Defining Dry Eye from a Clinical Perspective. — TEI-tagged view

Kazuo TsubotapersName, Stephen C. PflugfelderpersName, Zuguo LiupersName, Christophe BaudouinpersName, Hyo Myung KimpersName, Elisabeth M. MessmerpersName, Friedrich KrusepersName, Lingyi LiangpersName, Jimena Tatiana Carreno-GaleanopersName, Maurizio RolandopersName, Norihiko YokoipersName, Shigeru KinoshitapersName, Reza DanapersName (2020date). “Defining Dry Eye from a Clinical Perspective..” International Journal of Molecular Sciencestitle·j.

Object of study — the clinical definitionterm·key of dry eye diseaseterm·dom

Research question — how to make a proper diagnosis of dry eye diseaseterm·dom in the clinic

Contribution — a consensus clinical definitionterm·key of dry eye diseaseterm·dom whose key criteria are unstable tear filmterm·key, inflammationterm·key, ocular discomfortterm·key and visual impairmentterm·key

Full text — tagged

Defining Dry Eyeterm·dom from a Clinical Perspective.

Abstract Over the past decades, the number of patients with dry eye diseaseterm·dom (DEDterm·dom) has increased dramatically. The incidence of DEDterm·dom is higher in Asia than in Europe and North America, suggesting the involvement of cultural or racial factors in DEDterm·dom etiology. Although many definitionsterm·key of DEDterm·dom have been used, discrepancies exist between the various definitionsterm·key of dry eye diseaseterm·dom (DEDterm·dom) used across the globe. This article presents a clinical consensus on the definitionterm·key of DEDterm·dom, as formulated in four meetings with global DEDterm·dom experts. The proposed new definitionterm·key is as follows: “Dry eyeterm·dom is a multifactorial disease characterized by a persistently unstable and/or deficient tear filmterm·key (TF) causing discomfort and/or visual impairmentterm·key, accompanied by variable degrees of ocular surface epitheliopathyterm·key, inflammationterm·key and neurosensory abnormalitiesterm·key.” The key criteria for the diagnosis of DEDterm·dom are unstable TFterm, inflammationterm·key, ocular discomfortterm·key and visual impairmentterm·key. This definitionterm·key also recommends the assessment of ocular surface epitheliopathyterm·key and neurosensory abnormalitiesterm·key in each patient with suspected DEDterm·dom. It is easily applicable in clinical practice and should help practitioners diagnose DEDterm·dom consistently. This consensus definitionterm·key of DEDterm·dom should also help to guide research and clinical trials that, to date, have been hampered by the lack of an established surrogate endpoint.

Keywords: dry eyeterm·dom, definitionterm·key, inflammationterm·key, tear filmterm·key breakup, dry eyeterm·dom symptoms, dry eyeterm·dom signs, corneal epitheliopathyterm·key, neuropathic painterm·dom 1. Introduction and Existing Definitionsterm·key of Dry Eye Diseaseterm·dom (DEDterm·dom) Dry eye diseaseterm·dom (DEDterm·dom) is a common ocular disorder affecting tens of millions of people; its incidence and prevalence in Asia is higher than in Europe and North America, suggesting that cultural or racial factors are involved in DEDterm·dom etiology [ 1 , 2 , 3 , 4 , 5 , 6 ].

The common perception of DEDterm·dom is one of a simple disease, primarily caused by decreased tear production—such as the aqueous tear deficiencyterm·dom (ATDterm·dom) type of dry eyeterm·dom seen in Sjögren’s syndrome. However, evidence suggests that a number of conditions may contribute to an unstable tear filmterm·key (TF) [ 7 , 8 ]. DEDterm·dom owing to decreased tear production and DEDterm·dom resulting from tear instability alone share some features but could also exist independently. Severe ATDterm·dom also leads to a short tear breakup timeterm (TBUTterm).

The different clinical presentations of DEDterm·dom has led to some misunderstandings of the condition and the need for a consensus on a clinical definitionterm·key. Over the years, various organizations have proposed different definitionsterm·key and diagnostic criteria for DEDterm·dom.

In 2017, the most comprehensive of these was the Tear Filmterm·key & Ocular Surface Society Dry Eyeterm·dom Workshop (TFOS DEWS II ®) Report, which was the result of a workshop involving DEDterm·dom specialists, academic researchers, optometrists and ophthalmologists [ 8 ]. The Asia Dry Eyeterm·dom Society also proposed a new definitionterm·key in the same year [ 7 ], while the American Academy of Ophthalmology (AAO) proposed the new Dry Eyeterm·dom Syndrome Preferred Practice Patterns in 2018 [ 9 ]. All of these definitionsterm·key emphasize that an unstable TFterm is a key feature of DEDterm·dom, but several discrepancies exist among the criteria.

Several of the commonly used DEDterm·dom definitionsterm·key are summarized in Table 1 . Different criteria/parameters have been used in each definitionterm·key, some of which are difficult to measure clinically. Several definitionsterm·key have also used instability of TF as a primary or secondary criterion for DEDterm·dom.

Dry eye diseaseterm·dom definitionsterm·key proposed from 1995 onwards.

DEDterm·dom symptoms and short TBUTterm (≤5 s) are the criteria most often used to diagnose DEDterm·dom in three Asian countries (China, Japan and South Korea). Recent studies have emphasized the importance of an unstable TFterm, which can present as decreased TBUTterm in DEDterm·dom [ 18 , 19 , 20 ]. Consequently, in 2017, representatives from China, Japan and South Korea proposed the Asia Dry Eyeterm·dom Society definitionterm·key of DEDterm·dom as “a multifactorial disease characterized by unstable TFterm causing a variety of symptoms and/or visual impairmentterm·key, potentially accompanied by ocular surface damage” [ 7 ]. DEDterm·dom can be diagnosed by the presence of both decreased TBUTterm and subjective symptoms. However, ocular surface staining was not included as an essential diagnostic criterion in this iteration.

To achieve clinical consensus on the definitionterm·key of DEDterm·dom, physician-scientists who specialized in DEDterm·dom met four times: in Chicago at the AAO Annual Meeting (2016), in New Orleans at the AAO Annual Meeting (2017), in Barcelona at the World Ophthalmology Congress (2018) and in Chicago at the AAO Annual Meeting (2018). The documents produced were approved by all participants, a list of which is provided at the end of this article ( Appendix A ).

Clinical Implications The range of definitionsterm·key has contributed to confusion and a lack of consistent diagnosis of DEDterm·dom across the globe.

