The most common lesions are posterior blepharitis and lipid deficiency dry eye ( Lipid Tear Deficiency, LTD). Although these conditions are not life-threatening, the persistent ocular discomfort has a considerable impact on the patient’s quality of life. Previously, the treatment of MGD was mainly based on eyelid hygiene, hot compresses, lid gland massage, nutritional therapy, hormones, and antibiotic application. In this paper, we review the treatment of MGD.
[Keywords] MGD; treatment; ocular heater; thermodynamic device; blepharoplasty; N-acetylcysteine
I. Anatomy and physiology of the lid gland
The lid glands are metaplastic, tubular, vesicular sebaceous glands that are vertically distributed in the eyelid lid with an opening located at the lid margin immediately behind the eyelash follicles. There are approximately 30-40 lid glands in the upper lid and 20-30 in the lower lid. The main function of their secretions is to form the outermost lipid layer of the tear film, to prevent sebum contamination of the tear film, to maintain the stability of the tear film, to prevent evaporation of tears, and to close the closed lid slit during sleep. The lid glands secrete intermittently and their loss is mainly through the skin of the lid margin and the eyelashes, where the fluid phase of tears diffuses. The process of synthesis and excretion of lipids by the lid gland vesicles and formation of the tear film is influenced by neurological, hormonal, and blood supply factors. Various studies have shown that the lid gland is an androgen target organ and that androgen deficiency can lead to abnormal lid gland function.
II. Basic concepts, classification and epidemiology of MGD
MGD usually results from blockage of the lid gland secondary to hyperkeratosis of the ductal epithelium and concentrated solidification of secretions [1-2]. Blockage of the lacrimal ducts leads to concentration of lacrimal secretions, accumulation, and sometimes co-infection. This eventually leads to abnormalities in the lipid layer of the tear and causes dry eye.
There are several classifications for MGD, but none of them has gained widespread acceptance; the two most mentioned categories are obstructive and hypersecretory. In 2002, Goto et al. proposed the concept of “non-inflammatory lid gland dysfunction” based on previous studies [4], i.e., non-inflammatory, non-obstructive lid gland dysfunction in which the patient presents only with a change in the nature of the lid gland secretion and a change in the nature of the ocular secretion. The patient only presents with changes in the nature of the secretions and ocular surface discomfort. There is no single diagnostic criterion for MGD, and an examination that reveals any of the signs of glandular agenesis, abnormal lid margins and openings, and changes in the quantity and quality of lid secretions is sufficient to diagnose MGD, and further examination is necessary to determine where it falls in the classification and whether other complications are present.
MGD is an extremely common chronic disease of the eyelids [1], [5]. It has a high rate of misdiagnosis and is underappreciated by clinicians. MGD is closely related to dry eye and is the main cause of evaporative dry eye (LTD), while MGD is often associated with ATD, showing common signs and symptoms [6].
III. Treatment of MGD
Since the etiology of MGD has not been completely elucidated, treatment options are mainly symptomatic, with inexact efficacy and poor long-term results, so people continue to explore and research better treatment options relentlessly. In recent years, there have been new advances in physical therapy, immunomodulation, and environmental regulation, as well as new discoveries in the mechanism of antibiotic therapy.
(a) Basic treatment
1. Eyelid hygiene and hot compresses
Eyelid hygiene and hot compresses are the most commonly used treatments. Hot compresses on the eyelids help to increase local blood flow to the eyelids, melt the lipids of the lid glands, and contribute to the stability and uniformity of the lipid layer of the tear film, which may relieve irritation in patients with MGD. Lid margin scrubbing removes lid margin debris and cured secretions that block the lid duct openings, reducing external lid gland opening obstruction and is also a common treatment for staphylococcal and seborrheic blepharitis [7],[8] MGD is a chronic condition that requires long-term adherence to lid hygiene and hot compresses.
In the past, physicians often advised patients to use baby shampoo to clean the eyelids [9], but it has been suggested that, logically, baby shampoo has a saponifying effect that exacerbates inflammation and damage to the tear film from free fatty acids, and is not approved for use on the face, so it is not recommended for widespread clinical use [10].
2. lid gland massage
Blepharoplasty is simple and convenient, and is a common physical therapy performed by patients at home. It was first proposed by Thygeson [11] and has been used for more than half a century. It is performed by using the front of the index finger in a rotating motion on the lid margin or by scraping the lid margin with the index finger from the inner canthus toward the outer canthus. It is usually performed after a hot compress on the eyelid. The principle is to remove the obstruction of the lid gland by elevating the temperature and increasing the pressure to drain the thick secretions from the lid gland, thus relieving the patient’s symptoms.Solomon JD [12] and others found that hot compresses and massage of the lid gland resulted in changes in the physical properties of the cornea, causing transient blurring of vision. Therefore, it is advisable for patients to have family supervision when performing lid gland massage at home.
