Three prominent ophthalmologists, Lance Forstot, MD, Herbert Kaufman, MD and Marguerite McDonald, MD, had a cyberchat with influential and, at times, controversial fellow ophthalmologist Perry Rosenthal, MD, about dry-eye-related issues. One is a neuropathic model, and the other involves chronic eye pain.
Perry Rosenthal, MD: I will discuss two issues. The first is a new neuropathic eye pain model within the spectrum of disorders known as dry eye disease in which patients experience chronic dry eye symptoms and even devastatingly severe eye pain and sensitivity to light in the absence of supportive signs of its intensity or cause.
In the second I will describe an overlooked, devastating, chronic, suicide-provoking eye pain that can also include severe photophobia. Although centered in, around and behind the eyes, this pain is commonly associated with headaches and, in some cases, the pain is also perceived in the face and/or ears, jaws and even teeth. I have labeled this disease oculofacial pain.
The diagnosis of dry eye disease has been based on the presence of inappropriate chronic dry eye symptoms regardless of tear metrics — even for eyes that are not dry. The explanation for this common feature has been hyper-evaporation of tears associated with meibomian gland dysfunction. Nevertheless, despite the fact that these tears evaporate faster, this hasn’t explained why many of these eyes are not dry.
In my opinion, the traditional explanation of hyper-evaporating tears fails to comfortably explain why many of these patients experience chronic dry eye symptoms despite having normal tear metrics. I propose that at the source of these chronic dry eye symptoms is dysfunctional sensors designed to monitor the tear film thickness and its integrity.
Developing mechanisms for monitoring and maintaining the integrity of the optical corneal tear film was critical to maintaining uninterrupted, useful vision essential for sustaining life when our ancient ancestors transitioned from water to land. The key monitors of the tear film integrity are the TRPM8 sensors, known as the transient receptor potential channel membranes. These are located in many of the terminals of the superficial corneal nerves, which are highly sensitive to rapid drops in temperature such as those that occur during tear evaporation. Moreover, as the evaporating corneal tear film becomes thinner, the rate of cooling of the corneal surface and the nerves’ terminals increases until it reaches a trigger point and activates corneal-lacrimal gland loop activity, thereby inducing reflex tearing.
I suggest that chronic dry eye symptoms in eyes that are not dry are caused primarily by unidentified dysfunction in certain sensors located in many of the corneal nerve terminals tasked with monitoring corneal tear film thickness by sensing the increased rate of surface cooling caused by tear evaporation. Moreover, I argue that the neuropathic theory fully explains for the first time the common and often striking disparity between signs and symptoms demonstrated by these eyes.
My second topic is oculofacial pain, the name I have given to a previously unrecognized general syndrome in which pain is perceived as primarily originating in and around the eyes and orbit and is often accompanied by headaches. Pain also may be perceived as originating in the jaws, face, ears and, in some, even teeth.
The disparity between signs and symptoms is especially striking in this disorder, despite most of these eyes being healthy. How is this explained? There is some work that suggests that this pain syndrome originates in the pain circuitry of the trigeminal brainstem from where it is projected to peripheral structures. Although it can include severe dry eye symptoms in some, oculofacial pain is more typically described as burning, needle-like, sharp-cutting and/or pins and needles, and other descriptive terms. It is predictable that most of these patients feel abandoned by their doctors, which, in my opinion, is a major factor in nurturing the thoughts of suicide that are commonly experienced by this cohort.
Dr. Kaufman: I have two observations. There are a number of patients with pain where the symptoms don’t seem to correlate terribly well, and one of the most frequently missed diagnoses that I’ve seen to cause this is some degree of lagophthalmos.
Dr. McDonald, in your group, Henry Perry, MD (Ophthalmic Consultants of Long Island) and one of your younger colleagues noticed that sleeping position causes pain and apparent dry eye disease. And I think that’s probably due to the fact that the eyes are a little bit open at night [nocturnal lagophthalmos].
Nocturnal lagophthalmos has been documented in at least 7% of the population. As tear flow decreases with age, the surface dries out at night, even in the presence of some reasonable tears. Sometimes this is diagnosable by asking the patient to gently close their eyes [but not squeeze] and see if a pen light reflex from the cornea is visible.
But the important thing is that it is common in patients without obvious dry eye, and it is easily treatable. The old-fashioned ointments with a lanolin-petrolatum base that are sticky and last all night will often treat this [more comfortable ointments that wash out quickly are not effective].
