Ординатура / Офтальмология / Английские материалы / Ocular Disease Mechanisms and Management_Levin, Albert_2010

Tear volume ( l)

A

Box 16.5  Reflex tearing as an indicator

of tear reserve

•Reflex tearing occurs during delayed blinking and may indicate a tear reserve

•The upper tear meniscus would not be able to hold much fluid

•The tears appear to travel from the upper tear meniscus to the lower tear meniscus through the canthi, rather than through the corneal surface

when the eye is held open, resulting in significant changes in the tear system (Figures 16.1–16.4).16

Reflex tearing may indicate a tear reserve (Box 16.5). Video recording showed the early postblink temporal changes of the lower and upper tear menisci in the 10 seconds following a blink in young adults.53 The changes may be influenced by gravity, which moves the tears from the tear film to the lower tear meniscus, whereas few changes occur in the upper tear meniscus (Figure 16.4).16 The results of the tearing may also be independent on the period when the eye is held open, since different observations of the changes in the tear menisci were reported.16,53 If the eye was held open for about 10 seconds, as reported in the study of Johnson and Murphy,53 similar changes were obtained between upper and lower tear menisci. If the eye was held open for longer, greater changes in the lower tear meniscus were evident, due to a large amount of tears added into the system and the limit of the upper tear meniscus.16 The upper tear meniscus would not be able to hold much fluid. When the upper meniscus swells and the radius of curvature increases, the capillary pressure decreases to draw fluid towards the upper meniscus41,42,54 and gravity exerts a significant effect to draw fluid down to the lower tear meniscus. The lower tear meniscus is capable of holding a large amount of fluid because of its structure, with the aid of the gravity. The rapid swelling of the lower tear meniscus during reflex

Box 16.6  Tear distribution and drainage

•The tear drainage system has a reserve capacity in removing excessive tears out of the eye

•The magnitude of the tear output due to blinking appears to be dependent on the total overloaded tear volume

•Great fluid redistribution occurs between the tear film and tear menisci when the system is overloaded

tearing, with small changes in the upper tear meniscus, indicates that both tear menisci are connected. The tears appear to travel from the upper tear meniscus to the lower tear meniscus through the canthi, rather than through the corneal surface. This may prevent visual blur during the eye-opening period if there is excessive tearing.

During delayed blinking, after a period of time with the eye open, tearing supplies additional volume to the ocular surface, most of which is in the lower tear meniscus (Figure 16.3).20 However, tear film volume was found not to increase dramatically because the tears travel through the connection between the upper and lower eyelids.16 Once the volume collected in the lower tear meniscus reaches a level, the tear film volume appears to increase after a blink.16 This indicates that blinking is essential to spread tears from the menisci to the ocular surface.

Blinking with overloaded artificial tears

To keep a dynamic balance with a small amount of tears, the drainage system is thought to remove little fluid with each blink under normal circumstances (Box 16.6).23 The phenomenon has been supported by the fact that there were no significant changes in tear volume in tear meniscus and tear film during normal blinking imaged with OCT.16 While spreading during blinking and evaporation during

UTMC ( m)

A

UTMH ( m)

B

UTMA ( m2)

C

380

360

340

320

300

280

260

240

220

200

180

340

320

300

280

260

240

220

200

34000

32000

30000

28000

26000

24000

22000

20000

18000

16000

14000

12000

LTMC ( m)

D

LTMH ( m)

E

UTMA ( m2)

F

900

800

700

600

500

400

300

200

100

300000

250000

200000

150000

100000

50000

0

eye opening may cause variations in tear volumes in each compartment, it remains unknown how the surface keeps wet with such a small volume in a dynamic way. Clearly, the tear components and the ocular surface with its special structure like microvilli play a significant role. This mystery makes it complicated to restore the protection of the tears in dry-eye patients. The increase in tear volume within a short period of time may not be enough to protect the ocular surface from drying for a long time. The restoration of the tear system may be much more complex than had been thought.

