Predicted Phenotypes of Dry Eye: Proposed Consequences of Its Natural History

This paper reviews current knowledge of the pathophysiology of dry eye and predicts that the clinical picture in late disease differs in both severity and quality from that in early disease. It is hypothesized that hybrid forms evolve, in which aqueous-deficient dry eye (ADDE) takes on features of evaporative dry eye (EDE) and vice versa. As a consequence, early and late forms may require different diagnostic criteria and respond to different therapeutic regimes. Tear hyperosmolarity plays a key role in the damage mechanism of dry eye, and ADDE is recognized to be a low-volume, hyperosmolar state. As ADDE advances, a progressive decrease in lacrimal secretion occurs, exacerbated by loss of the corneal reflex. This causes a decrease in tear volume, thinning of the aqueous tear film, and retarded spreading of the tear film lipid layer. The latter is hypothesized to cause an increase in evaporative water loss and an added evaporative component to the dry eye. Thus, in advanced disease, the hybrid state would be an organic ADDE, accompanied by a functional EDE in the absence of meibomian gland dysfunction. This functional EDE would respond to agents that expand the tear volume, restore corneal sensitivity, or provide an artificial tear film lipid layer.Conversely, we propose that in EDE, a compensatory lacrimal flow is reflexly maintained via the Lacrimal Functional Unit, by sensory drive from the ocular surface, so that EDE is initially a normal-to-high volume hyperosmolar state. It is suggested that this compensation is lost in advanced disease, as hyperosmolar and inflammatory damage reduce sensory drive. Thus, when the primary phenotype is EDE, it is predicted that with disease progression, a hybrid form evolves in which an aqueous-deficient component is added to the dry eye. The unique features of this functional ADDE are a reduced Schirmer test score with normal tear proteins of lacrimal origin. Since the lacrimal gland is envisaged to be normal in structure, it would be anticipated that the aqueous-deficient component would respond to lacrimal secretagogues in addition to agents that would expand tear volume and restore corneal sensitivity.     

干眼病理损害中的炎症机制

干眼是一种泪液和眼表的多因素性疾病,可引起眼部不适、视觉障碍、泪膜不稳定和眼表损害,并伴有泪膜渗透性升高和眼表炎症。目前研究表明,炎症在干眼的发病和病理损害中起着重要作用。本文从炎症与泪液渗透压、眼表黏蛋白表达、角结膜上皮结构及功能、泪腺及睑板腺结构和功能等方面对炎症造成干眼眼表和泪液功能损害的可能机制进行综述。     

Transgenic dry eye mouse models: powerful tools to study dry eye disease

Dry eye disease (DED) is one of the most common chronic multifactorial ocular surface diseases with high prevalence and complex pathogenesis. DED results in several ocular discomforts, vision fluctuation, and even potential damage of the ocular surface, bringing heavy burdens both on individuals and the society. The pathology of DED consists of tear film hyperosmolarity and immune responses on the ocular surface. Mice are widely used for developing models that simulate human DED features for investigating its pathogenesis and treatment. DED can be classified into aqueous-deficiency dry eye (ADDE) and evaporative dry eye (EDE). ADDE can be further divided into Sjögren syndrome dry eye (SSDE) and non-Sjögren syndrome dry eye (NSSDE). SSDE mouse models include natural strains, typified by non-obese diabetic (NOD) mice, and genetically engineered ones, like Aire-/- and Id3 knockout mice. Intrinsic EDE mainly refers to meibomian gland dysfunction (MGD). Eda-/- Tabby, Sod1-/-, Elovl1-/- are the most common transgenic MGD mouse models. Transgenic mouse models provide useful tools for studying the pathogenesis of DED and evaluating its novel therapies. This review compares the major transgenic dry eye mouse models and discusses their applications in DED research.     

Ocular surface drying and tear film osmolarity in thyroid eye disease

Five factors potentially associated with corneal exposure--palpebral fissure width, exophthalmos, blink rate, lagophthalmos, and lid lag--were evaluated in 17 patients with Graves' disease to determine which were associated with ocular surface damage. Multiple regression analysis revealed that increased palpebral fissure width and increased blink rate were both significant predictors of ocular surface damage (as measured by rose Bengal staining). Tear osmolarity and tear film break-up time were measured to determine the type of drying mechanism involved in thyroid eye disease. All eyes examined except one had blink rates adequate to prevent dry-spot formation. Fourteen of 33 eyes had abnormally high tear osmolarity. Increasing palpebral fissure width and increasing blink rate were both significant predictors of elevated osmolarity in tears obtained from the inferior marginal tear strip. We suspect that increased palpebral fissure width accelerates tear film evaporation, thus increasing tear film osmolarity with resultant ocular surface damage.     

