Intense Pulsed Light Therapy for Meibomian Gland Dysfunction: A Review of Clinical Effectiveness and Guidelines

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1 CADTH RAPID RESPONSE REPORT: SUMMARY WITH CRITICAL APPRAISAL Intense Pulsed Light Therapy for Meibomian Gland Dysfunction: A Review of Clinical Effectiveness and Service Line: Rapid Response Service Version: 1.0 Publication Date: February 8, 2018 Report Length: 26 Pages

2 Authors: Steve Rennick, Lorna Adcock Cite As: Intense pulsed light therapy f or meibomian gland dy sf unction: a rev iew of clinical ef fectiveness and guidelines.. Ottawa: CADTH; 2018 Feb. (CADTH rapid response report: summary with critical appraisal). ISSN: (online) Disclaimer: The inf ormation in this document is intended to help Canadian health care decision-makers, health care prof essionals, health sy stems leaders, and policy -makers make well-inf ormed decisions and thereby improv e the quality of health care serv ices. While patients and others may access this document, the document is made av ailable f or inf ormational purposes only and no representations or warranties are made with respect to its f itness f or any particular purpose. The inf ormation in this document should not be used as a substitute f or prof essional medical adv ice or as a substitute f or the application of clinical judgment in respect of the care of a particular patient or other prof essional judgment in any decision-making process. The Canadian Agency f or Drugs and Technologies in Health (CADTH) does not endorse any inf ormation, drugs, therapies, treatments, products, processes, or serv ices. While care has been taken to ensure that the inf ormation prepared by CADTH in this document is accurate, complete, and up-to-date as at the applicable date the material was f irst published by CADTH, CADTH does not make any guarantees to that ef f ect. CADTH does not guarantee and is not responsible f or the quality, currency, propriety, accuracy, or reasonableness of any statements, information, or conclusions contained in any third-party materials used in preparing this document. The v iews and opinions of third parties published in this document do not necessarily state or ref lect those of CADTH. CADTH is not responsible f or any errors, omissions, injury, loss, or damage arising f rom or relating to the use (or misuse) of any inf ormation, statements, or conclusions contained in or implied by the contents of this document or any of the source materials. This document may contain links to third-party websites. CADTH does not hav e control ov er the content of such sites. Use of third-party sites is gov erned by the third-party website owners own terms and conditions set out f or such sites. CADTH does not make any guarantee with respect to any inf ormation contained on such third-party sites and CADTH is not responsible f or any injury, loss, or damage suf f ered as a result of using such third-party sites. CADTH has no responsibility f or the collection, use, and disclosure of personal inf ormation by third-party sites. Subject to the af orementioned limitations, the v iews expressed herein are those of CADTH and do not necessarily represent the v iews of Canada s f ederal, prov incial, or territorial gov ernments or any third party supplier of inf ormation. This document is prepared and intended f or use in the context of the Canadian health care sy stem. The use of this document outside of Canada is done so at the user s own risk. This disclaimer and any questions or matters of any nature arising f rom or relating to the content or use (or misuse) of this document will be gov erned by and interpreted in accordance with the laws of the Prov ince of Ontario and the laws of Canada applicable therein, and all proceedings shall be subject to the exclusiv e jurisdiction of the courts of the Prov ince of Ontario, Canada. The copy right and other intellectual property rights in this document are owned by CADTH and its licensors. These rights are prot ected by the Canadian Copyright Act and other national and international laws and agreements. Users are permitted to make copies of this document f or non-commercial purposes only, prov ided it is not modif ied when reproduced and appropriate credit is giv en to CADTH and its licensors. About CADTH: CADTH is an independent, not-f or-prof it organization responsible f or prov iding Canada s health care decision-makers with objectiv e ev idence to help make inf ormed decisions about the optimal use of drugs, medical dev ices, diagnostics, and procedures in our health care sy stem. 2

