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

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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.

The clinical and experimental significance of blinking behavior / Significado clínico y experimental del comportamiento del parpadeo

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

Las valoraciones de las funciones de la lágrima incluyen alguna forma de control voluntario del parpadeo. Hasta el punto de que el control voluntario del parpadeo puede tener su origen en el parpadeo espontáneo de rango normal, los hallazgos sobre función de la lágrima de dichos estudios pueden resultar confusos. Incluso la concienciación del sujeto acerca de que se está evaluando el parpadeo puede influir en los hallazgos, cuando dicha concienciación deriva en cualquier grado de control voluntario. De forma ideal, la influencia sobre las tasas de parpadeo y las funciones de la lágrima inducidas por intervenciones terapéuticas o experimentales podría medirse frente a una tasa de parpadeo espontáneo basal de rango normal, a fin de poder atribuir válidamente cualesquiera diferencias a dichas intervenciones. A veces, las tasas de parpadeo de referencia "relacionadas con el descanso" pre-intervención se han descrito incorrectamente como tasas de parpadeo "basal", sin especificar las condiciones "de descanso" pre-intervención, o la consideración de cualquier contribución del control voluntario. De igual modo, los estudios que utilizan únicamente tasas de parpadeo para medir la eficiencia del parpadeo, ignoran la contribución críticamente importante del parpadeo incompleto sobre la ineficiencia del mismo. Esta revisión encuentra que la valoración de las tasas de parpadeo espontáneo de rango normal depende de las condiciones de medición, que con frecuencia han sido ignoradas previamente. Por ejemplo, es más probable que se produzcan tasas de parpadeo espontáneo de rango normal con objetivos de fijación, que tienen un efecto de desactivación y una influencia neutra asociada sobre la actividad de la dopamina. De manera ideal, los objetivos de fijación deberían implicar también una carga cognitiva mínima y unas demandas de visión. Además, es más probable que las tasas de parpadeo espontáneo de rango normal (con ausencia de síntomas) se valoren en un entorno confortable, sin que el sujeto sea consciente de que se está valorando el parpadeo, y cuando el parpadeo voluntario no se ve implicado

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.

Tear instability importance, mechanisms, validity and reliability of assessment / Importancia, mecanismos, validez y fiabilidad de la evaluación de la inestabilidad de la lágrima

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

Objetivo: Examinar los factores que contribuyen a la estabilidad de la lágrima y a la validez y fiabilidad de los métodos utilizados para evaluar el tiempo de ruptura lagrimal, que forma parte esencial del examen de la estabilidad de la lágrima en los pacientes con ojo seco. Métodos: Revisión y evaluación de las publicaciones relevantes en cuanto a estabilidad de la lágrima. Resultados: La evaluación del tiempo de ruptura lagrimal puede ser más invasiva de lo previsto cuando la dificultad para evitar el parpadeo durante la evaluación origina un lagrimeo reflejo. No obstante el control del volumen instilado y la concentración de fluoresceína, la dilución en el ojo es altamente variable en función del volumen lagrimal residente. El parpadeo para distribuir uniformemente la fluoresceína puede mejorar la lágrima y el espesor de la capa lipídica, por lo que la función lagrimal habitual no se evalúa. Enfatizar el papel de la disfunción de la glándula de Meibomio como causa de la inestabilidad de la lágrima puede ser adecuado en muchos casos, pero ignora el papel de otras fuentes de lípidos lagrimales y las contribuciones no lipídicas a la inestabilidad de la lágrima tales como la deficiencia acuosa o mucosa, la epiteliopatía por sequedad o el parpadeo anómalo. Los métodos objetivos menos invasivos eliminan los problemas de variabilidad inter-observador, y pueden' mantener la vigilancia' fidedignamente sobre otras grandes áreas de la capa lagrimal. Sin embargo, hasta la fecha los resultados menos invasivos conllevan hallazgos sobre el tiempo de ruptura lagrimal medio que pueden ser más breves y más prolongados de lo esperado en los controles normales. Conclusiones: No pueden estandarizarse las evaluaciones del tiempo de ruptura lagrimal con fluoresceína, y aún no se han estandarizado métodos menos invasivos. No parece que las pruebas menos invasivas de evaluación objetiva y subjetiva del tiempo de ruptura con fluoresceína midan los mismos fenómenos lagrimales, aunque ambas pruebas deberán realizarse previamente a otros procedimientos invasivos

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.

