The Traditional Dry Eye Model: Unanswered Questions
The word “dry” in ‘dry eye disease’ (DED) reflects canonical belief that tear deficiency is the cause of this disorder. Although the conventional model fits the clinical profile of patients with desiccating dry eye disease such as caused by lacrimal gland damage in which symptoms match signs of corneal damage, it is problematic when applied to the far larger cohort whose chronic dry eye-like symptoms (CDELS) are not easily (if at all) explained by signs of ocular surface desiccation. For example, it does not explain why many people with CDELS exhibit tear metrics that are asymptomatic in others. Efforts to explain this puzzle have focused on the role of the Meibomian glands which have been accused of being insufficiently productive thereby resulting in accelerated tear evaporation. Indeed, that tears lacking Meibomian gland secretions evaporate more quickly has been amply confirmed. Further supporting this argument are observations that some of these patients report significant mitigation of symptoms for a limited period of time following treatments that enhance the function of their Meibomian glands. On the other hand, their role in this disorder is not as clear as this model suggests. There are too many unexplained exceptions. For example, it is not uncommon for some asymptomatic people to have poor or even seemingly nonfunctioning Meibomian glands. These observations seem to parallel the poor relationship between tear metrics and CDELS.
What Are Dry Eye Symptoms?
The insight that dry eye-like symptoms represent a type of corneal pain was a call to take a serious look at the corneal pain system, especially its unequalled density of sensory terminals (estimated to be 20 fold greater than that of dental pulp), that virtually all its nerve fibers are designed to carry pain signals (nociceptors), their notably high sensitivities and unusual high exposure to the noxious environment. This poses the question: Why are our corneas endowed with this unusually powerful and sensitivity pain system? As a mechanism to protect them from being damaged, it seems to be over-kill.
Although an adequate and continuing supply of tears is essential to maintain the health of the human cornea, I argue that the development its uniquely powerful, sensitive pain system was needed primarily to sustain the most powerful focusing lens of the eye; the optical tear layer. Moreover, I posit that the primary role of our corneas is to function as a transparent template that supports a mirror smooth tear layer on its otherwise optically flawed surface—an especially challenging goal considering the ongoing battle with evaporation. The key requirement of this system is an accurate, sensitive and real-time mechanism for monitoring the thickness of the tear film and triggering the cascade of reflex actions that reestablish the robust optical tear layer immediately prior to its breaking up. The solution turned out to be a highly complex system that exploits components of the peripheral corneal pain network as its core component.
The tear film thickness is monitored by specialized thermosensors of the TRP8 family incorporated in the neural membranes of many of the corneal nerve terminals. These transducers are highly sensitive to dynamic lowering of the temperature at the corneal surface such as caused by tear evaporation. Since the thermal insulating effectiveness of tears is inversely related to its pre-corneal thickness, the rate of temperature fall in the microenvironments of these thermoreceptors increases as it becomes thinner until their activation thresholds are breached and the cornea-lacrimal loop is activated to reestablish the robustness of the optical tear layer thereby silencing the activity of the cold nociceptors. Although this normally takes place at an unconscious level it is experienced as dry eye-like pain if the tearing response is inadequate or delayed.
The sensitivity of cold-sensitive receptors defines the tear alarm activation threshold of the tear film thickness. It normally is set to levels that set the tear alarm to respond appropriately to a range of evaporative environments appropriately, automatically and typically unconsciously. On the other hand, if this complex, fine-tuned, powerful alarm system goes awry the result can range from CDELS to devastating, unrelenting eye pain ± photophobia.
Hyperalgesia, defined as hypersensitivity and hyper responsiveness to noxious or near-noxious stimuli, is a physiological, protective response to tissue injury. I argue that tear evaporation is the human cornea’s most important potential noxious stimulus and that corneal hyperalgesia is manifested primarily as hypersensitivity to the cooling effects of tear evaporation–a phenomenon that I describe as corneal evaporative hyperalgesia (CEH).