3. Blepharoplasty
Blepharoplasty is usually performed in a hospital setting and requires the use of a surface anesthetic. The specific method: after surface anesthesia of the conjunctival sac, the left hand flips the eyelid, the thumb is located on the skin surface of the lid to apply pressure to the lid, and the right hand holds a glass rod or cotton swab on the conjunctival surface of the lid against the fornix of the lid towards the lid margin to compress the lid in a combined effort to unblock the lid gland opening and squeeze out the lid gland secretions. A domestic study [13] showed that most patients with obstructive MGD who were treated with lid gland compression had patency of the lid gland opening and significant relief of ocular discomfort. Blepharoplasty can effectively relieve the blockage of the lid gland, but the operation is performed under surface anesthesia and can produce significant pain, and some patients develop acute conjunctivitis and subconjunctival hemorrhage after treatment.
(ii) Instrument-assisted physical therapy
1.Ocular heater
Recently reported eye heaters have been marketed, including disposable heated eye masks (trade name Eye Warmer, a product of Kao Corporation, Tokyo) [14] and water vapor heaters [15] (trade name warm moist air device). Disposable heated eye mask processed into the form of an eye mask, the principle of the iron contained in the exposure to oxygenated water environment oxidation to iron hydroxide, and generate heat and water vapor, so as to achieve the effect of fumigation, hot compress; similarly, water vapor heater is processed into the shape of goggles with insulated steel plate with thermostat and rubber pad, the bottom of the goggles can hold 200 ml of water, and by controlling the water temperature to produce continuous Matsumoto Y [15] and other experts conducted a prospective controlled study by water vapor heater and towel hot compress on eyelids and found that both groups improved ocular surface symptoms, with the experimental group causing a significant increase in ocular surface temperature within 10 minutes, resulting in an increase in the thickness of the lipid layer of the tear film and a prolongation of the tear film break-up time (BUT). In contrast, the BUT of the control group did not change, and the increase in the thickness of the lipid layer of the tear film after 2 weeks was smaller than that of the experimental group. The superiority of the water vapor heater was illustrated.
The new device, although effective, still has significant drawbacks in application. For example, there is heat loss when heat energy is transferred from the skin surface of the eyelid to the conjunctival surface of the lid, and the lid tissue has a relatively insulating nature [16-17], resulting in inefficient heat energy transfer.
2. thermodynamic device ( novel thermodynamic treatment device)
This device is the first to deliver heat energy directly from the inner surface of the eyelid while performing lid pressure and avoiding pressure on the eyeball, making it more effective compared to traditional methods. The device consists of an eyelid heater and an eye cup. The eyelid heater is shaped like an eye mold, and its concave side contains insulating material that adheres to the sclera, preventing heat transfer to the cornea and ocular surface. Its convex surface is embedded with a precision heater and multiple temperature sensors that heat all the lid glands of the upper and lower eyelids at once in 12 minutes through the inner surface of the lid glands. The eye cup contains an expandable air sac that is fixed to the surface of the eyelid when the scleral lens is built into the eye, squeezing the lid gland in the direction of the lid gland opening so that it heats the lid gland while promoting lid gland secretion.In 2010, Donald R [18] et al. reported the LipiFlow thermokinetic device (manufactured by Tear Science) for the treatment of MGD and The device was evaluated clinically. The LipiFlow is already in use in Europe and is currently under approval by the US Food and Drug Administration.
3. Needle lancing of the lid gland
In 2010, Maskin SL [19] first used a physical method to access the gland to unblock it. Twenty-five patients with O-MGD were treated for obstructive lid gland dysfunction (O-MGD) by inserting a sturdy stainless steel probe into a sterile probe handle under surface anesthesia, and under a slit lamp, the probe was allowed to slowly enter the lid duct to unblock the lid gland. 25 patients with O-MGD were treated with lid gland acupuncture, and 16% of patients were treated with other dry eye treatments, including tear dots Embolization. The results showed that 96% of patients had immediate relief of symptoms, 100% of patients had relief after 4 weeks of 4 treatments, and 80% of patients required only one lid gland exploration to achieve results. After 11 months of follow-up, no adverse effects were seen. The ability to safely access the lid gland and achieve good results is important for exploring the pathophysiology and pathogenesis of the lid gland.
(iii) Drug therapy
When physical therapy is not completely effective, local and systemic antibiotic therapy is required. The main drugs are tetracyclines, doxycycline, and minocycline.
1.Tetracycline antibiotics
Tetracycline antibiotics, including tetracycline, doxycycline, and minocycline, can reduce the inflammatory response and reduce harmful components such as free fatty acids and glycerides in the secretions of the lid gland. Studies have also found that tetracyclines and their analogs have anti-MMP effects, inhibit MMPs, cytokines, and therefore affect inflammation, immune regulation, cell proliferation, and angiogenesis. The use of tetracyclines in the treatment of ophthalmic diseases is in its infancy [20-22].
