Evaluation of the Safety and Efficacy of Intense Pulsed Light Treatment with Meibomian Gland Expression of the Upper Eyelids for Dry Eye Disease

Introduction

Dry eye disease (DED) due to Meibomian gland dysfunction (MGD) is a common and growing health concern with >300 million people worldwide estimated to have some form of dry eye and 5 million in the United States alone. MGD can contribute to evaporative dry eye or occur as a result of chronic inflammation due to an unhealthy ocular surface. MGD is estimated to occur in as much as 70% of some populations, especially in Asia. ¹ Meibomian glands are exocrine glands on the inside that secrete sebaceous material onto the surface of the eye. The average adult has 30–50 glands in the upper lid and 20–40 on the lower. Each gland synthesizes and secretes a complex mixture of lipids and proteins to protect and nourish the ocular surface. ² Meibomian secretions should be clear liquid at body temperature, but may become thick or cloudy or blocked altogether with age or inflammation. Dysfunctional lipids may contribute to bacterial overgrowth, which may in turn contribute to the overall inflammation and worsening of the disease, making them an increasingly important factor in the eye care world. ³

While many factors are being studied to evaluate exactly what causes MGD, current research points to a combination of genetics, environmental factors, and diet. Current treatments for MGD include warm compresses, dietary supplements that include omega-3 fatty acids, meibomian gland probing, meibomian gland expression, topical and systemic nonsteroidal and steroidal preparations, and intense pulsed light (IPL) treatment. Approved topical US Food and Drug Administration (FDA) treatments for dry eye include cyclosporine 0.05%, cyclosporine 0.09%, and lifitegrast 5.0%. Most treatments currently target ocular surface inflammation. ⁴

IPL has FDA clearance (K142860) for a variety of dermatological conditions, including facial rosacea, port wine stains, telangiectasias, pigmented lesions, benign venous malformations, benign cavernous hemangiomas, hypertrophic scars, and seborrheic keratosis (Fig. 1). IPL emits light energy in a spectrum from 580 nm to near-infrared 1200 nm. ⁵ IPL was first noted by Dr. Rolando Toyos to be incidentally helpful for the symptoms of dry eye while patients were receiving treatment for facial rosacea. ⁶ Other researchers have confirmed these initial findings, and documented improvements in meibum quality, number of functional meibomian glands, and reduction of ocular surface inflammatory markers. ^{7 –9}

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FIG. 1.

Lumenis M22.

IPL seems to improve the signs and symptoms by several discrete mechanisms. First, the heat and infrared portion of the light heats the skin internally up to 50°C to help soften and liquefy abnormal meibum in a way that is not possible with normal warm compresses. Next, the light targets the chromophore in hemoglobin, so that abnormal telangiectasias preferentially absorb more energy to the point of closure for these vessels. Once closed, it is speculated that they are unable to continue secreting inflammatory markers that may perpetuate or even amplify the inflammatory response. IPL also kills bacteria and Demodex species, which may assist in reducing exotoxin and inflammatory loads. IPL has recently been shown to lower interleukins 17 and 6 on the ocular surface after a series of three consecutive treatments spaced 4 weeks apart. ¹⁰ Chronic surface inflammation has been shown to inhibit mucin-producing goblet cells and may play a role in suppression of meibomian glands as well. ¹¹ Finally, IPL has been shown to target cytochrome oxidases in mitochondria that may begin the cycle of photobiomodulation, which may lead to generate more energy and begin cellular repair and healing.

Prior IPL studies primarily treated lower lids because of the size of the light delivery device (sapphire-cooled light guides of 8 × 15 or 15 × 35 mm), the potential for excessive heat accumulation in the brow area, and the potential for hair loss in the eyebrow and upper lash areas. Although the lower lids tend to be the area of greatest pathology, many dry eye patients have significant MGD in the upper lids as well. For these patients, this study evaluated a unique new handpiece with a smaller cylindrical surface area was tested to evaluate both the safety and the efficacy in improvements of signs and symptoms of dry eye due to MGD (Figs. 2 and 3).

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FIG. 2.

Six millimeters cylindrical head.

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FIG. 3.

Six millimeters cylindrical head attached to Lumenis M22.

Methods

Patients were enrolled in this study if they were over the age of 18 and had visible signs of upper lid MGD at the slit lamp examination and persistent dry eye symptoms and ocular pain despite treatment with conservative dry eye therapies. Patients were excluded for the following: eyelid abnormalities, history of IPL treatments in the past year, currently on oral or topical retinoids, history of intraocular surgery in the past year, uncontrolled ocular disease, Fitzpatrick skin type V or VI, neuroparalysis in the planned treatment area, precancerous lesions in the planned treatment area, new topical eye treatments within the past 90 days, legally blind in one eye or some condition in the opinion of the investigator, which might make the patient unsuitable for treatment or follow-up purposes.

