Painful Dry Eye Symptoms: A Nerve Problem or a Tear Problem?

Abstract

Much interest has centered around dry eye disease (DED) in the past few years. Publications on DED first focused on the disease in the setting of Sjögren’s disease and graft-versus-host disease, 2 conditions frequently associated with aqueous tear deficiency. The diagnosis and disease expanded when population-based studies determined that many individuals reported dryness and other painful eye symptoms (burning, irritation, tenderness, foreign body sensation, aching) outside the purview of Sjögren’s disease.1Moss S.E. Klein R. Klein B.E. Prevalence of and risk factors for dry eye syndrome.Arch Ophthalmol. 2000; 118: 1264-1268Crossref PubMed Scopus (859) Google Scholar, 2Schaumberg D.A. Sullivan D.A. Buring J.E. Dana M.R. Prevalence of dry eye syndrome among US women.Am J Ophthalmol. 2003; 136: 318-326Abstract Full Text Full Text PDF PubMed Scopus (906) Google Scholar However, it was quickly noted that patient-reported symptoms did not correlate well with physician-assessed signs of dry eye (e.g., corneal staining, tear evaporation, tear production).3Schein O.D. Tielsch J.M. Munoz B. et al.Relation between signs and symptoms of dry eye in the elderly. A population-based perspective.Ophthalmology. 1997; 104: 1395-1401Abstract Full Text PDF PubMed Scopus (374) Google Scholar Additional components were added under the umbrella of DED, such as meibomian gland dysfunction and its associated evaporative tear deficiency.4Lemp M.A. Crews L.A. Bron A.J. et al.Distribution of aqueous-deficient and evaporative dry eye in a clinic-based patient cohort: a retrospective study.Cornea. 2012; 31: 472-478Crossref PubMed Scopus (322) Google Scholar However, these metrics did not improve the connection between symptoms and signs of disease.5Viso E. Rodriguez-Ares M.T. Abelenda D. et al.Prevalence of asymptomatic and symptomatic meibomian gland dysfunction in the general population of Spain.Invest Ophthalmol Vis Sci. 2012; 53: 2601-2606Crossref PubMed Scopus (132) Google Scholar Point-of-care tests were later developed to help diagnose DED, including measurement of tear osmolarity (TearLab, San Diego, CA) and ocular surface inflammation (Inflammadry, Quidel, San Diego, CA). Unfortunately, these tests followed the same pattern and did not correlate with DED symptoms.6Lanza N.L. McClellan A.L. Batawi H. et al.Dry eye profiles in patients with a positive elevated surface matrix metalloproteinase 9 point-of-care test versus negative patients.Ocul Surf. 2016; 14: 216-223Crossref PubMed Scopus (47) Google Scholar, 7Galor A. Feuer W. Lee D.J. et al.Ocular surface parameters in older male veterans.Invest Ophthalmol Vis Sci. 2013; 54: 1426-1433Crossref PubMed Scopus (72) Google Scholar Despite the complex relationship between symptoms and signs of DED, treatments focus on normalizing noted ocular surface abnormalities. These include replacing tear volume with artificial tears, targeting inflammation with topical cyclosporine8Ames P. Galor A. Cyclosporine ophthalmic emulsions for the treatment of dry eye: a review of the clinical evidence.Clin Investig (Lond). 2015; 5: 267-285Crossref PubMed Google Scholar and lifitegrast,9Lollett I.V. Galor A. Dry eye syndrome: developments and lifitegrast in perspective.Clin Ophthalmol. 2018; 12: 125-139Crossref PubMed Scopus (42) Google Scholar and treating lid margin disease with topical and oral antibiotics.10Chhadva P. Goldhardt R. Galor A. Meibomian gland disease: the role of gland dysfunction in dry eye disease.Ophthalmology. 2017; 124: S20-S26Abstract Full Text Full Text PDF PubMed Scopus (158) Google Scholar Of note, despite the disconnect between symptoms and signs, many, although not all patients, improve on 1 or more of these therapies. The interesting question is whether improvements in symptoms occur as the result of improvements in tear health or other mechanisms? An approach to examining this question is to break up DED symptoms into 2 categories: pain related and vision related (e.g., poor, fluctuating vision). Pain is more often a term applied to conditions such as scleritis and keratitis and less frequently to DED. However, when considering the International Association for the Study of Pain definition of