Some of the newer occlusive masks that are used after LASIK or even swim goggles will treat this. Undetected lagophthalmos is easy to confuse with the syndromes that Dr. Rosenthal elucidates, but this is important because it’s treatable.
Dr. Rosenthal: Yes. Moreover, individual differences are common. In some cases they are insignificant and in others they are not. This underlies the message that we can’t paint them all with the same brush. Moreover, I agree with Professor Kaufman that lagophthalmos can be a factor in some cases. However, I would expect there to be signs of corneal surface desiccation in these patients.
Dr. Kaufman: I’m sure Dr. Rosenthal is correct, that in some of these it might be worth a try to give a sticky ointment at night, or an occlusive patch for a week or so, just to see if lagophthalmos is the cause of some of these, because I suspect it might be.
Dr. Rosenthal: That’s easy to try. It’s noninvasive, and the results are available immediately.
Dr. McDonald: I diagnose nocturnal lagophthalmos four or five times a day, and sometimes it’s in somebody who had a very aggressive blepharoplasty 20 years ago. Those people can end up in trouble years later.
It seems like it’s Dr. Rosenthal’s theory that the monitoring of the tear film thickness, if it thins out, is part of the stimulus for one of the syndromes. Certainly, the next day if you measured tears they might be normal in someone with nocturnal lagophthalmos. As he says, it’s a heterogeneous group. Nocturnal lagophthalmos is not incompatible with what he’s describing.
Dr. Kaufman: You’re quite correct. As tear flow decreases, the opening in the lid becomes symptomatic, but it still may be reasonable. The important thing is it’s so easy to give it a try as Dr. Rosenthal points out, and if you help your patient you’ll know in a few days or a week. If not, then there’s not much lost.
Dr. McDonald: Dr. Rosenthal, in the first group you described, was there anything diagnostic about their response to a topical anesthetic? Does that help you sort this out at all?
Dr. Rosenthal: I suggest that the answer to your excellent question is complex, because sensory stimuli from the trigeminal fields are modified as they pass through the trigeminal brain stem, which is normally balanced by disinhibition, so as to avoid overabundance of pain. The mechanisms are complex and at this point poorly understood.
Dr. Forstot: Dr. Rosenthal, do some of the things like Lyrica (pregabalin, Pfizer) and Neurontin (gabapentin, Pfizer) work for this type of syndrome? It sounds like you need to treat them systemically.
Dr. Rosenthal: I suggest that the activated microglia in the central nervous system may be a prime target. If so, they need to be treated systemically with drugs that can penetrate the blood-brain barrier. But, in my experience, these analgesics are only modestly effective, typically disappointing and are limited by their side effects.
Dr. Forstot: Is there anything that is effective?
Dr. Rosenthal: Not that I know of. Furthermore, this is not surprising, since, to my knowledge, this subject has not been investigated seriously and I believe that the pain is exacerbated or even originates in some patients in the trigeminal brain stem.
Dr. Kaufman: One of the most exciting things about treating both dry eye disease and meibomitis is anti-inflammatories. Restasis (cyclosporine, Allergan) is old, Xiidra (lifitegrast, Shire) is much newer, and one physician we know is using spironolactone (Aldactone, Pfizer). But patients may not want to use these medications, for one reason or another.
There is a quick, cheap test that can be done by office staff for the inflammatory component called InflammaDry. It detects MMP-9, a tear cytokine given off when the eye is inflamed. Not all dry eyes are inflamed, but this lets you know whether it’s really worth using these expensive anti-inflammatory compounds and whether they’re likely to be successful. I think this is an underused test, and probably should be used before the anti-inflammatory compounds are prescribed for our dry eye patients. Also, anti-inflammatory drugs may not be necessary forever and it might be possible to stop them and test whether the MMP-9 indicates continued inflammation.
Also, some years ago I introduced bandage contact lenses and did all the original studies on bandage lenses. Some dry eye patients and Sjögren’s patients can really be helped with low-water-content, high-oxygen, permeable soft lenses. They don’t take the place of the much more complicated and specialized system that Dr. Rosenthal has. His is much more effective, especially in Stevens-Johnson syndrome, toxic epidermolysis and pemphigoid. But, for some dry eye patients, especially those with Sjögren’s syndrome, it might really be worth trying bandage contact lenses because they are cheap, simple and readily available. Although low-water-content, oxygen-permeable lenses that are not too thin seem most effective, others can work as well. OM
An original version of this article appeared online.