3 Context and Policy Issues Tears are a complex mixture of an aqueous phase, mucus, and multiple fatty acids all of which are essential components for maintaining healthy eyes. 1 Alterations in any of these components can result in the breakdown of this protective fluid and result in dry eyes. Dry eye disease (DED) is a widely occurring condition that results when the tears are not able to properly lubricate the ocular surface. 1-3 This disease affects the population to varying degrees and is the most common reason for visiting the ophthalmologist. 4,5 In Asia it has been estimated to affect sixty to seventy per cent of the population and in North America is estimated that between five and twenty per cent of people are affected. 1,2,4-6 DED is found in patients of all ages though the likelihood increases with age and with a history of cataract or refractive surgery. 4 Typical symptoms associated with this disease are dry, burning, itchy, watery eyes that may have swelling and redness in the surrounding skin. 6,7 The discomfort caused by these symptoms can disrupt the livelihood and productivity of a person who is afflicted with them. The two main types of DED are evaporative and aqueous. 5,8 Evaporative is the most common form and is typically associated with meibomian gland dysfunction (MGD). 4-6,8,9 The meibomian glands are found on the upper and lower eyelids and produce an oily fluid called meibum that coats the ocular surface when a person blinks. This oil will cover the tears and work to prevent excessive evaporation. In MGD the meibomian glands are dysfunctional and the meibum thickens. In severe conditions it has been described as a solid, toothpaste like substance. 1,2,5,10 This can result in capping of the glands which in turn will cause the glands to become truncated and then atrophy, also referred to as dropout. As a result of this the tears will evaporate at increased rates which allows bacterial populations to flourish and further exacerbate the symptoms. 8,11 Previous research has demonstrated that other skin conditions such as rosacea are commonly found in patients who have MGD. 1,5 Standard treatment options for MGD include therapies such as eyelid massage, artificial tears, warm compresses, and lubricants that contain fatty acids. 5,6,8,9 Unfortunately, these treatments provide brief respite from the symptoms and patients often seek out more effective, long lasting relief. In these situations doctors have prescribed either oral or topical antibiotics, steroids, and omega-3 fatty acids but all of these options come with a host of potential adverse side effects which may contraindicate their use. 6,7,9,12 Intense pulsed light (IPL) has been used in the treatment of many epidermal conditions, like rosacea, for many years. 1,3,5,9,10 In this treatment a wide range of non-coherent, polyspectrum light with wavelengths from 500nm to 1200nm is exposed to the skin in brief flashes. These wavelengths stimulate melanin and hemoglobin in the skin which will cause coagulation and ablation of blood vessels. 3,7,10 In 2002 Dr. Rolando Toyos recognized that patients who had MGD and were treated for rosacea appeared to have reduced symptoms of DED. 3,7,10 The method in which these benefits operate still remains unclear though several theories exist such as stimulating the release of inflammatory mediators or generating heat which softens the sticky glandular deposits. 3,4,10 Since the discovery of the benefits of IPL for MGD patients there has been an increased demand for this treatment approach. 1 In 2016 Health Canada released a warning about the use of IPL devices due to the risk of burns to the skin through their use. 13 Furthermore, they are commonly found in cosmetic and therapeutic retail clinics where personnel have little training or expertise in their use. The purpose of this report is to examine the clinical effectiveness and guidelines for IPL treatment of DED caused by MGD. 3

4 Research Questions 1. What is the clinical effectiveness of Intense Pulsed Light Therapy for the treatment of Meibomian Gland Dysfunction in adults? 2. What are the evidence-based guidelines regarding the use of Intense Pulsed Light Therapy for the treatment of Meibomian Gland Dysfunction in adults Key Findings All of the studies examined in this review reported a reduction in symptoms and an improvement in meibum quality and gland function for patients suffering from dry eye disease caused by meibomian gland dysfunction treated with intense pulsed light therapy. These results were produced by studies that in many cases lacked sufficient control populations for comparison and in one study with an active comparator improvements were not always different from alternative treatment (eye hygiene). The number of treatments required for these benefits remains unclear as no evidence-based guidelines were found. In addition, the majority of the methods used for intense pulsed light treatment varied widely from one study to another. The overall process appears to be safe as no study reported any severe adverse events and those that were found were not serious in nature and remedied themselves within one week without medical aid. Of note, all of the included studies were completed on small patient populations gathered mostly from a single centre therefore the absence of adverse events does not mean that they are not possible. Methods Literature Search Methods A limited literature search was conducted on key resources including PubMed, The Cochrane Library, University of York Centre for Reviews and Dissemination (CRD) databases and a focused Internet search. No methodological filters were applied to limit retrieval by publication type for the first research question. The guidelines filter was applied for the broader guideline question. The search was limited to English language documents published between January 1, 2013 and January 10, Internet links were provided, where available. Selection Criteria and Methods One reviewer screened citations and selected studies. In the first level of screening, titles and abstracts were reviewed and potentially relevant articles were retrieved and assessed for inclusion. The final selection of full-text articles was based on the inclusion criteria presented in Table 1. Table 1: Selection Criteria Population Intervention Comparator Outcomes Adults with Meibomian Gland Dysfunction (also called dry eye disease or evaporative dry eye disease ) Intense Pulsed Light Therapy Placebo or sham therapy, no treatment Q1: clinical effectiveness (benefit/harm), safety Q2: guidelines 4

5 Study Designs - Health technology assessments, systematic reviews, meta-analyses - Randomized controlled trials - Non-randomized studies - Exclusion Criteria Articles were excluded if they did not meet the selection criteria outlined in Table 1, they were duplicate publications, or were published prior to January Critical Appraisal of Individual Studies Randomized controlled trials (RCTs) and non-randomized studies were assessed using the Downs and Black checklist. 14 Summary scores were not calculated for the included studies; rather, a review of the strengths and limitations of each included study were described narratively. Summary of Evidence Details of study characteristics, critical appraisal, and study findings are located in Appendices 2, 3, and 4, respectively. Quantity of Research Available A total of 140 citations were identified in the literature search. Following screening of titles and abstracts, 126 citations were excluded and 14 potentially relevant reports from the electronic search were retrieved for full-text review. No potentially relevant publications were retrieved from the grey literature search. Of these potentially relevant articles, ten publications were excluded for various reasons, while four publications met the inclusion criteria and were included in this report. Appendix 1 describes the PRISMA flowchart of the study selection. Summary of Study Characteristics Study Design and Patient Population There were four investigations found to answer the question on clinical effectiveness. Two of them were prospective before and after studies. 7,12 The remaining two were made up of one randomized controlled trial 6 and one non-randomized controlled trial. 15 No evidencebased guidelines were identified. Details of each study may be found in Appendix 2. All of the studies found for this review followed the Declaration of Helsinki for the ethical treatment of humans in experimentation which was developed by the World Health Organization. The most recent study was performed by Guilloto Callabero et al. in and was a prospective before and after study. The study was conducted to determine the effectiveness of IPL therapy for the treatment of dry eye caused by reductions in tear production or over-evaporation as a result of MGD. This was conducted on patients from the Clinica Vistalaser Oftalmologia in Malaga. A total of 36 patients (72 eyes) were recruited from March 2016 who had an average age of 43 years and were 58.33% female. They also had Fitzpatrick skin types of either I or II and 60 of the included eyes had previously been 5