Enrolled subjects underwent physician-measured tear breakup time using the standard fluorescein staining method counting the number of seconds that elapse between the last blink of the eye to the appearance of the first dry spot in the tear film. Subjects were then asked to fill out a subjective assessment of their dry eye symptoms, which included an Global Eye Dryness score, an assessment of the patient's perception of their ocular dryness; an Ocular Discomfort Severity score, which measured how severe the patient perceived his or her discomfort over the past 24 h; and an Ocular Discomfort Frequency score, which evaluated how often over the past 24 h the patient had noticed ocular discomfort of any kind. After the initial evaluation was completed, the patient underwent the IPL treatment September 2018 through October 2018. The study protocol was a four-procedure treatment plan, with each procedure spaced no fewer than 2 weeks apart, and no longer than 4 weeks apart. The IPL therapy was performed using a Lumenis M22 IPL machine with the sapphire-cooled 6 mm cylindrical light guide set at a fluence of 10 J/cm² (Table 1). Honeywell IPL eye shields (Honeywell Safety Products, Smithfield, RI) were applied to the lower lids covering upper and lower eyelashes, leaving the upper lids exposed for the treatment (Fig. 4). This technique has been previously published with no adverse events. ¹⁰ Ultrasound gel was applied from tragus to tragus in a band approximately the height of the nose across the face. The specialized handpiece designed for the upper lids was attached to the machine. Two passes of light at a fluence of 10 J/cm² were used across the upper eyelids. Once completed, the shields and ultrasound gel were removed, and patients were moved to a slit lamp.

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FIG. 4.

Ocular image of treatment areas.

One drop of Proparacaine was instilled into each eye. Two cotton-tipped applicators were used, one inside the lid, and the other outside the lid, and gentle-to-moderate pressure was applied to push meibum out of the glands along the upper eye lid starting at the lower end of the gland and moving slowly toward the top. After digital expression, one drop of Prolensa (bromfenac 0.07%, Bausch & Lomb, Bridgewater Township, NJ) ophthalmic solution was instilled in each eye, followed by one drop of generic brimonidine (2% ophthalmic solution, Bausch & Lomb, Bridgewater Township, NJ). Patients were dispensed samples of Prolensa to use one drop nightly for four nights after the treatment. For patients who were using artificial tears, Xiidra, omega supplements, or any other type of dry eye treatment at the beginning of the study, they continued use of those treatments throughout the study.

Once the patients had completed four-treatment sessions, they were asked to repeat the same evaluation of Eye Dryness, Ocular Discomfort Severity, and Ocular Discomfort Frequency. Tear breakup time was objectively measured and recorded.

Results

A total of 19 patients had enrolled in the upper lid IPL study. Enrolled patients ranged in age from 23 to 65 with a mean age of 47 years. Women were 67% of enrolled patients. Sixteen of the 19 patients completed the entire four-treatment protocol. Average tear breakup time (TBUT) before the therapy was 1.5 sec. After the treatment, TBUT was increased to 5.2 sec.

As the table immediately below shows, paired t-tests showed that statistically significant improvement in tear breakup times was found for both eyes: TBUT right eye (OD) [t = 6.2; 95% confidence interval (CI): 2.6–5.3] and TBUT left eye (OS) (t = 5.4; CI: 2.6–5.4) (Table 2).

Each of the scores for the dryness survey was ranked on a scale from 0 to 100 and subjectively answered by enrolled patients. Results of the pretreatment survey revealed that patients in this study rated their Global Eye Dryness score to be an average of 73.74% with 100 being the most severe pain. Ocular Discomfort Severity or pain in the past 24 h scores pretreatment averaged 65.42%, and Ocular Discomfort Frequency of ocular pain episodes pretreatment averaged 76.53%.

Three patients did not complete the study as they were lost to follow-up after 2, 2, and 3 visits, respectively. Their last data values were carried forward. After completing the four-treatment therapy, subjects reported that their Global Eye Dryness score had improved to 27.27%, with an overall average improvement of 51.97%. Ocular Discomfort Severity decreased to 26.93%, with an average improvement of 53.05%. Hundred percent of patients enrolled in the study reported an improvement in the Ocular Discomfort Severity assessment. The improvement in severity ranged from 10% to 98.7%. Ocular Discomfort Frequency decreased to 28.27%, with an improvement of 55.52%. Fourteen of the 15 patients who completed the study reported an improvement in Ocular Discomfort Frequency, ranging from an improvement of −50% to 97% with 1 patient reporting an increase in severity from 8% to 12%.