pain as “an unpleasant sensory and emotional experience associated with actual or potential tissue damage,”11IASP terminology.http://www.iasp-pain.org/Education/Content.aspx?ItemNumber=1698Google Scholar one can see that many sensations experienced by individuals with a diagnosis of DED can be considered painful, including symptoms of dryness. Although symptoms of DED are not equivalent to those of other painful ocular disorders (e.g., scleritis) in character or severity, using the word “painful” reminds us that nerve activation underlies symptoms.12Belmonte C. Nichols J.J. Cox S.M. et al.TFOS DEWS II pain and sensation report.Ocul Surf. 2017; 15: 404-437Crossref PubMed Scopus (321) Google Scholar The cornea is one of the most highly innervated organs in the body, and the terminal nerve endings are located in the superficial layers of the corneal epithelium, in close contact to the environment.13Muller L.J. Marfurt C.F. Kruse F. Tervo T.M. Corneal nerves: structure, contents and function.Exp Eye Res. 2003; 76: 521-542Crossref PubMed Scopus (848) Google Scholar These nerves can be activated by a variety of stimuli, including touch, temperature drop (as is seen with evaporation),14Parra A. Madrid R. Echevarria D. et al.Ocular surface wetness is regulated by TRPM8-dependent cold thermoreceptors of the cornea.Nat Med. 2010; 16: 1396-1399Crossref PubMed Scopus (231) Google Scholar and protons (released in an inflammatory environment).15Rosenbaum T, Simon SA. TRPV1 receptors and signal transduction. In: Liedtke WB, Heller S, eds. TRP Ion Channel Function in Sensory Transduction and Cellular Signaling Cascades. CRC Press/Taylor & Francis: Boca Raton, FL: 2007.Google Scholar These triggers create action potentials that are propagated up the trigeminal pathway to the somatosensory cortex (where pain sensation is integrated) and to the limbic system (where the emotional response to pain is formed).16Rosenthal P. Baran I. Jacobs D.S. Corneal pain without stain: is it real?.Ocul Surf. 2009; 7: 28-40Crossref PubMed Scopus (116) Google Scholar Aqueous and evaporative deficiency, inflammation, and elevated osmolarity can all trigger this response and are thus considered nociceptive sources of pain, or “pain that arises from altered nociception despite no clear evidence of actual or threatened tissue damage causing the activation of peripheral nociceptors or evidence for disease or lesion of the somatosensory system causing the pain.”11IASP terminology.http://www.iasp-pain.org/Education/Content.aspx?ItemNumber=1698Google Scholar However, a less considered concept is that nerves themselves may become dysfunctional and transmit signals inappropriately, leading to neuropathic pain or “pain caused by a lesion or disease of the somatosensory nervous system.”11IASP terminology.http://www.iasp-pain.org/Education/Content.aspx?ItemNumber=1698Google Scholar In light of the dichotomy as to the origin of pain, is it possible that treatments targeting ocular surface abnormalities in fact improve DED symptoms by normalizing nerve function? Although there is no definitive evidence to answer this question, there is indirect evidence that both nociceptive and neuropathic mechanisms (both in combination and isolation) play a role in dry eye symptoms. The first line of evidence lies in animal studies that demonstrate the potential for corneal nerve sensitization (i.e., increased responsiveness to normal input or a response to a subthreshold input). Polymodal corneal nerves respond to a variety of stimuli (mechanical, chemical, and thermal) and have been shown to sensitize after exposure to an inflammatory milieu.17Belmonte C. Acosta M.C. Gallar J. Neural basis of sensation in intact and injured corneas.Exp Eye Res. 2004; 78: 513-525Crossref PubMed Scopus (395) Google Scholar, 18Parra A. Gonzalez-Gonzalez O. Gallar J. Belmonte C. Tear fluid hyperosmolality increases nerve impulse activity of cold thermoreceptor endings of the cornea.Pain. 2014; 155: 1481-1491Abstract Full Text Full Text PDF PubMed Scopus (95) Google Scholar Cold thermoreceptors respond to cooling (tear evaporation) and have been shown to sensitize after lacrimal gland transection.19Kurose M. Meng I.D. Dry eye modifies the thermal and menthol responses in rat corneal primary afferent cool cells.J Neurophysiol. 