泪液渗透压在干眼发病机制中的作用及诊疗进展

干眼是一种以眼表稳态丧失,泪膜不稳定性增加为特征的多因素疾病,伴有眼干涩、异物感、灼烧感、眼红、疼痛、畏光、流泪、眼疲劳、视力下降、分泌物增多、对外界刺激敏感等眼部症状,其病理生理机制主要是泪膜不稳定、泪液渗透压(tear osmolarity, Tosm)升高、眼表炎症和损伤及神经感觉异常。Tosm是维持泪膜稳定性和眼表舒适度的重要因素。Tosm升高可造成干眼患者眼部不适、角膜上皮损伤、杯状细胞丢失及眼部炎症反应,炎症反应可进一步降低泪膜稳定性和增加Tosm,使干眼陷入恶性循环。为了更全面地了解泪液高渗(tear hyperosmolarity, THO)与干眼的关系,本文将从病理生理学方面,重点讨论THO在干眼发病机制、干眼诊断、干眼严重程度分级中的作用,及其针对性治疗。     

Protection against corneal hyperosmolarity with soft-contact-lens wear

Hyperosmotic tear stimulates human corneal nerve endings, activates ocular immune response, and elicits dry-eye symptoms. A soft contact lens (SCL) covers the cornea preventing it from experiencing direct tear evaporation and the resulting blink-periodic salinity increases. For the cornea to experience hyperosmolarity due to tear evaporation, salt must transport across the SCL to the post-lens tear film (PoLTF) bathing the cornea. Consequently, limited salt transport across a SCL potentially protects the ocular surface from hyperosmotic tear. In addition, despite lens-wear discomfort sharing common sensations to dry eye, no correlation is available between measured tear hyperosmolarity and SCL-wear discomfort. Lack of documentation is likely because clinical measurements of tear osmolarity during lens wear do not interrogate the tear osmolarity of the PoLTF that actually overlays the cornea. Rather, tear osmolarity is clinically measured in the tear meniscus. For the first time, we mathematically quantify tear osmolarity in the PoLTF and show that it differs significantly from the clinically measured tear-meniscus osmolarity. We show further that aqueous-deficient dry eye and evaporative dry eye both exacerbate the hyperosmolarity of the PoLTF. Nevertheless, depending on lens salt-transport properties (i.e., diffusivity, partition coefficient, and thickness), a SCL can indeed protect against corneal hyperosmolarity by reducing PoLTF salinity to below that of the ocular surface during no-lens wear. Importantly, PoLTF osmolarity for dry-eye patients can be reduced to that of normal eyes with no-lens wear provided that the lens exhibits a low lens-salt diffusivity. Infrequent blinking increases PoLTF osmolarity consistent with lens-wear discomfort. Judicious design of SCL material salt-transport properties can ameliorate corneal hyperosmolarity. Our results confirm the importance of PoLTF osmolarity during SCL wear and indicate a possible relation between PoLTF osmolarity and contact-lens discomfort.     

Das „feuchte“ trockene Auge

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. The two main causes are reduced production of aqueous tears and increased evaporation of tears. The evaporative form of dry eye results in ocular surface irritation with a secondary increase in tear production; this presents to the examiner and patient as a wet eye or epiphora. Knowledge and understanding of the basic pathologies and differential diagnoses of dry eye disease are essential to differentiate this very common form of dry eye from disorders of the lacrimal drainage system and to initiate adequate management.     

Ocular surface investigations in dry eye

Dry eye is a complex clinicopathological entity involving tear film, lacrimal glands, eyelids, and a wide spectrum of ocular surface cells, including epithelial, inflammatory, immune, and goblet cells. From the tightly regulated lacrimal film functions and structure, a large variety of investigations have been developed, including tear meniscus measurements, fluorophotometry, meibometry, interference pattern analysis, evaporation rate, tear osmolarity, and thermography. Dry eye conditions also interfere with the ocular surface, causing corneal irregularities that may be explored using the techniques of videokeratography and in vivo confocal microscopy, or optical impairment, as confirmed by aberrometry. At the level of ocular surface cells, impression cytology remains a standard for assessing cell alterations. It has greatly benefited from new confocal microscopy, molecular biology, and flow cytometry techniques. Biological assessment of tear proteins or other mediators is also useful. Major limits should be acknowledged, however, such as technical issues in tear film collection, especially in dry eyes, and the lack of standardization of most measurements. Tear osmolarity, electrophoresis, and dosage of normal tear proteins, such as lysozyme or lactoferrin, remain the most useful tests. Finally, some extraocular explorations such as accessory gland biopsy or serum antinuclear antibody dosage may be useful for assessing the diagnosis of Sj?gren's syndrome.     