Consider the effects of increased sensitivity (lower activation thresholds) of the transducers in the corneal nerve terminals, a normally physiological phenomenon known as sensitization. It is expecte that corneas with sensitized cold nerve fiber terminals need a thicker-than-normal tear layer to avoid triggering the alarm. Note the animated figure illustrating the effects of evaporative tear film thinning on a ‘non-sensitized’ and ‘sensitized’ cornea. Because the threshold activation thickness of tear layer in the sensitized cornea is greater, its tear alarm is triggered before that of the normal cornea. This mechanism explains why patients can experience CDELS despite the presence of normal tear metrics and why their cornea are more sensitive to tear evaporation accelerators (moving air, dry environments, low rates of blinking, unstable tear layers, blepharochalasis, etc.) than those of asymptomatic people. Notably, this does not take into account the impaired responses of neuropathic to signals calling for more tears since tearing would otherwise be excessive.
Inflammation likely plays a significant role in the pain of non-desiccating dry eyes as indicated by reports of increased levels of sensitizing inflammatory mediators (proinflammatory cytokines and chemokines) in their tears. Proinflammatory cytokines are classic nociceptor sensitizers and their elevated levels can explain the presence of corneal hyperalgesia. What is the cause of chronic subclinical corneal inflammation? The traditional explanation is the presence of hyperosmolar tears induced by evaporation of an insufficient supply of tears. Nevertheless, although it has been shown that a single intense dry stimulus can trigger pathological responses to subsequent ocular surface drying in mouse models, the validity of using the eyes of murine species as a human surrogate has not been validated. This would seem to be a valid concern in view of obvious differences in the morphology of their corneal nerves with those of the human cornea. Moreover, proof that noxious drying stimuli can trigger CDELS in human eyes is lacking. On the other hand, increased levels of proinflammatory cytokines found in the tears of these eyes needs to be explained. A reasonable source is inflammation caused by ongoing discharges in the nerve terminals (neuroinflammation ) that promote amplification of pain signals in primary sensory nerve fibers (peripheral sensitization).
Scleral Lens: A Diagnostic Test for CEH
Since the non-evaporative, temperature insulating and hydrating environment provided by these devices avoids triggering CEH, the immediate, total suppression of symptoms is diagnostic. Conversely, corneal pain experienced while these devices are worn indicates spontaneous pain.
On the other hand pain, hyperalgesic or spontaneous, is pathological when it persists long after tissue appears to have healed or when it exists in the absence of provocations such as can occur in peripheral neuropathies. This type of pain has become a disease in its own right. It is labeled Neuropathic pain which is defined as “a direct consequence of a lesion or disease affecting the somatosensory system”. Because of its unusually high density of nociceptors, pain originating in the trigeminal sensory system can be particularly disabling.
How Does The Corneal Neuropathic Paradigm Explain Chronic Age-Related CEH?
Hypoesthesia typical of these corneas is explained by the associated attrition of their nerves. The conundrum is explaining the accompanying comorbid chronic evaporative corneal hyperalgesia. Apparently overlooked is the milestone study of Namer and others (The Journal of physiology 2009, 587(Pt 2):419-428) who in addition to confirming the attrition of intradermal C-fibers in healthy, elderly people, also found that many of the surviving nerves demonstrated sensitization and spontaneous activity. In view of the far greater density of corneal nociceptors, a similar process in this tissue would be expected to be far more symptomatic.
Nevertheless, symptoms of chronic corneal evaporative hyperalgesia are not limited to the elderly. A study of Chinese office workers with dry eye-like symptoms reported increased tortuosity of the nerve fibers in the subbasal plexus with preservation of their density as well as normal tear metrics. Although symptoms of both groups appear to be similar (if not identical), they appear to involve different mechanisms and, in my opinion, likely represent different forms of corneal neuropathy.
