Pathophysiology

Mechanisms of Dry Eye Syndrome (DES)

Several factors contribute to the development of DES, including:

• Lacrimal, meibomian and accessory gland function
• Goblet cell function
• Ocular surface and eyelid health and anatomy
• Inflammation in the tear film
• Hormonal abnormalities.

The core mechanism and hallmark feature of DES pathogenesis is tear film hyperosmolarity. Both aqueous tear deficient dry eye (ADDE) and EDE involve tear hyperosmolarity: in ADDE, it occurs because less solvent (water) is produced by the lacrimal glands and in evaporative dry eye (EDE) because too much water is lost by evaporation. The hyperosmolarity causes both direct and indirect (i.e., inflammatory) damage to the ocular surface, particularly to epithelial and goblet cells. This activates epithelial stress signaling, mediated by mitogen activated protein kinase (MAPK) and nuclear factor κB (NFκB), which in turn stimulates release of pro-inflammatory factors, including cytokines (e.g., IL-1), tumor necrosis factor α (TNFα) and matrix metalloproteases (MMPs). Inflammation of the ocular surface also disrupts the neuronal pathways that control blink rate, tearing and corneal sensation. Epithelial and neuronal disruption promotes further tear film instability and sets up a self-perpetuating positive feedback loop. The core and ancillary mechanisms contributing to DES are shown in Figure 1-3.

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It is important to note that tear film instability can start in the absence of hyperosmolarity. For example, conditions such as xerophthalmia, ocular allergy and topical preservative and contact lens use, may cause early tear film breakup, leading to local hyperosmolarity and initiating the inflammatory cascade downstream. This is an example of ocular surface-related EDE.

Finally, in line with the recognition that manifestations of DES fall on a spectrum between ADDE and EDE, it is important to keep in mind that multiple mechanisms may coexist and produce similar symptoms. This is illustrated in Figure 1-4, which shows that the four DES categories defined by CEDARS may have overlapping symptoms.

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