蒸发过强型干眼的泪膜脂质层成分变化及治疗策略

泪膜包括脂质层和由水及黏蛋白构成的凝胶层,其中脂质层又分为极性和非极性两层。非极性脂质的成分为蜡酯、固醇酯、甘油三酯等,而极性脂质层主要是磷脂类。蒸发过强型干眼患者的泪膜脂质层成分不同于正常者,而泪液脂质层对于稳定泪膜、减少蒸发具有重要意义,因此蒸发过强型干眼治疗的关键在于补充和稳定泪膜脂质,既可以作为单一疗法也可以联合补充泪液的治疗。     

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.     

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.     

中老年患者干眼症临床分析

目的探讨中老年患者干眼症的临床特点及诊治要点。方法通过问卷调查、泪膜破裂时间（BUT）、SchirmerⅠ试验、角膜荧光素染色以及DR-1泪膜干涉成像仪的检查，分析了60例（97只眼）中老年干眼症患者的临床资料。结果干眼症患者主要的眼部不适症状依次为眼疲劳（50．49％）、眼红（49．48％）、异物感（47．42％）、干涩感（39．18％）、分泌物（38．14％）、痒（29．90％）、水分过多感（21．65％）、烧灼感（9．28％）。SchirmerⅠ试验结果为（11．10±3．14）mm，BUT试验结果为（3．12±1．05）s，角膜荧光素染色评分结果为1．26±0．37。干眼仪的敏感度为63．75％，特异度为49．84％。泪液蒸发过强型、泪液分泌减少合并泪液蒸发过强型、单纯泪液分泌减少型所占比例依次为63．92％、30．93％、5．15％。60例患者中曾经误诊为其他眼病者43例（71．7％）。结论眼科医生应掌握中老年患者干眼症的临床特点，重视症状、病史的询问以及传统的三项检查（Schii-merⅠ试验、BUT试验、角膜荧光素染色），避免误诊误治。     

Abnormal of tear lipid layer and recent advances in clinical study of dry eye

Dry eye is a common disease in the ophthalmological clinic, which is related to the dysfunction of tear film. The tear film is composed of lipid layer, aqueous layer and mucin layer (or lipid layer, aqueous/mucin layer). The lipid of the outmost layer derived from Meibomian gland and distributed on the tear film after blinking can decrease the evaporation and stabilize the tear film. The thickness, quality, and distribution of lipid layer are impaired in many dry eye patients, hence restoring the physiological function of lipid layer may be crucial for the treatment of this kind of dry eye. The lipid artificial tears manifest great effects on increasing lipid layer thickness, stabilizing tear film, improving Meibomian gland dysfunction, and promoting tear film distribution.     

儿童干眼症病因学分析

干眼症是指任何原因引起的泪液质或量及动力学的异常,导致泪膜不稳定和(或)眼表面的异常,并伴有眼部不适症状的一类疾病。传统观念认为干眼症多见于40岁以上的人群,与泪液分泌功能随年龄增长而逐渐减弱有关,所以对成年人干眼症的研究较多,而忽视了儿童干眼症。临床上越来越多的儿童出现了类似于成年人干眼症的临床表现,而且通过常规的抗感染治疗病情反而加重。因此,儿童干眼症应该受到重视。重度维生素A缺乏(VitaminAdeficiency,VAD)导致的儿童眼干燥症曾是儿童致盲的重要原因。随着生活水平的提高,城镇儿童重度VAD十分少见。但亚临床维生素A缺乏(sub-clinical Vitamin Adeficiency,SVAD)、视频终端(video display terminal,VDT)的普及、不良的瞬目习惯、宠物和玩具等密切接触、系统免疫性疾病以及变态反应性疾病均可引起泪膜不稳定而导致干眼症。     

睑板腺脂质在干眼症发病机制中的作用

干眼症是眼科常见病,根据病因可分为泪液分泌不足和泪液蒸发过强两种类型。位于泪膜最外层的脂质层由睑板腺分泌,具有维持泪膜稳定和防止泪液蒸发的作用。脂质层的组成成分以及组织结构对它的稳定性有很大影响,睑板腺功能障碍患者由于脂质层功能紊乱,造成泪膜稳定性下降及眼表的破坏,引起蒸发过强型干眼症。（国际眼科纵览,2014, 38：316-319）     

