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OVERVIEW on ...

MEIBOMIAN GLAND DYSFUNCTION (MGD)

 

Meibomian Gland Dysfunction (MGD)

is a mainly obstructive Dysfunction of the Lipid-producing Meibomian Glands inside the tarsal plates of the eye lids that leads to a Lack of Lipids with resulting Tear Film Deficiency and Evaporative Dry Eye Disease.

Lipid deficiency due to MGD is the main underlying primary reason for Dry Eye Disease in about four fifths of patients.

Due to the obstruction of lipid outflow from the gland, it also causes a pressure atrophy of the gland inside the eye lid with dilatation of the ductal system and atrophy of the secretory acini.

 

Meibomian Gland Dysfunction (MGD) is Subtype of Blepharitis

Meibomian Gland Dysfunction (MGD) is sub-summarized under Blepharitis as the main form of posterior blepharitis which concerns the area of the posterior lid border and is typically not overt inflammatory. Anterior blepharitis of the outer lid border and eye lid skin, in contrast, is typically overt clinical inflammatory.

Meibomian Gland Dysfunction (MGD) is a pathological condition of the Meibomian Glands inside the tarsal plates of the eye lids. MGD is sub-summarized under BLEPHARITIS - as the main type of posterior Blepharitis.

Posterior Blepharitis concerns processes at, or related to, the posterior lid border that are typically not inflammatory. At least not as an overt clinical inflammation with the cardinal signs of warming, pain, redness, swelling - Subclinical inflammatory processes, however, will certainly be present in MGD.

Anterior blepharitis in contrast, occurs at the anterior lid border and outer lid skin and typically has clear signs of inflammation.

 

MGD has an initial stage (Non-Obvious MGD - NOMGD) without symptoms that is often un-diagnosed

The initial type of MGD is asymptomatic - since it goes without symptoms. It is also clinically inconspicuous and is termed as Non-Obvious MGD (NOMGD). A high proportion of elderly individuals conceivably has NOMGD which may already lead to an unnoticed destruction of the Meibomian glands inside the eye lids due to the increased pressure inside obstructed glands.

The sub-summarization of MGD under Blepharitis has its Pros and Cons.

It is certainly of advantage because blepharitis is a frequent disorder of the outer eye and therefore well known, which may increase the clinical diagnosis of MGD.

On the other hand it is some kind of a disadvantage because the clinician expects blepharitis as an inflammatory condition whereas this is typically not the case in MGD ... which may then inhibit the diagnosis of bland MGD.

This issue becomes even more critical as in MGD one form is without symptoms but must already be assumed to cause unnoticed pathology - this is termed Non-Obvious MGD (NOMDG).

 

The initial stage of MGD - Non-Obvious MGD (NOMGD) - is without symptoms

This initial stage of MGD typically goes undetected by the patient because it does not produce symptoms of Dry Eye ...  and it is also typically undetected by the clinician because the eye lids and the lid margin appear normal.

Only when specific but easy to perform diagnostic techniques are used, easiest in the form of a ´DIAGNOSTIC´ expression at low pressure, it can be seen that no clear oil occurs at the location of the orifices ... which points to an obstruction of the respective glands.

When forceful ´THERAPEUTIC´ expression of the glands is however applied - then typically distinctly inspissated whitish to yellow-brown secretum can be expressed and the obstruction thus be verified. 

 

How can NOMGD be asymptomatic ?

The question may occur why NOMGD does not produce any symptoms when there is clear obstruction of Meibomian glands is presennt ?  This can conceivably be related to the high number of Meibomian glands, that produce a large surplus of Meibomian oil. Therefore an effective lack of oil on the tear film will only occur when so many of the glands do no longer deliver oil that the high residual capacity becomes effectively too low and thus the tear film lipid layer becomes lipid deficient. 

The concept of deposition of Meibomian oil on the lid margin was developed by BON and TIFFANY and colleagues who assume that the oil forms an oil reservoir on the lid margin from where the oil gets onto the tear film. Different amounts of oil in different conditions, that appear to support the concept, have been measured by this group.    

