Dry Eye Concept 7 -

VICIOUS CIRCLES

VICIOUS CIRCLES are actions of pathogenetic negative factors that eventually act BACK onto themselves.

VICIOUS CIRCLES are not new in Dry Eye Disease and Members of the Ocular Surface Center Berlin (OSCB) have frequently suggested Vicious Circles in Concepts for Dry Eye Disease in various publications.(please see the little collection above, dating back to the year 2000).

Pathogenetic amplification loops termed Vicious Circles often have interposed further factors before they act back. Vicious circles are thus not always immediately detectable.

EFFECT of VICIOUS CIRCLES

=> By vicious circles a pathological process is amplified and progresses, gets worse and tends to perpetuate if it is not interrupted by suitable and timely therapeutic intervention.

It is an aim of this homepage to spread the knowledge of ocular surface disease and its important disease mechanisms in order to promote a timely diagnosis and therapy.

Vicious Circles are often over-simplified

When people had adopted the idea of Vicious Circles in Dry Eye Disease, as e.g. in the DEWS Workshop Report 2007, the concept was put in an over-simplified and thus misleading way as one large single Vicious Circle.

However, the idea of a single vicious circle is misleading - it is half true and half wrong ... such ideas usually cause most problems.

• it is right that Dry Eye Disease indeed has amplification mechanisms that perpetuate the disease process.
• but it is wrong and misleading that there is one single vicious circle - because this implies the misleading suggestion that therapy can interfere anywhere in this proposed circle ... and will still always successfully interrupt the disease process in Dry Eye.

The latter is obviously wrong ... as the experience in patients with Dry Eye Disease has shown over the years !

Vicious circles in Dry Eye Disease must be carefully identified in the individual patient - in order to find an effective therapy

When we think for example of Lipid Deficiency due to Meibomian Gland Dysfunction, that turned out to be the most frequent type of Dry Eye Disease it becomes obvious, that it actually does matter

• whether these patients use aqueous tear substitution which will conceivably quickly evaporate together with the patient´s own aqueous tears - because the evaporation limiting lipids are missing
  • OR
• whether tear film deficiencyis substituted what is missing - which is lipids in this case- and thereby a patho-physiologically adequate therapy option is applied that will conceivably be more effective

several, Different, interacting, Vicious Circles OCCUR in Dry Eye Disease - that were hitherto not recognized,

Members of the Ocular Surface Center Berlin (OSCB) have identified several different and interacting Vicious Circles in Dry Eye Disease - not just one as frequently assumed.

Vicious Circles do not necessarily depend on inflammation, even though inflammation, as a mighty cell biological process, gives rise to many of them.

Members of the Ocular Surface Center Berlin (OSCB) could identify several different interacting vicious circles in tissue and tears during Dry Eye Disease.

Vicious Circles "drive" the disease process - they are ´Patho-Physiology in a move´ and represent the dynamics that the practical clinical course of Dry Eye Disease in fact has.

In order to make these DYNAMICS IN DISEASE understandable - DYNAMIC VISUALIZATION tools such as the ANIMATIONS used here on the Internet pages of the Ocular Surface Center Berlin (OSCB) are superior in many aspects to ordinary static representations and diagrams.

Exact Identification of the different Vicious Circles and their interaction in the individual patient is essential for an effective therapy

It is important to be aware of the different Vicious Circles and their interactions in order to understand Dry Eye Disease and its progression sufficiently.

Understanding of the vicious circles that are active in an individual patient is important for an effective therapy - which is a notorious cardinal problem in Dry Eye Disease as we know !

One important Vicious Circle links the two Primary Pathologies of Tear Deficiency and Surface Damage

This makes the two primary pathologies closely interrelated and is based on the facts that:

• TEAR FILM DEFICIENCY induces Surface Damage through Chronic Mechanical Friction and/or Hyper-osmolarity
  • ... and in return ...
• SURFACE DAMAGE reinforces Tear Film Deficiency  -
  • because dry spots on the surface with loss of microvilli and mucus further deteriorate the wettability of the epithelial cell surface and thus the tear film stability
• ... and so on ...

The Dysfunction of the Ocular GLANDS in Dry Eye Disease proceeds in large Vicious Circles that constitute PATHOLOGICAL CAROUSELS of GLAND Dysregulation

The Surface Tissue Damage that occurs in Dry Eye Disease and proceeds via a sequence of secondary pathogenic factors - with chronic mucosal inflammation as a major amplifying factor -  also involves the tissue of the ocular GLANDS.

