Transdermal anti-inflammatory therapy for aqueous deficiency.

PURPOSE: Lacrimal gland inflammation has been identified as an important limitation on aqueous production and associated dry eye disease. Ocular surface inflammation in dry eye disease can be a downstream response to reduced quantities of warmer hyperosmotic aqueous being delivered from an inflamed lacrimal gland with high concentrations of inflammatory mediators. This review examines evidence which shows how topical applications of anti-inflammatory drugs have very limited access to the lacrimal gland and an associated limited capacity to increase aqueous flow by reducing inflammation in the main lacrimal gland. RECENT FINDINGS: Using cyclosporine as an exemplar immunomodulatory drug, this review examines problems associated with the topical administration of all anti-inflammatory drugs in the treatment of dry eye disease. SUMMARY: Limited access to the lacrimal gland for topical applications and their very short on-eye residence times are compared with the therapeutic potential of prolonged therapeutic episodes that could be achieved with transdermal applications of a drug to the skin at the site of the lacrimal gland. Poor access to the lacrimal gland for topically administered drugs is a major barrier to the treatment of aqueous deficiency. While topical inflammatory drug access to the ocular surface is direct, poor access to the lacrimal gland is partly due to drop placement being downstream to the flow of aqueous (Eye Vis 2020;7:1; Eye Vis 2019;6:1). This barrier is much greater according to the degree that reflex tear flow is stimulated by irritation associated with adverse drop temperature, and/or pH and/or tonicity for example.

Could contact lens dryness discomfort symptoms sometimes have a neuropathic basis?

Symptoms of dryness discomfort in soft contact lens wearers frequently lead to discontinuation from wear. The negative influence of pre-fitting tear dysfunctions appears likely to be exacerbated by the challenges to tear homeostasis caused by contact lenses. The corneal mechanisms for symptoms in contact lens wearers are different to those for dry eye disease because the cornea is insulated by the lens from ambient conditions as well as from lid wiper friction during blinking. Symptoms of dryness discomfort might be the consequence of increased lid wiper friction during blinking when the lens front surface becomes soiled and dry and exhibits very rapid tear break up. It is possible that some cases of contact lens intolerance and discontinuation could be a function of lid wiper neuropathy. In relation to the possibility of corneal neuropathy, a stagnant post-lens tear pool with the possibility of increased concentrations of metabolic by-products, cellular debris, and bacterial exotoxins, might have the potential to disturb the corneal epithelial and sub-basal nerves. Contributions by contact lens-induced inflammation to any neuropathic changes may partly depend on the degree to which inflammatory mediators are concentrated in a stagnant post-lens tear pool. It does not appear to be known if corneal neuropathic changes could develop under these conditions. The chances of neuropathic involvement may be greater if discomfort develops after a significant period of successful wear and there is a history of comorbid pain conditions. Esthesiometry and in vivo confocal microscopy in discontinued contact lens wearers may support a diagnosis of contact lens-related corneal neuralgia.

Why the symptoms and objective signs of dry eye disease may not correlate.

Cases of dry eye disease involving a neuropathic basis for symptoms and a poor correlation between symptoms and objective signs of dry eye disease can be associated with unsatisfactory responses to treatments which are limited to attempts to restore lacrimal function unit deficiencies. This review examines a wider range of circumstances under which the same kind of poor correlation between signs, symptoms and treatment results can be found. Some cases of computer vision syndrome can present for examination at times when objective signs related to reported symptoms have dissipated. A thorough history should explain this type of presentation for which symptoms might otherwise appear to be unexplained. However, mental health disorders can also be the basis for apparently unexplained levels of symptoms of dry eye disease. Anxiety, depression, hypochondriasis, stress, sleep and mood disorders as well as neuroticism for example, may be associated with exacerbation of symptoms to degrees that are not consistent with the levels of tear homeostasis anomalies that are assessed. The conclusion is drawn that failure to consider mental health comorbidities may result in symptomatic patients being exposed to less successful attempts to remediate tear dysfunctions when, for example, the symptoms have a somatic basis. Appropriate screening and referral to a psychologist or psychiatrist may be the key to managing some patients whose symptoms do not correlate with objective evidence of dry eye disease.

Aqueous deficiency is a contributor to evaporation-related dry eye disease.

