Understanding the true burden of dry eye disease

Abstract

The term ‘dry eye’ (DE) has evolved over the past two decades to include both symptoms (visual complaints and dysesthesias) and signs (aqueous and evaporative deficiency) of disease. DE is common in older individuals and is a source of morbidity. Confusion arises, however, on what combination of symptoms and signs constitute DE and how to best individualize treatment in patients. This editorial will discuss the evolution of DE, discuss potential sub-categorizations for the disease, and discuss their potential implications on treatment.

Keywords:

• dry eye
• neuropathic ocular pain
• tear evaporation
• tear production

The term ‘dry eye’ (DE) has undergone a revolution in the past 20 years. Prior to 1990, there were almost no publications on DE, other than in the context of Sjogren’s syndrome. A few large, population-based studies performed in the USA in the late 1990s and early 2000s brought DE into the limelight, when they reported that DE symptoms were a frequent complaint in the general, non-autoimmune population [1,2]. Studies conducted in several countries around the world, including Germany, Australia, Japan and Indonesia, reported similar findings [3]. A problem with many of these studies is that they did not include an ocular surface exam, and it was assumed that those with DE symptoms actually had dryness on their ocular surface. This is not the case, however, as symptoms and signs of DE have consistently been found not to correlate [4]. Furthermore, when considering DE symptoms, some DE patients complain of visual problems, reported as blurry or fluctuating vision, while others complain of dysesthesias, such burning, aching and dryness. Although the origin of these symptoms is likely different, an unhealthy tear film driving the former and corneal nerves driving the latter, these symptoms are generally lumped into one category. For example, the most common DE scale, the ocular surface disease index, arrives at a DE severity score by lumping both visual complaints and dysesthesias.

To add to the confusion, DE was first thought to be a problem of tear production (typically measured with the Schirmer’s test), as is certainly the case in specific DE syndromes such as Sjogren’s and graft versus host disease. In the general DE population, however, evaporative issues have been found to be much more common [4,5]. In fact, in Asian countries, over 60% of the population was found to have at least one abnormality on examination of the eyelid margin, including abnormal vascularity, plugging, collarettes, gland dropout and/or abnormal meibum quality [6,7]. Beyond eyelid health, other anatomic disturbances, not traditionally lumped in with DE, such as eyelid laxity and conjunctivochalasis, are also associated with DE symptoms [8,9].

On top of this, new DE biomarkers have been introduced, such as measurements of tear osmolarity (TearLab, San Diego, CA, USA) and matrix metalloproteinase 9 (Inflammadry, RPS, Tampa, FL, USA), and new devices are available to dynamically measure tear parameters (HD Analyzer; Visiometrics, Terrassa, Spain and Keratograph^® 5M; Oculus, Inc., Arlington, WA, USA). With all these measures (new and old), it is no wonder that everyone these days seems to have some form of ‘DE’. In a clinic-based study measuring many of the above metrics (osmolarity, tear break up, corneal staining, Schirmer, assessment of eyelid vascularity and meibum quality), we found that over 90% of our elderly population had at least one abnormality [Unpublished Data].

This reality signals that as a field, we need to re-visit our definition of DE. This concept was highlighted at the recent 2015 Association for Research in Vision and Ophthalmology meeting where dozens of DE posters all had different definitions for the disease. In 2007, the DE workshop defined DE as follows: ‘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. It is accompanied by increased osmolarity of the tear film and inflammation of the ocular surface’ [10]. While it is indeed true, not all patients fit all parts of this description. Given the various treatment options available for DE, it is time to take a step back and re-classify DE into sub-groups that make sense, based on underlying pathophysiology, clinical descriptors, diagnostic criteria and likely treatment response.

Our approach to DE starts with symptoms. Symptoms are the driver of DE morbidity and impair physical and mental functioning [11]. In fact, the impact of moderate-to-severe DE symptoms is equivalent to severe migraine [12]. We, therefore, categorize symptomatic patients into those with visual complaints and those with ocular pain.

Pain, as defined by the International Association for the Study of Pain, is ‘an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage’. Based on this definition, we consider any ocular dysesthesia a form of ocular pain. These dysesthesia descriptors include the common complaint of ocular dryness, but can also include other pain descriptors such as ‘throbbing’, ‘shooting’, ‘stabbing’, ‘sharp’, ‘hot-burning’, ‘aching’, ‘heavy’, ‘tender’ and ‘foreign body sensation’.