The ocular GLANDS are an integral part of the ocular surface (for details please see the chapter ´Anatomical Unit´) , like the main and accessory lacrimal glands and the Goblet cells of the conjunctiva. The Meibomian glands are only separated from the conjunctival sac by the conjunctival tissue itself - for details, please see the section ´Ocular Surface´.

Inflammation-dependent Vicious Circles in the Tissue booster SURFACE Damage and Progression to chronic inflammation

There are at least two clearly inflammation dependent vicious circles that occur during the pathology of Surface TISSUE DAMAGE.

Both of these Vicious Circles originate from the abnormal cell differentiation in the tissue with angiogenesis and driven by the chronic inflammation that gives rise to the corrupted tissue differentiation. Squamous metaplasia with loss of goblet cells and mucins is also, at least in part, promoted by inflammatory mediators.

The abnormal tissue cell and tissue differentiation acts in 2 Vicious Circles

• one acts back up and prevents the reparative reformation of normal morphology of the surface epithelium in dry eye disease
• the other directly feeds back to amplify inflammation, because chronic inflammation, with all its downstream pathways,
  • recruits large amounts of leukocytes and lymphocytes into the tissue from the vascular compartment and
  • corrupts the antigen presentation
  • thereby further deregulates the normal physiologic immune tolerance
  • which leads to further amplification of inflammatory process

Chronic Mucosal Inflammation of the Ocular Surface includes the Ocular Gland Tissue

Inflammatory events play a role in the Dysfunction of both main Ocular Glands - the Lacrimal Gland and the Meibomian Glands.

Lacrimal Gland Dysfunction (LGD) is the most prominent cause for Dry Eye Disease but, as now widely known, it is not the most frequent cause. Sjögren´s Syndrome, the main reason for primary LGD, is an auto-immune inflammation of this mucosa-associated gland. The more frequent sensory nerve impairment occurs as a secondary phenomenon mainly due to inflammatory events at the ocular surface. 

Meibomian Gland Dysfunction (MGD) is also promoted by inflammatory events of different kind that integrate MGD into the Vicious Circles of the ´Pathological Carousels´ of Gland Destruction - please see below.

• A major concept for understanding of aqueous Tear deficiency is sensory nerve impairment due to InflAmmation

A major concept for understanding of the ´typical´ ´ordinary´ aqueous tear deficiency due to LGD in Dry Eye Disease is

• an afferent sensory nerve fiber impairment
  • that is thought to occur due to ongoing inflammatory processes at the bulbar surface (cornea and conjunctiva)
• that leads to impairment of the neural reflex arc (via the cranial nerves V and VII) for driving the secretion of the lacrimal gland
• and will thus lead to dysfunction of the dependent efferent secreto-motor innervation to the lacrimal gland

  • as explained in two seminal papers by Mike Stern, Steven Pflugfelder and colleagues

The underlying reason for such ocular surface inflammation may be:

• either due to a primary disease of the Lacrimal gland such as Sjögren´s Syndrome or to viral infection such as e.g. by Epstein-Bar Virus
• or secondary due to any other condition that may lead to onset of an inflammatory chronic Dry Eye Disease. This can occur secondary to MGD, to systemic disease, to impairment of regulatory systems and to environmental risk factors - as explained in the ´Overview on Dry Eye Disease´. 

Meibomian Gland Dysfunction (MGD) depends at least in part on inflammatory events

In Meibomian Gland Dysfunction (MGD) at least parts of the pathology also depend on inflammatory events.

Inflammatory events in MGD, at some difference to the lacrimal gland, seem to be mainly subclinical

• which is supported by the observation in the available histological investigations that lymphoid cells do typically not occur.
• Some evidence from confocal investigations, which however have a very limited resolution in this respect, seem to indicate that inflammatory cells may sometimes be involved in the pathology.

