Defining Dry Eye from a Clinical Perspective

Abstract

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

Keywords: corneal epitheliopathy; definition; dry eye; dry eye signs; dry eye symptoms; inflammation; neuropathic pain; tear film breakup.

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 film (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 eye (ATDDE) or decreased wettability dry eye (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 eye (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.

Figure 2

Inflammation in dry eye disease (DED). (I) The innate immune response in DED 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 DED 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 inflammation, a small portion of Th17 cells convert into long-lived memory Th17 cells mediating chronic inflammation in DED.