Tear filmterm·key stability is a sensitive measure of tear dysfunction that can be easily measured, making it a clinically practical and reproducible marker of DEDterm·dom/tear dysfunction. It should be the key criterion in a clinical definitionterm·key of DEDterm·dom.

2. A Proposed New Clinical Definitionterm·key of Dry Eye Diseaseterm·dom Despite the various proposed definitionsterm·key of DEDterm·dom, a single global consensus does not exist. Our discussion about a global definitionterm·key started in 2016, and active discussions were held on four occasions based on the TFOS DEWS II ® Report, Asia Dry Eyeterm·dom Society, and the preferred practice patterns of AAO [ 7 , 8 , 9 ]. All discussions were conducted from a practical point of view. The primary question was how to make a proper diagnosis of DEDterm·dom in the clinic. The osmometer and noninvasive TBUTterm measurement were excluded, because these measurements are not available in all specialist eye clinics.

The final new definitionterm·key proposed is: “Dry eyeterm·dom is a multifactorial disease characterized by a persistently unstable and/or deficient tear filmterm·key causing discomfort and/or visual impairmentterm·key, accompanied by variable degrees of ocular surface epitheliopathyterm·key, inflammationterm·key and neurosensory abnormalitiesterm·key.”

The definitionterm·key emphasizes the importance of unstable TFterm, inflammationterm·key, discomfort and visual impairmentterm·key. In addition, epitheliopathyterm·key and neurosensory abnormalitiesterm·key are included. According to the definitionterm·key, a DEDterm·dom diagnosis can be made when patients have an unstable TFterm and ocular discomfortterm·key and or visual impairmentterm·key. Since a patient with decreased TBUTterm and/or ocular discomfortterm·key and no ocular surface dye staining is easily misdiagnosed as having neurosis, TBUTterm should be measured using fluorescein dye for each patient with ocular discomfortterm·key. As we describe later, clinicians need to be cautious in order to not miss visual impairmentterm·key due to DEDterm·dom, while ocular surface epitheliopathyterm·key, inflammationterm·key and neurosensory abnormalitiesterm·key should also be assessed in each patient. These important concepts will be discussed in detail in following sections.

Clinical Implications The proposed new definitionterm·key of DEDterm·dom is based on a consensus of agreement between DEDterm·dom experts in different regions worldwide.

The new definitionterm·key is aimed at providing practitioners with a practical tool that helps diagnose DEDterm·dom in the clinic.

Using this simple clinical definitionterm·key, all practitioners can make a precise and consistent diagnosis of DEDterm·dom.

As the diagnosis can be made using the DEDterm·dom questionnaire and a slit lamp examination with fluorescein, all practitioners can easily apply this definitionterm·key in their clinics following the recommendations outlined in this article.

3. Unstable Tear Filmterm·key: The Importance of Tear Filmterm·key Breakup Patterns The current published data on tears, the TF and DEDterm·dom suggest that the primary mechanisms associating tear abnormalities to DEDterm·dom symptoms on opening the eye and, at the time of blinking, are tear filmterm·key breakup (TFBU) and increased friction, respectively [ 21 ]. Ultimately, these mechanisms result in varying degrees of ocular surface epitheliopathyterm·key, inflammationterm·key and neurosensory response, each of which is responsible for specific DEDterm·dom symptoms [ 21 , 22 ].

3.1. Dynamic Process Involved in the Establishment of Tear Filmterm·key to Understand Tear Filmterm·key Breakup Tear filmterm·key dynamics comprise two processes, during which the precorneal TF is established. One process is the deposition of aqueous tears (ATs) to the corneal surface at eye opening [ 22 , 23 , 24 , 25 , 26 , 27 ], and the other is the redistribution of the TF after eye opening. During the deposition process, there are only polar lipids of the tear filmterm·key lipid layer (TFLL), and in this process, polar lipids may contaminate the corneal surface when wettability is impaired. When the deposition process is terminated, the surface tension gradient of the TFLL causes the upward spread of the TFLL [ 22 , 23 , 24 , 25 , 27 , 28 , 29 ]. During this upward spread, a dimple (i.e., a transient thinning) is produced behind the leading edge of the spreading TFLL due to the upward drag of the aqueous TF exerted by the TFLL [ 28 , 30 , 31 , 32 ]. Thus, TF redistribution occurs, and when the upward spread of the TFLL and upward movement of the aqueous TF finishes, the redistribution is terminated. During the redistribution process, lower-tear meniscus-induced aqueous-TF thinning [ 33 , 34 ] occur simultaneously with the upward movement of the aqueous TF [ 22 , 24 , 25 , 27 ].

3.2. Tear Filmterm·key Breakup Patterns for Tear Film-Oriented Diagnosisterm and Their Interpretations A tear film-oriented diagnosisterm is a concept in which information is obtained on the integrity of the TFLL, the aqueous TF and the wettability of the corneal surface that is responsible for TFBU [ 24 , 25 ]. Although presently not a quantitative assessment, this information allows for (1) identification of the insufficient component of the TF or of the corneal surface epithelium responsible for TFBU, (2) subclassification of DEDterm·dom and (3) selection of optimal topical therapy.

In severe ATDterm·dom, not enough ATs are available for deposition. The result can be observed as either “no” or “incomplete” upward movement of fluorescein-stained aqueous TF or spread of the TFLL [ 27 , 35 ] (we termed this breakup (BU) pattern “area break” [ 22 , 24 , 25 , 27 ]; see Figure 1 ). However, even if ATs are sufficient, BU of TF can occur even when aqueous tears are sufficient due to a lack of mucins, which reduce the wettability of the epithelium (i.e., “spot break” (SB) [ 22 , 24 , 25 , 27 ] in Figure 1 ). In mild-to-moderate ATDterm·dom, BU is likely to occur in the inferior part of the cornea (i.e., “line break” (LB) [22,24,25, in Figure 1 ). In addition, when the dimple encounters a corneal surface with decreased wettability, BU occurs (i.e., “dimple break” (DB) [ 22 , 25 , 27 ] in Figure 1 ). After the establishment of the TF, BU occurs even in normal eyes (i.e., “random break” (RB) [ 22 , 24 , 25 , 27 ] in Figure 1 ), and this happens more frequently in cases of DEDterm·dom with facilitated evaporation. The expansion of a tear filmterm·key breakup becomes more rapid, depending on the decrease of wettability of the corneal surface [ 22 , 27 , 36 , 37 , 38 ], and it is possible that “line break” and “random break” can accompany the rapid expansion of the dark spot (i.e., “line break with rapid expansion” (LB with RE) in Figure 1 ).

