Disparities in signs and symptoms demand a new research focus.

For most patients, dry eye-like symptoms following LASIK and photorefractive keratectomy typically last a few days and resolve within four weeks, requiring lubricating drops at most. However, for a small number of patients, keratorefractive surgery marks the beginning of a far more serious struggle.

In these patients, dry eye-like symptoms can persist for months and even a lifetime, despite being treated with optimal care. The cost to these individuals is enormous, and the need for significantly improved treatments is clear. Before we can deliver them, though, we may have to investigate a previously overlooked mechanism.

CANARY IN THE COAL MINE

Dry eye symptoms serve as our alarm signal of pending or actual precorneal tear film breakup that, if allowed to occur, would cause a sudden degradation of functional vision.

The rate of tear secretion needed to sustain the optimal quality optics of the optical tear film surface in the face of a rapidly changing external environment is controlled by specialized sensors in the TRPM8 channels. These are embedded in the terminals of the corneal nerves that are sensitive to increased rates of temperature drop,¹ such as those generated by tear evaporation. In other words, the rate of cooling at the corneal surface increases as the tear layer become thinner and when it breaches a threshold that triggers the activation of these sensors. This activation initiates a series of events resulting in increased tear secretion that restores the robustness of the precorneal tear film and preserves the optical quality of the tear film. When the thickness of the tear film falls below a certain threshold level, it triggers the dry eye alarm — dry eye symptoms — warning us our vision is at risk.

OF VOLUME AND EVAPORATION

The fact that impaired meibomian gland productivity, resulting in accelerated tear evaporation, is an important cause of these symptoms is supported by studies showing effective treatments can significantly attenuate them in some patients.¹ However, this does not explain anecdotal observations that the average tear volume in some of these eyes appears similar to the preoperative amount, and can even be overly generous in some. These patients are few, and their chronic dry eye-like symptoms have been attributed principally to accelerated evaporation of their tears.²

SPECULATIONS ON A MYSTERY

In this context, I propose that atypical dry eye symptoms of eyes with normally adequate tears are caused by a pathological increase in the sensitivity of the TRPM8 sensors and that accelerated tear evaporation, when it is present, is an additional secondary factor. While this scenario remains a theory, today its validity is supported by anecdotal observations that the tear supply of some of these patients is equal to or greater than it was preoperatively and that even the most aggressive treatments of their meibomian glands can fail to mitigate their dry eye symptoms significantly. These observations suggest the participation of an overlooked symptom-generating mechanism and pose the question of what could cause the proposed increased sensitivity of the dry eye sensors. I suggest that it is an unrecognized corneal neuropathy.

OVERLAPPING FEATURES PROVIDE A CLUE

Inappropriate dry eye symptoms are also a common feature of the ocular neuropathic pain syndrome.³ In addition to those of dry eye, symptoms may include burning and stabbing (see “Ocular neuropathic pain syndrome,” above). I also suggest that the striking disparity between the intensity of these symptoms and paucity of corresponding causal signs characteristic of dry eye disorders is a consequence of malfunctioning cooling sensors in the corneal nerve terminals that are opaque to current methods of study.

Although this pain syndrome can occur spontaneously or in association with diseases such as Sjogren’s syndrome and fibromyalgia, it is often preceded by ocular trauma and/or surgery — most commonly LASIK and PRK (I refer readers to the website of the nonprofit Boston EyePain Foundation, to a paper that was rejected by several peer-reviewed journals prior to the publication of the paper that introduced the concept of ocular neuropathic pain being a disease in its own right in 2012.²) The striking disparity in symptoms and signs has led clinicians to minimize or even discount the complaints of these patients because the scarcity of signs belies the severity of their disability, especially those patients who experience dry eye symptoms with adequate tears. I label the phenomenon “corneal evaporative hyperalgesia.”

If this mechanism of dry eye symptom generation is validated by future studies, it could open the door to the development of long-needed major advances in our effectiveness in rehabilitating these patients.

“SOLUTIONS” THAT DON’T REALLY SOLVE

Like all invasive surgery, LASIK can cause complications, most of which are poor visual results correctable with hard contact lenses (but not with soft contacts). But, the need to depend on hard contact lenses for useful vision is more than an inconvenience, especially when these patients require scleral lenses — huge hard contacts that fit most of the eye’s front surface. They are costly, inconvenient to care for and can be uncomfortable to wear.

The only alternative for these patients is corneal transplant surgery. However, this procedure is by far the worst option because it is often associated with severe complications, including loss of functional vision. What is more, patients who undergo keratorefractive surgery are burdened with the knowledge that these grafts will eventually fail and require additional transplants — which can lead to further complications, including the need for further transplants. Keep in mind that the younger the patient, the more transplants will be needed over the course of his or her lifetime.

Until better treatments are developed, the enormous personal and economic costs of treating the complications of LASIK and PRK will continue to escalate. Hopefully, the current lack of effective therapeutic options and the logic of the neuropathic paradigm will help to expedite the studies needed to validate its authenticity.

If they do, it could open a door to the development of substantially improved treatments for the considerable number of victims of what is currently known as dry eye disease. OM

REFERENCES

1. Bron AJ, Tiffany JM. The contribution of meibomian disease to dry eye. Ocul Surf 2004;2:149-165.
2. Rosenthal P, Baran I, Jacobs DS: Corneal pain without stain: is it real? Ocul Surf. 2009;7:28-40.
3. Rosenthal P, Borsook D. The corneal pain system. Part 1: The missing piece of the dry eye puzzle. Ocul Surf. 2012;6:2-14.

Dr. Rosenthal is assistant professor of ophthalmology, Harvard Medical School and founder and president of the nonprofit Boston EyePain Foundation.