干眼症眼表损害炎症机制

干眼症为一种多因素造成泪膜稳定性和眼表功能损害的疾病,易引起眼部不适、视力障碍、泪膜不稳定与眼表的潜在危害,可伴有泪液渗透压升高及眼表炎症反应。炎症是干眼发病中最关键因素,多种免疫细胞和炎症因子参与了干眼症的发生与发展过程。细胞凋亡、神经调节异常、性激素失调等也共同参与了干眼的发病过程。最近尽管在阐述干眼的病理生理和发病机制取得了一定进展,但目前还未形成统一标准。本文将对炎症造成干眼症眼表和泪液功能损害的可能机制进行综述。     

TFOS DEWS II pathophysiology report

The TFOS DEWS II Pathophysiology Subcommittee reviewed the mechanisms involved in the initiation and perpetuation of dry eye disease. Its central mechanism is evaporative water loss leading to hyperosmolar tissue damage. Research in human disease and in animal models has shown that this, either directly or by inducing inflammation, causes a loss of both epithelial and goblet cells. The consequent decrease in surface wettability leads to early tear film breakup and amplifies hyperosmolarity via a Vicious Circle. Pain in dry eye is caused by tear hyperosmolarity, loss of lubrication, inflammatory mediators and neurosensory factors, while visual symptoms arise from tear and ocular surface irregularity. Increased friction targets damage to the lids and ocular surface, resulting in characteristic punctate epithelial keratitis, superior limbic keratoconjunctivitis, filamentary keratitis, lid parallel conjunctival folds, and lid wiper epitheliopathy. Hybrid dry eye disease, with features of both aqueous deficiency and increased evaporation, is common and efforts should be made to determine the relative contribution of each form to the total picture. To this end, practical methods are needed to measure tear evaporation in the clinic, and similarly, methods are needed to measure osmolarity at the tissue level across the ocular surface, to better determine the severity of dry eye. Areas for future research include the role of genetic mechanisms in non-Sjögren syndrome dry eye, the targeting of the terminal duct in meibomian gland disease and the influence of gaze dynamics and the closed eye state on tear stability and ocular surface inflammation.     

Dysfunctional neural regulation of lacrimal gland secretion and its role in the pathogenesis of dry eye syndromes

Tears are a complex fluid consisting of three layers, each of which is secreted by a different set of tissues or glands. The aqueous portion of the tear film is produced predominantly by the lacrimal gland. Dry eye syndromes are diseases in which the amount and composition of tears are altered, which can lead to ocular surface damage. There are many causes for dry eye syndromes. One such cause is the alteration in the functions of nerves innervating the lacrimal gland and the ocular surface. The autoimmune disease Sjogren syndrome can deleteriously affect the innervation of the lacrimal gland. Damage to the sensory nerves in the ocular surface, specifically the cornea, as a result of refractive surgery and normal aging, prevents the normal reflex arc to the lacrimal gland. Both defects can result in decreased tear secretion and dry eye syndromes. This review will discuss the current information regarding neurally-stimulated protein, water, and electrolyte secretion from the lacrimal gland and delineate how nerve dysfunction resulting from a variety of causes decreases secretion from this gland.     