Fluorescein breakup (BU) patterns seen immediately after eye opening and after the eye is kept open. Related to the establishment of the tear filmterm·key (TF) on the cornea, there are three phases for each fluorescein breakup pattern that can be seen. In the first phase, an area break (AB) or a spot break (SB), respectively, can be seen in cases of severe aqueous tear deficient dry eyeterm·dom (ATDDE) or decreased wettability dry eyeterm·dom (DWDE). In the second phase, a line break (LB) or a dimple break (DB), respectively, can be seen in cases with mild-to-moderate ATDDE or DWDE. In the third phase, a random break (RB) can be seen in cases of evaporative dry eyeterm·dom (EDE). RB is also seen in normal eyes, in which the BU time is within the normal range, i.e., generally, >10 s. In addition, a modification of BU patterns suggesting the association with DWDE is the rapid expansion of BU spots sometimes seen in LB and RB.

3.3. Clinical Implications Tear-film oriented diagnosis is practical and clinically useful for clinicians engaged in the management of DEDterm·dom [ 22 , 24 , 27 ].

Further advancement of this approach is expected through a deeper understanding of the function of each component of the ocular surface.

TF stability is maintained by the components of the TF and ocular surface epithelium, and insufficiency of those components results in TFBU, a visible core manifestation of DEDterm·dom.

Classification of TFBU patterns may elucidate the pathophysiology of DEDterm·dom.

Clinicians can assess tear film-oriented diagnosisterm to learn more about the insufficient components responsible for TFBU, assess the specific DEDterm·dom subtype and, therefore, decide on the most appropriate treatment.

4. Ocular Discomfortterm·key: The Importance of Symptoms in Dry Eye Diseaseterm·dom DEDterm·dom can be a frustrating disease for patients and ophthalmologists. Ocular discomfortterm·key is the most common complaint, and as a central feature of the disease, it is a fundamental component of the definitionterm·key of DEDterm·dom [ 7 , 8 , 12 ]. In most cases, ocular discomfortterm·key is displayed before DEDterm·dom is diagnosed, and it is critical for monitoring the progression of the condition and response to treatments.

Common ocular discomfortterm·key can be described as dryness, redness, foreign body sensation, heavy sensation, pain, light sensitivity, discharge, itching and eye fatigue. The type of ocular discomfortterm·key experienced by patients may be associated with particular DEDterm·dom subtypes, although there is considerable overlap between them. For example, in diurnal variation, DEDterm·dom symptoms tend to become more evident later in the day in patients with ATDterm·dom dry eyeterm·dom [ 39 ]. In the classification proposed by the ADES, patients with short TBUT-type DEDterm·dom may experience more of the heavy sensation, and patients with staining-type DEDterm·dom may experience more of the foreign body-type sensation [ 7 ]. There is overlap among the symptoms of subtypes.

4.1. Evaluation of Ocular Discomfortterm·key with Questionnaires Ocular discomfortterm·key can be evaluated using patient-reported questionnaires ( Table 2 ). Each questionnaire has advantages in certain scenarios and reflects the impact of DEDterm·dom on everyday function and health-related quality of life [ 8 ]. It is recommended that a validated symptom questionnaire be administered at first patient presentation.

Questionnaires used to evaluate symptoms of dry eye diseaseterm·dom (DEDterm·dom).

4.2. The Pathophysiology of Ocular Discomfortterm·key In general, ocular discomfortterm·key is caused by an entity on the ocular surface activating the sensory nerve, and there are several reasons why this may occur. An unstable TFterm generates tear hyperosmolarity, inflammationterm·key and epithelial breakdown. This exposes and irritates nociceptive receptors on the ocular surface and leads to sensations of discomfort. Instability disturbs the optical property of the TF, becoming an additional source of discomfort. Sometimes, a patient may experience both problems. Mechanical abrasions from disorders of the lid margin, such as plugging of the meibomian gland orifice and conjunctivochalasis, can cause blink-related microtrauma to the ocular surface and affect tear dynamics. Insidious lid abnormalities, such as lagophthalmos, incomplete and decreased blinking or poor lid-to-globe apposition can prevent the formation of a stable TF and similar discomfort as DEDterm·dom. Inflammationterm·key is a result of a decreased or/and an unstable TFterm and epithelial defect and creates ocular irritation. Detailed note-taking to capture details of major symptoms and triggers helps to identify the origin of discomfort in DEDterm·dom.

4.3. Ocular Discomfortterm·key and Incongruity with Signs There are often discrepancies between signs and symptoms; thorough evaluation of both is critical in diagnosing DEDterm·dom.

When patients demonstrate severe epithelial breakdown and inflammationterm·key but have no related discomfort; the neurotrophic status should be considered. Neurotrophic keratopathy in the context of dry eye diseaseterm·dom usually stems from long-standing DEDterm·dom such as severe Sjögren’s syndrome and diffusive ocular surface keratinization in end-stage Stevens-Johnson syndrome, ocular cicatricial pemphigoid or chemical burn [ 51 ]. When patients report obvious discomfort without visible ocular surface signs, a component of neuropathic painterm·dom, also known as ocular neuralgiaterm·dom, is suspected. The typical complaint of neuropathic painterm·dom is hypersensitivity to light and wind, which is not relieved by topical anesthesia [ 52 ]. Depression and anxiety can cause chronic discomfort, which exceeds that predicted by clinical signs [ 53 ]. Patients with preclinical DEDterm·dom, such as long-term visual display terminal users or contact lens wearers, might also present with intermittent discomfort but very mild signs. In these cases, individuals may proceed to typical DEDterm·dom if risk factors are left uncorrected.

4.4. Clinical Implications Ocular discomfortterm·key is common and has a range of symptoms. A careful symptom consultation is recommended for diagnosis.

Ocular discomfortterm·key should be evaluated with a variety of patient-reported questionnaires.

A thorough evaluation of both signs and symptoms is critical for a correct diagnosis of DEDterm·dom and to determine treatment decisions.

5. Visual Impairmentterm·key Caused by Unstable Tear Filmterm·key Patients with DEDterm·dom often have impaired visual function that affects functional activities and is caused by an unstable TFterm [ 54 , 55 , 56 ]. The TF is the first part of the eye traversed by light entering the eye, and a smooth stable TF is essential for good visual function [ 57 , 58 , 59 ]. A recent study showed that an unstable TFterm causes increased accommodative microfluctuationsterm, placing a great burden on the ciliary muscle [ 60 , 61 ]. Once the TF has been stabilized, the symptoms are resolved when the fluctuations stop.

