We used to think dry eye was a fairly simple disease of tear production, a common affliction of the elderly responsible for significant morbidity and expense.1-3 But new research shows dry eye is complex and associated with pathological changes in several areas, including the lacrimal gland, meibomian glands, ocular surface and corneal somatosensory pathway. With this new understanding, it’s time to revisit our definition of dry eye so we can offer improved individualized therapy for patients.
Redefining dry eye
In 2007, the dry eye workshop (DEWS) defined dry eye as “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." 4 While true, the experience of all patients does not fit all aspects of this definition.
Since the definition was penned, all of its components have been studied under the heading “dry eye,” and included patients exhibiting a range of dry eye symptoms and signs, with symptoms defined as visual complaints (blurry vision, fluctuating vision) and/or ocular pain/dysesthesias (dryness, burning, aching, foreign body sensation), and dry eye signs including decreased tear production, increased tear evaporation, ocular surface staining, meibomian gland abnormalities and biomarkers, such as tear osmolarity (as measured with the TearLab Osmolarity Test, TearLab, San Diego)5 and ocular surface matrix metalloproteinase 9 (as measured with InflammaDry, Rapid Pathogen Screening, Inc., Sarasota, Fla.).6 Adding to the confusion, dry eye symptoms have consistently shown not to correlate with dry eye signs or biomarkers.7,8
Dry eye’s broad definition was on display at the 2015 Association for Research in Vision and Ophthalmology meeting, where “dry eye” posters examined various components of dry eye and had different inclusion and exclusion criteria that defined the disease. This suggests that it is time to revisit our definition of dry eye and ask: Do patients with the sensation of ocular dryness but without obvious tear dysfunction have dry eye? Do asymptomatic patients with telangiectasias on the eyelid margin have dry eye? Do asymptomatic patients with corneal staining have dry eye? In short, which components of the original DEWS dry eye definition and at what severity should be sufficient to warrant a diagnosis of dry eye?
While there are no immediate answers to these questions, they represent important avenues of study as the answers have implications for treating dry eye. Our approach to dry eye starts with patient symptoms because these are the drivers of dry eye morbidity.
Dry eye symptoms have been associated with limitations in reading, watching television, working on a computer and driving.9 A utility assessment study reported that severe dry eye patients had utility scores in the range of conditions like class III/IV angina.10
Symptoms of dry eye, however, are not uniform and likely have different origins: An unhealthy tear film likely drives visual complaints, and corneal nerve activity likely drives ocular pain/dysesthesias. Nevertheless, dry eye questionnaires don’t separate these facets and many lump both types of complaints to calculate a dry eye severity score.11
With all this complexity, sub-grouping dry eye patients into categories based on underlying pathophysiology is necessary to provide tailored therapy to individual patients. One logical sub-grouping already in use is identifying patients with tear film abnormalities likely associated with their visual complaints. Another potential sub-grouping is patients whose ocular pain may be driven by corneal somatosensory pathway dysfunction.
The corneal somatosensory pathway starts in the cornea with free nerve endings that interdigitate with the corneal epithelium. These corneal nerves have their cell bodies in the trigeminal ganglion and first synapse in the spinal trigeminal nuclear complex. From there, second-order axons decussate and join the contralateral spinothalamic pathways and synapse in the thalamus. Third-order neurons then relay information to the supra-spinal centers, including the somatosensory cortex.12
Abnormalities in both peripheral nerves (peripheral sensitization) and/or second- or third-order nerves (central sensitization) can occur with subsequent reduced activation thresholds, increased excitability, enhanced synaptic transmission and abnormal signal amplification. Pain in the setting of such changes is known as neuropathic pain, and it can be assumed that some patients with symptoms of “dryness,” “aching,” “burning” and “throbbing” have neuropathic ocular pain.
There is growing evidence that changes in the corneal somatosensory pathway underlie dry eye symptoms in some individuals. Some patients with dry eye report spontaneous pain, hyperalgesia (e.g., to wind) and allodynia (e.g., to light),13 all of which are features of neuropathic pain.14
Changes in the central sub-basal nerve plexus have been found in some, but not all, dry eye patients, including nerve sprouts, increased nerve thickness,15 beadlike formations16 and low density.17-19 Furthermore, changes in corneal sensitivity have been reported, with lower mechanical pain thresholds in patients with dry eye symptoms compared to controls on esthesiometry testing.20 More research is needed, however, to develop and study tools that will evaluate the function and anatomy of the corneal (and conjunctival) somatosensory pathway.
In conclusion, sub-grouping patients into various categories will lead to improved correlations between symptoms and signs and therefore improved individualized therapy for patients suffering from conditions known as “dry eye.”