The tear drainage system has a reserve capacity in removing excessive tears from the eye.21,51,55,56 Zhu and Chauhan55

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calculated tear output and/or drainage rate due to blinking and found the rate increases by factors that ranged from 3 to 50 for overloaded tear volume. By repeated instillation of saline solution over a period of time, a blink output of 2 l in the horizontal position and 4 l in the upright position have been documented.51,56 Using OCT, the blink output was found to be significantly increased during reflex tearing due to delayed blinking21 and after instillation of drops.20 Palakuru et al20 found that the magnitudes of the tear output due to blinking appeared to depend on the total overloaded tear volume. More output due to blinking was found with higher tear volume.20 Since the major tear volume was found in the lower tear meniscus, it can be hypothesized that the

lower tear volume may regulate the drainage system that may be dependent on lower tear meniscus volume.

Although the tear film and the tear menisci are physically and functionally interconnected,18,57 they appear to respond differently to blinking under different conditions, as shown in previous studies.20,21 When limited tears were added continuously into the system, as occurs during delayed blinking, the lower tear meniscus swelled first while other compartments, including the tear film and the upper tear meniscus, remained relatively unchanged.21 However, when a large amount of tears was added, as occurs when a drop is instilled, all compartments increased in volume, with the majority of the changes in the lower tear meniscus and tear film.20 Under both conditions, blinking appears to play almost no role in upper tear meniscus volume since it remained almost unchanged. However, under the latter condition with excessive tears, blinking caused the increases in both upper tear meniscus and tear film volume. Under both conditions, blinking caused a decrease in lower tear volume, possibly mainly due to drainage and evaporation. Clearly, blinking induces fluid redistribution among compartments and activates the drainage system to remove excessive fluid. It is not clear about the role of evaporation during such a short period of the blink since no data are available in the literature. In addition to the loss of tears from the lower tear meniscus volume, the lower tear meniscus volume appears to supply fluid to the tear film and upper tear meniscus if excessive tears are present. A portion of the decrease in lower tear meniscus volume after a blink was found to be due to redistribution to the tear film and upper tear meniscus.20

With the limited tears available during delayed blinking, it appears that both upper and lower tear menisci provide fluid to the tear film.21 This explains why tear loss from the lower tear meniscus was larger than that in total tear volume. However, the tear film volume may also depend on other sources. King-Smith et al58 proposed that the TFT may also depend on the amount of fluid under the lid, and blinking causes deposition of the fluid. In a previous study,19 TFT was increased when artificial tears were added into the lower tear meniscus. During the open-eye period, tear secretion, redistribution due to gravity, evaporation, and drainage occur. This period is of much greater duration than the blink itself, and most of the tear drainage may occur in the very first instant during the opening of the lid.

The tear volume during the open-eye period has been reported to be mainly influenced by tear secretion, evaporation, and absorption.22 Redistribution of tears also affects the tear volume in different compartments.22 The tear film begins to thin during the open-eye period.50,58 This complex process involves mechanisms such as evaporation, dewetting, pressure gradient flow, Marangoni flow, and gravity.50 Flow in the middle of the film has been suggested to be mediated by gravity which is proportional to the thickness of the tear film.53 Thus the change in volume of the tear film during normal blinking could be negligible because of large flow resistances in thin films.53 On the other hand, with thicker tear films, gravity may play a significant role in thinning.53,59 Palakuru et al16 found a significant reduction in TFT at the end of the open-eye period after drop instillation. The tear film was also found to be redistributed into the lower tear meniscus, most likely due to fluid flow.20 The flow towards the lower tear meniscus appears to be aided by gravity