In the context of DEDterm·dom, functional visual acuity assesses the visual functions related to the unstable TFterm [ 58 , 62 ]. As compared with the normal visual acuity measurement, functional visual acuity provides a measure of the real-life functional ability of visual perception. Impaired functional visual acuity can be recovered by treating DEDterm·dom with punctal occlusion [ 63 ] or diquafosol sodium [ 64 , 65 , 66 , 67 ], which stabilize the TF. Blue light, often used in computer and smartphone screens, has a short wavelength, which is easily scattered by an uneven surface, i.e., an unstable TFterm. Thus, DEDterm·dom patients have more difficulty seeing blue light, and the light environment can be improved by removing blue light components [ 68 ]. The recent acceptance of blue light-reducing glasses for computer users should help with clinical or preclinical DEDterm·dom.

Clinical Implications Given that DEDterm·dom can impair visual function, practitioners should properly evaluate DEDterm·dom symptoms and visual impairmentterm·key.

As simple visual acuity measurements cannot detect visual impairmentterm·key associated with DEDterm·dom, it is possible that practitioners underestimate the extent of visual impairmentterm·key.

Assessments such as functional visual acuity can be used to assess visual function related to unstable TFterm.

Simple measures such as reducing blue light emitted by devices can be used to improve visual function in those with unstable TFterm.

6. Epitheliopathyterm·key Epitheliopathyterm·key commonly occurs in DEDterm·dom and contributes to the instability of TF. The distribution and severity of corneal disease and conjunctival epithelial disease differ among aqueous tear deficient and sufficient dry eyeterm·dom/tear dysfunction conditions and may not be clinically detectable [ 55 , 69 , 70 , 71 ].

6.1. Corneal Disease Corneal epithelial disease is more prevalent and severe in ATDterm·dom syndromes, particularly in Sjögren’s syndrome and inflammatory conditions such as Stevens–Johnson syndrome and graft versus host disease, than aqueous tear sufficient dry eyeterm·dom [ 55 , 71 ]. Fluorescein is most frequently used to identify and measure the severity of corneal epithelial disease [ 72 ], and several severity grading schemes have been proposed [ 71 , 73 ]. Staining develops due to corneal epithelial death, dysfunction or an altered permeability barrier that has been observed in DEDterm·dom patients and experimental mouse models [ 72 , 74 , 75 , 76 , 77 , 78 ]. Corneal epithelial disease may also be detected by imaging techniques.

Increased levels and activity of matrix metalloproteinases (MMPs) such as MMP-9 and its activator MMP-3 contribute to corneal barrier disruption [ 79 , 80 ]. MMP-9 knockout mice are resistant to corneal barrier disruption when exposed to desiccating stress, and MMP inhibitors such as corticosteroids and doxycycline have shown potential in preventing desiccation-induced corneal epithelial barrier disruption in animal models [ 81 ]. This can lead to accelerated desquamation of the apical epithelium and, in some cases, full thickness epithelial sloughing, which can predispose one to sight-threatening stromal ulceration and opacification. Mice subjected to desiccating stress show increased expression of cornified envelope precursors in the corneal epithelium, and patients with Stevens–Johnson syndrome can show cornification of the corneal epithelium [ 80 , 82 , 83 ].

6.2. Conjunctival Disease The conjunctiva has a stratified columnar epithelium with goblet cells that produce tear-stabilizing gel-forming mucins and immunomodulatory factors such as retinoic acid and transforming growth factor (TGF)-β2 [ 84 , 85 , 86 ]. Desiccation and lacrimal hyposecretion with a loss of tear trophic factors, activation of stress kinases and inflammatory cytokines, such as interferon gamma (IFN-γ), alter conjunctival differentiation [ 82 , 87 ]. The Th2 cytokine interleukin (IL)-13 stimulates proliferation and mucus production, while the Th1 cytokine IFN-γ induces goblet cell entrapment, the expression of cornified envelope precursors, decreased mucus production, unresponsiveness to cholinergic stimulation, endoplasmic reticulum stress and unfolded protein response and apoptosis [ 88 , 89 , 90 , 91 , 92 , 93 , 94 , 95 ]. Conjunctival disease is detected by vital dye staining with lissamine green or Rose Bengal dyes.

Goblet cell loss in the conjunctival epithelium is a well-recognized feature of ATDterm·dom [ 96 , 97 , 98 , 99 , 100 , 101 , 102 ]. The most severe ocular surface diseases, such as Stevens–Johnson syndrome, mucous membrane pemphigoid, graft versus host disease and severe alkali burns involving the conjunctiva, often have a complete loss of conjunctival goblet cells [ 69 , 103 , 104 , 105 ]. Goblet cell loss is accompanied by decreased concentration of the goblet cell mucin, MUC5AC, in tears [ 106 ] and correlates with increased conjunctival lissamine green and Rose Bengal dye staining and rapid TBUTterm [ 70 , 107 , 108 , 109 ]. Eyes with extensive goblet cell loss often have instantaneous TBU.

6.3. Clinical Implications Epitheliopathyterm·key is frequently observed in DEDterm·dom but may be clinically undetectable in some patients.

Epitheliopathyterm·key can contribute to instability of TF, blurred vision, altered permeability, nociceptor exposure and sensitization and pain in DEDterm·dom.

7. Dry Eye Diseaseterm·dom and Inflammationterm·key The surface epithelium and the TF contain dendritic cells, macrophages, mast cells, lymphocytes, fibroblasts, cytokines and additional immune mediators, which guard against pathogens and other environmental threats. DEDterm·dom may develop when this homeostasis is disrupted by aqueous tear deficiencyterm·dom, TF hyperosmolarity and inflammationterm·key of the ocular surface microenvironment [ 84 ]. Local, autoimmune-mediated ocular surface dysfunction may also play a role in DEDterm·dom pathogenesis [ 70 , 87 ].

Other factors that may contribute to inflammationterm·key of the ocular surface include: microtrauma; hyperosmotic stress; aging; irritants such as microbial antigens and UV light and infection and systematic inflammatory diseases, conditions and disorders (i.e., auto- and allo-immune diseases, neuroinflammation and sterile inflammationterm·key). In early phase inflammatory DEDterm·dom, any of these factors can stimulate the production of inflammatory cytokines and their subsequent immune responses.