2013; 110: 495-504Crossref PubMed Scopus (54) Google Scholar In humans, individuals frequently report that their DED symptoms are chronic and use terminology shared with nonocular neuropathic pain, such as spontaneous burning pain and evoked pain to wind and light.20Kalangara J.P. Galor A. Levitt R.C. et al.Characteristics of ocular pain complaints in patients with idiopathic dry eye symptoms.Eye Contact Lens. 2017; 43: 192-198Crossref PubMed Scopus (50) Google Scholar Evoked pain to wind can be thought of as the ocular equivalent of hyperalgesia, or “increased pain from a stimulus that normally provokes pain,” and evoked pain to light can be thought of as the ocular equivalent of allodynia, or “pain due to a stimulus that does not normally provoke pain.”11IASP terminology.http://www.iasp-pain.org/Education/Content.aspx?ItemNumber=1698Google Scholar Hyperalgesia and allodynia are common findings in individuals with neuropathic pain outside the eye. Similar to neuropathic pain elsewhere, DED symptoms are often associated with other pain syndromes such as migraine,21Diel R.J. Hwang J. Kroeger Z.A. et al.Photophobia and sensations of dryness in patients with migraine occur independent of baseline tear volume and improve following botulinum toxin A injections.Br J Ophthalmol. 2018 Sep 29; (pii: bjophthalmol-2018-312649. doi: 10.1136/bjophthalmol-2018-312649. [Epub ahead of print])Crossref PubMed Scopus (18) Google Scholar, 22Diel R.J. Kroeger Z.A. Levitt R.C. et al.Botulinum toxin A for the treatment of photophobia and dry eye.Ophthalmology. 2018; 125: 139-140Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar fibromyalgia, and pelvic pain.23Vehof J. Kozareva D. Hysi P.G. Hammond C.J. Prevalence and risk factors of dry eye disease in a British female cohort.Br J Ophthalmol. 2014; 98: 1712-1717Crossref PubMed Scopus (142) Google Scholar A subset of individuals with DED symptoms report persistent pain after placement of topical anesthesia, an indication of central nervous system dysfunction,24Crane A.M. Feuer W. Felix E.R. 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: 1238-1243Crossref PubMed Scopus (56) Google Scholar and alterations in corneal anatomy and sensitivity have been described in DED. Many studies found that individuals with DED had decreased sub-basal corneal nerve density compared with controls, but some studies reported increased nerve density, and others reported no change in density.25Stapleton F. Alves M. Bunya V.Y. et al.TFOS DEWS II Epidemiology Report.Ocul Surf. 2017; 15: 334-365Crossref PubMed Scopus (1056) Google Scholar In a similar manner, both increased26Spierer O. Felix E.R. McClellan A.L. et al.Corneal mechanical thresholds negatively associate with dry eye and ocular pain symptoms.Invest Ophthalmol Vis Sci. 2016; 57: 617-625Crossref PubMed Scopus (65) Google Scholar and decreased27Bourcier T. Acosta M.C. Borderie V. et al.Decreased corneal sensitivity in patients with dry eye.Invest Ophthalmol Vis Sci. 2005; 46: 2341-2345Crossref PubMed Scopus (171) Google Scholar corneal nerve sensitivity have been reported in DED. Although DED was not uniformly defined in these studies and different machines and strategies were used to assess anatomy and sensitivity, taken together, this suggests that nerve dysfunction is present in some individuals with DED. In fact, it is not surprising that both increased and decreased nerve anatomy and sensitivity have been reported because both positive and negative sensory signs can be seen in individuals with neuropathic pain.28Pfau D.B. Geber C. Birklein F. Treede R.D. Quantitative sensory testing of neuropathic pain patients: potential mechanistic and therapeutic implications.Curr Pain Headache Rep. 2012; 16: 199-206Crossref PubMed Scopus (52) Google Scholar We use the term “neuropathic ocular pain” to describe painful DED symptoms in the setting of nerve dysfunction to highlight the fact that pain generation can initiate from nerves on the ocular surface (cornea and conjunctiva), from secondary and tertiary neurons, or both. When central neurons are involved, the origin of pain is not from the eye itself but from higher order neurons that connect the eye to the brain. Bringing this concept