Effect of blinking on tear dynamics

whereas the flow towards the upper tear meniscus goes against the force of gravity.53 This explains the unequal changes in upper and lower tear menisci during the open-eye period. With a large amount of instilled tears, as tested in this study,20 a greater decrease in tear film volume at the end of the open-eye period occurred compared with that during delayed blinking.21 This indicates that great fluid redistribution occurs between the tear film and tear menisci when the system is overloaded. It appears that there is a threshold of total tear volume that is required to increase the tear film volume. Thus, TFT may not change when the total tear volume is less than approximately 5–7 l.20,21 Because normal tear volume is about 3 l,21 it may require doubling the production of tears to increase TFT, as shown during delayed blinking21 and immediately after drop instillation.20

The tear film is a couple of microns thick and covers the entire ocular surface. Its integrity is maintained during eye opening between blinks and the ocular surface is protected. In healthy eyes, the long-lasting film is formed and renewed by spreading by the eyelid during blinking with supply from other compartments like tear menisci, secreted mainly from the lacrimal glands. If the breakup of the tear film occurs before the next blink, the ocular surface may be impaired, resulting in dry-eye symptoms. Many mechanisms have been proposed to resolve the puzzle of tear breakup. Clearly, the quality and quantity of the tears play roles and interaction between blinking and tears also has some impact on tear breakup. A balanced tear system needs to be maintained with a limited variation in tear volume and continuous renewal of the tear film. The tear film thins during eye opening and thickens after blinking. The thinning of the tear film may be the result of numerous factors, such as tear quality, tear volume, and blinking. Many factors can impact tear distribution on the ocular surface. The structures and locations (upper or lower) of the tear menisci determine the tear distribution during normal and delayed blinking. The upper lid may not hold much fluid and the lower lid can host a large amount of tears if excessive tears are present. Both the upper and lower tear menisci are connected through both canthi, during the open-eye period, and tears could travel through these connections without disturbing vision during eye opening. Blinking mixes and distributes the tears for a fresh and uniform tear film with no need for a large amount of tears.

In conclusion, the thin tear film on the ocular surface is essential for maintaining ocular health and sharp vision. The tear film forms and breaks during the blink cycle and blinking plays an important role. A minimal quality and quantity of tears appears to be necessary to form a long-lasting tear film. The blink dynamics and tear film breakup are intimately linked. The quality and/or quantity of tears are compromised; the tear film becomes susceptible to tear film breakup. Tear volume in both upper and lower tear menisci may regulate the TFT with the aid of blinking. When excessive tears are present, increased drainage capability takes action to remove the tears and restore the tear volume to a regular level. Reflex tearing may be an indicator of tear reserve and occurs during delayed blink. Upper and lower tear menisci are linked through both canthi to facilitate tears traveling in between without disturbing the vision. The detailed mechanism of tear breakup is not completely understood; further studies are needed to model the tear system with consideration of all impacting factors.

1.Dogru M, Ishida K, Matsumoto Y, et al. Strip meniscometry: a new and simple method of tear meniscus evaluation.

Invest Ophthalmol Vis Sci 2006;47: 1895–1901.

2.Sharma A, Ruckenstein E. Mechanism of tear fiml rupture and formation of dry spots on cornea. J Colloid Interface Sci 1985;106:12–17.

3.Holly FJ, Lemp MA. Tear physiology and dry eyes. Surv Ophthalmol 1977;22:69– 87.

4.Dohlman CH, Friend J, Kalevar V, et al. The glycoprotein (mucus)content of tears from normals and dry eye patients. Exp Eye Res 1976;22:359–365.

5.Holly F, Lemp M. Wettability and wetting of corneal epithelium. Exp Eye Res 1971;11:239–250.

6.King-Smith PE, Fink BA, Fogt N, et al. The thickness of the human precorneal

tear film: evidence from reflection spectra. Invest Ophthalmol Vis Sci 2000;41:3348–3359.

12.Wang J, Fonn D, Simpson TL, et al. Precorneal and preand postlens tear film thickness measured indirectly with optical coherence tomography. Invest Ophthalmol Vis Sci 2003;44:2524–2528.