6 treated with refractive surgery, six with phacoemulsification, and six without any previous surgery. Patients were excluded if they had previous ocular or systemic pathology, allergy to sunlight, skin exposed to sunlight in the previous month, skin lesions of unusual appearance, or were pregnant. Every patient had previously been treated with ocular lubricants, lacrimal occlusion agents or food supplements with omega-3 fatty acids which was continued throughout this study. The non-randomized controlled trial was conducted by Yin et al. in The purpose of this research was to compare the functionality and morphology of the meibomian glands after undergoing either IPL or eyelid hygiene regimens. Patients were recruited from the ophthalmology clinic at the Eye and ENT Hospital of Fudan University. A total of 35 patients were included, 18 in the IPL group and 17 in the control group. The researchers included a single eye from each patient, in those where both eyes were affected the more severely afflicted eye was included. The average age of patients in the IPL group was and included nine males and nine females. In the control group the average age was and there were nine males and eight females. Patients were included if they were diagnosed with MGD according to the 2011 International Workshop on MGD and had not been treated with any sort of therapy for at least three months. They were excluded if they had previous ocular surgery or trauma, blepheral dysraphiam, a history of blepharal and preorbital skin disease within one month prior to study initiation, acute inflammation, or rheumatic immune system disease. In addition they were excluded from the IPL group if they had excessive exposure to the sun in the past month, a history of herpes zoster infection, a Fitzpatrick skin type of V or VI, were pregnant, or used of photosensitive drugs/foods. In 2016 Jiang et al. conducted a prospective before and after investigation. 7 The purpose of this study was to examine the results of IPL treatment in Chinese patients with MGD to clarify effectiveness and safety profiles. Patients were recruited from the outpatient department of the Department of Ophthalmology of Peking University Third Hospital. Between April of 2014 to January 2015 random selection resulted in the left eye of 40 patients being chosen for treatment. They were included if they were adults, complained of eye dryness/foreign body sensation/burning/tearing for >3 months/diagnosis of MGD, and had a willingness to follow directions and return for follow-up visits. In order to be diagnosed with MGD two of the following conditions were required redness or thickening of the lid margin, telangiectasia, reduced or no secretions, poor quality secretions, or gland capping. Patients were excluded if they had severe ocular surface deformations; a history of ocular trauma or surgery; punctal occlusions; use of drops other than artificial tears in previous month; active allergy, infection or inflammatory disease at the ocular surface other than MGD; alterations of the lacrimal drainage system; systemic disease affecting the ocular surface; uncontrolled systemic disease; pigmented lesions in the treatment area currently used a treatment for MGD; used systemic medications that alter tear film; used contact lenses; received skin treatments within the previous two months; and were pregnant or nursing, In 2015 Craig et al. conducted a randomized, double-blinded, controlled study. 6 The goal of this study was to examine the effect of IPL treatment to the lower periocular area of skin and examine changes to tear film and symptoms of patients suffering from MGD in a prospective double-blinded manner. In total 28 patients were recruited and they had an average age of 45 years old. Patients were excluded if they had clinical skin treatment in last two years, implants beneath the treatment area or tattoos in the region, semipermanent make-up or pigment lesions in treatment area, had used contact lenses within 48 hours of IPL initiation or during the study, and if light therapy was contraindicated by 6

