"The definition and classification of dry eye disease: report of the Definition and Classification Subcommittee of the International Dry Eye WorkShop"

The Ocular Surface 2007;5(2):75-92. PMID# 17508116

DEWS: Dry Eye WorkShop 2007

The goals of the DEWS Definition and Classification Subcommittee were to develop a contemporary definition of dry eye disease and to develop a three-part classification of dry eye, based on etiology, mechanisms, and disease stage.

Dry Eye Definition:

1995: Dry eye is a disorder of the tear film due to tear deficiency or excessive evaporation, which causes damage to the interpalpebral ocular surface and is associated with symptoms of ocular discomfort

2007: Dry eye is a multifactorial disease of the tears and ocular surface that results in symptoms of discomfort, visual disturbance, and tear film instability with potential damage to the ocular surface. It is accompanied by increased osmolarity of the tear film and inflammation of the ocular surface.

Dry eye is recognized as a disturbance of the Lacrimal Functional Unit (LFU), an integrated system comprising the lacrimal glands, ocular surface (cornea, conjunctiva and meibomian glands) and lids, and the sensory and motor nerves that connect them

Trigeminal sensory fibers arising from the ocular surface run to the superior salivary nucleus in the pons, from whence efferent fibers pass, in the nervus intermedius, to the pterygopalatine ganglion. Here, postganglionic fibers arise, which terminate in the lacrimal gland, nasopharynx, and vessels of the orbit.
Another neural pathway controls the blink reflex, via trigeminal afferents and the somatic efferent fibers of the seventh cranial nerve. Higher centers feed into the brainstem nuclei, and there is a rich sympathetic supply to the epithelia and vasculature of the glands and ocular surface

This functional unit controls the major components of the tear film in a regulated fashion and responds to environmental, endocrinological, and cortical influences

The corneal and conjunctival epithelia are in continuity, through ductal epithelia, with the acinar epithelia of the main and accessory lacrimal glands and the meibomian glands, which themselves arise as specialized invaginations from the ocular surface. This broader concept, which has additional features, has been termed the Ocular Surface System

An important aspect of the unit is the part played by sensory impulses, which arise from the ocular surface, in the maintenance of resting tear flow

Currently, it is considered that waking tear flow is a reflex response to afferent impulses deriving particularly, but not entirely, from the ocular surface. Sensory input from the nasal mucosa also makes a contribution

Disease or damage to any component of the LFU (the afferent sensory nerves, the efferent autonomic and motor nerves, and the tear-secreting glands) can destabilize the tear film and lead to ocular surface disease that expresses itself as dry eye

Tear film stability, a hallmark of the normal eye, is threatened when the interactions between stabilizing tear film constituents are compromised by decreased tear secretion, delayed clearance, and altered tear composition

Ocular surface inflammation is a secondary consequence.

Reflex tear secretion in response to ocular irritation is envisioned as the initial compensatory mechanism, but, with time, inflammation accompanying chronic secretory dysfunction and a decrease in corneal sensation eventually compromises the reflex response and results in even greater tear film instability.

The panel proposed changing the name of dry eye disease to dysfunctional tear syndrome, suggesting that the name more accurately reflected pathophysiological events in dry eye; however, they concluded that retention of the name dry eye had much to recommend it and that its use was embedded in the literature.

There is an influence of environment on an individual’s risk of developing dry eye. The term environment is used broadly to include physiological variation between individuals (their milieu interieur), as well as the ambient conditions that they encounter (their milieu exterieur).

Milieu interiur includes:
1. Blink rate - slower blink rate increases evaporation
2. Aperature size - larger aperature leades to increased evaporatin
3. Levels of sex hormones - low androgens and high estrogens give more dry eye
***female sex and postmenopausal estrogen therapy are important risk factors for dry eye***
4. Systemic drugs - Lacrimal tear secretion is reduced by a number of systemic drugs

Milieu exterieur includes:
1. Low relative humidity - geographic location, air-conditioning, air travel, etc
2. High wind velocity
3. Video display terminal use - causes a slow blink rate
4. Upgaze

Major classes of dry eye
1. Aqueous tear-deficient dry eye (ADDE)
2. Evaportive dry eye (EYE)

ADDE
1. Sjogren's syndrome (SS) dry eye
autoimmune exocrinopathy which targets the lacrimal and salivary glands
T-cells infiltrate causing cell death and hyposecretion of tears/saliva
A. Primary SS: ADDE and dry mouth + autoantibodies
B. Secondary SS: Primary SS + autoimmune disease
2. Non-Sjogren's syndrome dry eye
lacrimal gland dysfunction (most common: age related dry eye)
A. Primary lacrimal gland deficiencies
B. Secondary lacrimal gland defeciencies
C. Obstruction of the lacrimal glands
D. Reflex hyposecretion

secondary to systemic medications: antihistamines, beta blockers, antispasmodics, and diuretics, and, with less certainty, tricyclic antidepressants, selective serotonin reuptake inhibitors, and other psychotropic drugs
ACE inhibitors - lowers the incidence of dry eye