 

 

MGD is typically due to a Gland OBSTRUCTION with LOW oil dElivery - but there are also other types of MGD

  The Meibomian Glands can have different types of pathology  that are differentiated easiest into  High vs. Low  Delivery   Conditions. In both cases this can be   either   due to the  secretion rate  of the secretory acini deep in the tissue   or   due to influences on the  amount of delivery  out of the gland onto the lid margin, typically by obstruction. Other influences on the secretum can possibly occur inside the ductal system, as e.g. inflammation and bacterial colonization, and may influence the amount of delivery. The  most frequent condition  is  Low Delivery    Obstructive  MGD  by  Blocking of the Terminal Duct   and Orifice  (top in right diagram)whereas the secretion rate of the acini appears to remain normal.

The Meibomian Glands can have different types of pathology that are differentiated easiest into High vs. Low Delivery Conditions. In both cases this can be either due to the secretion rate of the secretory acini deep in the tissue or due to influences on the amount of delivery out of the gland onto the lid margin, typically by obstruction. Other influences on the secretum can possibly occur inside the ductal system, as e.g. inflammation and bacterial colonization, and may influence the amount of delivery. The most frequent condition is Low Delivery Obstructive MGD by Blocking of the Terminal Duct and Orifice (top in right diagram)whereas the secretion rate of the acini appears to remain normal.

The pathologies of the Meibomian glands were historically often described as processes where masses of purulent excreta were produced by the glands and/ or could be expressed onto the lid margin. This points to a HIGH DELIVERY Type of MGD. also termed as ´Meibomian Seborrhea´ which may very well encompass infections of the Meibomian Glands or at least severe colonization with the commensal lid margin microbes - resulting in pus mixed with Meibomian Lipids .

Hyper-Secretory MGD, is a type where the high delivery ofsecretum is indeed based on increased lipid secretion. It is often associated with skin disease such as seborrheic dermatitis or Rosacea. A nice overview on MGD can be found in an article by FOLKS and BRON 2003. In certain regions of the world, e.g. in Korea, hyper-secretory MGD is apparently relatively frequent ( ... personal communication)

More frequent in general is the LOW DELIVERY Type of MGD where, as the term indicates, less oily Meibomian secretum is delivered onto the lid margin. The terms of the different MGD types refer to "Delivery" instead of "Secretion"/Production because these two issues occur separated in the Meibomian Gland due its long shape where both processes occur in different places that are relatively far apart - for more detailed information please see ´Overview on Meibomian Gland´.

 

Obstructive MGD results in LOW DELIVERY of OIL and in Destruction of the Gland Structure

In contrast to the schematic morphology of a normal Meibomian gland (right side) an OBSTRUCTED gland in MGD (left side) typically has signs of dilatation of the ducts and an atrophic destruction of the secretory acini due to the increased pressure inside the blocked gland that can not get out its oily secretum.

In both cases of LOW vs. HIGH Delivery it is a question whether the amount of delivered secretum is indeed equivalent to the production, i.e. secretion rate.

The fact that in the most frequent obstructive type of MGD, typically a dilatation of the ductal system occurs together with an atrophic pressure atrophy of the secretory acini points to the suggestion that both of these pathologies may be caused by a continuing (normal) rate of secretion ... which then gradually induces an increased pressure inside the gland and a pressure atrophy of the tissue. The supposed patho-mechanism is schematically shown in the animation at the bottom of this page.

Therefore at least in obstructive MGD the amount of delivery is not equivalent to the rate of secretion. Low-Delivery MGD is conceivably based on low secretion rate of the acini and may be due to the influence of Regulatory Systems that influence the activity of tissue differentiation and secretory activity, which is in the Meibomian glands mainly based on the division of basal cells and the velocity of maturation.