A new approach for better comprehension of diseases of the ocular surface

The mechanistic view of dry eye disease aims at completing the classic etiological approach that classifies the disease as parallel ocular surface disorders leading to lacrimal film impairment and dry eye. This approach proposes two levels of ocular surface impairment (with standard etiologies, previously validated in the NEI/Industry workshop), which may not be independent diseases but rather risk factors and/or ways to enter a self-stimulated biological process involving the ocular surface. All external disorders proposed in this model, although unlikely to be fully exhaustive, are classical mechanisms considered to be causes of tear film impairment and ocular surface damage, by tear instability and evaporation, tear hyposecretion, or both. These mechanisms, sometimes alone--when severe or becoming chronic or repeatedly present on the ocular surface and when two or more are present--may cause the patient to enter the self-stimulated loop. Tear film instability/imbalance can be considered as the key point of dry eye disease. It will cause local or diffuse hyperosmolarity of the tear film and therefore of superficial epithelial cells of the cornea and/or conjunctiva, stimulating epithelial cells and resident inflammatory cells. Cell damage in the cornea and conjunctiva, by means of apoptosis and direct mechanical and/or osmotic stress, will stimulate the reflex neurosensory arc, in turn stimulating lacrimal gland and neurogenic inflammation, with inflammatory cytokine release, MMP activation, and inflammatory involvement of the conjunctival epithelium. Goblet cell loss is thus directly related to chronic inflammation and surface cell apoptosis subsequent to cell hyperosmolarity and chronic damage, resulting in further tear film instability/imbalance. On the other hand, bacterial changes and an imbalance resulting from specific diseases or from tear film abnormalities may trigger release of endotoxins, lipopolysaccharides, and/or lipase activation, causing eyelid inflammation, meibomian gland dysfunction, and lipidic changes, directly influencing tear film stability and favoring tear evaporation. The lipidic hypothesis therefore participates in the vicious circle as a parallel, independent, or complementary loop. This mechanistic approach proposes a synthetic combination of mechanisms previously validated independently, with two levels of ocular surface impairment, a first level including many possible acute or chronic causes that favor or trigger the imbalance and can be reversible if correctly and specifically managed when possible, and the further involvement of a series of biological cascades centered by tear film imbalance and inflammatory stimulation, finally acting as an independent vicious circle, however the patient entered the loop. Clinically, this approach may explain examples of dry eye syndrome occurring after ocular surgery, contact lens wear, chronic allergy or systemic or topical drugs, and the long-lasting effect even though all causal factors have been removed or have disappeared. This model should be considered as a basis for further reflection on biological mechanisms that could be even more complex but individually constitute potential leads for targeting therapeutic strategies to allow patients to leave the loop even though the triggering factors are still present or can only be attenuated, such as in Sj?gren syndrome or ocular rosacea. It also should be considered a complement to more classic etiological and severity classifications aimed at understanding and classifying the large number of diseases that may cause dry eye disease and better assessing the major impairment it causes on the patient's quality of life.     

Dry eye disease: an immune-mediated ocular surface disorder

Dry eye disease is a multifactorial disorder of the tears and ocular surface characterized by symptoms of dryness and irritation. Although the pathogenesis of dry eye disease is not fully understood, it is recognized that inflammation has a prominent role in the development and propagation of this debilitating condition. Factors that adversely affect tear film stability and osmolarity can induce ocular surface damage and initiate an inflammatory cascade that generates innate and adaptive immune responses. These immunoinflammatory responses lead to further ocular surface damage and the development of a self-perpetuating inflammatory cycle. Herein, we review the fundamental links between inflammation and dry eye disease and discuss the clinical implications of inflammation in disease management.     

Dry eye: an update on clinical diagnosis,management and promising new treatments

Dry eye conditions are prevalent with one in four to five patients presenting to eye care practitioners having dry eye signs and/or symptoms. An intimate relationship exists between the ocular surface and the tear film. The cycle of tear film instability and ocular surface damage characteristic of dry eye conditions suggests that dry eye represents a dysfunction of an integrated ocular surface‐lacrimal gland unit. Therefore, dry eye is a multifactorial condition and an approach based on clinical subtypes is required for diagnosis and management. There is increasing evidence that inflammation is a contributing and exacerbating factor in dry eye conditions and anti‐inflammatory or immunomodulatory therapy for chronic dry eye conditions may facilitate ocular surface healing. Other promising new treatments for dry eye include new generation artificial tear polymers and preservative systems, secretagogues, topical androgen supplements and surgical techniques for ocular surface reconstruction.     

The contribution of meibomian disease to dry eye

The tear film lipid layer is the major barrier to evaporation from the ocular surface. A decrease in its thickness or functional integrity may cause evaporative dry eye (EDE). Obstructive meibomian gland dysfunction (MGD) is the most common cause of EDE and occurs as a primary disorder or secondary to acne rosacea, seborrheic or atopic dermatitis, and with cicatrizing conjunctival disorders, such as trachoma, erythema multiforme, and cicatricial pemphigoid. MGD may be an incidental finding in asymptomatic eyes, or it may be responsible for irritative lid symptoms in the absence of dry eye. MGD-dependent EDE is diagnosed on the basis of a defined degree of MGD in a symptomatic patient showing typical ocular surface damage in the absence of an aqueous tear deficiency. When MGD occurs in a background of aqueous tear deficiency (ATD), then an additional evaporative component may assumed, depending on the extent of meibomian obstruction. However, definitive criteria are not yet established. The clinical severity of dry eye is greatest when ATD and EDE occur together, particularly in Sjogren syndrome. A hypothesis is proposed to explain the steps leading to primary, simple MGD and subsequent EDE.     