The Conundrums Of Uneven Tear Metrics
How does the neuropathic paradigm explain the inconsistency between the statistical lower tear metrics in this cohort as a group and its variability among individuals? I argue that it is a predictable consequence of dysfunctional peripheral corneal nerves (neuropathy) and that, while being the cause of symptoms and the attrition of tear metrics, their clinical expression can have different time frames. Supporting this suggestion are my observations while following a number of these patients (including some suffering from Sjogren’s syndrome) that symptoms of CDELS preceded tear deficiency by many years.
Centralized (Projected) Corneal Neuropathic Pain
Central pain signaling pathways are more than passive conduits of nociceptive impulses. In addition to modulating the activity of higher brain centers (as well as being modified by their activity), ascending pain signals are also altered in many ways on their way to the somatosensory cortex where they are decoded into conscious sensations. Studies point to the brainstem’s trigeminal nuclei as the major location for activity-driven corneal pain signal amplification, a physiological feed forward and feedback system known as central sensitization. To prevent uncontrolled meltdown, central pain signal amplification is held in check by a negative feedback system in which increasing ascending increasing nociceptive signals trigger countervailing descending inhibitory impulses that limit the intensity of central sensitization and extinguishes it after the termination of afferent pain signals.
Under certain poorly understood pathological conditions the central pain pathways themselves can become self-sustaining pain signal generators. Known as centralized pain, it is believed to be caused by maladaptive neuroplastic responses of the brain pain circuitry to afferent pain signals and they typically take the form of spontaneous projected (phantom) pain that in some cases can include those of CEH.
Clinical Features Of Centralized Corneal Neuropathic Pain (CCNP)
Signs and symptoms that support this diagnosis are those that reflect dysfunctional comorbid changes in the central nervous system such as high pain intensity, their descriptors such as hot/burning, aching/pressure, sharp, needle or cutting-like, etc. Radiating patterns are not unusual and, in my opinion, are diagnostic. More than one type of pain is often reported and often involves receptive fields of all 3 major branches of the trigeminal nerve including the head (headaches), ears, orbits, face, teeth and jaws. Complaints of otherwise unexplained photophobia (photoallodynia) are not uncommon and, in some cases, represent the primary disability. Notably, this neuropathic photophobia is often particularly exacerbated by the lights of fluorescent and metal halide fixtures and computer screens, and least with incandescent lights. (I argue that photoallodynia represents a surrogate of CCNP). Moreover, I posit that the presence of tactile hyperalgesia and allodynia (non-noxious symptoms perceived as painful) in skin innervated by the trigeminal nerve is diagnostic of CCNP. Although its incomplete suppression during chemically-induced corneal anesthesia is diagnostic, complete pain suppression does not rule out the presence of early stages of this disease (personal observations). Interestingly, this form of trigeminal eye pain was reported by 3 patients as being exacerbated by visual focusing.
I have observed that a significant number of these patients report impaired recent memory, difficulty in word retrieval, deterioration of executive functions and other cognitive and affective disorders over time; findings that are well known complications of long-standing neuropathic pain.
Because symptoms of CCNP are typically far more severe than those of evaporative hyperalgesia, the disparity between their intensity and supportive external signs is especially striking. Since tear insufficiency cannot remotely be blamed for this pain, doctors are often seduced into believing that “it isn’t real” or is “exaggerated”. It is not surprising that many, if not most, of these patients report ideations of suicide.
What Are Its Possible Triggers?
Noxious corneal insults are on of the leading triggers of CCNP; the classical one being the extensive axotomies associated with LASIK and PRK. Nevertheless, they also include corneal abrasions (perhaps those followed by recurrent erosions), acute exposure to noxious fumes and even more rarely, painful stimulation of the teeth, face and lids. Nevertheless, CCNP can also occur in the absence of a preceding corneal insult in association with immune-mediated diseases including Sjogren’s syndrome, fibromyalgia, thyroid disease (personal observations). It can also represent a complication of small fiber neuropathies and channelopathies. Nevertheless, its underlying cause is often unknown.