7.1. Innate Immune Responses in Dry Eye Diseaseterm·dom The immunopathogenic mechanisms in DEDterm·dom are complex and are summarized below and in Figure 2 . In DEDterm·dom, multiple cell types of the innate immune system mediate inflammatory damage to the ocular surface. Innate immune responses include the upregulation of Toll-like receptors (TLRs) and nucleotide-binding domain, leucine-rich containing family and pyrin domain containing-3 (NLRP3) [ 110 , 111 ]. TLR signaling pathways stimulate the production of transcription factors, including activator protein (AP)-1, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and interferon regulatory factor (IRF)-5 [ 112 ].

Inflammationterm·key in dry eye diseaseterm·dom (DEDterm·dom). (I) The innate immune response in DEDterm·dom is mediated by multiple cells. Natural killer (NK) cells secrete interferon gamma (IFN-γ), which, along with other proinflammatory cytokines upregulated at the ocular surface, such as interleukin (IL)-1, IL-6 and tumor necrosis factor alpha (TNF-α, promote the maturation of antigen-presenting cells (APCs) through inducing the upregulated expression of major histocompatibility complex (MHC)-II, CD40, CD80 and CD86. In addition, these proinflammatory cytokines lead to the production of matrix metalloproteinases (MMPs) in epithelial cells, which further abrogate the corneal epithelial barrier. (II) The adaptive immune response in DEDterm·dom is initiated by the activation and migration of activated APCs toward the regional draining lymph nodes, where they prime naïve T cells (Th0) to differentiate and expand into IL-17-secreting T-helper cell 17 (Th17) cells and IFN-γ-secreting Th1 cells. IL-17 inhibits the regulatory T cells (Treg) suppressive function. Effector T cells migrate to the ocular surface, where they secrete an array of effector cytokines. Th1 cells secrete IFN-γ, which leads to the upregulated production of chemokines such as IL-9 (CXCL9), CXCL10, CXCL11, CXCR3 and cell adhesion molecules (CAMs), facilitating the ingress of more inflammatory cells to the ocular surface. IL-17 stimulates the production MMP-3 and MMP-9, leading to epithelial cell damage. IL-17 also increases the expression of vascular endothelial growth factor (VEGF)-A, VEGF-C, VEGF-D, VEGFR-2 and VEGFR-3. With the resolution of ocular inflammationterm·key, a small portion of Th17 cells convert into long-lived memory Th17 cells mediating chronic inflammationterm·key in DEDterm·dom.

The conjunctival epithelium and tears of patients with DEDterm·dom also contain elevated levels of inflammatory mediators such as ILs-6 and -23, tumor necrosis factor (TNF)-α and TGF-β1. These inflammatory mediators promote differentiation of CD4+ T-helper cell 17 (Th17), which secretes IL-17 cytokines (IL-17A and IL-17F), the major pathogenic cells promoting DEDterm·dom (see below), which will be described in the next section. Other proinflammatory cytokines produced by epithelial cells and macrophages participating in the innate immune response include IL-1α, IL-1β, IL-2, IL-5 and chemokines such as IL-8 (CXCL8) [ 113 ].

TNF-α and IL-1β promote the expression of intercellular adhesion molecule 1 (ICAM-1), as well as the expression of major histocompatibility complex (MHC) class II and co-stimulator B7 (CD80 and CD86) on antigen-presenting cells (APCs), which mediate APC-T-cell interactions. IL-1β stimulates the production of TNF-α and MMP-3 [ 95 , 114 , 115 , 116 ]. IL-1β and IFN-γ are associated with squamous metaplasia of epithelial cells [ 87 , 117 ]. IFN-γ decreases goblet cell differentiation and mucus production. In vitro, corneal epithelial cells express MHC class II with the stimulation of IFN-γ. Conjunctival epithelia overexpress MHC class II in a cytokine-rich environment, with a decrease of goblet cells. Some studies suggest that goblet cells play a critical role in maintaining ocular surface immune tolerance [ 85 ], and their disruption leads to dendritic cell maturation [ 118 ]. Fas and the Fas ligand are also elevated in DEDterm·dom [ 119 , 120 , 121 ] and regulate the apoptosis of ocular surface cells in the extrinsic pathway [ 122 ].

7.2. Adaptive Immune Responses in Dry Eye Diseaseterm·dom T cell infiltration in the ocular surface is a hallmark of chronic inflammationterm·key, and multiple studies show that autoreactive T cells play a central role in DEDterm·dom [ 91 , 121 , 123 ]. APCs activated by inflammatory mediators migrate to local lymph nodes, where they prime naïve T cells to polarize into effector CD4+ T-helper (Th1) and Th17 cells [ 123 , 124 ]. These effector cells then migrate to the conjunctiva, secreting IFN-γ and IL-17, and upregulate the production of a variety of chemokines [ 113 , 125 , 126 ] and cell adhesion molecules (CAMs), as well as vascular endothelial growth factor (VEGF)-C and VEGF-D.

Th17 cell differentiation is promoted by the transcription factor RORγt, which is expressed in response to IL-6, TGF-β and IL-23 [ 127 ]. Th17 cells secrete IL-17 [ 128 , 129 ], which increases proinflammatory cytokines and MMP3/MMP9 expression in response to desiccating stress. IL-17-secreted by Th17 cells also increase the expression of VEGF-C and VEGF-D, and their receptors VEGFR-2 and VEGFR-3, promoting corneal lymphangiogenesis [ 113 ] without associated hemangiogenesis [ 130 , 131 ]. In DEDterm·dom, Th17 homing is mediated by CCL20 [ 128 ]. In addition, a unique Th17 population, secreting both IL-17 and IFN-γ (Th17/1), was identified that amplifies ocular surface inflammationterm·key in DEDterm·dom, and the generation of Th17/1 is facilitated by environmental IL-12 and IL-23 [ 132 ]. Furthermore, chronic inflammationterm·key in DEDterm·dom is mediated in the long term principally by long-lived Th17 effector cells, namely memory Th17 cells [ 133 ]. These pathogenic memory Th17 cells are maintained by environmental IL-7 and IL-15 [ 134 ]. When IL-17 is blocked, DEDterm·dom severity significantly decreases.