14.Mishima S, Gasset A, Klyce SD, et al. Determination of tear volume and tear flow. Invest Ophthalmol 1966;5:264– 276.

15.Mathers WD, Lane JA, Zimmerman MB. Tear film changes associated with normal aging. Cornea 1996;15:229–234.

16.Palakuru J, Wang J, Aquavella J. Effect of blinking on tear dynamics. Invest Ophthalmol Vis Sci 2007;48:3032–3037.

22.Zhu H, Chauhan A. A mathematical model for ocular tear and solute balance. Curr Eye Res. 2005;30:841–854.

31.Konnur R, Kargupta K, Sharma A. Instability and morphology of thin liquid films on chemically heterogeneous substrates. Phys Rev Lett 2000;84:931– 934.

45.Yokoi N, Bron AJ, Tiffany JM, et al. Relationship between tear volume and tear meniscus curvature. Arch Ophthalmol 2004;122:1265–1269.

50.Nichols JJ, Mitchell GL, King-Smith PE. Thinning rate of the precorneal and prelens tear films. Invest Ophthalmol Vis Sci 2005;46:2353–2361.

55.Zhu H, Chauhan A. A mathematical model for tear drainage through the canaliculi. Curr Eye Res 2005;30:621– 630.

Clinical relevance of lipids in the tear film

Lipids play a critical role in the health of the eyelids and the tear film. Abnormalities of these lipids are common in the general population and provoke frequent disease manifested by clinical conditions of eyelid inflammation and tear film instability. Such conditions, although not life-threatening, cause considerable irritation to patients and interference with their quality of life. The most common clinical problems are meibomian gland disease (MGD) and dry-eye disease, but focal lesions of hordeola and chalazia are also often a nuisance.

Normal anatomy and production

Lipids are normally produced by the meibomian glands of the eyelid and the main and accessory lacrimal glands, as well as epithelial cells of the ocular surface. The lipids are distributed in five pools including within the eyelid, the eyelid margin, the surface of the tear film, within the aqueous layer of the tear film, and on the ocular surface.

Most of the lipid is thought to be produced by the meibomian glands of the eyelid, although contributions are also made by the main lacrimal gland, the glands of Wolfring, and the glands of Krause.1 The meibomian glands are modified sebaceous glands, that is, tubuloacinar, holocrine glands whose acini discharge their entire contents in the process of secretion. They are distributed vertically in the substance of the tarsal plate of the eyelid with their openings on the eyelid margin just posterior to the eyelash follicles. There are about 30–40 glands in the upper eyelid and 20–30 glands in the lower eyelid.2 Their secretion is conditioned by hormonal influences particularly of androgens with neural control by parasympathetic, sympathetic, and peptidergic innervations.2–7

It is estimated that there are over 30 000 molecular species of lipids in human meibum,8 which complicates their quantification. The accuracy and precision of measurements of the lipid composition of meibum are also complicated by the large variation in composition from person to person,9 and the paucity of sample.10 Because of these complications, it is not surprising that the value reported for the predomi-

nant class of meibum lipid, esters, composes between 20 and 80% of the meibum.9–11 There is also loose agreement on the composition of other meibum lipids; for instance, alkanes compose 0–36% of the meibum (Box 17.1).9–11 In an older study using column chromatography, phospholipids constituted as much as 16% of meibomian gland secretions10; however, more sensitive mass spectroscopic techniques indicate that phospholipids are not present.12 Of the total lipid hydrocarbon chains 58% are saturated. Most of the saturated hydrocarbon chains are in the form of sterol esters, which are 85% saturated.10 The wax esters and triglycerides are the least saturated, at 22% and 38%, respectively.10

Chromatographic13 and spectroscopic data14,15 indicate major compositional differences between the lipids in tears and meibum. This is consistent with the compositional differences reported in the only comprehensive study of tear fluid lipids.16

Meibum normally has a melting point between 19 and 39°C.17–20 At ambient lid temperature, the lipid is about 37% ordered, in between a solid (gel phase) and liquid (liquid crystalline phase; Box 17.2).15 As the temperature increased from 25 to 45°C, lipid delivery to the margins was observed to increase.21 Under similar conditions, other studies show a concomitant decrease in the refractive index,22 hydrocarbon disorder,15 and meibum lipid hydrocarbon motion.14 This raises the possibility that hydrocarbon chain order and motion could contribute to the delivery of meibum lipid from the meibomian glands to the lid margins.