Dry eye disease aetiologies can be classified dichotomously into aqueous deficient and evaporative types although many cases involve combinations of both. Differential diagnosis can be confounded by some features of dry eye disease being common to both aetiologies. For example, short tear break-up times are prime diagnostic findings of tear instability due to lipid and/or mucin deficiencies, but thin tear layers in aqueous deficient eyes also shorten tear break-up times, even at normal range rates of evaporation in eyes without lipid and/or mucin deficiencies. Because tear instability and short tear film break-up times due to thin tear layers can be independent of lipid and/or mucin deficiency, aqueous deficiency can be another form of evaporation-related dry eye. Conversely, tear layers which are thickened by punctal occlusion can be less susceptible to tear break-up. An inflamed lacrimal gland producing reduced quantities of warmer tears can be a basis for thin tear layers and tear instability demonstrated by shorter tear break-up times. Commonly used clinical tests for aqueous deficiency can be unreliable and less sensitive. Consequently, failure to detect or confirm aqueous deficiency as a contributor to short tear break-up times could result in too much weight being given to a diagnosis of meibomian gland deficiency. Less successful treatment outcomes may be a consequence of failing to detect aqueous deficiency. Refining disease classification by considering aqueous deficiency as a contributor to, or even a form of evaporation-related dry eye, could be the basis for more comprehensive and appropriate treatment strategies. For example, some treatment methods for evaporation-related dry eye might be appropriate for aqueous and mucin-deficient as well as lipid-deficient dry eyes. Anti-inflammatory treatment for the lacrimal gland as well as the conjunctiva, may result in increased aqueous production, reduced tear temperature, tear instability and evaporation rates as well as lower osmolarity.

The clinical and experimental significance of blinking behavior.

Evaluations of tear functions frequently involve some form of voluntary control over blink behaviour. To the degree that voluntary control of blinking risks departure from normal-range spontaneous blinking, the tear function findings from such studies may be confounded. Even subject awareness that blinking is being assessed may influence findings if such awareness results in any degree of voluntary control. Ideally, the influence on blink rate and tear functions induced by therapeutic or experimental interventions could be measured against a normal-range baseline spontaneous blink rate in order that any differences found could be validly attributed to those interventions. Sometimes pre-intervention 'rest-related' baseline blink rates have been incorrectly described as 'basal' blink rates without specification of pre-intervention conditions of 'rest' or consideration of any contributions from voluntary control. Also, studies which use only blink rates to measure blink efficiency ignore the critically important contribution of incomplete blinking to blink inefficiency. This review finds that the assessment of normal-range spontaneous blink rates depends on measurement conditions which have frequently been ignored previously. For example, normal-range spontaneous blink rates appear more likely to occur with fixation targets which have a disengaged affect and an associated neutral influence on and from dopamine activity. Ideally, fixation targets should also involve minimal cognitive loading and vision demands. In addition, normal-range (symptom free) spontaneous blink rates are more likely to be assessed in a comfortable ambient environment without subject awareness that blink behaviour is being assessed and when voluntary blinking is not involved.

Dry eye disease immune responses and topical therapy.

There is accumulating evidence that inflammation is one of the key components of dry eye because chronic ocular surface inflammation can be both a result as well as an initiator of dry eye. The need for continuing anti-inflammatory therapy may be determined in part by the extent that non-modifiable factors such as gender and age-related aqueous or lipid or mucus production deficiencies contribute to its chronicity. This perspective examines how the need for increased dosage of a topical anti-inflammatory drug may be determined by the degree of difficulty that a topically administered drug has in accessing different sites of tear deficiency and associated inflammation.

An Amplifying Cascade of Contact Lens-Related End-of-Day Hyperaemia and Dryness Symptoms.