Reactive oxygen species, oxidative stress, glaucoma and hyperbaric oxygen therapy / Especies reactivas de oxígeno, estrés oxidativo, glaucoma y terapia de oxígeno hiperbárico

This review examines the role of oxidative stress in damage to cells of the trabecular meshwork and associated impaired aqueous drainage as well as damage to retinal ganglion cells and associated visual field losses. Consideration is given to the interaction between vascular and mechanical explanations for pathological changes in glaucoma. For example, elevated intraocular pressure (IOP) forces may contribute to ischaemia but there is increasing evidence that altered blood flow in a wider sense is also involved. Both vascular and mechanical theories are involved through fluctuations in intraocular pressure and dysregulation of blood flow. Retinal function is very sensitive to changes in haemoglobin oxygen concentration and the associated variations in the production of reactive oxygen species. Reperfusion injury and production of reactive oxygen species occurs when IOP is elevated or blood pressure is low and beyond the capacity for blood flow autoregulation to maintain appropriate oxygen concentration. Activities such as those associated with postural changes, muscular effort, eye wiping and rubbing which cause IOP fluctuation, may have significant vascular, mechanical, reperfusion and oxidative stress consequences. Hyperbaric oxygen therapy exposes the eye to increased oxygen concentration and the risk of oxidative damage in susceptible individuals. However, oxygen concentration in aqueous humour, and the risk of damage to trabecular meshwork cells may be greater if hyperbaric oxygen is delivered by a hood which exposes the anterior ocular surface to higher than normal oxygen levels. Oronasal mask delivery of hyperbaric oxygen therapy appears to be indicated in these cases (AU)

Esta revisión examina el papel del estrés oxidativo en el daño celular de la red trabecular, la disfunción del drenaje acuoso, así como las lesiones de las células ganglionares de la retina y las pérdidas de campo visual asociadas. Se tiene en cuenta la interacción entre las explicaciones a los cambios patológicos en el glaucoma, desde el punto de vista vascular y mecánico. Por ejemplo, la elevación de las fuerzas de la presión intraocular (PIO) puede contribuir a la isquemia, aunque existe evidencia creciente de que también está implicada la alteración del flujo sanguíneo, en un sentido más amplio. También están implicadas las teorías vasculares y mecánicas a través de las fluctuaciones de la PIO y la desregulación del flujo sanguíneo. La función de la retina es muy sensible a los cambios de la concentración de oxígeno en la hemoglobina y a las variaciones asociadas a la producción de especies reactivas de oxígeno. Las lesiones por reperfusión y la producción de especies reactivas de oxígeno se producen cuando la PIO es elevada o cuando la presión sanguínea es baja, y sobrepasa la capacidad de autoregulación del flujo sanguíneo para mantener la concentración de oxígeno adecuada. Las actividades tales como las asociadas a cambios posturales, esfuerzo muscular, lavado y frotamiento de ojos, que causan fluctuación de la PIO, pueden tener repercusiones considerables de tipo vascular y mecánico, y de reperfusión y estrés oxidativo. La terapia de oxígeno hiperbárico expone al ojo a un incremento de la concentración de oxígeno y al riesgo de daño oxidativo en individuos susceptibles. Sin embargo, la concentración de oxígeno en el humour acuoso y el riesgo de lesiones de las células de la red trabecular pueden ser superiores cuando el oxígeno hiperbárico es liberado por una campana que expone la superficie ocular anterior a unos niveles de oxígeno más elevados de lo normal. La liberación de oxígeno hiperbárico mediante mascarilla oronasal parece más indicada en estos casos (AU)

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.

Reactive oxygen species, oxidative stress, glaucoma and hyperbaric oxygen therapy.

This review examines the role of oxidative stress in damage to cells of the trabecular meshwork and associated impaired aqueous drainage as well as damage to retinal ganglion cells and associated visual field losses. Consideration is given to the interaction between vascular and mechanical explanations for pathological changes in glaucoma. For example, elevated intraocular pressure (IOP) forces may contribute to ischaemia but there is increasing evidence that altered blood flow in a wider sense is also involved. Both vascular and mechanical theories are involved through fluctuations in intraocular pressure and dysregulation of blood flow. Retinal function is very sensitive to changes in haemoglobin oxygen concentration and the associated variations in the production of reactive oxygen species. Reperfusion injury and production of reactive oxygen species occurs when IOP is elevated or blood pressure is low and beyond the capacity for blood flow autoregulation to maintain appropriate oxygen concentration. Activities such as those associated with postural changes, muscular effort, eye wiping and rubbing which cause IOP fluctuation, may have significant vascular, mechanical, reperfusion and oxidative stress consequences. Hyperbaric oxygen therapy exposes the eye to increased oxygen concentration and the risk of oxidative damage in susceptible individuals. However, oxygen concentration in aqueous humour, and the risk of damage to trabecular meshwork cells may be greater if hyperbaric oxygen is delivered by a hood which exposes the anterior ocular surface to higher than normal oxygen levels. Oronasal mask delivery of hyperbaric oxygen therapy appears to be indicated in these cases.