7 medical history. A single eye from these patients was chosen for IPL treatment using a computer-based randomization program and the remaining eye was used as a control. Country of Origin Two of the studies were produced in China 7,15 and the remaining two investigations were produced in New Zealand 6 and Spain. 12 Interventions and Comparators All of the investigations included in this review evaluated the clinical effectiveness of IPL treatment, and used opaque goggles which were placed over the eyes of the patients in order to protect them from the light produced during IPL treatment. The IPL devices came from a variety of manufacturers. The E>Eye device from the E-Swin company of Paris France was used in two of the investigations. 6,7 Jiang et al. 7 used a technique where four overlapping flashes were used on the area below the lower eyelid. They did not apply any pressure during treatment and treatment was completed at day 1 (D1), D15, D45 and D75. Craig et al. 6 utilized a similar approach where four flashes were used. For both studies flash intensity was determined using Fitzpatrick skin types and ranged from 13 J/cm 3 for skin type I ( pale white ) to 9 J/cm 3 for skin type V ( dark brown ). Guilloto Callabero et al. 12 used a modified version of this machine for their study in which the flash of light is regulated and a controllable range of sub-pulses are produced. This process is termed intense regulated pulsed light (IRPL) and was used with three flashes in the left middle face starting at the internal canthus of the eye and finishing in the temporal region. Treatments were completed in four sessions with fifteen days between each session. The intensity was set at 11.4J/cm 3 at the first session, at 12.2j/cm 3 in the second session and at 13J/cm 3 for the third and fourth sessions. If it was required, maintenance sessions would be completed six months after the final session. The M22 OPTIMA device from Lumenis in the USA was used in investigation by Yin et al. 15 The treatment area was the periorbital region surrounding the eye including the nose and avoiding the eyebrow. They used this device to deliver treatment one time monthly for three months. Fitzpatrick skin types III and IV were treated at intensities of 17J/cm 3 with a 560nm filter and 16J/cm 3 with a 590nm filter respectively. All participants in this study were given artificial tears four times daily for three months. Two of the studies used comparator groups in their research. 6,15 The non-randomized controlled trial by Yin et al. 15 included a patient population of 17 individuals in their control group who were treated using eyelid hygiene. This process was completed one time daily for the three month study period. The eyelids were warmed to approximately 40 o C for ten minutes and were then massaged with traction used on the lateral canthus to immobilize the upper and lower lids. Then they were mildly compressed either downwards or upwards five times for each treatment regimen. In the RCT by Craig et al. 6 one eye of each patient was used as the control group. This eye was left untreated and went through the same examinations as the treated eye. Outcomes The outcomes of interest in the study by Guilloto Callabero et al. 12 were completed in a sequential manner. The protocol sequence was anamnesis (i.e., taking the patient s history), TBUT using the Sirius CSO tomography from Italy, lacrimal meniscus measurement, and Schirmer II test. The TBUT and lacrimal meniscus measurements were 7

8 completed three times and averages were calculated. All testing was conducted in similar setting with dim lighting and an even temperature of 23 o C. The patients were not advised of the results of any of the testing and all information that could have influenced the results was kept confidential. The goal of this investigation was to determine the efficiency of IPL therapy for the treatment of dry eye syndrome caused by reduced tear production due to MGD. Yin et al. 15 examined all of their clinical outcomes before and after each IPL treatment. The clinical outcomes of interest were ocular surface density index (OSDI), TBUT, Schirmer test, corneal staining and conjunctival staining. TBUT was measured three consecutive times after fluorescein instillation and the median values were provided. The Schirmer test was performed for five minutes without any anesthesia and used a sterile Schirmer strip. In corneal staining, the cornea was divided into five sections; upper, lower, nasal, temporal, and optical-diameter. Fluorescein was used to examine for superficial punctate keratopathy of the cornea. Conjunctival staining was completed in the same manner as corneal but used lissamine green instead and was broken into; upper, lower, temporal, and nasal regions. Meibum quality and expressibility were also examined on the upper lid. When examining quality, eight glands in the nasal and middle were scored. Expressibility utilized five glands in the nasal area for scoring. Finally, the authors examined Meibomian gland dropout and acini parameters in the upper lids. The Meibomian gland macrostructure was examined after the glands were everted using a noncontact infrared meibography system. The area of the tarsal plate was divided into four boundaries; proximal, distal, nasal, and temporal. String-like structures were considered Meibomian glands if they crossed the palpebral surface. Dropout was acknowledged if these structures were partially lost or truncated and were tallied using ImageJ software. Gland microstructure was examined histologically using a confocal microscope after glands were everted. Three aspects were quantified; gland acinar longest diameter (ALD), gland acinar shortest diameter (ASG), and gland unit density (AUD). Finally, during histological examination inflammatory cells were noted. The goal of this study was to compare the functionality and morphology of the meibomian gland of patients with MGD after undergoing IPL treatment of eyelid hygiene. The investigation by Jaing et al. 7 examined the clinical outcomes of interest three days before treatment began and immediately before treatment at D15, D45 and D75. The testing was completed in order where symptom evaluation was completed first followed by; best spectacle corrected visual acuity, intraocular pressure (IOP), conjunctival injection, upper and lower tear meniscus height (TMH), TBUT, corneal staining, lid margin and Meibomian gland assessments, and finally meibography. A total of five minutes separated each test and the data were collected by two doctors with the average as the final result. The evaluations were carried out before each IPL treatment. Symptom evaluation was a complex scheme where dryness, foreign body sensation, watering, itchiness, visual fatigue, blurred vision, burning, sensitivity to light, secretion disturbance and pain were scored. Each symptom constituent was scored between 0 and 10 where 0 was normal and 10 is the worst case and a total was then calculated. IOP was measured using a noncontact tonometer and three readings were taken with the average being the result provided. Both Conjunctival injection and TMH were measured at the slit lamp according to the Institute for Eye Research. Eyelid margins and Meibomian gland assessments were completed in accordance with the International Workshop on Meibomian Gland Dysfunction. Finally, safety was examined at every visit using best spectacle corrected visual acuity, IOP and corneal and conjunctival staining, eyelash abnormalities, and the skin around the eye was checked for blistering/depigmentation/swelling/redness/hair loss. The purpose of this 8