 

OBSTRUCTIVE MGD is typically caused by two Pathogenetic Factors - Hyperkeratinization and Increased Viscosity of Lipids

The pathology of the Meibomian Glands can be derived from characteristics of the anatomical structure that predispose the glands for certain types of pathology: 

The DUCTAL SYSTEM has long ducts and narrow lumina - with a risk for OBSTRUCTION

  • Compared to the size of the globular acini where the lipid secretum is produced by disruption of the whole secretory cells - the DUCTAL SYSTEM is
    • (1) relatively long and
    • (2) the ducts are relatively narrow
      • particularly the terminal excretory duct, shortly before the opening onto the lid margin, is the narrowest part.
    • (3) the ductal system has signs of incipient cornification, in addition to the relatively limited narrow lumina

 

The terminal duct of the Meibomian glands is an ingrowth of the cornified surface epithelium. The wall of the Meibomian orifice (open arrow) therefore consists of fully cornified epidermis with luminal anuclear keratin squames. The shed epitheliallamellae are typically located inside the lumen of the orifice and can easily obstruct it when additional factors occur, such as Meibomian Lipids with increased melting point.

KERATINIZATION of the Ductal System is a RISK FACTOR for Gland Obstruction

  • The EPITHELIAL WALL of the Excretory Duct and ORIFICE
    • consists of fully cornified epidermis with luminal anuclear keratin lamellae/ squames that are shed into the lumen
    • this occurs in the region of the terminal duct, shortly before the orifice, which is the narrowest part of the ductal system
    • because it is an ingrowth of the surface epidermis from the free lid margin into the gland (please see image)
  • The EPITHELIAL WALL of the DUCTS
    • the rest of the ductal system shows signs of an incipient keratinization in the form of small keratohyaline granules
      • which is probably no surprise because the embryological development of the Meibomian glands has many similarities with that of the fully cornified ciliary hairs
    • This indicates that the whole ductal system has an inherent tendency to increased keratinization and is prone to cornification upon any suitable stimulus, such as e.g. inflammatory mediators or androgen deficiency.

 

INCREASED VISCOSITY of the Meibomian Lipids is another RISK FACTOR for Gland Obstruction

  • The Lipid SECRETUM that the acini produce
    • consists of different types of lipids that all have a different melting point.
    • normally the lipids are liquid so that the secretum is an oil and can flow freely within the ductal system
    • BUT ... the summarized melting points of the mixture of lipids translate into a melting zone that lies only a few degrees centigrade under the temperature of the eye lids and lid margin - as detailed in an article by John TIFFANY
    • THUS only a slight decrease of the ambient temperature or change in the composition of the lipids can lead to increased viscosity and solidification/ inspissation of the lipids inside the ductal system that is embedded with the rest of the gland in the tarsal plates of the eye lids.

 

 

FINDINGS in MGD verify inspissated Secretum and Hyper-Keratinization

FINDINGS in Patients with MGD has verifed the presence of Meibomian Gland OBSTRUCTION by inspissated lipids mixed with keratinized cell material.

INSPISSATED SECRETUM blocks the Glands

  • Inspissated Material is observed as the obstructing material in patients with MGD
    • either still inside the terminal duct and leads to a protrusion of the orifice and its surrounding area (pouting)
    • or is already seen to reach outside as a plug (plugging)
    • typically the lipid material is mixed with keratin from Hyper-Keratinized ductal epithelium
    • This was already shown in the first study that identified MGD and in contact lens wearers and introduced the term Meibomian Gland Dysfunction in the title of a publication by KORB and HENRIQUEZ 1980 (please see image above).
    •  

HYPER-KERATINIZATION of the Ductal System and of the Lid Margin is a typical finding in MGD

  • Keratinized material occurs inside the terminal duct and orifice
  • and often also on the lid margin, including the formation of membranes that appear to cap the Meibomian orifice and cover inspissated secretum underneath (see clinical image to the right).

 

 

 

GLAND ATROPHY in OBSTRUCTION consists of DILATATION of the Ducts and CELL LOSS of the secretory Meibocytes in the Acini

Histological Studies of the Ocular Surface Center Berlin (OSCB) have revealed some typical alterations of Meibomian Glands in MGD (right) compared to normal glands (left).  This concerns an obstruction of the orifice by keratinized material (top right) and signs of gland atrophy (bottom right). This is explained in more detail for the higher resolution image below.