The regulatory T cell (Treg; CD4+CD25+Foxp3+) attenuates the immune response by reining in the autoreactive T cells. Treg expresses integrin αEβ7 (CD103), which limits naïve T cell priming via the secretion of the anti-inflammatory cytokines (TGF-β and IL-10) and Treg/APC or Treg/T effector cell interactions [ 135 ]. There are two subsets of Tregs: one originating from the thymus (natural Treg, nTreg) and the other induced in the periphery in the presence of IL-2 and TGF-β (induced Treg, iTreg). Inadequate suppression by Tregs leads to disruption of immune tolerance and the generation of effector T cells. The Th17 cells in DEDterm·dom were found to be resistant and functionally antagonistic to Treg activity [ 123 ]. The dysfunction of Treg suppression exacerbates ocular surface inflammationterm·key in models of DEDterm·dom [ 123 ].

7.3. Neurogenic Inflammationterm·key Mechanical and inflammatory damage to the ocular surface may lead to the synthesis of neurotrophic factors that stimulate nerve growth but can also alter the corneal nerve structure, as seen in the sub-basal corneal nerve plexus, and promote inflammationterm·key, which can lead to nerve degeneration. Epithelial damage induced by hyperosmolarity stimulates the release of vasoactive neuropeptides and the activation of immune cells, resulting in plasma extravasation and local inflammationterm·key [ 136 ].

Neuropeptides and neurotrophins found at the ocular surface have also been associated with nonspecific corneal pain and other DEDterm·dom symptoms.

These neuropeptides maintain neurogenic inflammationterm·key and work together with the immune responses, not only protecting the ocular surface but, also, initiating the immune response in DEDterm·dom and regulating its chronicity. Thus, nerve-derived factors can both attenuate and amplify DEDterm·dom severity depending on the context in which they function.

Hormonal variations may also affect the ocular surface in DEDterm·dom. Studies in animals have reported that estrogen may upregulate MMP-2 and MMP-9 and increase the expression of inflammatory genes such as IL-1β, IL-6 and IL-8 in human corneal epithelial cells. By contrast, androgens may reduce macrophage TNF-α and IL-1β expression. However, some studies have found that estrogen also may decrease DEDterm·dom severity [ 137 ].

In summary, there is increasing evidence that a wide array of immune and nerve-derived factors can influence one another through complex mechanisms that result in damage to the ocular surface epithelium, changes in the sub-basal nerve plexus nerve density and function and development of DEDterm·dom symptoms. Much work remains to be done to better elucidate the interaction of these factors in chronic DEDterm·dom.

7.4. Clinical Implications Inflammationterm·key is a key aspect of DEDterm·dom pathogenesis and severity.

Methods for identification of DEDterm·dom include the RPS InflammaDry Detector, an immunoassay test for the detection of elevated levels of the MMP-9.

The control of inflammationterm·key, chronically or during clinical flares, is necessary for managing patient discomfort and ocular surface disease.

While there can be a lack of correlation between patient symptoms and signs of ocular surface disease, managing inflammationterm·key can help attenuate both the signs and symptoms of DEDterm·dom.

8. Neurosensory Abnormalitiesterm·key In its new definitionterm·key of DEDterm·dom [ 8 ], DEWS II introduced the concept of neurosensory abnormalitiesterm·key, emphasizing the central role of the corneal nerves and the neurosensory loop driven by the trigeminal pathway. The role played by corneal innervation has extensive consequences in terms of neurotrophic balance, the regulation of tear secretion and ocular surface inflammationterm·key, with the emerging concepts of neuroimmune synapse or neurogenic inflammationterm·key illustrating the interactions between the immune system and the trigeminal pathway.

The human cornea is densely innervated by the sensory fibers of the trigeminal nerve, with relatively few nerve bundles penetrating the cornea, but, also, a very dense network of intraepithelial nerve endings with a variety of mechanical, chemical and thermal receptors [ 52 ]. Corneal nerves also play a major role in controlling lacrimal gland secretion, thus regulating tear volume and composition through the trigeminal–facial nerve loop.

Neurosensory abnormalitiesterm·key in the ocular surface may participate in three different but closely related mechanisms in DEDterm·dom, which may act as initiators or consequences of the disease—namely, neurogenic inflammationterm·key, neuropathic painterm·dom and neurotrophic keratopathy.

Neurogenic inflammationterm·key is a key factor of the vicious cycle involved in DEDterm·dom [ 138 ]; neuropathic painterm·dom and neurotrophic keratopathy may explain the frequent discrepancies between DEDterm·dom signs and symptoms, with corneal hypoesthesia leading to the paradoxical condition of a highly damaged cornea with few or no symptoms, whereas neuropathic painterm·dom corresponds to highly symptomatic patients despite no, or barely detectable, corneal damage.

As a causative role in DEDterm·dom, alterations of the corneal innervation loop are primary mechanisms of a wide variety of conditions—among them, corneal refractive surgery, where DEDterm·dom has become the most frequent and disabling complication. Most causes are iatrogenic. However, structural and functional alterations of the sub-basal corneal nerves were identified in other types of DEDterm·dom, with reduced nerve density and branching, increased tortuosity, bead-like patterns, greater nerve width and aspects of neuromas, a pattern that would appear more closely associated with neuropathic painterm·dom [ 139 , 140 ]. The reduction in nerve density was highly correlated with an increased density of inflammatory cells and the ocular surface disease index, illustrating the close relationships between nerves, symptoms and corneal inflammationterm·key [ 141 ].

A key role of sustained neural stimulation in response to increased osmolarity, epithelial alterations and mechanical stress is the release of proinflammatory neuropeptides by the nerve endings, leading to neurogenic inflammationterm·key, a prominent mechanism of DEDterm·dom.

However, some patients do not show significant tissue damage that would explain their high levels of symptoms. This raises the concept of neuropathic painterm·dom, where the symptoms may resemble those of DEDterm·dom, and the signs are mostly limited or only associated with mild tear abnormalities or subclinical changes or are only detectable using confocal microscopy or impression cytology through the expression of tear or conjunctival biomarkers of inflammationterm·key [ 140 , 142 , 143 ]. DEDterm·dom and neuropathic painterm·dom often have similarities in their development [ 144 ], but the continuous firing of corneal nerve receptors may result in a lowered stimulatory threshold. This is typically experienced as persistent irritation or pain in response to a normally innocuous stimulation—namely, allodynia and/or increased impulse transmission following suprathreshold stimulation, with abnormally increased pain sensation—namely, hyperalgesia [ 52 ].

When stimulation persists, patients may progressively develop mechanisms of central neuronal sensitization within the trigeminal complex in the brainstem and, in higher-order neurons in the brain, leading to neuropathic painterm·dom symptoms [ 52 , 145 , 146 ]. Chronic neuropathic painterm·dom persists irrespective of the ocular surface findings and initial mechanisms, thus resisting etiologic or symptomatic treatments [ 52 , 145 ]. Indeed, a significant part of these cases are associated with depression or anxiety and may also involve patients with a general pain syndrome. Small fiber neuropathy has been frequently associated with Sjögren’s syndrome, and a patient’s general condition should be addressed for holistic patient care [ 147 ].