End-of-day (EOD) symptoms of dryness are too often the cause of poor soft contact lens (SCL) tolerance and abandonment of wear. This review examines an amplifying cascade model for these symptoms, which involve thin tear layers on contact lens (CL) front surfaces being susceptible to evaporation-related short tear breakup (TBU) times. Susceptibility to faster tear loss by evaporation may be exacerbated by other forms of tear instability, such as lipid and mucin deficiencies as well as lens surface soiling. Bulbar and palpebral conjunctival hyperaemia and associated faster evaporation of warmer pre-conjunctival tears could also contribute to evaporative dry eye EOD symptoms. In CL wearers, a cascade of increasing hyperaemia toward the end of day, associated increasing tear temperature and evaporative loss, shortened TBU times (TBUTs) and increased osmolarity, all elevate the risk of higher symptom levels according to progressive amplification of this cascade. Chronic wound healing responses to SCL wear, perhaps related to limbal conjunctival trauma, stem cell deficiency and persistent epitheliopathy, as well as one or more immune responses, may contribute directly or indirectly to inflammation and the amplifying evaporative dryness cascade. A diurnal cycle that culminates in EOD symptoms appears to involve a process of recovery from causal mechanisms after lens removal, which allows lenses to be worn comfortably, at least initially the next day. Possible recovery processes are discussed in this review as are procedures that may help de-amplify an inflammatory, evaporative dryness cascade and alleviate EOD symptoms. Evidence of an accrual of adverse responses over long periods of more or less successful lens wear indicate an incremental failure to recover from EOD hyperaemia. Such incremental failure could help explain how SCL wear too often needs to be abandoned after many years of comfortable wear.

Tear instability importance, mechanisms, validity and reliability of assessment.

PURPOSE: To examine the factors which contribute to tear stability and the validity and reliability of methods used for assessing tear break up time which is a core part of an examination of tear stability in dry eye patients. METHODS: A review of publications which are relevant to tear stability and its assessment. RESULTS: Tear break up time may be more invasive than intended if difficulty avoiding blinking during assessment results in reflex tearing. Notwithstanding control of instilled volume and concentration of fluorescein, on-eye dilution is highly variable according to resident tear volume. Blinking to evenly distribute fluorescein may improve tear and lipid layer thickness so habitual tear function is not assessed. Emphasis on a role for Meibomian gland dysfunction as a cause of tear instability may be appropriate in many cases but ignores the roles for other sources of tear lipid and other non-lipid contributions to tear instability such as aqueous or mucus deficiency, desiccated epitheliopathy or anomalous blinking. Objective less-invasive methods eliminate problems of inter-observer variability and can reliably 'maintain vigilance' over wide areas of the tear layer. However less-invasive results to date include mean tear break up findings which are both shorter and longer than expected for normal controls. CONCLUSIONS: Fluorescein tear break up time assessments cannot be standardised and less-invasive methods are not yet standardised. Objective less-invasive and subjective fluorescein break up time tests do not appear to be measuring the same tear phenomena although both should be performed before other invasive procedures.

Conjunctival Tear Layer Temperature, Evaporation, Hyperosmolarity, Inflammation, Hyperemia, Tissue Damage, and Symptoms: A Review of an Amplifying Cascade.

PURPOSE: This review examines the evidence for and significance of pre-conjunctival tear temperature being higher than central pre-corneal temperature with associated more rapid evaporation of warmer pre-conjunctival tears in normal eyes but especially in hyperemic dry eye disease. METHODS: PubMed searches using the terms "evaporative dry eye," "conjunctival tear evaporation," "tear evaporation," and "dry eye conjunctival hyperemia" indicated 157, 49, 309, and 96 potentially relevant papers, respectively. Selections from these lists were the basis for examining the significance of the evidence relevant to pre-conjunctival tear layer temperature and evaporation. RESULTS: There is evidence supporting an amplifying inflammatory and para-inflammatory hyperemia dry eye cascade, which increases pre-conjunctival tear temperature and the risk of accelerated pre-conjunctival tear evaporation with exacerbated osmolarity elevation and inflammation. Dry eye cascade amplification is consistent with increases in symptoms and inflammatory as well as para-inflammatory hyperemia toward the end of the waking day. Apart from age-related conjunctivochalasis, dry eye-related conjunctival epithelial cell pathology including reduced goblet cell numbers and associated mucin deficiency, squamous metaplasia, and increased separation of cell layers could help to destabilize tears and facilitate evaporation as part of an amplifying cascade. CONCLUSIONS: Greater difficulty in assessing conjunctival tear break up may contribute to an underestimation of a role for faster evaporation of pre-conjunctival tears in dry eye disease and help explain any non-correspondence between symptoms and corneal signs of dry eye disease. Success with anti-inflammatory therapies for dry eye disease may be at least partly due to reductions in conjunctival hyperemia and deamplification of evaporative cascades. Conjunctival inflammatory hyperemia in other diseases may contribute to accelerated pre-conjunctival tear evaporation and the risk of tear-deficiency- associated exacerbation of those diseases including impaired responses to therapeutic approaches to them. Similarly, postsurgical conjunctival inflammation and associated acceleration of tear evaporation could contribute to delayed wound healing.