The meaning of “dry eye” has transformed over the years. Prior to 2000, the majority of dry eye (DE) publications centered around Sjögren’s, a disease in which the term “dry eye” truly reflected disease pathophysiology. Then, in the early 2000s, U.S. population-based studies demonstrated that many individuals, beyond those with Sjögren’s, reported DE symptoms.1,2 Similar findings were seen when evaluating the frequency of DE symptoms around the world.3 Although most studies did not perform a concomitant ocular surface exam, it was assumed that these DE symptoms were propagated by dryness on their ocular surface.
We now know that this is not the case: Many subsequent studies demonstrated a disconnect between DE symptoms and signs.4-6 In fact, dryness on the ocular surface, or aqueous tear deficiency, is the least common form of DE, while evaporative DE is much more common.5,7,8
What does all this mean to clinicians treating DE? How does this reality change the way we should approach patients?
To start, the term “dry eye” is not necessarily representative of what we see on the ocular surface (i.e., dryness) but an umbrella term that includes both symptoms and signs. Symptoms can include visual complaints, such as poor or fluctuating vision, and pain complaints, such as aching, burning and tenderness.9 Also, DE signs are varied and include decreased tear production, increased evaporation, ocular surface inflammation, tear hyperosmolarity and corneal epithelial disruption, to name a few. In addition, eyelid margin disease can be present, which would include abnormal vascularity, plugging, collarettes, gland dropout and/or abnormal meibum quality.10,11 Beyond eyelid health, other anatomic disturbances not traditionally lumped in with dry eye, such as eyelid laxity and conjunctivochalasis, associate with DE symptoms.12,13
This complexity is nicely captured by the refined TFOS DEWS II global definition as “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.”14
PINPOINT THE PROBLEM
Given this reality, it is important to perform a focused yet comprehensive DE examination to understand each patient’s symptoms and signs of disease. Many standardized questionnaires are available to profile patient symptoms. For example, the ocular surface disease index (OSDI) asks about various symptoms (visual complaints and pain) along with functional implications of symptoms.15 Allowing patients to fill out the questionnaires in the reception area helps optimize the visit. When reviewing the questionnaire, evaluate a patient’s actual complaints (pain, blurry vision, both) and not just a summation score that lumps together these various components. Different symptoms suggest different underlying issues — poor or fluctuating vision suggests tear film dysfunction, while pain suggests nerve activation.
Once an individual is found to have DE symptoms, perform a fast but comprehensive DE evaluation. This comprehensive assessment can be performed in less than two minutes with equipment available in any eye clinic.
It starts with an external examination to evaluate the periocular skin and eye lid position. Then, perform a dynamic assessment of the eyelids to assess for laxity and/or sub-clinical pathology (e.g., spastic entropion). Place a drop of fluorescein to evaluate tear break-up time, corneal staining, tear lake height and the presence of conjunctivochalasis. A quick examination of the eyelid margin assesses for collarettes, telangiectasias and gland inspissation. Gentle pressure on the meibomian glands with a cotton applicator evaluates meibum quality.
To further evaluate the ocular surface and tear film, consider incorporating the available point-of-care tests and imaging devices as needed.
Some of these tests have minimal upfront costs while others have a higher price tag, so each practice needs to prioritize extra testing equipment based on need and feasibility. Point-of-care tests include measurement of tear osmolarity (TearLab) and matrix metalloproteinase 9 (InflammaDry, Quidel). Available imaging devices include the Keratograph 5M (Oculus), LipiView (J&J Vision) and various high-resolution anterior segment OCT machines. Keep in mind that these tests and devices help refine the DE examination — they do not replace a good clinical exam.
A good symptoms-and-signs profile provides information that impacts subsequent patient care. For example, a patient with low tear lake and ocular surface inflammation might be treated with artificial tear replacement and anti-inflammatory therapy. A patient with a healthy tear lake, fast tear break-up time and eyelid disease might be treated with lid hygiene (office- or home-based treatment) and oral or topical antibiotics. And a patient with significant conjunctivochalasis, tearing and a high tear lake might be treated with conjunctivoplasty.
PAIN AND DE
Until recently, the term pain was not used to describe DE symptoms. The International Association for the Study of Pain (IASP) defines pain as “an unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage.” Based on this definition, one can reconsider this assumption as many individuals with chronic DE symptoms would describe their symptoms as an unpleasant experience.