9 investigation was to examine the results of IPL treatment in Chinese patients with MGD to clarify effectiveness and safety profiles. The final study included in this review was completed by Craig et al. 6 who collected results at four time points which occurred five minutes after each IPL treatment. The clinical results of interest were completed in order from least to most invasive; best spectacle corrected vision acuity (logmar), bulbar conjunctival injection graded on a visual analogue scale (VAS), non-invasive tear break-up time (NIBUT), and fluorescein and lissamine green corneal and conjunctival staining. In addition, tear film was examined in more detail using lipid payer grade (LLG) using tear film interferometry, TMH, tear osmolarity, and tear evaporation rate (TER). Symptoms were examined before each visit using the SPEED questionnaire where each patient scored their symptoms before and after each IPL treatment. The researcher collecting data was blinded to which eye is which and the patient was also blinded with the use of opaque goggles during treatment sessions. The goal of this study was to evaluate the effect of IPL treatment on the periocular area of MGD patients in a prospective double-blinded manner. Summary of Critical Appraisal Details of the critical appraisal can be found in Appendix 3. A total of four publications were found to address the question on the effectiveness of IPL treatment. These studies are made up of two prospective before and after investigations, one randomized controlled trial, and one non-randomized controlled trial. All of the publications included clearly defined characteristics for patient exclusion and all but one provided details on patient inclusion. In the analysis by Craig et al. 6 the inclusion criteria are not clearly defined and the clinic where the patients originated from is not provided. This indicates that the results of the study may not be representative of the general population where they were recruited from. The goals of the studies have been well defined in all of the publications that were included. They have all used well characterized analyses in their methodology and no undocumented experimentation was added in toward the end of the discussion. Unfortunately, all of these publications suffer from having included a small patient population; the largest patient population was found in the study by Jiang et al. 7 and included 40 individuals. This indicates that caution must be taken when using the results for the general population since they may lack the statistical power to detect clinically important effects or uncommon adverse events. Furthermore, none of these investigations included power analysis calculations to ensure that the size of the patient population was substantial enough to provide statistical significance. Control groups were utilized in two of the four included studies. 6,15 This lack of appropriate controls makes it difficult to ascribe any observed changes specifically to the intervention. In addition, in investigations where the researchers score results based on their own observations, bias could be introduced without having a population in the examination that has gone without treatment. 15 Only one of the included studies 6 randomized one of two eyes to treatment with IPL for each patient. Randomization minimizes the potential for selection bias and the influence of known and unknown confounders, and when it is not included the results that are generated must be interpreted with caution. The statistical calculations used in the majority of these studies were well documented and appropriate for the investigations being conducted. Unfortunately, this is not the case for the 9

10 article by Guilloto Caballero et al. 12 where details have not been provided. They reported the computer program that was used to complete the calculations but many of the results provide percentages or averages without any statistical function used to demonstrate significance. Additionally the authors state that 51% of the patients were satisfied with the overall treatment process but no data or analysis is provided on how they reached this conclusion. Additionally, throughout the results section of the study outcomes are provided for TBUT without any statistical calculation used to determine if the results are significant or not. The two studies produced in China 7,15 both included well represented populations from the centres where they were recruited from and the study by Yin et al. 15 stated that they were chosen consecutively. All of the included participants were adult Asians, so the results that were found may not be applicable to people of other ethnicities since IPL treatment is dependent on skin type therefore caution must be used when extrapolating their results for other ethnicities. In the investigation by Jiang et al. 7 the final IPL treatment was at D75 which is also the same time that the final assessments were done. Because of this, it is highly unlikely that the potential benefits of this final treatment have been quantified in the data gathering process. Therefore, the full benefits of the treatment used in this study may have not been recognized. The study by Yin et al. 15 is also limited in that during their patient recruitment when an individual had MGD in both eyes only the more severely affected eye was included. This may not be representative of the spectrum of patients who would receive IPL treatment. The papers included in this review are of limited quality for the reasons that have been provided above therefore care must be used when applying the results. Summary of Findings Clinical effectiveness of Intense Pulsed Light Therapy for the treatment of Meibomian Gland Dysfunction in adults. Guilloto Callabero et al. 12 found an overall increase in TBUT from baseline up to the last treatment in 54.17% of patients; 29.17% of patients had increases of more than three seconds. When examining the surgical subpopulations, those who had not previously had surgery and those who previously had phacoemulsification or refractive photo-keratectomy (PRK) had a TBUT of 5.85 seconds at the time of initial treatment and at the final treatment of 7.7 seconds. Patients who had previously undergone refractive surgery with femtosecond laser (FS) or mechanical microkeratome (MM) had stable TBUT from the first treatment (6.47 seconds) to the last treatment (6.68 seconds). Schirmer II testing improved in 62.5% of the patients, with 37.5% reporting a substantial improvement (statistical significance not reported). In these patients the lacrimal meniscus increased from the first treatment to the last. Overall, it was reported that 51% of the patients reported satisfaction with the treatment regimen for all subjective parameters. Adverse events occurred in two of the 36 patients who reported reddening of the face and light sensitivity. These conditions were transient in nature and within one week had remedied themselves without any medical intervention. In the study by Yin et al. 15 significant improvements were found for OSDI and TBUT in the control group and the IPL group. Before IPL treatment the OSDI score was 38.02±26.86 and post IPL treatment it decreased to 21.76±21.44 (P=0.001, Δ=16.26±18.23). In the control eyes, OSDI pre-treatment was 43.32±23.39 and post-treatment was 24.72±

