qilu Pharmaceutical co. LTD, China) repeatedly (Fig.1). (4) eventually, Tobradex eye ointment (Alcon, Belgium) was applied to the conjunctival sac. All MGP procedures were performed by the first author (HXD).
2.2.2 Intense pulsed light
A M22 Multi-pulse therapeutic apparatus was used for treatment. Prior to treatment, 1-2 mm thick ultrasound gel was applied to participants’ faces, covering the area from tragus to tragus beneath the eyelid margin, temple, and forehead. Then, the Pre-set Toyos parameters were administered to 1 or 2 treatment area test points to test patient tolerance and comfort. The intensity of the IPL treatment was adjusted to 14J/cm2-15J/cm2, which was determined via Fitzpatrick Skin Type Grading. Placement of an IPL eye shield over the eyes was necessary to protect eyes from the stimulus of bright light. After this, one back-and-forth flash emitted by an IPL hand piece was placed on each skin area without pressure. Finally, chalazion forceps were used to squeeze MG tissues. Care should be taken to ensure that the treatment areas were identical for each participant and all procedures were conducted by the same doctor (LL).
All participants were required to use artificial tears (Hailu, German) four times a day during the entire follow-up period.
2.3 Clinical Evaluation
The eye examiners (Jiao Zheng and Linping Wang) were blind in regard to the groups participants were assigned to.
2.3.1 SPEED, CFS and TBUT
A Standard Patient Evaluation of Eye Dryness (SPEED) validated questionnaire (0–28) was used to assess the symptoms, as previously described15. Corneal fluorescein staining (CFS) was evaluated by dividing the cornea into four equal quadrants, and the staining of each section was recorded on a 0-3 scale: 0=no punctate staining; 1=less than half staining; 2=more than half staining; 3=whole staining; and a composite score for each quadrant (0–12 score)16. Tear break-up time (TBUT) was evaluated 3 times and an average value was recorded17.
2.3.2 Meibum grade
The lower and upper eyelids were divided into 3 parts– nasal, bitamporal, and middle– with a total of 15 glands in each eyelid. The characteristics of each glandular expressate were graded on a scale of 0 to 3: 0=no secretion; 1=inspissated-filamentary secretion; 2=cloudy liquid secretion; and 3=clear liquid secretion. The scores of each expressed orifice in the 3 different eyelid sections were added together to provide the final meibum grade scores (0-90 score) for the right and left eyes18.
2.3.3 Lid margin finding results
Lid margin finding results we evaluated included the abnormality of meibomian gland orifices, lid tenderness and telangiectasia, and were noted on a 0-4 scale, with 0 being absent and 4 being the most severe8,19.
2.4 Statistical Analysis
Statistical significance was set at p<0.05, and data analysis was performed using SPSS version 23. Continuous data was presented as means ± SD. A paired Wilcoxon test was employed to compare the parameters prior to and following treatment. Then, comparison was made between the different groups via non-parametric Mann-Whitney U tests with Bonferroni correction, Kruskal-Wallis tests.