“Absence of evidence is not evidence of absence” Marin D Rees
Conformity has been an essential tool in the evolution of the extended family unit to civilizations. Although adapting to changing environments has been essential to the survival of the human species, meeting the aspirations of contemporary societies to improve the human condition has depended on implementing new ideas. Considering that unforced change is at odds with the comfort of following paths well-trodden, this is easier said than done. I submit that this tension is in play with dry eye disease in which the status quo has been so vociferously protected by the professional stakeholders of the canonical tear-based model that it borders on censoring new theories.
Even its diagnosis, dry eye disease, declares with implied certainty that its cause is tear deficiency (quantity or quality) thereby discouraging the consideration of alternative ideas. Does it matter? Consider that despite this disorder having attracted huge investments in financial and intellectual capital we are not close to finding a cure. Vast quantities of new research findings on this disorder continue to fill the pages of the medical and scientific journals that burnish the academic careers of some of the most brilliant minds in medical research and provide a major economic boost to the pharmaceutical industry. But, where are the cures? If voices that point out that the emperor wears no clothes exist, they are lost in the cacophony of vigorous, unquestioning support of the ancient, unproductive tears-based model.
It is not surprising that the canonical model has not served patients well. For example, how does it explain that while dry eyes feel dry, wet eyes can also feel dry? The latter has been blamed on the tears evaporating too quickly because the surface of the corneal tear film lacks sufficient oily material produced by Meibomian glands to slow its evaporation. This disease known as evaporative dry eye, seemed to be consistent with reports that chronic dry eye-like symptoms can be mitigated by treatments that improve the productivity of the Meibomian glands. The problem is that it does not exist. A recent study has proven that people with chronic Meibomian gland disease are no more likely to develop abnormal dry eye symptoms than those with healthy glands. This suggests that diseased Meibomian glands can worsen symptoms but not cause them. How can this be reconciled? Blame the victim. After all, how can accusations that these symptoms are imagined, exaggerated or otherwise self-serving be refuted?
Consider that dry eye-like symptoms represent a type of corneal pain powered by the most sensitive and powerful pain generator in the human body. This would seem to be overkill if its principal role as a biological alarm system were limited to keeping the corneal surface wet to prevent it from losing its transparency. In fact it has a second and far more challenging role; that of monitoring and preserving the mirror-smooth optical tear layer that if it breaks up, results in the immediate degradation of vision to nonfunctional levels. The unrivaled density of naked nerve endings located at the corneal surface serve as sensors of our dry eye alarm that monitor the thickness of our pre-corneal tear film. When they sense that the overlying tear film is about to break up, the sensors call for the release of more tears to re-build it. Although this normally occurs at an unconscious level, if the initial tearing response is insufficient the intensity of the alarm escalates to symptoms of dry eye-like pain while signaling for the opening of the tears floodgates. On the other hand, that this biological system is highly complex, powerful and sensitive means that it is especially vulnerable to breaking down.
As in all alarm systems its efficient operation is determined by the sensitivity of its sensors. Consider the consequences of a short circuit in the wiring of a fire alarm that causes it to be triggered by the heat of an adjacent light bulb. The fastest and simplest way of silencing the false alarm is to turn off the light switch. On the other hand, the only way of correcting the problem is to identify the source of the malfunction and repair it. This is no less true of our dry eye alarm which I argue that in being activated also becomes hypersensitive to tear evaporation (corneal evaporative hyperalgesia). I further suggest that using artificial tears to treat these symptoms is equivalent to lowering the room temperature to abort the activity of that hypersensitive fire alarm.
The neuropathic theory explains false dry eye alarms as caused by hypersensitivity of the specialized corneal nerve sensors that monitor the thickness of the evaporating tear film. Like all pain sensors, their sensitivity is probably increased by increased concentrations of the products of inflammation, including that caused by desiccating drying of the ocular surface. On the other hand, hyperactivity of these nerves itself causes a type of inflammation (neuroinflammation) that increases their sensitivity, a normal phenomenon known as peripheral sensitization. However, that cold sensors in other parts of the body are known to become pathologically hypersensitive suggests that those of our corneas can be similarly affected.
Nevertheless, based on the neuroscience literature of the cornea and of pain, it is clear that several mechanisms can be invoked to explain pathological dry eye-like symptoms in patients with normally adequate tears. For example, the symptoms of age related dry eye disease may be caused by the inherent hyperactivity of the surviving corneal nerves similar to that found in the skin of elderly subjects but because of their far greater densities, would be expected to be symptomatic. On the other hand, unusually severe dry eye symptoms are often associated with corneal hypersensitivity to chemicals (in fumes and eyedrops) and less commonly to cold, are experienced by a younger population who suffer from centralized oculofacial pain and have a normal density of corneal nerves.
Nevertheless, any serious model of dry eye disease must also account for the weak relationship between intensity of symptoms and supply of tears, and the statistical fact that as a group, patients with inappropriate dry eye symptoms have fewer tears. The neuropathic theory predicts this since the presence of underlying corneal neuropathy can compromise the tears-release system in addition to increasing the sensitivity to tear evaporation. Moreover, my informal observations indicate that dry eye symptoms can precede the reduction of tears by substantial periods of time that, if validated, would explain this long-standing enigma.
My underlying message is this: Until scientists involved in the study of these diseases face the possibility that by focusing on tears as the cause of this spectrum of diseases, they have confused association with causation. We should encourage them to open their minds and widen their horizons beyond the limitations of conventional wisdom.
Source: Peer Review