Efficacia della luce pulsata per il trattamento del dry eye

Combined intense pulsed light and low

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level light therapy for the treatment of refractory Meibomian gland dysfunction


Alessandro Meduri1, Giovanni William Oliverio1, Giovanni Tedesco2 and Pasquale Aragona


Abstract Purpose: To evaluate the efficacy of combined Intense Pulsed Light (IPL) and Low-Level Light Therapy (LLLT) in treatment of Meibomian Gland Dysfunction (MGD). Methods and Analysis: In this prospective study, 70 patients with refractory MGD were enrolled; group 1 received 3 consecutive sessions of IPL+LLLT treatment using Eye-light® on day 1, day 15 and day 45; group 2 received hyaluronate sodium 2 mg/ml drops 3 times a day for 6 months. Patients underwent at baseline, and after 3 and 6 months Ocular Surface Disease Index (OSDI) questionnaire, Symptom Assessment in Dry Eye (SANDE), tear-film breakup time (TBUT), fluorescein ocular surface staining, meibum expressibility and quality evaluations. Keratograph 5M (Oculus, Germany) was used to assess NIBUT, tear meniscus height (TMH), meibography, and bulbar redness score. Results: At 6 months a significant improvement of OSDI (p=0.03), SANDE (p=0.02), NIBUT (p=p < 0.0001), TMH (p =0.04), TBUT (p=0.02), corneal-conjunctival staining score (p=0.02), lid margin score (p < 0.0001), and bulbar redness score (p=0.001) were recorded in group 1. Comparing the two groups, statistically significant differences were observed at 6 months in TBUT (p=0.03), lid margin score (p < 0.001), Meibum expressibility (p=0.03) and NIBUT (p < 0.001). No adverse events were recorded throughout the follow-up period. Conclusion: This study confirmed the efficacy and safety of combined IPL and LLLT demonstrating its superiority compared to topical treatment. Keywords Intense pulsed light, low-level light therapy, dry eye disease, Meibomian gland dysfunction, ocular surface, IPL


Introduction

Meibomian gland dysfunction (MGD) is the main cause of evaporative dry eye disease (DED) and one of the most common disorders encountered in the ophthalmology clinic, as numerous ocular surface diseases result in this condition.1,2 Indeed, MGD is characterized by morphologic changes, atrophy and drop-out of the Meibomian glands, that lead to altered composition of meibum and consequent instability of tear film.3,4 According to the classification of the International Workshop on MGD, two main conditions could be recognized: the low-delivery and high-delivery state.1 In particular, the low-delivery state is the most prevalent form and is correlated with aging, sex, hormonal changes and topical treatments.1–4 Whereas the high-delivery state is commonly related to seborrheic dermatitis and rosacea.4 However, numerous other causes could be recognized such as eye surgery, systemic hormonal treatments, aniridia, Demodex follicolorum infestation and floppy eyelid syndrome.4 The main goal of the treatment of MGD is to improve the quality and quantity of Meibomian glands expression and thus reduce ocular discomfort, with early treatment being of particular importance.3–5 Numerous studies demonstrated the fundamental role of eyelid warming and massaging, topical antibiotics like macrolides and tetracycline in the treatment of MGD4–6 ; however, a large number of patients are refractory to these topical treatments with unsatisfactory results.6–8 Even though oral tetracycline has been demonstrated effective to treat ocular surface diseases like MGD, evaporative DED and posterior blepharitis, long-term results are controversial.7–9 Recent papers assessed Intense Pulsed Light (IPL) efficacy to improve signs and symptoms in patients with DED and MGD.10–14 Although the exact mechanisms of actions are still not completely understood, the thermal effect produced by a series of pulses of non-coherent polychromatic light results in lessening and liquefaction of meibum, reducing pro-inflammatory mediators and matrix metalloproteinases’ production.6,15,16 Furthermore, Low-Level Light Therapy (LLLT), using light-emitting diodes (LEDs) at wavelengths insufficient to create a thermal effect, has demonstrated promising results in dermatology through a mechanism of action known as photobiomodulation.17–21 This treatment produces a photochemical cascade and a non-thermic cellular photo-activation, improving metabolic functions and repairing damaged cells.17–21 However, few studies proved the effectiveness of the combinations of IPL and LLLT in the treatment of MGD patients.17,21 This study aims to compare the safety and efficacy of combined IPL and LLLT in treatments of refractory MGD to topical treatments.