Conversely, an opposite condition may be observed in DEDterm·dom when chronic damage to corneal nerves may cause decreased sensitivity of the cornea, with low levels of symptoms despite a highly damaged ocular surface. This might explain one aspect of the well-known sign/symptom discrepancy in DEDterm·dom, but, additionally, the neurotrophic consequences of nerve abnormalities may participate in highly aggravating corneal damage. Indeed, even if nerve transection is mostly transient in DEDterm·dom induced by refractive surgery, sustained anatomical or functional nerve dysfunction deprive the cornea of neurotrophic factors and prevent the corneal epithelium from recovering and, in the most severe cases, leading to a neurotrophic keratopathy. Decreased corneal sensitivity has been observed in patients with high variability, but there is a significant correlation with disease severity, indicating progressive corneal nerve damage and/or dysfunction in a chronically damaged ocular surface [ 148 ].

Three stages of neurotrophic keratopathy have been described [ 149 ], and the features observed in stage 1 are very similar to those of severe DEDterm·dom. Patients may present with painless sensations or few symptoms, despite damaged corneas. However, symptoms driven by conjunctival inflammationterm·key or hyperactive nerve fibers may mask localized areas where the cornea is anesthetized, which may lead to the delay or underestimation of the neuropathic mechanisms. In this case, inappropriate treatment can lead to more severe damage and the involvement of deeper layers of the cornea. Therefore, an assessment of corneal sensitivity is required for weakly symptomatic patients with corneal epitheliopathyterm·key or epithelial damage resisting adapted therapies [ 150 ].

From the clinical point of view, neurosensory abnormalitiesterm·key play multiple roles in DEDterm·dom, as the primary source of disabling symptoms and sensations, as well as by disrupting the homeostasis of the ocular surface, blocking the secretion of neurotrophic factors or stimulating chronic inflammationterm·key. Their role, therefore, deserves much attention, and developments of new therapies can benefit from recognition of this core mechanism and from further research.

Clinical Implications The human cornea is densely innervated and corneal nerves participate in the stability of the ocular surface. Their continuous stimulation by a disrupted TF may cause symptoms.

Neurosensory abnormalitiesterm·key may participate in three different but closely related mechanisms in DEDterm·dom: neurogenic inflammationterm·key, neuropathic painterm·dom and neurotrophic keratopathy. These may contribute to the lack of correlation often observed between DEDterm·dom signs and symptoms.

Neurosensory abnormalitiesterm·key in DEDterm·dom must be studied further but should be considered when assessing signs, symptoms and treatment responsiveness in the clinic.

9. Implications for Regulatory Science Novel treatment pathways for DEDterm·dom are being explored with innovative pharmaceutical agents. Initial studies at the basic research level are followed by translational research, aimed at investigating efficacy using in vitro and animal experiments. At this stage, it is vital to determine if a newly discovered agent or molecule has been accepted for medical use in other fields by government regulatory agencies, so that the requirements for nonclinical studies, including toxicology studies, may not be necessary.

There are important issues to be addressed when considering the introduction of medical products for the treatment of DEDterm·dom, including that only a few products specifically aimed at the treatment of DEDterm·dom have been officially approved by government regulatory agencies. It is likely the result of conceptual discrepancies between academic science, and regulatory science could account for the small number of products approved by regulatory agencies for DEDterm·dom. In many countries, approved medical products are categorized into three major groups: pharmaceutical agents (drugs), medical devices and products for regenerative medicine. Of those, most medical products designed for DEDterm·dom treatment fall into the categories of pharmaceutical agents and medical devices and, as such, are strictly regulated by the laws and/or guidelines set by each government.

Academic research scientists tend to focus on efficacy, while regulatory agencies are primarily concerned with safety, which is a vital perspective of regulatory science. It is always possible that patients will unexpectedly have adverse events caused by pharmaceutical agents and/or contaminated pathologic microorganisms and viruses, illustrating why strict government regulation is important. In order to assess the safety and efficacy in clinical trials, the primary endpoint should be set not only from the perspective of clinicians and researchers but should also seek to assess the restoration of visual function.

In the field of DEDterm·dom research, one of the difficulties is the absence of global consensus between regulatory agencies on the definitionsterm·key of TF abnormalities, including the cut-off value for TBUTterm and the Schirmer 1 test. Each country has established its own cut-off value ( Table 3 ). Moreover, regulations for the approval of DEDterm·dom products in clinical trials vary between the US, the EU and Japan ( Table 4 ) [ 151 , 152 , 153 , 154 ]. Another difficulty is the lack of an established surrogate endpoint for global clinical trials.

Abnormal values of the tear breakup timeterm and Schirmer I test in each country.

Current approval requirements in the US, EU and Japan.

Several important points differ slightly between the processes of research and development and those of product development, especially on the equal quality of products. These points might be essential for future internationally harmonized clinical trials for DEDterm·dom products—again, illustrating the importance of regulatory science with its requirement for an accumulation of well-controlled evidence-based data.

In summary, the safety profile of study drugs should be the object of thorough attention. Real-world data analysis could be useful in such circumstances, following government approval of pharmaceutical agents, and a rational use of medicine has also been proposed [ 155 , 156 ].

Clinical Implications Academic science tends to focus on efficacy; however, safety—a critical consideration for drug research—is key for regulatory agencies.

The establishment of a well-organized surrogate endpoint is important for worldwide clinical research, as currently there is no global consensus on the measure of TF abnormalities in clinical trials.

10. Conclusions Many common diseases, including ocular diseases, are caused by the interaction of human genes and the environment. The numbers of DEDterm·dom patients have increased dramatically in the past decades (up to 30–40% in some populations) [ 2 , 3 , 4 , 5 , 6 ], likely to be predominantly caused by environmental changes. The increase in visual tasks, an aging society, sleep deprivation, impairments in circadian rhythms, lack of exercise, increase in obesity and sedentary lifestyles could also contribute to the increase in DEDterm·dom incidence [ 157 , 158 , 159 , 160 , 161 ]. In one sense, DEDterm·dom can be considered a lifestyle disease. Although we have emphasized the importance of TFBU, the control of inflammationterm·key is also important by employing various therapeutics [ 84 , 162 , 163 , 164 ]. Since the consensus of the National Eye Institute/Industry Workshop on Clinical Trials in Dry Eyeterm·dom in 1995 [ 10 ], the definitionterm·key and diagnostic criteria have been changing partially to reflect the changing nature of DEDterm·dom and the causes of DEDterm·dom, in our modern, visually oriented society where the prolonged use of computers or smartphones is common in daily life. The activities of society will continue to evolve over the next generations and will affect the characteristics of DEDterm·dom in the future.