back to treatment, all therapies that target nociceptive mechanisms in DED also affect corneal nerves. Lubrication protects nerve endings from environmental signals, inflammation reduction improves nerve function as inflammation is a driver and result of nerve sensitization,29Galor A. Moein H.R. Lee C. et al.Neuropathic pain and dry eye.Ocul Surf. 2018; 16: 31-44Crossref PubMed Scopus (123) Google Scholar and omega 3s, which are used to treat meibomian gland dysfunction, have also been studied in nonocular pain.30Galan-Arriero I. Serrano-Munoz D. Gomez-Soriano J. et al.The role of Omega-3 and Omega-9 fatty acids for the treatment of neuropathic pain after neurotrauma.Biochim Biophys Acta Biomembr. 2017; 1859: 1629-1635Crossref PubMed Scopus (22) Google Scholar As such, it is possible the DED symptoms improve with these therapies because of improvements in nerve function, irrespective of changes to the ocular surface. There are many clinical implications to this paradigm. First, it highlights the need for easily accessible diagnostic techniques that quantify corneal nerve structure and function. Although many investigators have used confocal microscopy to image nerves,31Hamrah P. Qazi Y. Shahatit B. et al.Corneal nerve and epithelial cell alterations in corneal allodynia: an in vivo confocal microscopy case series.Ocul Surf. 2017; 15: 139-151Crossref PubMed Scopus (38) Google Scholar, 32Zhang M. Chen J. Luo L. et al.Altered corneal nerves in aqueous tear deficiency viewed by in vivo confocal microscopy.Cornea. 2005; 24: 818-824Crossref PubMed Scopus (146) Google Scholar, 33Ferdousi M. Petropoulos I.N. Kalteniece A. et al.No relation between the severity of corneal nerve, epithelial, and keratocyte cell morphology with measures of dry eye disease in type 1 diabetes.Invest Ophthalmol Vis Sci. 2018; 59: 5525-5530Crossref PubMed Scopus (14) Google Scholar these devices are not in widespread clinical use and do not have built-in automated software to quantify nerve parameters and compare results with a normative population, as is the case for retinal and optic nerve imaging with OCT. In fact, artificial intelligence software is now being investigated to diagnose and monitor disease progression using OCT technology.34Zheng C. Johnson T.V. Garg A. Boland M.V. Artificial intelligence in glaucoma.Curr Opin Ophthalmol. 2019; 30: 97-103Crossref PubMed Scopus (47) Google Scholar Furthermore, confocal microscopy requires contact with the ocular surface (through gel coupling) and is thus less comfortable for the patient compared with noncontact imaging, as with OCT. Similar issues arise with the instruments commercially available to measure corneal sensitivity. Second, this paradigm has implications for clinical trial design. Specifically, if DED symptoms are not predominantly driven by ocular surface signs, the requirement of aligning symptoms and sign improvement in clinical trials is likely not a biologically appropriate one. Third, this paradigm may improve the treatment of painful DED symptoms in individuals who fail traditional DED therapies. In these patients, the presence of unaddressed nerve dysfunction should be considered. Although there are no standard diagnostic tests for neuropathic ocular pain, we suspect a neuropathic component in individuals with (1) a discordance between painful dry eye symptoms and signs, with symptoms outweighing signs;35Vehof J. Sillevis Smitt-Kamminga N. Nibourg S.A. Hammond C.J. Predictors of discordance between symptoms and signs in dry eye disease.Ophthalmology. 2017; 124: 280-286Abstract Full Text Full Text PDF PubMed Scopus (85) Google Scholar (2) no or inadequate response to therapies that target the ocular surface and tears;36Galor A. Batawi H. Felix E.R. et al.Incomplete response to artificial tears is associated with features of neuropathic ocular pain.Br J Ophthalmol. 2016; 100: 745-749Crossref PubMed Scopus (56) Google Scholar (3) presence of chronic overlapping pain conditions,37Maixner W. Fillingim R.B. Williams D.A. et al.Overlapping chronic pain conditions: implications for diagnosis and classification.J Pain. 2016; 17: T93-T107Abstract Full Text Full Text PDF PubMed Scopus (209) Google Scholar, 38Galor A. Covington D. Levitt A.E. et al.Neuropathic ocular pain due to dry eye is associated with multiple comorbid chronic pain syndromes.J Pain. 2016; 17: 310-318Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar depression, and anxiety39Galor A. Felix E.R. Feuer W. et al.Dry eye symptoms align more closely to non-ocular conditions than to tear film parameters.Br J Ophthalmol. 