The function of the meibomian gland secretion is most importantly to retard evaporation of the tear film by distribution across the surface of the tear film. The secretions also function to provide a smooth optical surface for the cornea at the air–lipid interface, enhance stability of the tear film, enhance spreadability of the tear film, prevent contamination of the tear film by sebum of the cutaneous sebaceous glands, and to help seal the eyelid margin during eyelid closure (Table 17.1). Although the initial concept of the tear film as that of a three-layer structure of surface lipid layer, bulk aqueous layer, and ocular surface-wetting mucin layer has been replaced by the characterization of the tear film as a lipid-coated hydrated mucin gel with multiple interacting components of electrolyte, protein, and lipid entities, the

Box 17.1  Composition of meibum

Conflicting information9,10

>30 000 molecular species present8 Esters: 20–80%9–11

Sterol esters 85% saturated10 Wax esters 22% saturated10 Triglycerides 38% unsaturated10

Alkanes: 0–36%9–11

Phospholipids: 0%12

Box 17.2  Properties of meibum

Melting point: 19–39°C17–20

At ambient lid temperature: 37% ordered lipid15

(in between gel phase and liquid crystalline phase)

As temperature increases:

•Delivery to eyelid margin increases

•Refractive index decreases

•Lipid becomes more disordered

•Lipid motion increases

Table 17.1  Functions of the meibomian gland lipid secretions

1.  Retard evaporation of the preocular tear film

2.  Maintain smooth optical surface of the eye at the air–lipid interface

3.  Enhance stability of the tear film

4.  Enhance spreadability of the tear film

5.  Prevent contamination of tear film by cutaneous sebum

6.  Seal the apposed margins of the eyelids during eyelid closure

H

Figure 17.1  Fourier transform infrared demonstration of trans versus gauche rotamers of lipid conformation.

lipid component is still responsible for stability of the tear film and protection of the ocular surface.23

Changes occurring with age

The tear film is incredibly stable in infancy yet with advancing years such tear stability decreases. This progressive instability is associated with changes in the conformation of the lipids of the tear film and meibomian gland secretion. With increasing age, the ordering of the lipid changes from that of a more ordered conformation to that of a less ordered conformation as determined by Fourier transform infrared spectroscopy (FTIR) (Figures 17.1 and 17.2).14,15 If the lipid disorder is maintained by the lipid on the tear film surface, lipid–lipid interactions would be weaker with increasing age (Box 17.3). Hence, the rate of evaporation would be expected to be greater since water escaping through the lipid layer would have to pass through lipid less tightly packed. Furthermore, if lipid–lipid interactions are weaker, one might expect that this could contribute to faster tear breakup times observed with age.

Figure 17.2  Lipid conformation changes occurring with age and meibomian gland dysfunction. as measured by Fourier transform infrared analysis.

Box 17.3  Changes of meibomian gland secretion

with age

•More ordered conformation (trans) changes to less ordered conformation (gauche) (as measured by Fourier transform infrared (FTIR) spectroscopy (Figures 17.1 and 17.2)14,15

•Decrease in ordering of lipid correlates with decreased tear film stability

•Decrease in ordering of lipid correlates with increased tear evaporation

Lipid–protein interactions

Lipocalin, present in tears, is capable of sequestering cholesterol, fatty acids, glycolipids, and glycerophospholipids.24 Lipid binding promotes protein conformational changes.25 It has been proposed that lipocalin scavenges lipid from the corneal surface26 and may enhance the transport and equilibration of lipid in the lipid surface layer. An in vitro fluorescent probe study14 shows components in tears bind to the surface of tear film lipids. If similar interactions occur in vivo at the tear film lipid–aqueous interface, they would reduce the rate of evaporation. Mucins, lysozyme, lipocalin and other proteins present in tears could potentially bind to tear film surface lipids.

