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Dry eye pain without clinical signs could be neuropathic
A satisfactory clinical diagnosis method is still lacking, researchers say.
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Neuropathic mechanisms may be the missing link in eyes with seemingly adequate tears that feel chronically dry, according to Perry Rosenthal, MD, assistant professor of ophthalmology at Harvard Medical School and founder of the Boston EyePain Foundation and the Boston Foundation for Sight.
“Failure to consider the possibility that neuropathic mechanisms can contribute to dry eye syndromes may reduce accuracy of diagnosis and suitability of treatment provided,” McMonnies said in the Journal of Optometry.
Consideration of neuropathic mechanisms are encouraged when dry eye symptoms, “lack commensurate evidence of tear dysfunction and unsatisfactory response to tear dysfunction therapies,” McMonnies wrote.
“It’s an intriguing idea that would explain a lot of the things we don’t know about dry eye,” Kelly K. Nichols, OD, MPH, PhD, dean of the School of Optometry, University of Alabama Birmingham, told Primary Care Optometry News.
Image: Belmonte C
“What we wrestle with is having enough evidence to say how this fits completely into the dry eye arena,” she said. “You can have patients who have symptoms but don’t have obvious signs and you can call that dry eye or not. Could that then lead to a neuropathic dry eye status? I think the answer is, ‘yes.’”
New area of research
The research in this area is new, and there is still much to uncover, Rosenthal told PCON. His goal is to continue pursuing treatment and encouraging academic discussion of this explanation.
“It’s a dramatic, new hypothesis,” he said. “The power of it and the reason that it’s gaining a lot of support is that it asks questions that haven’t been answered and couldn’t be answered based on traditional theories.”
Rosenthal has received hundreds of emails from patients all over the world who, when their eyes are examined are perfectly normal but present with painful symptoms, one of which is dry eye, a unique type of pain.
“Doctors just aren’t familiar with this, and we have been taught that what causes chronic, severe, life-changing eye pain and often sensitivity to light should be visible, and this is not,” he said.
“If they are having irregularity in nerve firing, sensory processing, that can disrupt the ocular surface system and exacerbate what’s already there ... you can see how it would make sense that if there were patients who had the sensory processing deficit, that could explain why signs and symptoms do not correlate or treatments are not effective on timelines that make sense,” Nichols said.
Spierer and fellow researchers described why nociceptive dysfunction may develop in some dry eye patients, in Investigative Ophthalmology & Visual Science.
“Peripheral nerve injury is the typical initiating event, and virtually any ocular surface perturbation can create ocular surface inflammation and corneal primary afferent neuronal damage,” they wrote. “This can lead to a temporary (or prolonged) change in the structure and function of peripheral nociceptors, with altered neuronal nuclear, cytosolic and membrane signaling mechanisms and increased responsiveness to stimuli.”
These changes may lead to central nervous system changes with pain no longer related to ocular surface pathology, but attributed to centralized mechanisms, they explained.
Carlos Belmonte, MD, PhD, a professor from the Instituto de Neurociencias de Alicante at Universidad Miguel Hernandez-CSIC, in southeastern Spain, has researched ocular discomfort and neuropathic pain for more than a decade.
“Neuropathic pain is caused by a lesion or disease of the somatosensory nervous system,” Belmonte said in an interview. “This is the result of the malfunctioning pain alarm system, producing abnormal signals that the brain reads as pain in spite of the fact that the lesion is in the peripheral nerves or higher order neurons in the brain.”
He added how ocular pain that persists long after surgery, such as photorefractive or cataract surgery, without persistence of a lesion, or after herpetic keratitis has healed is peripheral neuropathic pain. It is due to persisting damage of the peripheral branches or trigeminal ganglion ocular neurons sending aberrant signals to the brain.
“When ocular pain is associated to a central nervous system lesion, we talk about central neuropathic pain,” he said.
“In my opinion, the dryness sensation or distinct pain experienced long after refractive surgery is the cleanest example of peripheral neuropathic pain, caused by the destruction of corneal nerves,” Belmonte continued.
Currently, Belmonte is interested in understanding how discomfort sensations are produced by eye dryness, how sensory information modulates tear secretion and what are the short- and long-term molecular and cellular effects of injury on the different functional classes of sensory nerve fibers innervating the front of the eye and the consequences of these disturbances on eye sensation and homeostasis.