Pain disorders are broadly grouped into two categories: nociceptive and neuropathic pain. Nociceptive pain occurs when normally functioning nerves respond appropriately to a stimulus, such as tear evaporation, inflammation and high osmolarity, all known components of DE. Neuropathic pain occurs when dysfunction in the somatosensory system causes nerves to fire spontaneously or to a lower stimulus than normal.16 Corneal nerves can become dysfunctional, which has been demonstrated both in primary afferents (peripheral sensitization) and in second or third order nerves (central sensitization).17 In fact, a challenging subset of patients have DE symptoms but minimal signs of disease. Nerve dysfunction is thought to underlie DE symptoms in these individuals.
The cornea is the most densely innervated organ in the body. Different nerves imbedded in the cornea each respond to different stimuli, including mechanical, chemical and thermal stimuli.18 Different components of DE, such as inflammation and high osmolarity, have been found to sensitize corneal nerves in animal models.19,20 In humans, many individuals with DE have abnormalities in nerve structure and function, both on the cornea21 and in areas remote from the eye.17,22
Despite this reality, dry eye examinations have not traditionally incorporated nerve status. This exclusion is largely due to the limited number of commercially available devices to assess nerves (Cochet-Bonnet, confocal microscopes). Until new modalities become available, my practice has found that questionnaires can help identify individuals more likely to have a neuropathic etiology to their DE symptoms. Specifically, individuals with the specific ocular complaints of “burning” sensation, “sensitivity to wind” and “sensitivity to light” are more likely to have a chronic symptoms course23 that is less likely to response to artificial tears.24
Another quick test is ocular pain assessment before and after topical anesthetic placement. The finding of persistent pain after anesthesia suggests a central component to pain, because peripheral afferent firing should be completely quieted after topical anesthesia.25 Finally, a disconnect between symptoms and signs of disease can further suggest that neuropathic mechanisms are at play.26,27
TARGET THE TREATMENT
After identifying an individual with suspected neuropathic ocular pain, how should that patient be treated? Unfortunately, the answer to that question is not known — no commercially available drugs or devices have been tested specifically in this group of patients. However, I have found some success using alternative DE therapies, such as autologous serum tears.28 I also apply strategies successful in the treatment of non-ocular pain to ocular pain. For instance, my practice has anecdotally used gabapentin at doses of 600-900 mg t.i.d., or higher, with positive effects. The main side effect of alpha α2δ ligands is central nervous system depression, which can manifest as drowsiness, dizziness, headache and/or loss of balance. In most patients, side effects are absent or subside with time. I have also used periocular nerve blocks, stimulation therapies and cognitive behavioral therapies as adjuvant treatments in appropriate patients.29
DE is not a “simple” disease of tear production. It is a complex and heterogeneous disorder with diverse neuropathologic mechanisms. Each practice needs to consider this when optimizing its algorithm for the assessment and treatment of DE patients. OM
- Moss SE, Klein R, Klein BE. Prevalence of and risk factors for dry eye syndrome. Arch Ophthalmol 2000;118:1264-1268.
- Schaumberg DA, Sullivan DA, Buring JE, Dana MR. Prevalence of dry eye syndrome among US women. Am J Ophthalmol 2003;136:318-326.
- Stapleton F, Alves M, Bunya VY, et al. TFOS DEWS II Epidemiology Report. Ocul Surf 2017;15:334-365.
- Schein OD, Tielsch JM, Munoz B, et al. Relation between signs and symptoms of dry eye in the elderly. A population-based perspective. Ophthalmology 1997;104:1395-1401.
- Galor A, Feuer W, Lee DJ, et al. Ocular surface parameters in older male veterans. Invest Ophthalmol Vis Sci 2013;54:1426-1433.
- Martinez JD, Galor A, Ramos-Betancourt N, et al. Frequency and risk factors associated with dry eye in patients attending a tertiary care ophthalmology center in Mexico City. Clin Ophthalmol 2016;10:1335-1342.
- Viso E, Rodriguez-Ares MT, Abelenda D, et al. Prevalence of asymptomatic and symptomatic meibomian gland dysfunction in the general population of Spain. Invest Ophthalmol Vis Sci 2012;53:2601-2606.