An important concept for the understanding of MEIBOMIAN GLAND DYSFUNCTION is Obstruction

An important concept for the understanding of MEIBOMIAN GLAND DYSFUNCTION is Obstruction of the terminal duct and orifice of the Meibomian Gland due to mainly 2 factors:

• INCREASED VISCOSITY of the Meibomian lipid secretum
  • conceivably due to the influence of metabolic products such as lipolytic enzymes
  • produced by an increased colonization with the normal commensal bacterial species
  • together with
• INCREASED EPITHELIAL KERATINIZATION (termed hyper-keratinization) due to
  • irritant lipid species or bacterial products or
  • soluble inflammatory mediators produce in the gland during sub-clinical inflammation
  • the influences of age
  • a lack of sufficient androgen sex hormone levels
  • or potential other factors

Meibomian Gland Dysfunction (MGD) seems to be negatively influenced inflammatory and/or friction effects

• by chronic mechanical irritation in contact lens wear because long-term contact lens wear leads to a distinct reduction of the gland tissue by disappearance (drop-out).
• by chronic inflammatory Ocular Allergy which is largely affecting the tarsal conjunctiva where the Meibomian glands are located. This has a similar negative effect on the glands. 

  • as observed by Arita and colleagues

• I may therefore be concluded that
  • mechanical and inflammatory stimuli both reach the Meibomian Glands, either by direct translation of mechanic friction to the glands, or by the diffusion of soluble inflammatory mediators through the conjunctiva
  • since chronic mechanical irritation can lead, via activation of the the epithelial cells, to production of inflammatory mediators the stimulus on the Meibomian glands may in both cases be due to the diffusion of soluble inflammatory mediators

The progression of Dry Eye is Promoted by Gland Dysregulation -  driven by Vicious Circles that form PATHOLOGICAL CAROUSELS

It is evident, that the progression of pathology in the glands affects and drives the disease process in Dry Eye Disease - on the other hand inflammation of the conjunctival surface will impair the innervation and thus promote Gland Dysregulation. This constitutes a Vicious Circle

• It must be assumed, that a progression of pathology by the described sequences of secondary pathogenetic factors, i.e. cell activation, inflammation, progressive tissue destruction and loss of function, also applies to the ocular gland tissue and propagates the disease process inside the glands
• the progression and worsening of disease in the glands would certainly negatively influence the function of the ocular surface which mainly serves, as described above, for the maintenance of moisture - and thus a LACK of Secretion was identified as one of the two basic causative factors for Dry Eye Disease.
• it must therefore be concluded that the described interaction between the "surface´, of conjunctiva and cornea, and the associated glands acts BACK in a Vicious Circle that reinforces the disease process in both of them.

The Vicious Circles of Gland Destruction are termed as a PATHOLOGICAL CAROUSELS of Gland Destruction by members of the Ocular Surface Center Berlin. This appears to represent an important new factor in Dry Eye Disease.

tissue pathology OF the eye ball can induce pathology of the Eye LID

Pathology of the Surface TISSUE that feeds into Pathological CAROUSELS of GLAND DYSFUNCTION can further promote Pathology of the Eye LID.

Clinical Observation:

Patients with pathological conditions of the ocular surface that go along with increased mechanical friction - Dry Eye Disease and Contact Lens wear - have a high prevalence of a pathological vital stainable alteration of the epithelium of the Lid Wiper zone at the posterior lid border. This was termed LID WIPER EPITHELIOPATHY (LWE) 

• and described by Donald Korb and colleagues

• for more detailed information please see the section on the ´Lid Wiper´.

Histological Observation:

Members of the Ocular Surface Center Berlin (OSCB) could show by histological examination that frequent pathological cells occur at the epithelial surface in Lid Wiper Epitheliopathy (LEW) and in such zones were less Goblet cells than typical for the Lid Wiper and necessary there as a buit-in lubrication system.

Pathology of the Lid Wiper is linked via a Vicious Circle to pathology of the bulbar surface ... and reverse  

It must therefore be assumed that patients with epithelial lid border defects in LWE and consequent reduced lubrication

• will have decreased adherence of the aqueous tear film and
• this will exert an increased friction on the epithelium of the cornea and conjunctiva over which it travels more than accumulated 100 meters a day
• this will induce or amplify mechanical alteration of the bulbar epithelium

The described interaction of Bulbar Surface and Lid Wiper constitutes another VICIOUS CIRCLE

• tissue pathology at the eye ball is
• translated into the ocular glands
  • by the above described pathological carousels of gland dysfunction and
• eventually is translated into lid wiper epithelium of the posterior lid border
• from where is acts BACK, as characteristic for vicious circles, onto the eye ball  

NEXT we will look for THERAPY of Dry Eye Disease and will start with BASICS for THERAPY