Cold thermoreceptor fibers
Belmonte has shown that cold thermoreceptor fibers of the cornea are critical to detect ocular dryness and to adjust tear secretion accordingly.
“They do this by measuring the small temperature changes in the cornea and tear osmolarity occurring during interblink periods,” he said. “Their information possibly evokes conscious sensations of dryness only when those with the lowest sensitivity to cooling are also stimulated.”
He suspects that cold thermoreceptors are the fibers more affected by eye dryness and are largely responsible for the discomfort and altered tear flow observed in chronic eye dryness. He and his team wish to extend these studies to the molecular and cellular level.
They also intend to analyze the origin of contact lens-evoked pain.
Diagnosing neuropathic pain is challenging, as a chronic peripheral lesion of the cornea could lead to local nerve damage that may persist after apparent healing, thus evoking pain, Belmonte explained.
“For instance, my interpretation is that in chronic dry eye there is a combination of ocular surface inflammation with injury of epithelium cells and nerve endings, which become abnormally active, causing unpleasant dryness sensations and pain,” he said.
When the ocular surface tissues and corneal tearing are normal and pain persists, ocular neuropathic pain can be suspected, he continued.
If the pain is due to abnormal activity of ocular surface nerve fibers, it will improve with a topical anesthetic, he explained. If it involves an abnormal activity at higher levels of neural pathways, pain is expected to persist.
“Specific questionnaires and tests are being developed to define the probability of a pain to be neuropathic, but a satisfactory, secure clinical diagnosis method is, to the best of my knowledge, still lacking,” he added.
“Optometrists are manipulating the ocular surface,” Belmonte said. “A healthy and normally functioning innervation is critical for the success of any intervention on the eye surface, for instance contact lens fitting. Thus, optometrists need to know in detail the potential source of complications derived from nerve damage and to evaluate the functional state of ocular sensory nerves to decide and to follow the effect of their actions on the eye’s surface.”
Potential treatment
Belmonte said the treatment for patients who have clinically well established neuropathic pain with no response to “conventional eye-directed therapies ... is the same used for other forms of neuropathic pain. These include gabapentin, pregabalin and a full family of drugs that reduce central nervous system excitability.”
Rosenthal noted that all patients respond differently.
“In my experience, gabapentin and the other traditional analgesics only take the edge off the pain at best,” he said.
“My personal advice to the patients,” Belmonte added, “is that at this point the best they can do is go to a good pain unit in a hospital and be followed by doctors who specialize in these treatments.” – by Abigail Sutton
- References:
- Batawi H, et al. Invest Ophthalmol Vis Sci. 2015;56(7):4445.
- Kaido M, et al. Invest Ophthalmol Vis Sci. 2016.doi:10.1167/iovs.15-18447.
- Lazzarini D, et al. Invest Ophthalmol Vis Sci. 2016;57(12):6165.
- McMonnies CW. J Optom. 2016.doi:10.1016/j.optom.2016.06.002.
- Rosenthal P, et al. Invest Ophthalmol Vis Sci. 2011;52(14):3855.
- Rosenthal P, et al. Invest Ophthalmol Vis Sci. 2016.doi:10.1167/iovs.16-20557
- Spierer O, et al. Invest Ophthalmol Vis Sci. 2016.doi:10.1167/iovs.15-18133.
- For more information:
- Carlos Belmonte, MD, PhD, is a professor at the Instituto de Neurosciencias de Alicante at Universidad Miguel Hernandez-CSIC in Alicante, Spain. He can be reached at: carlos.belmonte@umh.es.
- Kelly K. Nichols, OD, MPH, PhD, is dean at the School of Optometry, University of Alabama Birmingham, and can be reached at: nicholsk@uab.edu.
- Perry Rosenthal, MD, is an assistant professor at Harvard Medical School and founder of the Boston EyePain Foundation and the Boston Foundation for Sight. He can be reached at: prosenthal@bostoneyepain.org.
Disclosures: Belmonte and Rosenthal reported no relevant financial disclosures. Nichols is a consultant for Allergan, Insite/Sun Pharmaceutical, Kala, Parion, Santen, ScienceBased Health and Shire and conducts research for Allergan, Eleven, Johnson & Johnson Vision Care, Kala, the National Institutes of Health, Oculus and TearScience.