2015; 99: 1126-1129Crossref PubMed Scopus (68) Google Scholar or known nerve injury in the setting of surgery;40Levitt A.E. Galor A. Weiss J.S. et al.Chronic dry eye symptoms after LASIK: parallels and lessons to be learned from other persistent post-operative pain disorders.Mol Pain. 2015; 11: 21Crossref PubMed Scopus (72) Google Scholar (4) specific descriptors, including spontaneous burning pain and sensitivity to wind and light;20Kalangara J.P. Galor A. Levitt R.C. et al.Characteristics of ocular pain complaints in patients with idiopathic dry eye symptoms.Eye Contact Lens. 2017; 43: 192-198Crossref PubMed Scopus (50) Google Scholar, 41Crane A.M. Levitt R.C. Felix E.R. et al.Patients with more severe symptoms of neuropathic ocular pain report more frequent and severe chronic overlapping pain conditions and psychiatric disease.Br J Ophthalmol. 2017; 101: 227-231Crossref PubMed Scopus (53) Google Scholar and (5) persistent ocular pain after topical anesthesia (e.g., proparacaine).24Crane A.M. Feuer W. Felix E.R. 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: 1238-1243Crossref PubMed Scopus (56) Google Scholar Of note, these descriptors are not mutually exclusive with the presence of objective findings of DED (e.g., decreased tear production, increased evaporation) because nociceptive and neuropathic mechanisms often coexist in individuals with chronic pain.42Kogure T. Sumitani M. Abe H. et al.Ischemic ulcer pain is both nociceptive and neuropathic pain based on a discriminant function analysis using the McGill Pain Questionnaire.J Pain Palliat Care Pharmacother. 2017; 31: 98-104Crossref PubMed Scopus (3) Google Scholar, 43Ibor P.J. Sanchez-Magro I. Villoria J. et al.Mixed pain can be discerned in the primary care and orthopedics settings in Spain: a large cross-sectional study.Clin J Pain. 2017; 33: 1100-1108Crossref PubMed Scopus (10) Google Scholar In this population, treatments used to treat chronic nonocular pain may be considered. Data are limited in this regard, but studies have suggested that treatments targeting corneal and conjunctival afferent (e.g., autologous serum tears,44Aggarwal S. Kheirkhah A. Cavalcanti B.M. 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: 250-262Crossref PubMed Scopus (84) Google Scholar amniotic membrane45Morkin M.I. Hamrah P. Efficacy of self-retained cryopreserved amniotic membrane for treatment of neuropathic corneal pain.Ocul Surf. 2018; 16: 132-138Crossref PubMed Scopus (26) Google Scholar), cutaneous afferents around the eye (botulinum toxin injection,21Diel R.J. Hwang J. Kroeger Z.A. et al.Photophobia and sensations of dryness in patients with migraine occur independent of baseline tear volume and improve following botulinum toxin A injections.Br J Ophthalmol. 2018 Sep 29; (pii: bjophthalmol-2018-312649. doi: 10.1136/bjophthalmol-2018-312649. [Epub ahead of print])Crossref PubMed Scopus (18) Google Scholar, 22Diel R.J. Kroeger Z.A. Levitt R.C. et al.Botulinum toxin A for the treatment of photophobia and dry eye.Ophthalmology. 2018; 125: 139-140Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar transcutaneous electrical stimulation46Sivanesan E. Levitt R.C. Sarantopoulos C.D. et al.Noninvasive electrical stimulation for the treatment of chronic ocular pain and photophobia.Neuromodulation. 2018; 21: 727-734Crossref PubMed Scopus (21) Google Scholar), and central neurons (gabapentin, pregabalin, tricyclic antidepressants)29Galor A. Moein H.R. Lee C. et al.Neuropathic pain and dry eye.Ocul Surf. 2018; 16: 31-44Crossref PubMed Scopus (123) Google Scholar can improve spontaneous and evoked ocular pain. As a closing point, the information presented in this editorial highlights the need for future studies that can definitively prove neuropathic pain as a component of dry eye symptoms in some individuals and robustly evaluate which therapies will be most effective in targeting neuropathic ocular pain in an individual patient.