Changes occurring with disease

The most characteristic clinical change associated with lipid abnormalities of the eyelid and tear is tear film instability. Tear film instability is a hallmark feature of dry-eye disease as well as MGD.27 Tear breakup time of less than 2–3 seconds often accompanies dry eye and MGD compared to normal tear breakup times of greater than 10–20 seconds. This functional disturbance seen in dry-eye disease can be due either to inadequate volume of secreted aqueous tear that is below that necessary to sustain the normal evaporative rate (aque- ous-deficient dry eye), or to overly rapid evaporation of the tear film (evaporative dry eye). In the case of MGD, the functional disturbance of tear film instability is most likely due to increased evaporation of the tear film.28,29

In 18 of 20 patients with meibomian dysfunction, an infrared study showed lipid order (stiffness) increased (Figure 17.2). As discussed in the previous paragraph regarding lipid melting, stiffer meibum lipid could impede the flow of meibum, resulting in less lipid on the lid margin, creating a higher rate of tear evaporation (Box 17.4).

Specific abnormal polar lipids have been reported in meibum of patients with dry eye associated with meibomianitis by chromatography techniques, but the precise meaning of such findings is unclear, since subsequent mass spectroscopy studies have shown very little polar lipid in meibomian secretion.12,30

Clinical manifestation of disease: dry-eye disease and meibomian gland disease

The most common clinical manifestations of abnormality of the lipids in the eyelid and tear film are evaporative dry-eye

Box 17.4  Changes of meibomian gland secretion

with disease

•Clinically, the most prominent change of the tear film is decreased stability

•This decreased stability is associated with increased evaporation of tears

•In 18 of 20 patients with meibomian dysfunction, infrared study showed lipid order (stiffness) increased in meibomian gland secretion (Figure 17.2)

•In patients with meibomitis, breakdown of the more complex lipid structures (triglycerides) into diglycerides and increased free fatty acids proves irritative to the tissues and ocular surface43

Box 17.5  Categories of meibomian gland disease2

Congenital absence Dystichiasis Obstructive

Simple

Epithelial hypertrophic plugging Inspissated meibomian secretion

Cicatricial Postinflammatory

Medication-induced (13-cis retinoic acid; chlorobiphenyls)44–48

Hypersecretory Meibomian seborrhea Rosacea

disease and MGD. Dry eye is etiopathologically categorized into aqueous production-deficient or evaporative dry eye.27 The evaporative aspect of dry eye occurs in many dry-eye sufferers and the most common cause of evaporative dry eye is meibomian gland dysfunction.2,27 Dry-eye disease has been documented by numerous epidemiological studies to affect 7–30% of the older (>55 years) population depending upon geographic location.31 It is more frequent in women, particularly those who are postmenopause.32

Several clinical studies have identified MGD as a frequent problem in the general population, with prevalence at 39% of patients (Box 17.5). MGD occurs most frequently in older men but also affects postmenopausal women. MGD is often a major reason for discontinuing contact lens wear.33–36

The clinical characteristics of meibomian gland disease

MGD includes a broad spectrum of etiopathogenic events that are discussed in depth elsewhere.2 Nonetheless a brief synopsis identifies the most common pathogenic events as obstructive, hypersecretory, infectious, inflammatory, or obliterative (Table 17.2). Obstructive disease can occur due to hypertrophy of the epithelium lining the orifice of the meibomian gland or due to inspissation of the secretion produced2,37,38–40 (Figure 17.3). Clinical evaluation of the

Table 17.2  Classification of meibomian gland disease

Reduced number of glands: congenital absence or deficiency

Replacement of glands: dystichiasis, metaplasia

Meibomian gland dysfunction:

 Hyposecretory*

 Hypersecretory*

 Obstructive

     Epinephrine (rabbit) Other

 Internal hordeolum

 Chalazion

 Concretions

Modified from Foulks GN, Bron AJ. Meibomian gland dysfunction: a clinical scheme for description, diagnosis, classification, and grading. Ocul Surf 2003;1:107–126.