11 (P=0.001, Δ=20.60±20.17). TBUT improved in a similar manner as pre-treatment was 2.94±2.10 seconds and post-treatment it was 5.78±4.17 (P=0.002, Δ=2.83±3.38). In the control eye TBUT increased from 3.53±2.04 seconds pre-treatment to 7.00±3.69 seconds (P=0.002, Δ=3.47±3.86) post-treatment. No significant difference was found for SIT or corneal staining in either group (P>0.05). Pre-treatment conjunctival staining was slightly higher in the IPL group compared to the control group (P=0.040) and accordingly decreased in the IPL group after treatment while there was no significant change in the control group (P=0.079). Meibomian gland function index showed no significant difference in the quantity or expressibility between the IPL group and the control group prior to treatment (P>0.05). Meibum quality and gland expressibility improved in both groups post-treatment. Meibum quality in the IPL group pre-treatment was 2.78±2.34 and post-treatment was 1.17±1.86 (P=0.014, Δ=1.61±2.50). In the control group it was 2.00±2.12 pre-treatment and posttreatment it was 0.47±0.94 (P=0.023, Δ=1.53±2.50. Expressibility in the three regions for the IPL group pre-treatment was 1/11/6 and post-treatment was 13/3/2 (P=0.000, Δ=4/12/2). In the control group pre-treatment it was 3/11/3 and post-treatment was 10/6/1 (P=0.014, Δ=10/5/2). Overall meibum quality and expressibility improved for both groups (P<0.05). The meibomian gland morphological index demonstrated no significant difference between the IPL and the control groups for gland dropout, gland ALD, gland ASD, gland AUD and IC (P>0.05 for all). There was mild improvement in dropout of meibomian glands in the IPL group compared to the control group (IPL=-5.44±6.18%, P=0.002; Control=-4.05±5.04%, P=0.008). In the IPL group significant improvements were found in ALD, AUD and IC between pre-treatment and post-treatment (ALD=101.89±21.44µm to 84.67±20.25µm; AUD=91.50±37.42/mm 2 to ±40.12/mm 2 ; IC=44.44% to 16.67%; P<0.05 for all). There were no significant differences in ASD in either group. No significant difference was found for morphological index in the control group between pre and post-treatment. OSDI related factors were examined in both groups. In the IPL group the improvement in OSDI was found to be correlated to the improvement in AUD. No correlations were detected in the control group. Jiang et al. 7 had all 40 of their patients complete all stages of the study. When compared to baseline (BL) all symptoms significantly improved at D15, D45, and D75 (P<0.05) except for blurred vision. Between D15 and D45 there was significant improvement for dryness (P<0.01) and pain (P<0.03) but between D45 and D75 no significant improvements could be detected for any symptom. When compared to BL the total symptom scores improved across all visits (P<0.01) and this trend continued between D15 to D45 (P<0.04). Between D45 and D75 no significant improvement was observed (P=1). Eyelid margin and meibomian gland assessment had significant improvement after treatment with IPL in all signs (P<0.05 for all) except for trichiasis compared to BL. The number of glands within the central one centimetre were significantly improved at D15 (4.3±3.1), D45 (5.3±3.5), and D75 (4.9±3.3) compared to BL (P<0.01). Between visit D15 to D45 the number of glands continuously increased (P=0.02) but between D45 and D75 there was no increase (P=0.96). Compared to BL, meibomian gland secretion quality and expressibility significantly improved at visit D15 (P<0.05). Between D15 and D45 this was also true (P<0.05) but this was not true for the time between D45 and D75 where no improvement was found for secretion quality (P=0.68) or expressibility (P=0.29). 11

12 TBUT and corneal staining also had significant improvements when compared to BL (2.2±1.5) at all time points (D15=4.2±1.8; D45=5.0±1.9; D75=4.5±2.5; P<0.01 for all). Between D15 and D45 TBUT continuously increased but not significantly (P=0.07). This was also true between D45 and D75 (P=0.51). No significant difference in staining was found at any time point. When conjunctival injection and TMH were compared to BL it was found that conjunctival injection was significantly relieved at D15, D45 and D75 (P=0.01 for all). Between each visit there was no significant difference and no significant difference was found for TMH at any time point. No adverse events of any type were found in the study. In the study by Craig et al. 6 the LLG in the treated eye improved from BL at all time points: - Freidman P< BL-D45 Wilcoxon P< D1-D45 Wilcoxon P< D15-D45 Wilcoxon P<0.002 In the control eye, no improvement over the three visits was found (P=0.802). There was no difference detected between the treated and the control eye on D1 for lipid grade (Wilcoxon P=0.932), or D15 (Wilcoxon P=0.101). By D45 the treated eye was improved over the control eye (Wilcoxon P=0.002). NIBUT increased from BL to D45 in the treated eye (ANOVA 5.28±1.42 seconds to 14.11±9.75 seconds, P<0.001) but not in the control eye (5.29±1.42 to 7.31±1.50 seconds, P<0.001). At D1 there was no significant difference between treated and control eye (P=0.991) or at D15 (P=0.055) but by D45 it was higher in the treated eye over the control eye (P<0.001). The evaporation rate was more variable between visits in the treated eye (Freidman P=0.003) and control eye (Freidman P=0.012) but there was no trend. TER was highly correlated between the eyes at each visit (P<0.001) but no difference could be found between control and treated eyes at any visit. There was also no change in tear osmolarity between the treated eye and the control eye (ANOVA P=0.741 and P=0.308 respectively) over the four visits. Similarly there was no change in TMH from BL in either control or treated eyes (ANOVA P=0.559 and P=0.348 respectively). There was also no change in bulbar conjunctival hyperemia in the control or treated eyes (Freidman P=0.414 and P=0.348 respectively). Questionnaires on self-reported results for the severity of dry eye symptoms showed significant improvement in the treated eye over the control eye over time but not in control eyes (Freidman P=0.015 and P=0.245 respectively). Post hoc testing showed a decrease in VAS score in the treated eye at D45 (median 30.5; IQR ) compared to BL (median 35; IQR , P=0.015). Median SPEED scores decreased indicating a reduction in symptoms between D1 and D45 in the treated eye (Freidm an , P<0.001) and also in the control eye (Freidman , P<0.001). Scores between eyes were highly correlated between each visit (Spearman s r; D1= 0.922, P<0.001; D15 =0.874, P<0.001; D45=0.871, P<0.001). No significant difference in SPEED scores was found between treated and control eyes at any visit. Limitations This review is limited by the fact that no evidence-based publications could be found to provide insight into the established guidelines for the use of IPL treatment for patients suffering from DED caused by MGD. 12