Financial disclosures: This paper was supported by a Clinical Sciences Research and Development’s Career Development Award CDA-2-024-10S grant to Dr. Galor from the Department of Veterans Affairs; a National Institutes of Health grant; and a Research to Prevent Blindness unrestricted grant. The contents of this paper do not represent the views of the Department of Veterans Affairs or the United States government.
- The epidemiology of dry eye disease: report of the Epidemiology Subcommittee of the International Dry Eye WorkShop (2007). The Ocular Surface. 2007;5(2):93-107.
- Pouyeh B, Viteri E, Feuer W, et al. Impact of ocular surface symptoms on quality of life in a United States veterans affairs population. American Journal of Ophthalmology. 2012;153(6):1061-1066.e3.
- Clegg JP, Guest JF, Lehman A, Smith AF. The annual cost of dry eye syndrome in France, Germany, Italy, Spain, Sweden and the United Kingdom among patients managed by ophthalmologists. Ophthalmic Epidemiology. 2006;13(4):263-274.
- The definition and classification of dry eye disease: report of the Definition and Classification Subcommittee of the International Dry Eye WorkShop (2007). The Ocular Surface. 2007;5(2):75-92.
- Lemp MA, Bron AJ, Baudouin C, et al. Tear osmolarity in the diagnosis and management of dry eye disease. American Journal of Ophthalmology. 2011;151(5):792-798.e1.
- Sambursky R, Davitt WF, 3rd, Latkany R, et al. Sensitivity and specificity of a point-of-care matrix metalloproteinase 9 immunoassay for diagnosing inflammation related to dry eye. JAMA Ophthalmology. 2013;131(1):24-28.
- Galor A, Feuer W, Lee DJ, Florez H, Venincasa VD, Perez VL. Ocular surface parameters in older male veterans. Investigative Ophthalmology & Visual Science. 2013;54(2):1426-1433.
- Gibbons A LN, Valenzuela F, Perez V, Galor A. Dry eye profiles in patients with a positive elevated surface matrix metallopeptidase 9 point of care test versus negative patients. Paper presented at: The Association for Research and Vision in Ophthalmology; May 2015; Denver, CO.
- Miljanovic B, Dana R, Sullivan DA, Schaumberg DA. Impact of dry eye syndrome on vision-related quality of life. American Journal of Ophthalmology. 2007;143(3):409-415.
- Schiffman RM, Walt JG, Jacobsen G, Doyle JJ, Lebovics G, Sumner W. Utility assessment among patients with dry eye disease. Ophthalmology. 2003;110(7):1412-1419.
- Schiffman RM, Christianson MD, Jacobsen G, Hirsch JD, Reis BL. Reliability and validity of the Ocular Surface Disease Index. Archives of Ophthalmology. 2000;118(5):615-621.
- Galor A, Levitt RC, Felix ER, Martin ER, Sarantopoulos CD. Neuropathic ocular pain: an important yet underevaluated feature of dry eye. Eye. 2015;29(3):301-312.
- Galor A, Zlotcavitch L, Walter SD, et al. Dry eye symptom severity and persistence are associated with symptoms of neuropathic pain. British Journal of Ophthalmology. 2015;99(5):665-668.
- Costigan M, Scholz J, Woolf CJ. Neuropathic pain: a maladaptive response of the nervous system to damage. Annu Rev Neurosci. 2009;32:1-32.
- Tuisku IS, Konttinen YT, Konttinen LM, Tervo TM. Alterations in corneal sensitivity and nerve morphology in patients with primary Sjogren's syndrome. Experimental Eye Research. 2008;86(6):879-885.
- Benitez del Castillo JM, Wasfy MA, Fernandez C, Garcia-Sanchez J. An in vivo confocal masked study on corneal epithelium and subbasal nerves in patients with dry eye. Investigative Ophthalmology & Visual Science. 2004;45(9):3030-3035.
- Benitez-Del-Castillo JM, Acosta MC, Wassfi MA, et al. Relation between corneal innervation with confocal microscopy and corneal sensitivity with noncontact esthesiometry in patients with dry eye. Investigative Ophthalmology & Visual Science. 2007;48(1):173-181.
- Labbe A, Alalwani H, Van Went C, Brasnu E, Georgescu D, Baudouin C. The relationship between subbasal nerve morphology and corneal sensation in ocular surface disease. Investigative Ophthalmology & Visual Science. 2012;53(8):4926-4931.
- Labbe A, Liang Q, Wang Z, et al. Corneal nerve structure and function in patients with non-sjogren dry eye: clinical correlations. Investigative Ophthalmology & Visual Science. 2013;54(8):5144-5150.
- McClellan A SO, Ehrmann K, Parel JM, et al. Corneal Mechanical Hypersensitivity is Correlated with Wind Hyperalgesia, Ocular Symptoms, and Systemic Complaints. Paper presented at: The Association for Research and Vision in Ophthalmology; May 2015; Denver, CO.