The Complexity Of The Pain System
The pain network has been likened to an open complex adaptive system (Chapman CR: Painful Multi-Symptom Disorders: A Systems Perspective. 2010) that includes numerous subsystems, each of which responds to its own microenvironment in (unpredictable) ways that affect the system as a whole. Although striving to achieve homeostasis, they are basically unstable. Failures are often unforeseeable and unexplainable. The aphorism that every person is different is especially evident in CCNP. The onset of centralized pain can transition seamlessly from physiological post operative pain or be delayed, sometimes for many years (see accompanying posted Post LASIK paper).
Treating Corneal Neuropathic Pain
Corneal Evaporative Hyperalgesia
Neuropathic hypersensitivity to tear evaporation is most often generated in the corneal nociceptors but, based on my anecdotal observations and pain literature, it can also originate in the brain. If traditional dry eye treatments fail to provide adequate relief and the beneficial effects of wearing moisture conserving goggles are notable, an in-office trial of scleral lenses can often be helpful in curbing the intensity of the centralized pain—at least for a while. Nevertheless, there is one caveat: scleral lenses will not be tolerated in the presence of increased mechanosensitivity of the sclera, which I speculate likely represents a form secondary hyperalgesia associated with CCNP.
Recent reports of the use of topical mucin secretagogues indicate that they may also be helpful in mitigating symptoms of CEH, presumably by increasing the temperature insulation of the corneal surface. Theoretically, this may have a salutary (if temporary) effect on CCNP as well.
Centralized Corneal Neuropathic Pain
Treatment of CCNP begins by validating patients’ symptoms. A simple such statement can be life-changing. The ideal goal is to downregulate the entrenched hyperexcitability of the synapses in the central pain circuitry sufficiently and long enough to reverse the maladaptive plasticity responsible for sustaining the disease. Examples might include interventions that suppress corneal afferent activity that trigger symptoms of corneal evaporative hyperalgesia. Nevertheless, it should be kept in mind that any beneficial effects of treating corneas of patients with this disease are often temporary (personal observations).
In my experience, the value of systemic antinociceptive drugs used for treating centralized pain is limited by their modest effectiveness and significant cognitive and other side effects. The chronic use of opiates should be avoided because of their well known risks, lack of proven efficacy and incontrovertible evidence that they can increase pain intensity over the long-term.
I believe that our misplaced dependence on the slitlamp for judging the validity of corneal symptoms has been the most important obstacle to progress in this field. Although doctors have an intellectual appreciation that corneal nerves (especially those of the central pain circuitry) are invisible to this instrument, many continue to assume that corneal pain does not exist without visible evidence of its cause despite this disparity being a recognized hallmark of neuropathic pain that involve other body surfaces. Nor have we taken into account that pain generated in and projected from the central corneal pain network can, in some cases, be associated with corneal nerves that show little if any morphological abnormalities even in vivo laser scanning confocal images (personal observations).
First person vignettes of victims of CCNP that appear in the PATIENTS’ CORNER of this website are eloquent appeals for help. Recognizing the existence of this disease and the intensity of its pain is a start. It has also become apparent that the living, human cornea is an ideal model for studying neuropathic pain because of its transparency, accessibility to topical drugs (including anesthetics) without significant systemic overflow, ease of performing non-invasive laser scanning confocal microscopy and the ability to assess patients’ subjective responses to treatments. In my opinion, collaboration with pain scientists and clinicians represents the ideal platform from which new advances can be made for rescuing these victims of invisible but life-devastating, eye pain.
The principal mission of the nonprofit Boston EyePain Foundation is to expand our conversations about these disorders, look beyond tears and consider the role of the powerful peripheral and central corneal pain systems in their pathogenesis, and support new paths of research that may lead to effective treatments.