Effect of an oil-in-water emulsion on the tear physiology of patients with mild to moderate dry eye

PURPOSE: To determine the effect of an oil-in-water emulsion eye drop compared with a conventional dry eye supplement (hypromellose) on tear physiology in dry eye. METHODS: A randomized parallel, longitudinal, and investigator-masked study of the efficacy of 1.25% castor oil emulsion and 0.32% hypromellose solution was carried out. A total of 53 patients with mild to moderate dry eye (27 in emulsion group and 26 in hypromellose group) were recruited for the study. Patients were enrolled if they reported at least 2 symptoms on a McMonnies Dry Eye Questionnaire together with 1 of the following screening tests: noninvasive tear breakup time (5-10 seconds) and Schirmer test without anesthesia (2-5 mm in 5 minutes). Patients were instructed to use the test solutions 3 times a day for 30 days. Tear production, evaporation, lipid layer structure, and osmolality were measured before and 30 days after use of the drops. RESULTS: A statistically significant decrease was seen after 1 month in tear evaporation rates with both emulsion (7.25 +/- 5.43 g/m2/h) and hypromellose (2.02 +/- 4.75 g/m2/h). However, the decrease with emulsion was significantly greater than with hypromellose (P < 0.001). Lipid layer structure improved from day 1 to day 30 of the study with the emulsion but not with the hypermellose. No significant changes were seen in tear production and osmolality with either of the drops. CONCLUSIONS: The oil-water emulsion was more effective in reducing tear evaporation than hypromellose after repeated application over a 1-month period. This finding signifies the potential of the emulsion in the management of evaporative dry eye.     

Role of Hyperosmolarity in the Pathogenesis and Management of Dry Eye Disease: Proceedings of the OCEAN Group Meeting

Dry eye disease (DED), a multifactorial disease of the tears and ocular surface, is common and has a significant impact on quality of life. Reduced aqueous tear flow and/or increased evaporation of the aqueous tear phase leads to tear hyperosmolarity, a key step in the vicious circle of DED pathology. Tear hyperosmolarity gives rise to morphological changes such as apoptosis of cells of the conjunctiva and cornea, and triggers inflammatory cascades that contribute to further cell death, including loss of mucin-producing goblet cells. This exacerbates tear film instability and drives the cycle of events that perpetuate the condition. Traditional approaches to counteracting tear hyperosmolarity in DED include use of hypotonic tear substitutes, which have relatively short persistence in the eye. More recent attempts to counteract tear hyperosmolarity in DED have included osmoprotectants, small organic molecules that are used in many cell types throughout the natural world to restore cell volume and stabilize protein function, allowing adaptation to hyperosmolarity. There is now an expanding pool of clinical data on the efficacy of DED therapies that include osmoprotectants such as erythritol, taurine, trehalose and L-carnitine. Osmoprotectants in DED may directly protect cells against hyperosmolarity and thereby promote exit from the vicious circle of DED physiopathology.     

Osmolality and tear film dynamics

The tear film is a nourishing, lubricating and protecting layer that bathes the ocular surface. It is continuously replenished through cycles of production and elimination via evaporation, absorption and drainage. These processes are often referred to as tear film dynamics. Osmolality is an objective clinical measurement that provides insight into the balance of these complex tear film dynamics. Balanced tear production and elimination is vital for tear film integrity, stability and normal osmolality. Imbalances cause alterations of the tear film structure and composition, ultimately leading to tear film instability and measurable tear film hyperosmolality. Elevated tear film osmolality is considered a core mechanism in dry eye, forming the basis of dry eye symptoms and leading to ocular surface damage. Despite its immense potential in the diagnosis of dry eye, tear film osmolality is not commonly assessed. This review will focus on the current knowledge of tear film dynamics and tear film osmolality.     