*Conditions have not been validated clinically.

abnormal secretions is usefully described as clear, turbid, turbid with clumps, or solid (paste-like).2 Associated inflammatory changes include telangiectasis of the eyelid margin or more severe changes of notching, dimpling, or scarring of the eyelid margin if the disease has been chronic (Figure 17.4). Since the meibomian eyelid secretions are a rich cho- lesterol-containing culture medium for bacteria, stasis of the secretions can be accompanied by bacterial superinfection, most commonly by Staphylococcus species.41,42 Such focal infections can produce hordeola (styes) of the eyelid with associated swelling, erythema, and pain (Figure 17.5). A more chronic inflammation due to the stasis of the lipid secretion in the meibomian glands is a lipogranulomatous reaction (chalazion) that is probably due to breakdown of

Box 17.6  Therapeutic options for meibomian

gland disease49

Physical measures Heat application Massage of eyelids

Medicinal measures Antibiotics

Tetracyclines (tetracycline, doxycycline, minocycline) Macrolides (azithromycin, erythromycin)

Anti-inflammatory agents Corticosteroids Ciclosporin

Macrolides (azithromycin) Nutriceutical measures

Omega-3 essential fatty acids Hormonal measures

Androgenic steroids

the complex lipids into more inflammation-provoking small digylcerides and free fatty acids (Figure 17.6).

Analysis of the lipid secretion during active inflammation of the eyelid (blepharitis or meibomianitis) has revealed breakdown of the more complex lipid structures (triglycerides) into diglycerides and increased free fatty acids that prove irritative to the tissues and ocular surface.43 This breakdown can occur both due to the presence of lipase enzymes of colonizing bacteria and due to tissue lipases associated with inflammation.

Less common but very important pathophysiology that is productive of MGD is obliteration of the glandular tissue. This occurs primarily by toxicity to external agents or cicatrization of the tissue due to longstanding inflammation. The most notable toxins are 13-cis retinoic acid (Accutane) or exposure to chlorobiphenyl chemicals.44–48 Loss of meibomian gland structure is visible with transillumination of the eyelid and persistent dry-eye irritation is a consequence of the toxic exposure.

Therapeutic implications

Attempts to treat clinical disease of the meibomian glands include physical, medicinal, nutritional, and hormonal measures49 (Box 17.6). Physical treatment options include thermal and mechanical techniques designed to express inspissated secretions and thus relieve meibomian gland congestion. The simplest physical method is application of a warm compress to the eyelids followed by mechanical lid massage to express the melted secretions. The lipid secretions vary in melting temperature, but application of external heat increases the flow of the secretion from the glands and provides comfort.50 Although effective in melting and expressing secretions when done properly in most cases, this therapy depends entirely upon patient understanding and compliance. It is helpful to reinforce the demonstration of the proper technique with a patient handout summarizing the disease concepts and the massage techniques. If selftreatment fails to relieve meibomian gland congestion and

plugging of the orifices persists, the ophthalmologist can express the secretions in the office by compressing the eyelid between two cotton-tipped applicators. Topical anesthetic drops should first be instilled into the conjunctival cul-de- sac for patient comfort. This in-office maneuver may open the gland orifices and facilitate the efficacy of the patient’s efforts.

When physical measures alone are not effective in controlling the disease, systemic treatment with oral antibiotics is usually the next option. The tetracycline family of drugs is the most used and most effective since there is not only an antibacterial effect on any infecting organisms, but also the calcium and magnesium-chelating properties of the drug inhibit the lipolytic enzymes that break down the complex

Figure 17.5  Example of acute inflammation of eyelid gland: hordeolum.

