Laboratory ScienceThe Corneal Pain System. Part I: The Missing Piece of the Dry Eye Puzzle∗
Introduction
Dry eye disease (DED) has been a conundrum. Many patients who report dry eye symptoms do not have obvious dry eyes, and others who have low tear metrics are asymptomatic. Symptoms appear to be the most consistent feature of DED. Nevertheless, while the corneal surface and tear quantity and quality have been objects of intense scrutiny, symptoms have received scant attention. In this paper, we explore the mechanisms of neuropathic pain and how they are likely to be clinically manifested in the corneal-trigeminal system.
Dry eye disease (DED) is one of the most common ophthalmological disorders, affecting up to 20% of adults older than 45 years.1 Given the extraordinary resources that have been invested in improving the treatment of this disease, the lack of progress is particularly striking. Although considerable advances have been made in identifying many of its mechanisms, DED remains a major public health challenge that continues to exact enormous personal, economic, and societal tolls.2, 3 Its refractoriness to treatments and the troubling weak association between symptoms and signs4, 5 give voice to the question of whether some of our fundamental assumptions about this disease are valid. Although evaporative DED may explain the underlying mechanism of chronic dry eye-like symptoms for some patients who lack otherwise supporting signs, the premise that it is the sole cause stretches the limits of credulity for others, suggesting that our current DED model is wanting.
Defining DED has been problematic. Although symptoms are central to the diagnosis,6 they have attracted little attention because their underlying mechanism seems obvious: Dry eye symptoms feel like those expected of dry eye, are exacerbated in high evaporation environments, and mitigated by interventions that enhance the robustness of the tear layer. The logic of tear deficiency as the principal underlying etiopathology seems unassailable — except for that troublesome fly-in-the-ointment: although dry eyes provoke dry eye symptoms, dry eye-like symptoms are not always associated with dry eyes, meibomian gland dysfunction (MGD) or reduced corneal tear film breakup time — no matter how far the definitions are stretched.
The fallacy of assuming that all dry eye symptoms are a consequence of aqueous tear deficiency was pointed out by Carlos Belmonte, the pioneer investigator of the physiology of corneal sensations; his insight that they represent nonspecific corneal pain7 challenges some of our basic assumptions about this disorder. Substituting pain for dry in describing these symptoms transforms the disease model and unmasks a novel therapeutic target—the corneal pain system.
Section snippets
Functional Anatomy
Corneal pain signals evoked by suprathreshold noxious stimuli are transmitted along small-caliber primary afferents (C and Aδ fibers) that synapse in the trigeminal brainstem nuclear complex (TBNC). From there, second-order neurons decussate and join the contralateral spinothalmic tract to synapse with third-order neurons in the thalamus. These ascending pain signals are further modified by input from subcortical structures associated with emotions and memory before terminating in the
How Does the Cornea Monitor Tear Evaporation?
Maintaining the integrity of the optical tear layer during waking hours is a constant battle with evaporation. In this context, it can be argued that tear evaporation is the cornea’s foremost noxious threat. In order to maintain stable, acute vision, it is necessary for the cornea to signal the need for more tears just prior to degradation of the optical tear layer. How does the cornea sense the optimal timing for this pre-emptive action? The most plausible mechanism involves a recently
Central Sensitization
A unique feature of physiological pain is that repeated application of a constant low-frequency noxious stimulus results in pain amplification (wind-up)45 in contrast to the sensory systems of touch, hearing, smell, taste, and moderate temperature change that undergo some degree of adaptation. First order synapses in the TBNC serve as an important modulating center for incoming corneal pain and are a major site of central, activity-driven pain signal amplification, a phenomenon known as central
Definition
Outside the pain field, the terms chronic and neuropathic have often been used interchangeably. This ignores the mechanistic differences that exist between these two states. Physiological pain can be chronic (duration longer than 3 months) and, like acute nociceptive pain, it functions as a biological alarm system that reminds us of the presence of ongoing injury, identifies its location, reflects the extensiveness of the damage, and resolves when healing is complete. On the other hand, the
Corneal Evaporative Hyperalgesia as the Sole Symptom
Symptoms typical of CEH are especially common in the older population, in which it is typically labeled as age-related DED. Eyes in this age group are associated with lower corneal nerve density, reduced tears, higher incidence of MGD,81 and lower corneal tactile sensitivity.82 It has been suggested that the underlying mechanism of evaporative hyperalgesia in this cohort is sensitization and hyperactivity of the remaining cold corneal thermoreceptors.24 The observation that small incremental
Behavioral and Cognitive Comorbidities
Long-standing neuropathic pain is often associated with impairment of cognitive functions and affect, such as diminished recent memory, difficulty in word retrieval, pain catastrophizing,118 depression, and anxiety. Moreover, pre-existing depression and anxiety can themselves enhance the transition of nociceptive pain to a chronic disease.119 (See review.120) Finally, some forms of neuropathic pain appear to be associated with atrophy of the cerebral cortex grey matter,121 a possible anatomical
Signs of CNP
Since corneal nerve damage is invisible to the slitlamp and neurogenic inflammation is typically occult, signs associated with CNP (Table 1) are limited to those caused by the functional interruption of peripheral nerves, such as corneal hypoesthesia, reduced tear metrics and, in some patients, secondary hyperalgesia. Rarely, patients exhibit tactile allodynia of the skin of their face and scalp (personal observations). Zoster keratopathy is a classical example of corneal pain that can be
The Corneal Nociceptive Network as An Open Complex Adaptive System
Complex adaptive systems have evolved to provide highly responsive mechanisms that enable them to continuously adapt to their environment. The behavior of the overall system is the result of the collective responses of its subsystems which, although independent, are interrelated. (See C. Richard Chapman for an excellent basic review of complex systems.127)
The output of the over-arching (superordinate) system is dynamically regulated by negative and positive feedback controls that operate to
Summary
Substituting pain for dry eye in describing chronic corneal symptoms points to the dysfunctional nociceptive system as the principal pathoetiology of a group of diseases currently labeled as DED. Symptoms of CEH, which mimic those of DED, can be the result of overt inflammation such as caused by ocular surface desiccation or subclinical inflammation typical of what is currently labeled as evaporative dry eye.
Spontaneous corneal pain can arise from ectopic activity in the cornea/TG and/or the
Acknowledgement
The authors wish to acknowledge the pioneering work of Prof. Carlos Belmonte that forms the basis of our current understanding of corneal pain and to thank Todd Margolis, MD, for his helpful suggestions.
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Cited by (0)
Supported by The Boston Foundation for Sight.
The authors have no commercial or proprietary interest in any concept or product discussed in this article.
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Part II of this article, “A Proposal for Evaluating and Categorizing Ocular Surface Pain,” will be published in an upcoming issue of this journal. Part II is cited parenthetically in Part I to reference concepts that will be further clarified in the subsequent article.