Methods

This prospective study enrolled 70 patients (50 females, 20 males) with a diagnosis of MGD and DED symptoms, refractory to previous topical treatments. The study protocol was approved by the local institutional review board of the University of Messina and followed the tenets of the Helsinki declaration. Informed consent was obtained from all the patients enrolled in the study, after a discussion of the potential risks and benefits and the nature of this study. Inclusion criteria were: age >18 years, clinical diagnosis of bilateral MGD and DED, tear film break up time (TBUT) < 10 s, meibomian gland expressibility score comprised between 1 and 2, Ocular Surface Disease Index (OSDI) score higher than 12, and previous failed treatments with eyelid hygiene, warm compresses, topical antibiotics and anti-inflammatory drops, including steroids and NSAIDs in the last 6 months. Exclusion criteria were history of glaucoma, allergic keratoconjunctivitis, use of contact lenses, corneal ulcer, recent ocular surgery, as well as medical conditions in which IPL is contraindicated. The only treatments allowed were the tear substitutes, whose use was stable for at least three months before the beginning of the study. Patients were assigned to two groups; group 1, where 35 patients received 3 consecutive sessions of IPL and LLLT (on day 1, day 15 and day 45; respectively) and hyaluronate sodium drops 2 mg/ml (Hyalistil, SIFI, Italy) 3 times a day for 6 months; group 2 received only the topical treatment (Hyalistil 3 times a day).


IPL and LLLT procedure The instrumental device used for treatment was Eye-light® (Espansione Marketing S.p.A., Bologna, Italy) which allows the application of both the IPL and LLLT therapies. The procedure consists of two parts; IPL is first applied to the lower periorbital area providing 5 spots for the eye (4 at the inferior eyelid and 1 at the lateral canthus), meanwhile, the patients’ eyes were covered by a protective device. The parameters for IPL treatment were set considering the meibography and the Fitzpatrick prototyping scale of the patients (fluence 6–14 J/cm2 ). After 15 min the LLLT red mask containing a matrix of LEDs (wavelength 633±10 nm, and emission power of 100 mW/cm2 ) was placed covering the whole superior and inferior eyelid and periorbital region of the patient for 15 min of treatment.


The ophthalmologic assessment included - OSDI questionnaire; a test intended to evaluate the severity of dry eye, consisting of twelve questions about ocular symptoms, vision-related functioning, and environmental triggers. The scores of these three subscales were sum and the total OSDI score was recorded; The OSDI score ranges from 0 to 100, and it is considered normal (0–12 points) or as mild (13– 22 points), moderate (23–32 points), and severe >33 points. - The Symptom Assessment in Dry Eye (SANDE) score was considered for both severity and frequency of symptoms based a horizontal 0–100 mm visual analog scale, to evaluate symptoms of dryness and ocular irritation; the patient was asked to put a mark on these horizontal lines, one for frequency and one for severity, to describe the level of their symptoms. The mean value of severity and frequency scores was calculated for statistical purposes.


- Lid margin evaluation scored from 0 to 4, established on the presence of 4 signs: irregular lid margin, vascular irregularities, plugging of meibomian gland orifices, and change of the mucocutaneous junction; for each parameter was considered as 0 (absent) or 1 (present)22; - The Meibum expressibility was evaluated according to the number of expressible glands in the central lower lid margin, from 0 (all glands expressible) to 3 (no gland expressible)23,24; - The Meibum quality in the lower eyelid was graded from 0 to 3 as follows: Grade 0, clear; Grade 1, cloudy; Grade 2, cloudy with granular debris; Grade 3, thick like toothpaste or nonexpressible glands23,24; - Tear-film break-up time (TBUT) was carried out on a slit-lamp using a cobalt blue light and a yellow filter. Fluorescein drops were prepared using a fluorescein strip wetted with a drop of saline solution and instilled onto the lower fornix. The patient was invited to blink, to allow a distribution of the fluorescein on the cornea, and then to stare without blinking; the time gap between the last complete blink and the appearance of a dark spot was measured 3 consecutive times, and the mean was considered for statistical purpose; - Fluorescein ocular surface staining was graded according to the modified Oxford scale from grade 0 (absence of epithelial damages) to grade 5 (severe epithelial damages) considering together corneal and conjunctival staining25; - Keratograph 5M (Oculus, Wetzlar, Germany) was used to assess non-invasive breakup time (NIBUT), tear meniscus height (TMH), meibography and bulbar redness score (Jenvis grading scale). NIBUT is based on the projection on the corneal surface of Placido rings, and was evaluated by recording automatically the time between the last blink and the first sign of distortion of the ring pattern; the mean of three consecutive measurements was considered for statistical purposes. TMH was assessed using the tear film scanning function of the Keratograph 5M, which allows to capture pictures of the lower tear film meniscus and measure its height. Meibography was performed in both upper and lower eyelid, to evaluate the Meibomian gland dropout considering grade 0 (no glands loss), grade 1 (area of loss smaller than 1/3), grade 2 (area of lass between 1/3 and 2/3) and grade 3 (area of glands loss greater than 2/3), using the automatic assessment function of the Keratograph 5M (JENVIS Meibo Grading Scale).26 Bulbar redness score was assessed using the R-Scan module of the Keratograph, detecting the blood vessels in the conjunctiva and automatically evaluating the degree of redness.