In the pain field, pain disorders are broadly grouped into two categories, nociceptive pain and neuropathic pain, and we hypothesize that both are involved in DE. Nociceptive pain occurs when the normally functioning corneal somatosensory pathway responds to a noxious stimulus, such as a drop in temperature, elevated osmolarity and/or pollution. This type of pain is typically a result of tissue damage and inflammation and is usually transient. Neuropathic pain, on the other hand, occurs when there is dysfunction in the somatosensory system and tends to be more chronic [13]. Abnormalities in the corneal somatosensory pathway may occur in peripheral nerves (peripheral sensitization) or in second- or third-order nerves (central sensitization). Changes in nerves can include alterations in ion channel activity (sodium, calcium and potassium currents), signaling molecules and genes, as well as in anatomy, with phenotypic changes that involve reduced activation thresholds, increased excitability, enhanced synaptic transmission and abnormal signal amplification. Common findings in patients with neuropathic pain are spontaneous pain, hyperalgesia (e.g., to wind) and allodynia (e.g., to light), and all these features have been described in groups of patients with DE [14,15]. Furthermore, secondary hyperalgesia, a phenomenon associated with neuropathic pain, may manifest in DE as concomitant craniofacial disturbances such as blepharospasm and migraine [16]. Further support for the presence of central sensitization in some patients with DE comes from animal models, for example, rats developed enlarged convergent periorbital receptive fields after exorbital gland removal [17].

Despite this biologic plausibility, corneal somatosensory nerve structure and function have not been traditionally incorporated into the DE examination, in large part due to the limited number of commercially available devices to assess nerves (Cochet-Bonnet, confocal microscopes). Pain questionnaires, however, may prove to be useful in this situation. Pain questionnaires are widely used to assess features of neuropathic pain in non-ocular pain disorders, as certain descriptors are more common in patients with neuropathic pain, that is, ‘burning’, ‘tingling’ or ‘electric’. Asking patients to describe their ocular pain using well-established metrics [18] and assessing for the presence of sensitivity to wind and light may be a low cost, first-line approach to identify features of neuropathic ocular pain (NOP).

Putting all this information together brings us back to the definition of DE. As DE likely has a natural history [19], with each patient somewhere on the continuum, where do we put our limits? In short, which components of the original dry eye workshop (DEWS) 2007 definition are sufficient to warrant a diagnosis of DE? Do patients who report ocular dryness, but who have normal tear production have DE? Do patients with elevated tear osmolarity, but no evidence of corneal staining have DE? Do asymptomatic patients with evaporative deficiency have DE? Do patients with fluctuating vision and conjunctivochalasis have DE? In addition, just as important as the definition, there is much debate in the literature on which of these scenarios should be treated and with which agents.

For example, some advocate treating asymptomatic patients with DE signs, as failure to do so may lead to suboptimal results after surgery (cataract, refractive) [19]. Others put more weight on symptoms, but it is known that many patients remain symptomatic on therapy (artificial tears, topical anti-inflammatory agents, lid hygiene) and that physicians cannot predict which patient will benefit most from which therapy. Sub-typing DE patients into clinically meaningful categories may allow for better research designs and more targeted therapy. For example, patients with detectable ocular surface inflammation may respond better to topical anti-inflammatories than those with a healthy ocular surface and evidence of NOP. More research is needed to evaluate these important questions.

Regarding ocular pain, no data is currently available on the best management of patients with features of NOP. Anti-inflammatory therapy has been shown to improve neuropathic pain in other models [20], and thus, topical anti-inflammatory agents may be useful in this group. It is possible, however, that such patients will need multi-modal therapy that includes anti-neuropathic pain treatment. With many agents available to treat neuropathic pain, research is needed to understand the role, if any, of these agents.

To conclude, DE is now acknowledged as a public health problem given its prevalence, morbidity and cost implications. While DE was initially thought to be a ‘simple’ disease of tear production, exciting new research has revealed that it is a complex and heterogeneous disorder with diverse neuropathologic mechanisms. In fact, what we currently refer to as ‘DE’ likely represents a group of different disease sub-types. More research is needed on whether categorizing sub-types within DE by features of NOP can improve the diagnosis and treatment of DE in the future.

Financial & competing interests disclosure

This paper was supported by the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Clinical Sciences Research and Development’s Career Development Award CDA-2-024-10S (Galor), NIH Center Core Grant P30EY014801, Research to Prevent Blindness Unrestricted Grant, Department of Defense (DOD- Grant# W81XWH-09-1-0675); and NIH NIDCR R01 DE022903 (Levitt and Martin). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.