What’s new in dry eye disease diagnosis? Current advances and challenges

Background

With a global prevalence ranging from 20 to 50%, dry eye disease (DED) is a significantly growing health problem worldwide¹. DED has been diagnosed in about 16.4 million adults in the US, and 6 million more experience DED symptoms without a formal diagnosis. DED is more prevalent in older individuals and women¹. However, it is on the rise among the young as well, and recent studies report DED symptoms in 30 to 65% of office workers^2,3 and 25% of high school students^4,5. DED symptoms in young individuals have been linked to the use of digital devices^6,7 and refractive treatments, including contact lens wear and refractive laser. Also, increased awareness of the association between DED and autoimmune diseases, hormonal changes, and systemic drug therapies has increased the recognition of DED symptoms by physicians in other specialties.

DED has a marked negative impact on the physical and psychosomatic well-being of patients because of discomfort, pain, and altered visual acuity, preventing them from carrying out basic activities of daily living, such as reading, watching television, driving, and working¹. Symptom severity correlates positively with patient-reported depression, anxiety, and stress scores^8–11. Increased suicidal ideation in patients with severe DED underscores the extreme impact that DED can have on quality of life¹².

DED also exerts a substantial economic impact. One healthcare utility assessment study found that DED symptoms were comparable to those of angina¹³. The estimated average annual direct cost of ophthalmologist-managed care of one DED patient ranges from $270 USD in France, $530 USD in Japan, and $800 USD in the US to $1100 USD in the UK¹⁴. Additionally, the economic burden increases exponentially when loss of work productivity is taken into account. In the US, the annual direct healthcare cost of DED is about $4 billion and loss of productivity accounts for up to $55 billion annually^1,15.

Given the increasing public health importance of DED, there has been significant research in the field of DED and ocular surface health. This article addresses the newly evolving strategies and highlights the persistent gaps in our understanding of this challenging condition and future directions of research.

Discussion

Our approach to DED has undergone a paradigm shift in the past few decades as new research and the use of sophisticated imaging modalities have improved our understanding of the pathophysiology of DED. The first formal definition of DED, published in 1995 by the National Eye Institute/Industry working group on Clinical Trials in Dry Eye, was “Dry eye is a disorder of the tear film due to tear deficiency or excessive tear evaporation which causes damage to the interpalpebral ocular surface and is associated with symptoms of ocular discomfort”¹⁶. One major limitation in this definition is that it suggests that dry eye is one disease. An emerging paradigm in dry eye is the recognition that DED is an umbrella term that represents a spectrum of disease. This led to the new refined definition by a panel of experts in the field at the Tear Film and Ocular Surface Dry Eye Workshop II in 2017: “Dry eye is a multifactorial disease of the ocular surface characterized by a loss of homeostasis of the tear film, and accompanied by ocular symptoms, in which tear film instability and hyperosmolarity, ocular surface inflammation and damage, and neurosensory abnormalities play etiological roles”¹⁷.

Inflammation has played a central role in DED given that the disease was first described in individuals with Sjögren’s. Animal models highlighted the central role of inflammation in DED by demonstrating that hyperosmolar stress on the ocular surface triggered the release of inflammatory mediators such as interleukin 1 beta (IL-1β), tumor necrosis factor-alpha (TNF-α), and matrix metalloproteinase 9 (MMP-9)¹⁸. Similar inflammatory mediators have been found on the ocular surface of individuals with DED^19,20. The importance of T cells in the pathophysiology of DED was demonstrated by triggering disease in naïve mice solely by the transfer of T cells from affected animals^21,22. However, it needs to be considered that the definition of DED in these mice consisted of corneal epithelial staining, which is a component—but does not represent the full spectrum—of DED in humans. Furthermore, inflammation and resulting ocular surface damage form a vicious cycle in which inflammation both triggers and results from chronic DED.

In humans, however, DED is typically diagnosed by symptoms, an aspect of DED that does not have a good animal model counterpart. Even the symptoms of DED vary; some individuals present with symptoms of pain (described in terms of dryness, burning, aching, tenderness, and foreign body sensation) and others with poor or fluctuating vision. The etiology of these two diverse symptoms suggests two different underlying mechanisms in DED. In the former, nociceptor activation from terminal nerve endings on the cornea and conjunctiva leads to symptoms of pain; in the latter, an unhealthy tear film and ocular surface disruption result in fluctuating or poor vision. Adding to the complexity, it is well known that symptoms of DED do not correlate well with observed ocular surface signs²³. Given this reality, to understand DED in the context of an individual patient, the treating physician needs to properly diagnose and treat the specific pathophysiologic mechanisms that drive symptoms in a particular patient.

Tear film stability

The tear film comprises three layers: an innermost mucin layer composed of gel and soluble mucins secreted by conjunctival goblet cells that adhere the tear film to epithelial cells, a middle aqueous layer secreted by lacrimal and accessory glands to provide hydration and lubrication, and an outer lipid layer secreted by Meibomian glands to decrease tear evaporation^24,25. Recently, a two-tiered model in which the mucin and aqueous interact in a muco-aqueous layer was proposed²⁶. Tear production is controlled by sympathetic and parasympathetic stimulation of the lacrimal glands, which in turn is controlled by a neural reflex arc originating from the ocular surface^27,28. Innervation of the Meibomian glands and goblet cells is less well understood but is also likely under parasympathetic control²⁹.

Aspects to be considered in patients with dry eye disease symptoms

Conclusions

DED is a common, multifactorial condition with a variable clinical presentation and frequent discordance between symptoms and signs of disease. As such, the elucidation of distinct pathways underlying the various clinical phenotypes is critical. Thus, it is essential to perform a standardized examination and to evaluate the different components of DED while considering local findings like MGD and systemic diseases, including autoimmune conditions like Sjögren’s, rosacea, chronic overlapping pain, and migraine. Objective and quantitative diagnostic methods can be used to detect the hallmarks of DED: ocular surface inflammation, epithelial damage, and tear film hyperosmolarity. However, it is important to note that new diagnostic tests are needed to evaluate some aspects of DED, particularly the presence of nerve dysfunction. For optimal management, DED in an individual patient should be subcategorized in terms of underlying pathophysiology and clinical severity and a treatment plan should be tailored with objective tests used to follow therapeutic response.