- The safety profile was assessed with a slit lamp biomicroscopy evaluation of the anterior segment to evaluate the transparency of cornea and lens, corneal endothelial cells density was carried out with Perseus (CSO, Scandicci, Florence, Italy), intraocular pressure was measured with Corvis ST (Oculus, Wetzlar, Germany) and fundus examination was carried out with Daytona (Optos, Dunfermline, Scotland, UK); All patients were evaluated at baseline, 3 and 6 months.


Statistical analysis

The numerical data are expressed as mean and standard deviation, whereas the categorical variables as absolute frequency and percentage. The fitting of the data to a normal distribution was tested by the Kolmogorov-Smirnov test. The preoperative and postoperative values of the variables of Group 1 and Group 2 were compared using the Chi-Square test for categorical variables, the Student t-test for parametric data, and the Mann-Whitney U test for nonparametric data. The postoperative outcomes were compared with preoperative values within each group using the Wilcoxon signed-rank test and Student-t test for paired data. The sample size was estimated using mean preoperative OSDI score and considering an alpha error of 0.05 and a beta error of 80%, the required sample size to detect differences between the 2 groups was 30 patients, therefore 35 patients were enrolled in order to allow a possible drop out.27


Results

Characteristics of the study populations Thirty-five patients (26 females and 9 males; mean age 61.2 ±11.8 years) were enrolled in group 1, whereas 35 patients (24 females and 11 males; mean age 62.3±10.5 years) were enrolled in group 2. No significant differences in gender distribution, mean age, females in menopause ratio, and the number of video display terminal (VDT) workers were observed between these groups. Three patients (2 in Group 1, and 1 in Group 2) presented seborrheic dermatitis, and only 1 patient (Group 1) presented rosacea. Ocular surface assessment Baseline ocular surface assessments of patients is reported in Tables 1 and 2; no significant differences were observed between group 1 and group 2 (Table 3). At 3 months after treatment a significant improvement of NIBUT was recorded in group 1, that was maintained at 6 months (p=0.005 and p < 0.001; respectively) (Table 1). Furthermore, in group 1 at 6 months there were significant improvements of mean tear meniscus height (p=0.04), TBUT (p=0.02), corneal-conjunctival






staining score (p=0.02), lid margin score (p < 0.001), meibum expressibility (p=0.04) and bulbar redness (p < 0.001) (Table 1); no significant changes in meibography scale were noted after treatment. In group 2, at 6 months a significant change was observed in staining score (p=0.05), NIBUT (p=0.04) and bulbar redness (p=0.03) (Table 2). Additionally, comparing the two groups statistically significant differences were observed at 3 months in lid margin score (p < 0.001), Meibum quality (p=0.02) and NIBUT (p=0.02), as well as at 6 months in TBUT (p= 0.03), lid margin score (p < 0.001), Meibum expressibility (p=0.03) and NIBUT (p < 0.001) (Table 3).


SANDE and OSDI scores were significantly reduced at 6 months in group 1 (p=0.02 and p=0.03; respectively), whereas in group 2 these were not significantly reduced (Tables 1 and 2). Safety parameters No pain, burning, or redness of the periorbital region and facial skin were reported during treatments, as well as no adverse events were noted at 3 and 6 months after treatment. No significant changes in BCVA, intraocular pressure, corneal and lens transparency, endothelial cells count and retinal evaluation were observed in both groups.