13 The prospective before and after investigations all suffer from being conducted over limited time periods and lacked control groups. The longest study duration that was found was in this review was 12 weeks in length. Many of the studies documented that benefits were cumulative in nature in which case short study follow-up times may prevent the realization of the full benefits from the IPL treatment. They also do not provide information into the longevity of the changes that have occurred so it is unknown if patients will have to seek maintenance treatments or whether the treatments in the studies are sufficient. Furthermore, a single study 15 included an active control (eye hygiene) so the effectiveness of IPL compared with other treatment options remains unclear. All of these articles were also developed with different criteria for patient inclusion and exclusion and for the process of IPL treatment. Each of the studies is unique in this regard, which makes it difficult to formulate generalized conclusions. There does not appear to be a unified approach to conducting research into IPL treatment which is likely a result of it only recently being suggested as beneficial to MGD patients. This may also be a result of the lack of any evidence-based guidelines for the use of IPL in treating MGD. Until a defined methodology is established for treating patients it is unlikely that studies will show consistent results. One of the four studies that were included conducted an examination on safety. 7 The patient population in this study included 40 individuals that were recruited from a single outpatient clinic. Additionally the data collected for safety in this study was done through observation only. Since there was a small population of patients included this investigation, simply because an adverse event did not occur does not mean that it does not have the possibility of happening in a larger clinical population. In order for it to be ruled out entirely larger, broader spectrum investigations need to be completed. The study conducted by Guillato Caballero et al. 12 did mention that two patients had adverse reactions that resolved themselves without medical treatment but this was not a focus of the publication. Finally, every study that was reviewed included a statement regarding the lack of understanding on the molecular mechanisms of IPL action on improvements to meibomian glands. The majority of them also indicate that in future examinations patient populations need to be larger and randomized in order to establish that the benefits are solely attributable to IPL treatment. Conclusions and Implications for Decision or Policy Making The evidence identified on the clinical effectiveness of IPL treatment for dry eye disease consists of two uncontrolled before and after studies, one non-randomized controlled trial, and one RCT comparing IPL with placebo. Each study showed statistically significantly reduced symptom results with IPL use. However the studies that were included are of limited quality and included patient populations that were very small. Two studies lacked control groups and one included an active comparator (eye hygiene) so the effectiveness of IPL compared with other treatment options remains uncertain. The criteria for patient inclusion and exclusion were also unique for each of the included reports and there does not appear to be any standardized procedure making definitive conclusions difficult to make. There is also discrepancy on how many treatment visits are required to reach the benefits that were found. Three of the studies completed IPL treatments in four sessions though the timing of these sessions is unique for each investigation. One of these examinations was completed after 45 days, 12 another went for 75 days, 7 and the final one lasted for three months 15. In the future studies incorporating randomization, blinding, 13

14 controls, and larger patient populations are required in order to confirm the benefits that have been demonstrated here and address uncertainties. The safety of IPL treatment was analyzed in one of the examinations. This was completed using observational techniques and found that no adverse events were reported at any time during the study period. This investigation was completed on a small patient population recruited from a single clinic and therefore adverse events cannot be ruled out simply because they did not occur. The study by Guillato Caballero et al. 12 did not directly examine safety in their methodology but they did mention that two patients encountered reddening of the face and/or light sensitivity during the treatment procedure. In both instances, these conditions remedied themselves within one week without medical intervention. 14

