“Researchers systematically work out one concept and own it.” (Ellen Langer, Harvard)
What’s in a name?
As a diagnosis, ‘Dry Eye Disease’ could not be more explicit. But is it accurate? Consider the enigmas of its statistics. Although the tear metrics of the group that reports inappropriate chronic dry eye-like symptoms are lower than those of asymptomatic controls , the disparity between symptoms and signs between individuals in this group is striking . Experts explain this on the increased evaporation rates of tears of patients with Meibomian gland dysfunction (MGD)  supported by the many reports of significant (if temporary) mitigation of symptoms after treatments that enhance their productivity . On the other hand, a 2013 study of mostly older males did not find a significant relationship between MGD and chronic dry eye symptoms . Moreover, the lack of effective treatments despite the enormous investments in financial and intellectual resources supports the need to revisit our fundamental assumptions about this group of corneal pain disorders. Not only do we not know all the answers, we don’t know many of the important questions. Is it hubris to suggest that we have allowed ourselves to be led by the cacophony of herd behavior? The data are out there for everyone to see. It is long past time for them to be recognized.
What are dry eye-like symptoms?
Dry eye-like symptoms are a unique type of corneal pain triggered by specialized corneal nerve receptors  designed to preserve the integrity of the mirror smooth corneal tear film. This tear film is essential to provide the optical quality of the external corneal surface needed for it to serve as the most powerful focusing lens of the human eye. Although keeping it wet and transparent is no less important, achieving this goal is a far lesser challenge. Our complex, powerful and sensitive pre-corneal tear film thickness monitoring and alarm system integrated with a responsive tear supply mechanism evolved to meet an existential need in the migration of our ancient ancestors from water to land. Dry eye-like symptoms function as our corneas’ alarm warning us when evaporative thinning of the tear film is approaching its break-up point or has already has done so. On the other hand, descriptive terms such as “powerful, sensitive, complex” indicates a greater potential for the development of a panoply of symptoms uncoupled from the intensity of the stimulus if any of its components break down.
The tear film sustaining system
Specialized sensors in many terminals of the dense array of corneal nerves monitor the overlying tear film thickness and osmolarity in real time . The efficiency of this system is determined by the levels of their activation thresholds. If they are too low, the frequency of tear film breakup will be greater thereby causing unstable vision. On the other hand, if their activations levels are set too high the alarm will be triggered and rise to conscious levels prematurely, thereby generating dry eye symptoms in the presence of normally adequate tears (false alarms). These corneas are described as sensitized and require thicker-than-normal tear films to maintain the dry eye alarm in a silent mode. On the other hand, these sensitive, powerful and complex systems are more vulnerable to breaking down and cause neuropathic dry eye-like pain, a disease in its own right.
The activation thresholds of corneal tear film thickness monitors are lowered in the presence of products of inflammation (proinflammatory cytokines) . Notably, increased activity of sensory nerves causes inflammation (neuroinflammation) that promotes the activity of pain-carrying nerves. This self-perpetuating phenomenon known as peripheral sensitization  is a key factor in prolonging the state of increased corneal sensitivity to noxious stimuli of which the most important is surface tear evaporation (corneal evaporative hyperalgesia). Notably, eyes with neuropathic activity of the nerves in their corneal subbasal plexus (as diagnosed by the presence of axon degeneration/regeneration and numerous mature dendritic cells) can exist in the absence of external signs of inflammation (personal observations). Therefore corneas that feel drier than expected by their tear film metrics cannot be assumed as being morphologically and functionally normal without a laser scanning confocal microscopy study.
The dry eye alarm and the brain
The transmission of dry eye pain signals to the somatosensory cortex is not a direct or passive process. Along the way these electrical signals are modified by feed-forward and feedback systems that typically intensify them as well as capping their maximum intensity levels. This highlights the unique property of pain to become amplified during a continuing noxious stimulus in contrast to all other types of sensory responses that are attenuated through adaptation. Known as central sensitization , this physiological phenomenon applies to dry eye-like pain as well. I speculate that the trigeminal brainstem may also be the origin of symptoms of so-called DED including corneal algesia  and photophobia caused by noxious light stimuli .
The dry eye alarm and dry eye disease
Eyes with symptoms consistent with signs of surface desiccation (such as can be associated with Sjogren’s syndrome) have obvious desiccating dry eye disease. On the other hand, what about eyes that feel dry but are not dry? Although typically attributed to malfunctioning Meibomian glands and the consequent accelerated tear evaporation, this explanation is debatable in the many cases in which tears are far too generous for a change in the rate of their evaporation alone to make a significant difference in symptoms. On the other hand it is conceivable that disorders of the dry eye alarm system itself may be responsible for the range of clinical expressions of dry eye-like pain. Moreover, depending on the locations of its dysfunctional elements and the intensity and duration of their effects, they can alter the functional anatomy of the pain system through the innate, powerful neuroplasticity of the central nervous system . These dysfunctional changes are described as maladaptive.
Age-related dry eye disease
This disorder of the older population is characterized by the attrition of corneal nerve fibers and increased corneal sensitivity to tear evaporation (corneal evaporative hyperalgesia). It is consistent with deafferentation hypersensitivity-like properties of the skin of healthy elderly subjects in which the attrition of pain fibers and resulting hypoesthesia is associated with increased activity of the surviving nerves . The parallels are striking.
“Dry” eye disease following keratorefractive surgery
Sensory nerve injuries such as caused by LASIK axotomies trigger a phenotypic change in the somata of the surviving nerves from conducting to regenerating that promotes the expression of hypersensitive and hyper responsive ectopic pain generators in their somata . Those in the trigeminal ganglion are transmitted to the regenerating corneal nerve sprouts and central terminals of severed axons and are likely responsible for the complaints of the dry eye symptoms that commonly follows these procedures. The persistence of the regenerating phenotype as indicated by the presence of the characteristic morphology of regenerating nerves and increased numbers of mature dendritic cells after external healing has occurred could explain the chronic dry eye pain symptoms that commonly follow these procedures. They typically resolve over time but in some patients they persist, intensify and become associated with the development of hypersensitivity to chemicals (fumes), cold and corneal evaporative hyperalgesia. (Personal observations).
Inappropriate dry eye-like symptoms may be initiated in and/or sustained in the trigeminal brainstem
(See the blog Dry Eye and the Brain.) It is likely that normal afferent signals generated by corneal surface tear evaporation can be augmented and distorted during their passage through a malfunctioning trigeminal brainstem. If my anecdotal observations are validated, they could suggest that certain systemic diseases characterized by defective central sensory processing issues such as fibromyalgia can mimic symptoms of dry eye including photophobia, despite the absence of any signs of their cause .
Although conventional wisdom points exclusively to abnormal tears as the underlying cause of so-called dry eye disease, it fails to explain certain important clinical observations such as tears that are obviously too generous to explain dry eye-like symptoms on hyper evaporating tears secondary to MGD. On the other hand, they are consistent with the theory that the underlying disease might be an as yet unidentified neuropathy involving the peripheral and/or central trigeminal pain system.
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