Discussion

MGD is a multifactorial and heterogeneous disease involving several pathophysiological mechanisms including eyelid inflammation, conjunctival inflammation, corneal damage, microbiological changes and tear film instability.1,3,28 Recent studies reported the beneficial role of IPL in treatment of MGD improving tear film stability, symptoms and signs of ocular surface damages.10–16 Indeed, the non-coherent polychromatic light of the IPL produces a thermal effect in the periorbital area, improving the functionality of Meibomian glands.9 Although IPL is a safe and simple treatment, there are some limitations that could reduce its applicability in clinical practice.5,6,9 Indeed, the most common IPL protocol treatments include the skin below the lower eyelids and both temporal parts, but not the upper eyelid reducing the potential beneficial role on the whole ocular surface.5,6,9 In this study, the combination of IPL and LLLT therapy demonstrated to be effective in patients with refractory MGD and DED symptoms, allowing the treatment of both lower and upper eyelid, and improving the glands functions. LLLT produces endogenous heat through a process known as photobiomodulation that implicate conversion of light energy to metabolic energy, activating several biological pathways. Indeed, photobiomodulation regulates the biological functioning of cells, increasing level of ATPase, activation of cAMP, and synthesis of procollagen in fibroblasts, fundamentals for wound healing. Recently, LLLT demonstrated to be effective in treatment of dermatologic diseases, wound healing, skin rejuvenation, viral diseases, allergic related conditions, and pain control.17–21


Furthermore, recent studies demonstrated the improvement of tear film stability in patients with MGD.17–21 Stonecipher et al. in a large retrospective study reported the effect of combined IPL and LLLT in a group of patients with refractory MGD to topical treatments, demonstrating a significant improvement of symptoms as well as TBUT and MGD signs.17 In our paper, we found consistent results of combined IPL and LLLT in refractory MGD, demonstrating its superiority to a control group treated with hyaluronate sodium drops.

Our groups included prevalently low-delivery MGD patients, three patients with seborrheic dermatitis and only patient with rosacea. The treatment of MGD subjects using IPL could be very effective in these groups of patients. IPL has a warming effect on meibum, changing its viscosity and improving its expression and delivery on the tear film.5,15,16 Furthermore, IPL treatment target the vascular component of the lid margin, reducing the extravasation of inflammatory cytokines.15 Indeed, in ocular rosacea telangiectasia and vasodilation release inflammatory mediators that are at the basis of the pathophysiology of the associated MGD.5,29 Additionally, the combination of IPL and LLLT required fewer treatment sessions compared to conventional IPL therapy, as reported in previous studies.10–16 Indeed, Pérez-Silguero et al. in a recent retrospective study reported one-year results after 4 sessions of combined IPL and LLLT in patients with DED, demonstrating an important reduction of signs and symptoms of dry eye sustained throughout the follow-up period.21 The device provides internal software that regulates energy levels for optimum effect according to the MGD grade and skin pigmentation of the patient, allowing to customize treatment for the subject’s characteristics.17,19,21 Furthermore, the device maintains temperatures at a non-traumatic level to the skin and therefore no gel isrequired to perform the treatment, unlike most IPL devices currently available.17,19,21 To the best of our knowledge, this is the first study in the literature that evaluated the safety and efficacy of combined IPL and LLLT in patients with MGD, comparing the results with a control group. However, further prospective and randomized studies that compare the combination of IPL and LLLT with only IPL are warranty to demonstrate the effectiveness of this treatment, and to assess the long-term results. In conclusion, this study confirmed the efficacy and safety up to 6 months after combined IPL and LLLT in association to hyaluronate sodium drops, demonstrating the superiority of this association compared to the only topical treatment.


Author contributions

Alessandro Meduri: Conceptualization, Writing, Review, Editing. Giovanni W Oliverio: Conceptualization, Writing, Review, Editing, Data analysis. Giovanni Roberto Tedesco: Conceptualization, Data collection. Pasquale Aragona: Conceptualization, Writing, Review, Editing; Original draft preparation, Data analysis and Supervision.


Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iDs

Alessandro Meduri https://orcid.org/0000-0001-7546-9178 Giovanni William Oliverio https://orcid.org/0000-0003-3127- 9756 Pasquale Aragona https://orcid.org/0000-0002-9582-9799

Data availability