- Lemp MA, Crews LA, Bron AJ, et al. Distribution of aqueous-deficient and evaporative dry eye in a clinic-based patient cohort: a retrospective study. Cornea 2012;31:472-478.
- Kalangara JP, Galor A, Levitt RC, et al. Characteristics of Ocular Pain Complaints in Patients With Idiopathic Dry Eye Symptoms. Eye Contact Lens 2017;43:192-198.
- Jie Y, Xu L, Wu YY, Jonas JB. Prevalence of dry eye among adult Chinese in the Beijing Eye Study. Eye (Lond) 2009;23:688-693.
- Uchino M, Dogru M, Yagi Y, et al. The features of dry eye disease in a Japanese elderly population. Optom Vis Sci 2006;83:797-802.
- Ansari Z, Singh R, Alabiad C, Galor A. Prevalence, risk factors, and morbidity of eye lid laxity in a veteran population. Cornea 2015;34:32-36.
- Chhadva P, Alexander A, McClellan AL, et al. The impact of conjunctivochalasis on dry eye symptoms and signs. Invest Ophthalmol Vis Sci 2015;56:2867-2871.
- Craig JP, Nichols KK, Akpek EK, et al. TFOS DEWS II Definition and Classification Report. Ocul Surf 2017;15:276-283.
- Schiffman RM, Christianson MD, Jacobsen G, et al. Reliability and validity of the Ocular Surface Disease Index. Arch Ophthalmol 2000;118:615-621.
- Geber C, Baumgartner U, Schwab R, et al. Revised definition of neuropathic pain and its grading system: an open case series illustrating its use in clinical practice. Am J Med 2009;122(10 Suppl):S3-12.
- Belmonte C, Nichols JJ, Cox SM, et al. TFOS DEWS II pain and sensation report. Ocul Surf 2017;15:404-437.
- Muller LJ, Marfurt CF, Kruse F, Tervo TM. Corneal nerves: structure, contents and function. Exp Eye Res 2003;76:521-542.
- Belmonte C, Acosta MC, Gallar J. Neural basis of sensation in intact and injured corneas. Exp Eye Res 2004;78:513-525.
- Belmonte C, Gallar J. Cold thermoreceptors, unexpected players in tear production and ocular dryness sensations. Invest Ophthalmol Vis Sci 2011;52:3888-3892.
- Spierer O, Felix ER, McClellan AL, et al. Corneal Mechanical Thresholds Negatively Associate With Dry Eye and Ocular Pain Symptoms. Invest Ophthalmol Vis Sci 2016;57:617-625.
- Galor A, Levitt RC, McManus KT, et al. Assessment of Somatosensory Function in Patients With Idiopathic Dry Eye Symptoms. JAMA Ophthalmol 2016;134:1290-1298.
- Ong ES, Alghamdi YA, Levitt RC, et al. Longitudinal Examination of Frequency of and Risk Factors for Severe Dry Eye Symptoms in US Veterans. JAMA Ophthalmol 2016.
- Galor A, Batawi H, Felix ER, et al. Incomplete response to artificial tears is associated with features of neuropathic ocular pain. Br J Ophthalmol 2016;100:745-749.
- Crane AM, Feuer W, Felix ER, et al. Evidence of central sensitisation in those with dry eye symptoms and neuropathic-like ocular pain complaints: incomplete response to topical anaesthesia and generalised heightened sensitivity to evoked pain. Br J Ophthalmol 2017;101:1238-1243.
- Vehof J, Sillevis Smitt-Kamminga N, Nibourg SA, Hammond CJ. Predictors of Discordance between Symptoms and Signs in Dry Eye Disease. Ophthalmology 2017;124:280-286.
- Ong ES, Felix ER, Levitt RC, et al. Epidemiology of discordance between symptoms and signs of dry eye. Br J Ophthalmol. 2018 May;102:674-679. Epub 2017 Aug 18.
- Aggarwal S, Kheirkhah A, Cavalcanti BM, et al. Autologous Serum Tears for Treatment of Photoallodynia in Patients with Corneal Neuropathy: Efficacy and Evaluation with In Vivo Confocal Microscopy. Ocul Surf 2015;13:250-262.
- Sivanesan E, Levitt RC, Sarantopoulos CD, et al. Noninvasive Electrical Stimulation for the Treatment of Chronic Ocular Pain and Photophobia. Neuromodulation 2017Dec 28. [Epub ahead of print]