The Ductal System is dilated and the epithelium compressed

Several histological studies in the literature and own investigations by members of the Ocular Surface Center Berlin (OSCB) verify (please see histologic photomicrographs to the right):

  • an obstruction of the terminal duct and orifice by cornified epithelial material
  • a dilation of the ductal system including the long central duct and also the connecting ductules to the acini
  • an atrophic destruction of the secretory acini

The ductal system is at least in parts distinctly widened and the epithelium appears compressed at the wall which clearly points to the presence of an increased pressure inside the glands.

The narrow connecting ductules are typically also dilated and often appear shortened.

 

Atrophy of the Meibomian ACINI includes a loss of secretory Meibocytes

The obstruction in MGD results, due to continuing secretion, in an increased pressure inside the gland. This leads to dilatation of the ductal system with the long central duct (cd) and the connecting ductules (de) to the acini. The epithelium appears distinctly thinned in places compared to the normal about four cell layers Increased pressure also affects the secretory cells (a). The susceptible secretory cells disappear (asterisk) and the acini transform from solidly filled cell clusters into hollow sacs (encircled) with a loss of secretory capacity. Eventually, destroyed acini with residual secretory cells can be integrated into the wall of the central duct as seen here indicated by double arrowheads on the left side of the duct.

The delicate arrangement of the secretory Meibocytes that normally completely fill the holocrine acini is rarefied and an empty space is formed in the center of the acini where the most fragile cells, shortly before their disruption, are located. Empty spaces begin to occur in the center of the acini.

In progressed atrophy the empty spaces in the acini become larger and often almost the whole acinus is replaced by a hollow sac. Only a basal layer of cells or only the epithelial basement membrane remains then. Sometimes secretory cells, that are conceivably remnants of atrophic acini, appear to be integrated into the wall of a dilated central duct.

It may be assumed that these histological findings represents the gland drop-out that is seen by the technique of Meibography where the gland morphology can be clinically visualized in the patient.

From the histological findings it becomes clear that in the obstructive glands the secretory capacity for lipid production is increasingly lost.

 

 

 

OBSTRUCTIVE MGD has at least 2 CONSEQUENCES:

The Pathomechanism of Obstructive MGD is schematically shown in this ANIMATION. In the NORMAL state the OIL is first SECRETED in an acinus and then driven towards the orifice by the secretory pressure that results from continuing secretion. In OBSTRUCTION of the terminal duct and orifice, the secreted oil can not get out of the gland to be delivered onto the lid margin - which results in a lack of oil on the tear film. The continuing secretory pressure inside the gland leads to a dilatation of the ductal system and apparently the stasis of oil in the gland pre-disposes the secretum to become inspissated. Eventually the increased pressure enters the secretory acini and destroys the secretory cells (Meibocytes).

  • A lack of lipids OUTSIDE of the glands ... on the lid margin and on the tear film resulting in
    • increased tear film stability
    • increased evaporation of the aqueous phase of tears
    • Evaporative Dry Eye Disease

 

  • An overflow of lipids INSIDE the glands ... resulting in
    • atrophic destruction of the gland tissue with
    • dilatation of the duct system
    • atrophy of the secretory acini

This is tragic because it would mean that in gland obstruction there is not only an immediate Lack of DELIVERY of lipids inside the glands ... but the obstructed glands will conceivably also loose the ability to PRODUCE/ SECRETE Lipids in the future.

 

 

It is unclear at present whether the atrophy of the Meibomian glands may be reversible

The destruction of the Meibomian glands may be reversible in principle - this is however presently unknown. In any case it would depend on whether any stem cells for the Meibocytes can survive the atrophic process.

Therefore a potential reversibility of atrophic gland destruction conceivably depends:

  • on the actual amount of PRESSURE inside the glands
    • that will in turn depend on the completeness of the obstruction.
  • another factor of importance will be the DURATION of the obstructive condition of the gland
    • this in turn points to the necessity of a timely diagnosis and therapy of Meibomian Gland Dysfunction ... which is particularly important of the first unnoticed, asymptomatic type of MGD - the Non-Obvious MGD ´NOMGD´

 

 

 

The THERAPY of Meibomian Gland Dysfunction MGD

 

LIPID TEAR SUPPLEMENTATION

 

 

PHYSICAL THERAPY

 

ANTI-INFLAMMATORY & LIPID MODIFICATION