Inflammation in dry eye

Dry eye is a condition of altered tear composition that results from a diseased or dysfunctional lacrimal functional unit. Evidence suggests that inflammation causes structural alterations and/or functional paralysis of the tear-secreting glands. Changes in tear composition resulting from lacrimal dysfunction, increased evaporation and/or poor clearance have pro-inflammatory effects on the ocular surface. This inflammation is responsible in part for the irritation symptoms, ocular surface epithelial disease, and altered corneal epithelial barrier function in dry eye. Anti-inflammatory therapies for dry eye target one or more of the inflammatory mediators/pathways that have been identified in dry eye.     

Trockenes Auge bei Kontaktlinsenträgern

Contact lens-associated dry eye symptoms have mostly been therapeutically addressed using artificial tears containing hyaluronic acid to supplement tear film volume with often unsatisfactory results. However, the main reason for contact lens-associated dry eye is not the lack of tear fluid but the lack of tear film stability due to meibomian gland dysfunction leading to reduction of the lipid film of tears. This is associated with increased evaporation of the aqueous phase of tear fluid and a measurable hyperosmolarity of the residual “denatured” tear film. A subsequent inflammatory reaction of the ocular surface then leads to the vicious circle of dry eye. The aim of this review is to summarize current study results on this topic and to give practical advice on how to address dry eye symptoms in contact lens wearers more accurately. For most contact lens-associated dry eye symptoms a combined therapy with unpreserved artificial tears plus phospholipid-liposome eye spray yields the best results. In cases of additional signs of blepharitis the regular use of phospholipid-liposome solution for lid margin hygiene is beneficial.     

A mass and solute balance model for tear volume and osmolarity in the normal and the dry eye

Tear hyperosmolarity is thought to play a key role in the mechanism of dry eye, a common symptomatic condition accompanied by visual disturbance, tear film instability, inflammation and damage to the ocular surface. We have constructed a model for the mass and solute balance of the tears, with parameter estimation based on extensive data from the literature which permits the influence of tear evaporation, lacrimal flux and blink rate on tear osmolarity to be explored. In particular the nature of compensatory events has been estimated in aqueous-deficient (ADDE) and evaporative (EDE) dry eye.The model reproduces observed osmolarities of the tear meniscus for the healthy eye and predicts a higher concentration in the tear film than meniscus in normal and dry eye states. The differential is small in the normal eye, but is significantly increased in dry eye, especially for the simultaneous presence of high meniscus concentration and low meniscus radius. This may influence the interpretation of osmolarity values obtained from meniscus samples since they need not fully reflect potential damage to the ocular surface caused by tear film hyperosmolarity.Interrogation of the model suggests that increases in blink rate may play a limited role in compensating for a rise in tear osmolarity in ADDE but that an increase in lacrimal flux, together with an increase in blink rate, may delay the development of hyperosmolarity in EDE. Nonetheless, it is predicted that tear osmolarity may rise to much higher levels in EDE than ADDE before the onset of tear film breakup, in the absence of events at the ocular surface which would independently compromise tear film stability. Differences in the predicted responses of the pre-ocular tears in ADDE compared to EDE or hybrid disease to defined conditions suggest that no single, empirically-accessible variable can act as a surrogate for tear film concentration and the potential for ocular surface damage. This emphasises the need to measure and integrate multiple diagnostic indicators to determine outcomes and prognosis. Modelling predictions in addition show that further studies concerning the possibility of a high lacrimal flux phenotype in EDE are likely to be profitable.     

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.     

干眼仪在干眼诊断中的价值初步评价

目的：评价干眼仪对干眼的诊断价值。方法：对25例(25只眼)正常人和35例(35只眼)干眼患者分别行泪膜破裂时间(BUT)、泪液分泌试验(Schirmer 1)、角膜荧光素染色(FL)、干眼仪检查和泪高度测量五项检查。结果：干眼患者的干眼仪检测等级与正常人差异显著(χ^2=32．22，P=0．000)。干眼仪诊断干眼的特异度为80％，灵敏度为83％。干眼仪检查为Ⅲ级脂质层形态图像者患干眼的机率约为。75％(15／25)。干眼患者的干眼仪检测等级越高，BUT和Schirmer 1试验越短(r=-0．783，-0．368，P=0．000，0．015)，角膜荧光素染色越多(r=0．806，P=0．000)，而与泪河高度无相关(P=0．178)。正常人的干眼仪检测等级也与BLrr和SchirmerI试验呈负相关(r=-0．398，-0．656，P=0．024，0．000)。干眼患者的干眼仪显示图像的稳定性较正常人差。干眼仪的检查结果具有较高的重复性。结论：干眼仪能较直观地观察角膜中央脂质层的光干涉图像，是一种快速、无创伤、重复性强、操作简单的检查方法。对干眼的诊断及客观反映病情的严重程度具有临床应用价值。     

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.     