眼部不同手术与干眼症的研究新进展

眼表(角膜、结膜、副泪腺和睑板腺)、主泪腺和它们之间的泪腺功能单位共同维护眼表的健康,其中任一环节的损害均可导致泪膜完整性和正常功能的破坏。随着医学的发展,越来越多的眼部手术用来治疗眼部疾病,然而手术在实施过程中的各个环节如术前表面麻醉药物的应用、术中的操作过程、术后滴眼液中的防腐剂均有可能导致泪膜不稳定和/或眼表面的异常而引起干眼症。     

蒸发过强型干眼诱发因素研究进展

干眼主要分为水样液缺乏型干眼和蒸发过强型干眼。蒸发过强型干眼是在泪液分泌功能正常的情况下,由各种因素导致暴露的眼球表面泪液过量损失引起的。诱发此类干眼的因素包括泪膜脂质层异常、瞬目频率降低、配戴角膜接触镜、眼表障碍及眼表疾病、环境因素等。随着信息社会的发展,人们生活和工作方式的改变,蒸发过强型干眼的发病率逐渐增高,发病年龄年轻化,而临床上蒸发过强型干眼容易被忽视或误诊,就其主要诱发因素及其诊断和治疗的研究进展进行综述。     

Diagnosis of dry eye

Dry eve disease is characterized by symptoms, ocular surface damage, reduced tear film stability, and tear hyperosmolarity. There are also inflammatory components. These features can be identified by various kinds of diagnostic tests (symptom questionnaires, ocular surface staining, tear break-up time, and osmometry), although there may not be a direct correlation between the number or severity of symptoms and the degree of ocular surface damage or tear deficiency. Once the diagnosis of dry eye disease has been established, further tests can be used to classify the condition into tear-deficient or evaporative dry eve. The two forms of dry eye are not mutually exclusive and often co-exist. The optimal diagnosis of dry eye disease, therefore, depends on the results of several tests, and this article suggests an appropriate order for performing these tests at a single clinic visit.     

糖尿病性干眼发病机制及治疗进展

糖尿病是一种主要以损害微血管为主的病变。随着生活水平的提高,糖尿病患者的数量也逐渐增加,据最新数据显示,全球的糖尿病患病率高达9.3%(4.63亿人)。糖尿病相关的视网膜病变是导致工作人群视力障碍最主要的原因,近年来人们逐渐认识到高糖也可以引起眼表泪膜的不稳定、角膜神经功能障碍、角膜感知功能下降、泪液渗透压升高。糖尿病引起的眼表功能障碍原因复杂,机制多样,包括高糖导致泪膜各层结构破坏、树突状细胞-神经沟通障碍、炎性因子破坏泪腺分泌泪液等。本文就糖尿病性相关干眼的发生机制、研究进展进行综述,以期眼科医师在诊疗糖尿病干眼患者时更多考虑全身情况。     

Management of the ocular surface and tear film before, during, and after laser in situ keratomileusis

PURPOSE: To identify evidence-based, best practice strategies for managing the ocular surface and tear film before, during, and after laser in situ keratomileusis (LASIK). METHODS: After a comprehensive review of relevant published literature, evidence-based recommendations for best practice management strategies are presented. RESULTS: Symptoms of ocular irritation and signs of dysfunction of the integrated lacrimal gland/ocular surface functional gland unit are common before and after LASIK. The status of the ocular surface and tear film before LASIK can impact surgical outcomes in terms of potential complications during and after surgery, refractive outcome, optical quality, patient satisfaction, and the severity and duration of dry eye after LASIK. Before LASIK, the health of the ocular surface should be optimized and patients selected appropriately. Dry eye before surgery and female gender are risk factors for developing chronic dry eye after LASIK. Management of the ocular surface during LASIK can minimize ocular surface damage and the risk of adverse outcomes. Long-term management of the tear film and ocular surface after LASIK can reduce the severity and duration of dry eye symptoms and signs. CONCLUSIONS: Strategies to manage the integrated ocular surface/lacrimal gland functional unit before, during, and after LASIK can optimize outcomes. As problems with the ocular surface and tear film are relatively common, attention should focus on the use and improvement of evidence-based management strategies.