Figure 17.6  Example of chronic inflammation of meibomian gland of eyelid: chalazion.

lipids into the more inflammatory diglycerides and fatty acids. Bacterial lipolytic exoenzymes such as triglyceride lipase, and fatty wax and cholesteryl esterases can contribute to breakdown of the normal meibum’s complex lipids into potentially inflammatory smaller free fatty acid fragments. Dougherty et al51,52 demonstrated that S. aureus, coagulasenegative staphylococci, and Propionibacterium acnes all produce such enzymes, and that similar secretional lipid profile abnormalities occur in patients with blepharitis or meibomianitis in which coagulase-negative staphylococci predominate.

Attempts to use topical measures to stabilize the tear film while other treatment modalities are in progress include over-the-counter formulations that include lipid emulsions. Refresh Endura (Allergan, Irvine, CA) has been shown to prolong tear breakup time, as has a metastable emulsion, Soothe (Bausch & Lomb, Rochester, NY).53,54 Another lipidcontaining formulation, Freshkote (Focus Laboratories, North Little Rock, AR) has been reported to improve symptoms in dry-eye patients.

Systemic therapy with antibiotics such as tetracycline, doxycycline, and minocycline reduces meibomian gland inflammation and the associated symptoms of ocular irritation.51 Tetracycline has been shown to decrease S. epidermidis lipase activity in vitro, and it is thought that its related compounds act similarly. Such treatment can return the lipid profile of the meibomian secretion to a more normal composition.43

Omega-3 essential fatty acid supplements have been advocated for treatment of chronic MGD.55 Limited small studies have been completed but such supplements have been shown to improve symptoms in patients with dry eye.56 The active components of these preparations are probably linolenic acid and its congeners. This family of essential fatty acids provides the building blocks for the prostaglandins that modulate tissue inflammation. These essential fatty acids have been shown in other tissue systems to reduce inflammation and exert beneficial effects on vascular, cardiac, and other physio­ logic functions.57 Linoleic and oleic acids, unsaturated fatty acids, have been shown to inhibit keratinocyte proliferation

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and are present in normal human meibomian secretions.58 Although no controlled clinical trials have validated the efficacy of fatty acid supplements for control of meibomian gland dysfunction, a pilot study of 8 patients with refractory meibomitis who received dietary supplements of linoleic and linolenic fatty acids showed improved clinical symptoms, despite only minimal improvement in the slit-lamp appearance of the meibomian glands.44 This symptomatic improve- mentcouldbeattributedtothesupplements’anti-inflammatory and antikeratinizing effects, but controlled trials are necessary to validate this hypothesis.

Control of inflammation associated with MGD can be achieved with topical corticosteroids and topical ciclosporin.59,60 The chronic use of corticosteroids is to be avoided given the risks of cataract and glaucoma, but topical ciclosporin has been used safely for prolonged periods.

Given the evidence that decreased androgenic hormonal influence on meibomian gland secretion and inflammation may result in disease, supplementation of androgen by topical administration has been advocated.4–7 Application of topical testosterone to the external eyelid skin has been reported to improve symptoms of dry eye and such improvement could be a sign of stimulation of meibomian gland function.61 Controlled clinical trials will be needed to verify such a beneficial effect.

Future research and management

The 2007 Report of the International Dry Eye Workshop62 has identified a need for additional information about the biology of ductal keratinization in MGD as well as more detailed information about the structure and function of the lipid layer in the tear film. The powerful techniques of fluorescence, FTIR, nuclear magnetic resonance, and mass spectroscopies argue in favor of a better understanding of the composition, structure, and function of meibomian gland lipids and the lipids of the tear film. Our understanding of the age-related changes and changes occurring with disease will increase our ability to manage and treat the disease.