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.     

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.     

Tear dynamics and dry eye

Tears undergo four processes: production by the lacrimal gland, distribution by blinking, evaporation from the ocular surface and drainage through the nasolacrimal duct. Abnormalities in any of these steps can cause dry eye. There are two kinds of tear production, basic and reflex, which can be distinguished from each other by the Schirmer test with nasal stimulation. Reflex tearing is important because it supplies such essential components as EGF and vitamin A, whose deficiency may cause squamous metaplasia. There is no reflex tearing in Sjogren's syndrome because of destruction of the lacrimal gland. In cases of diminished or absent reflex tearing, topical autologous serum is the treatment of choice. Even when there is adequate tear production, insufficient distribution, such as occurs with the decreased blinking associated with the use of video display terminals (VDT), may cause dry eye. Any process or activity that suppresses blinking interferes with tear distribution. Tear evaporation increases under certain conditions and in some diseases. When the exposed ocular surface area is increased, such as in VDT work, tear evaporation increases. Meibomian gland dysfunction (MGD) also causes increased tear evaporation by altering the quality of the oily layer in tears. Tear evaporation can be suppressed by using a warm compresser or a humidifier, narrowing the palpebral fissure, or wearing protective eyeglasses. The tear clearance rate is measured by fluorescein dye dilution in the conjunctiva. When the tear clearance is low, inflammatory cytokines or preservatives accumulate in the conjunctival sac, resulting in ocular surface diseases. Frequent use of artificial tears without preservative is the key treatment. A differential diagnosis of the abnormalities of tear dynamics can give us a proper understanding of the pathogenesis of dry eye. With this knowledge, we can formulate an efficient therapeutic approach.     

Sequential changes of lipid tear film after the instillation of a single drop of a new emulsion eye drop in dry eye patients

PURPOSE: The lipid tear film stabilizes the tears by lowering the surface tension and preventing aqueous tear evaporation and may be analyzed by kinetic analysis of the tear interference images. This study investigated changes in the lipid film after application of a new emulsion-based eye drop of Refresh Endura (Allergan, Irvine, CA) in normal subjects and patients with dry eyes. DESIGN: Comparative, nonrandomized interventional study. PARTICIPANTS: Five normal subjects and 10 aqueous tear deficiency (ATD) patients with or without lipid tear deficiency were enrolled prospectively. METHODS: A complete eye examination was performed, including symptom score, tear break-up time, dye staining, and fluorescein clearance test. One eye received a single dose of emulsion eye drop (EED), whereas the other eye received nonpreserved saline as a control. Kinetic analysis of tear interference images taken by DR-1 (Kowa, Japan) was performed before and at various times after instillation of the drops. MAIN OUTCOME MEASURES: Symptoms, pattern, thickness, and spread time of the tear film. RESULTS: Compared with the control, all eyes receiving EED showed rapid restructuring of the preexisting lipid film. In normal persons, restructuring resulted in a thick lipid band across the cornea and a significant increase of the lipid film thickness. For ATD patients, EED application resulted in either a scant, irregular tear film, which became covered by the lipid film, or a modified lipid film changed without forming a band or irregularities. Emulsion eye drops tended to be more comfortable in patients with more severe ATD. Kinetic analysis showed that the mean spread time improved for all patients after EED when compared with baseline or with controls (P<0.05). CONCLUSIONS: Emulsion eye drop produces significant changes in the tear film of normal and dry eye patients. Further investigation with a prolonged period of treatment is warranted to establish whether EED may help improve the spread and thickness of the lipid tear film in moderate and severe dry eyes.