The purpose of this paper was to reach a global consensus among ophthalmologists who examine DEDterm·dom patients almost every day. There have been alternative definitionsterm·key of DEDterm·dom in the past, but here, we proposed a simple definitionterm·key, with emphasis on the importance of TBU and subjective symptoms or visual impairmentterm·key. As stated in Section 2 , the new definitionterm·key proposed is: “Dry eyeterm·dom is a multifactorial disease characterized by a persistently unstable and/or deficient tear filmterm·key causing discomfort and/or visual impairmentterm·key, accompanied by variable degrees of ocular surface epitheliopathyterm·key, inflammationterm·key and neurosensory abnormalitiesterm·key”. We hope this consensus will contribute to the diagnosis of DEDterm·dom in clinics and aid progress in the DEDterm·dom research field.

Acknowledgments N. YokoipersName wishes to thank John Bush (Dept. of Foreign Affairs, Kyoto Prefectural University of Medicine, Kyoto, Japan) for reviewing part of the manuscript. Editorial support was provided by Synergy Vision (London, UK) and funded by the Asia Dry Eyeterm·dom Society. The authors wish to thank Catherine Oshima (Keio University) for providing administrative support.

Abbreviations Appendix A: Participant List Christophe BaudouinpersName, Quinze-Vingts Hospital, Paris, France Reza DanapersName, Massachusetts Eye & Ear, Boston, MA, USA Hyo Myung KimpersName, Korea University Medical Center, Anam Hospital, Seoul, South Korea Shigeru KinoshitapersName, Kyoto Prefectural University of Medicine, Kyoto, Japan Friedrich KrusepersName, University of Erlangen-Nuremberg, Erlangen, Germany Zuguo LiupersName, Eye Institute of Xiamen University, Xiamen, China Elisabeth M. MessmerpersName, Ludwig Maximilian University, Munich, Germany Stephen C. PflugfelderpersName, Baylor College of Medicine, Houston, TX, USA Maurizio RolandopersName, University of Genoa, Genoa, Italy Kazuo TsubotapersName, Keio University School of Medicine, Tokyo, Japan Norihiko YokoipersName, Kyoto Prefectural University of Medicine, Kyoto, Japan Author Contributions Conceptualization, K.T., S.C.P. and R.D.; active discussion on the definitionterm·key and supporting information, K.T., S.C.P., Z.L., C.B., H.M.K., E.M.M., F.K., M.R., N.Y., S.K. and R.D.; writing—original draft preparation, K.T.; writing—review and editing, K.T., S.C.P., Z.L., C.B., H.M.K., E.M.M., L.L., J.T.C.-G., F.K., M.R., N.Y., S.K. and R.D.; supervision, R.D., S.C.P. and Z.L. and funding acquisition, K.T., Z.L., H.M.K. and N.Y. All authors have read and agreed to the published version of the manuscript.

Funding This research was funded by Asia Dry Eyeterm·dom Society and, for N.Y., “Grants-in-Aid for scientific research from the Japanese Ministry of Education, Culture, Sports, Science and Technology (Grant number: 16K11269).

Conflicts of Interest The funders had no role in the design of the study; in the collection, analyses or interpretation of data; in the writing of the manuscript or in the decision to publish the results. Lingyi LiangpersName and Jimena Tatiana Carreno-GaleanopersName have no conflicts of interest to report. Christophe BaudouinpersName acts as a consultant for Alcon, Allergan, Dompe, Horus Pharma, Santen and Sifi, Thea Labs. Reza DanapersName reports research support from Allergan and Shire, consulting from Aldevra, Dompe, Novaliq, Kala and Santen and owns equity at Claris Bio. Hyo Myung KimpersName reports research funding from Santen Pharmaceutical Co., Ltd. Shigeru KinoshitapersName reports grant support from Santen Pharmaceutical Co., Otsuka Pharmaceutical Co., Senju Pharmaceutical Co., KOWA Co. Ltd., HOYA Co., Oncolys Biopharma. Friedrich KrusepersName received financial support for traveling from TRB Chemedica and Santen and acts as a consultant for KOWA. Zuguo LiupersName reports research funding from Alcon, Santen, Senju, Yuejia, Xingqi, Zhuhaiyisheng and Dakai, as well as consultancies and travel grants from Allergen, Novartis, Johnson & Johnson Vision, Santen, Senju, Yuejia, Xingqi, Zhuhaiyisheng, Reilin and Dakai. Elisabeth M. MessmerpersName acts as a speaker or consultant for: Alcon/Novartis, Dompé, Kala, Pharm-Allergan GmbH, Santen GmbH, Sun, Théa Pharma GmbH, TRB-Chemedica AG, Ursapharm and Visufarma. Stephen C. PflugfelderpersName reports research support from Allergan and Santen and consulting from Allergan, Shire and Senju. Maurizio RolandopersName reports consultancies received from Alcon, Kala, SIFI, Sun Pharma and Théa, as well as travel and speaker grants from Allergan, Bausch and Lomb, Alfa Intes, Bruschettini, Dompé, Medivis, Off, Santen. Kazuo TsubotapersName reports consultancies and research funding received from Santen Pharmaceutical Co., Ltd. and Otsuka Pharmaceutical Co., Ltd., consultancies for Théa Laboratories and Novaliq GmbH and research funding from Wakamoto Pharmaceutical Co., Ltd., Kowa Company, Echo Electricity Co., Kao, Rohto and Ophtecs. He holds the patent rights for the method and the apparatus used for the measurement of functional visual acuity (US patent no: 255 7470026). He holds a joint patent with Jins, Inc. for moisture glasses. TsubotapersName is the CEO of TsubotapersName Laboratory, a company in the dry eyeterm·dom field. Norihiko YokoipersName has received personal fees from Santen Pharmaceutical Co., Ltd., Otsuka Pharmaceutical Co., Ltd. and consultancies from Rhoto Co., Ltd. and Alcon Japan Co., Ltd. and patents for the ophthalmologic apparatus with Kowa Co., Ltd.

Footnotes References