2. Macrolides
In the same way as tetracyclines, macrolides also have antibacterial and anti-MMP effects. Topical application of macrolides has also been one of the hot topics in recent years.In a 2008 study [23], patients with posterior blepharitis treated with macrolides-azithromycin (1%) eye drops significantly improved the quality of the lid gland secretions and significantly relieved symptoms such as eyelid redness.In 2010, Gary N [24] et al. showed that by treated 22 patients with MGD with 1% concentration of azithromycin eye drops (manufactured by Inspire Pharmaceuticals, Daramu, New Caledonia) and collected the lid gland lipids for analysis after 4 weeks and found that the phase transition temperature (PTC) of the lid gland lipids was altered. Low phase transition temperature is one of the indicators of enhanced mobility of the lid gland lipids [25]. Therefore, this study confirms that azithromycin can improve the symptoms of the lid gland by improving its lipid conformation, increasing the mobility of the lid gland, and relieving the blockage of the glandular ducts.
3. N-acetylcysteine (NAC)
NAC is an acetylated derivative of natural L-cysteine, a mucolytic antioxidant that affects a variety of inflammatory metabolic pathways and regulates intracellular redox status, as well as having anti-keratinocyte proliferative effects. Due to its mucolytic and anticollagenolytic properties, NAC has been successfully used in ophthalmology for the clinical treatment of corneal diseases such as keratoconjunctival desiccation syndrome and filiform keratitis. the control group and was able to significantly improve the symptoms of ocular pruritus [26].
(iv) Immunomodulation
The treatment of dry eyes with cyclosporine A has been agreed upon, but the treatment of MGD is still being explored. in 2004, an attempt was made to treat inflammatory MGD and MGD that did not respond to other medications with glucocorticoids, 0.05% cyclosporine A eye drops, and encouraging results were achieved [27]. Cyclosporine A interrupts the immune-mediated process by binding to specific nuclear proteins that initiate T-cell activation and inhibiting T-cell production of inflammatory cytokines such as IL-2; glucocorticoids inhibit inflammatory cytokine and chemokine production, reduce the synthesis of lipid mediators such as MMP (e.g. prostaglandins), decrease the expression of cell adhesion molecules, and stimulate lymphocyte apoptosis [28].
Rubin M and Rao SN [29] found that MGD patients treated with cyclosporine showed improvement in symptoms and objective indicators, time to tear film rupture. Therefore, cyclosporine can be applied to reduce inflammation when the lid gland is decongested by hygienic care and physical therapy. Topical application of corticosteroids can be effective in treating dry eyes and suppressing the inflammatory response, but given their side effects, they can only be used short-term.
(v) Androgen therapy
The lid gland has androgen receptors and other sebaceous glands throughout the body are not sensitive to androgens. Antiandrogen therapy has been shown to improve the secretory function of the lid gland. In patients with abnormal sex hormone levels, androgens can improve the structure of the lid gland and improve the quality of the lipid layer [30-31]. However, systemic application of androgens can have significant side effects, and topical androgens are being evaluated as a possible treatment for MGD.
(vi) Nutritional support
The use of dietary supplements to treat MGD is now the latest area of research in ophthalmology. one of the symptoms of MGD patients, namely altered TFLL, and supplementation of fatty acid intake could theoretically improve the nature of the lid secretions. w-3 FAS and w-6 FAS essential fatty acid supplements have been used as over-the-counter medications to help MGD patients improve their symptoms [32].
The w-3 FAS is an essential nutrient for human growth and development. w-3 FAS and w-6 FAS compete to bind the same enzyme and are eventually catalyzed by the enzyme into prostaglandins (PGE 3), leukotrienes and PGE 2, and leukotrienes, respectively, which have anti-inflammatory effects. However, the exact mechanism of efficacy is unknown.BY Marian S. Macsai MD [33] demonstrated in a prospective randomized placebo-controlled trial that the administration of w-3 dietary supplements reduced the levels of w-3 and w-6 in red blood cells and plasma; reduced the saturated fatty acid content of lipids secreted by the bleb glands, and improved overall OSDI scores, TBUT, and lipid quality. The application of lipid-containing artificial tears such as phospholipids, saturated and unsaturated fatty acids, and triglycerides has also been attempted to treat MG D patients with still satisfactory results.
(vii) Lacrimal punctal embolism [34]
Since MGD is often accompanied by ATD and both often show common signs and symptoms, tear punctal embolization is often performed in such patients.Eiki Goto et al. in 2003 analyzed the kinetics of tear punctal occlusion (PO) images before and after treatment of 17 patients with tear-deficient dry eyes and found that PO significantly shortened lipid transmission time and improved lipid layer uniformity and thickness, suggesting that the performance of lipid membranes also depends on the amount of tear fluid. These studies provide new insights into the interactions between lipid membranes and the tear aqueous layer.
(viii) Environmental regulation
Exposure to lower humidity conditions such as deserts, air-conditioned rooms, and airplane cabins with higher temperatures increases the rate of tear evaporation, and avoiding these environments may reduce dry eye symptoms and decrease the use of artificial tears. Aqueous/mucous egg analogs are the most commonly used artificial tears for the treatment of MGD, improving patient symptoms and promoting uniform distribution of lid gland lipids over the entire surface of the eye.
IV. Summary
MGD is a common clinical condition that is associated with changes in the composition and function of the lipids produced by the lid gland. Traditional approaches are only symptomatic, and in recent years, more and more new therapies have begun to explore the pathogenic mechanisms with some success.