Overall, patients tolerated the treatment protocol well. There were no serious adverse events. During the IPL therapy administration, 24% of patients reported mild stinging from the light therapy. Sixty-five percent of patients reported moderate discomfort during the digital expression. No patients requested to discontinue the study due to discomfort from IPL or expression. Seventy-one percent of patients reported a subjective improvement in ocular comfort throughout the day. Forty-eight percent of patients reported reduced use of artificial tears throughout the day. Other less commonly occurring (>10%) events patients reported included less redness, less itching, and improved contact lens tolerance. Fifteen of 16 patients were noted to have improved meibum secretion quality (clearer, less viscous) and less intense pressure needed for adequate expression at the conclusion of the study visits.

Discussion

MGD and accompanying DED are prevalent and growing public health conditions. Because inflammation can be self-perpetuating and amplifying, anti-inflammatory treatments are needed to stop the process and reverse the damage caused to the ocular surface. ¹² Many patients are intolerant to, not compliant with, or incompletely relieved by current treatment modalities for this disease. IPL therapy has been used extensively in dermatology and has now been used for two decades in ophthalmology for treatment of dry eye with the potential to stop and reverse chronic inflammatory damages in patients with dry eye of variable severity.

Significant progress in illuminating the mechanisms of action has occurred since more and more researchers are contributing to the body of knowledge regarding IPLs effects on the ocular surface, on periocular skin and meibomian glands and their secretions. ¹³ Normal meibum naturally suppresses bacterial overgrowth, and a return to normalized secretions may in fact be protective of future disease once a subject is sufficiently treated.

Eyelid telangiectasias that occur on the lid margin due to chronic and prolonged exposure to inflammation are particularly responsive to the effects of IPL as the periocular skin is among the thinnest of the body and easily penetrated. The pathophysiology of rosacea, a skin disease that involves the eyes, consists of decade-long slow process of thinning of the skin, loss of connective tissues, passive dilation of blood vessels, and the ingress of new abnormal blood vessels in the affected areas. Closing these abnormal blood vessels should result in reduced amounts of secreted inflammatory mediators and improvements both in skin and on the ocular surface. ¹⁴

The role of photobiomodulation in IPL treatment of eyelids is also now being understood. Photobiomodulation is the term used for light-induced photochemical reactions in biological systems and may be due to laser, LED, broadband and near-infrared light, including IPL with a filtered wavelength of ≥590 nm. ¹⁵ It is well known that IPL used in dermatology produces a rejuvenating effect and improvement in skin quality. ¹⁶ Photobiomodulation or low-level laser therapy is known to target cytochrome c in mitochondria, which is believed to increase mitochondrial energy production, cell proliferation, and cell migration. This technology has been used to reduce inflammation in various tissues to upregulate antioxidant levels and downregulate genetic material associated with stress-related cell death. ¹⁷ This may also be part of the mechanism in which a series of IPL treatments over time result in meibomian glands becoming more functional with the corresponding improvement in the quality of secretions. ¹⁸

Upper lids differ in significant ways from lower lids. On average, there are 25–40 glands in the upper eyelid with the average being 31; the central tarsal gland is ∼5.5 mm in length with each gland having the potential to secrete 26 μL of meibum total in the upper lid. Contrasting that with the lower lid that contains 20–30 glands (average 26), the length of the central tarsal gland is 2 mm with a capacity of 13 μL, making the secretory capacity of the upper lid approximately double that of the lower lid. ¹⁹ Gland secretion is typically worse in the lower lids, presumably due to the effect of gravity during the day and the extended contact time of an unhealthy tear film with the lower lids. ²⁰

The M22 model of IPL is unique in that it uses a cooling sapphire crystal tip to cool the skin, minimizing accumulated thermal damage and reducing both discomfort and side effects associated with treatment. It also allows treatments to be given at shorter intervals, 2 weeks compared with older generation IPL machines that required 4 weeks between treatments for epithelium to recover. Second, the M22 utilizes optimized pulse technology that can deliver more homogeneous pulsed energy to target tissues not found in other IPL models. ²¹

The limitations of our pilot study consisted of a small sample size, a lack of sham or placebo control, a single center and nonrandomization of patients. Further study is warranted in this area to explore the reproducibility of data, and to expand the protocol to additional patients and sites.

In this small study, a 6 mm cylindrical cooling sapphire tip applied to the upper eye lids gave patients a significant improvement in tear breakup time as well as in dry eye symptoms. Further study is required to understand which patients would best benefit from upper lid treatment and how to use it in conjunction with lower lid IPL treatments. This study does suggest that the 6 mm cylindrical light guide is a safe and effective addition to the dry eye arsenal in patients suffering from the symptoms of dry eye and visible signs of MGD.