15 References 1. Geerling G, Baudouin C. Emerging strategies for the diagnosis and treatment of meibomian gland dysfunction: Proceedings of the OCEAN group meeting. Ocul Surf Apr;15(2): Liu R, Rong B, Tu P, Tang Y, Song W, Toyos R, et al. Analysis of cytokine levels in tears and clinical correlations after intense pulsed light treating meibomian gland dysfunction. Am J Ophthalmol Nov;183: Mandal P, Khan MA, Shah S. Drugs - do we need them? Applications of nonpharmaceutical therapy in anterior eye disease: a review. Cont Lens Anterior Eye Dec;40(6): Dell SJ. Intense pulsed light for evaporative dry eye disease. Clin Ophthalmol [Internet] [cited 2018 Jan 11];11: Available from: 5. Dell SJ, Gaster RN, Barbarino SC, Cunningham DN. Prospective evaluation of intense pulsed light and meibomian gland expression efficacy on relieving signs and symptoms of dry eye disease due to meibomian gland dysfunction. Clin Ophthalmol [Internet] [cited 2018 Jan 11];11: Available from: 6. Craig JP, Chen YH, Turnbull PR. Prospective trial of intense pulsed light for the treatment of meibomian gland dysfunction. Invest Ophthalmol Vis Sci Feb 12;56(3): Jiang X, Lv H, Song H, Zhang M, Liu Y, Hu X, et al. Evaluation of the safety and effectiveness of intense pulsed light in the treatment of meibomian gland dysfunction. J Ophthalmol [Internet] [cited 2018 Jan 11];2016: Available from: 8. Gupta PK, Vora GK, Matossian C, Kim M, Stinnett S. Outcomes of intense pulsed light therapy for treatment of evaporative dry eye disease. Can J Ophthalmol Aug;51(4): Albietz JM, Schmid KL. Intense pulsed light treatment and meibomian gland expression for moderate to advanced meibomian gland dysfunction. Clin Exp Optom Jan;101(1): Vora GK, Gupta PK. Intense pulsed light therapy for the treatment of evaporative dry eye disease. Curr Opin Ophthalmol Jul;26(4): Toyos R, McGill W, Briscoe D. Intense pulsed light treatment for dry eye disease due to meibomian gland dysfunction; a 3-year retrospective study. Photomed Laser Surg [Internet] Jan [cited 2018 Jan 11];33(1):41-6. Available from: Guilloto Caballero S, Garcia Madrona JL, Colmenero RE. Effect of pulsed laser light in patients with dry eye syndrome. Arch Soc Esp Oftalmol Nov;92(11): Notice: Risk of thermal harm from therapeutic medical lasers, intense pulsed light and light emitting diodes [Internet]. Ottawa: Health Canada; 2016 Feb 8. [cited 2018 Jan 24]. Available from: Downs SH, Black N. The feasibility of creating a checklist for the assessment of the methodological quality both of randomised and non-randomised studies of health care interventions. J Epidemiol Community Health [Internet] Jun;52(6): Available from: Yin Y, Liu N, Gong L, Song N. Changes in the meibomian gland after exposure to intense pulsed light in meibomian gland dysfunction (MGD) patients. Curr Eye Res Dec 4;

16 Appendix 1: Selection of Included Studies 140 citations identified from electronic literature search and screened 126 citations excluded 14 potentially relevant articles retrieved for scrutiny (full text, if available) 0 potentially relevant reports retrieved from other sources (grey literature, hand search) 14 potentially relevant reports 10 reports excluded: -irrelevant population (1) -irrelevant intervention (5) -irrelevant outcomes (1) -other (review articles, editorials)(3) 4 reports included in review 16

17 Appendix 2: Characteristics of Included Publications Table 2: Characteristics of Included Publications First Author, Publication Year, Country, Study Name Caballero et al., , Spain Study Design Prospective before and after study completed in accordance with the Declaration of Helsinki Patients must have skin type I, II or III according to the Fitzpatrick grading scale Exclude if: Have previous ocular or systemic pathology Allergy to sunlight Pregnancy Have skin exposed to sunlight during the previous month before study initiation Have skin lesions of unusual appearance IPL intensity ranges from low, 8 J/cm 2, to high, 20 J/cm 2 and the power is regulated at each successive visit according to: Impression of patient Severity of disease Obtained test results IRPL treatment completed in four sessions with 15 days between each (at 0, 15, 30, and 45 days) and if needed an additional session at 6 months after final All testing was completed in a similar room with low light intensity and at 23 Celsius Patients were not advised of the testing results and all information that may have impacted the results was kept confidential All patients had treatment with ocular lubricants, lacrimal occlusion agents or food supplements with omega-3 fatty acids which were continued throughout the study Schirmer II and lacrimal meniscus Patient Characteristics, Sample size Study conducted in March of 2016 at the Clinica Vistalaser Oftalmologia clinic in Malaga, Spain 36 patients included (72 eyes) with a mean age of 43 ±25 and 58.33% were female and had Fitzpatrick score of II or III 60 eyes had previously been treated with refractive surgery, six with phacoemulsification, and six had no previous surgery Intervention(s) Comparator(s) Clinical Outcomes / Goal IRPL from E-Swin of Adainville, France used 3 flashes in the left middle face starting at the internal canthus of the eye and finishing at the temporal (procedure repeated in the right side) Intensity at first session was at 11.4J/cm 3, the second at 12.2J/cm 3 and the third and fourth at 13J/cm 3 None used To determine the efficacy of IPL therapy for the treatment of dry eye syndrome that is caused by reductions in tear production or over-evaporation as a result of MGD Clinical outcomes were a sequential procedure of: anamnesis, TBUT, lacrimal meniscus measurement, and Schirmer II testing 17