Lacirmal gland dysfunction
causes hyperosmolarity due to tear evaporation with a reduced aqueous pool
tear hyperosmolarity leads to epithelial cell hyperosmolarity
surface epithelial cell hyperosmolarity leads to inflammation
inflammation cascade:
MAP kinases
NFkB signalling pathways
inflammatory cytokines
interleukin (IL)-1A
interleukin (IL)-1B
tumor necrosis factor (TNF)-A
matrix metalloproteinases (MMP-9)
Conjunctiva water secretion dysfunction (not as common)

EDE - Evaportive Dry Eye
Excessive water loss with normal lacrimal function
1. Intrinsic conditions - lids and ocular surface (lid structure or dynamics)
A. Meibomian Gland Dysfunction (MGD) or posterior blepharitis
-meibomian gland obstruction
-most common cause of evaportive dry eye
-accutane or isotretinoin can cause a reversible MG atrophy
B. Disorders of the lid/globe
-increased palpebral fissure width
whether from disease or anatomical
more surface area/evaporation
-upgaze
-poor lid apposition or lid deformity
C. Low Blink Rate
-parkinson's (proportional to disease severity)
1. reduced blink rate (poor lipid delivery, no removal of bad lipid-mucin)
2. low levels of androgens--affect lacrimal and MG function
3. decrease reflex tearing in PD (autonomic dysfunction)
-looking at microscope or computer while concentrating

2. Extrinsic conditions - outside factors/exposure
A. Ocular surface disorders
*Vitamin A deficiency (xerophthalmia dry eye due to vit A defeciency)
vit A needed for goblet cells development
vit A needed for expression of glycocalyx
can cause lacimal acinar damage
*topical Drugs and Perservatives
BAC - benzalkonium chloride
surface epithelial cell damage and PEE
common cause of dry eye in glaucoma patients
B. Contact Lens Wear - 50% of all wearers report dry eye symptoms
*pre-lens tear film thinning time - correlated to pre-lens lipid layer thinning
*poor lens wettability - higher evaporative loss
*high water content - more dry eye

The surface wetting ability of the CL materials was the same, regardless of special surface lens treatments.

Efron et al found that patients wearing low water CLs, which maintained their hydration, were free from symptoms

However, other studies reported no correlation between CL hydration and dry eye symptoms and no relationship between lens hydration and tear film thinning time and dry eye symptoms or evaporative water loss.

Symptoms (using the McMonnies Dry Eye Questionnaire), non-invasive tear break up time (NITFBUT), and tear meniscus height predicted potential CL intolerant subjects with high accuracy

Contrast sensitivity in soft CL wearers is significantly reduced in the middle-to-high spatial frequencies, when the precorneal lens tear film dries and causing breakup.

C. Ocular Surface Disease
-loss of goblet cell numbers
D. Allergic Conjunctivitis
-seasonal, vernal, atopic
-antigen, degranulation of IgE-primed mast cells--release of inflammatory cytokines
-a Th2 response is activated at the ocular surface (conj and cornea)
-loss of surface membrane mucines, surface epithelial cell death (conj and cornea)
-allergic symptoms and reflex tearing/lacrimal gland stimulation

tear hyperosmolarity and tear film instability: the core mechanisms at the center of the dry eye process that can initiate, amplify, and potentially change the character of dry eye over time.

Tear hyperosmolarity
regarded as the central mechanism causing ocular surface inflammation, damage, and symptoms, and the initiation of compensatory events in dry eye.
Tear hyperosmolarity arises as a result of water evaporation from the exposed ocular surface, in situations of a low aqueous tear flow, or as a result of excessive evaporation, or a combination of these events
There is evidence that these inflammatory events lead to apoptotic death of surface epithelial cells, including goblet cells; thus, goblet cell loss may be seen to be directly related to the effects of chronic inflammation and therefore reduced levels of gel mucin MUC5AC in dry eye
corneal sensitivity is impaired in chronic dry eye disease, suggesting that an initial period of increased reflex sensory activity is followed by a chronic period of reduced sensory input
the result of the longterm effects of inflammatory mediators on sensory nerve terminals supplying the ocular surface
the reflex sensory drive to lacrimal secretion becomes reduced--causing worse dry eye

Tear film instability

tear film instability in the form of early tear film break up may readily be accepted as a component of dry eye
causative agents: xeropththalmia, allergic disease, toxicity 2' preservatives, CL wear

Dry eye symptoms, possible causes:
tear and ocular surface hyperosmolarity – including tear film break-up in the interblink, shear-stress between the lids and globe in response to reduced tear volume, and/or the reduced expression of mucins at the ocular surface, the presence of inflammatory mediators at the surface of the eye, and, finally, hypersensitivity of the nociceptive sensory nerves.