Dry eye, beyond MGD

This fall, three prominent ophthalmologists: S. Lance Forstot, MD, Herbert Kaufman, MD and Marguerite McDonald, MD, cyber-chatted with fellow ophthalmologist Perry Rosenthal, MD, about two, under-the-radar dry-eye-related issues. Dr. Rosenthal discusses his two new papers: one deliberates a neuropathic model in which there are chronic symptoms but no signs, and the other concerns chronic, searing pain; it might start in the eyes, but ultimately it could involve the whole face.

Dr. Rosenthal: I will discuss two issues. The first is a proposed new neuropathic model in the spectrum of disorders known as dry eye disease and characterized by chronic dry eye symptoms despite the absence of supportive signs of their cause or intensity.

Second is a description of an overlooked, devastating chronic eye pain that can include severe photophobia. Although centered in, around and behind the eyes, it 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. This diagnosis has been applied to eyes that are not dry and has contributed to the classic enigma between signs and symptoms in the group of disorders known as dry eye disease. The explanation for this common phenomenon has pointed to the hyper-evaporation of tears associated with meibomian gland dysfunction. Nevertheless, although these tears do evaporate faster, this frequently does not explain these symptoms in some eyes with plentiful tears. In my opinion, the explanation of hyper-evaporating tears fails to comfortably explain why the eyes of some patients fail to experience chronic dry eye symptoms despite having normal tear metrics and its high prevalence. Instead, I propose that at the source of these chronic dry eye symptoms is dysfunctional changes in the sensors designed to monitor the thickness of the tear film and its integrity.

Developing the mechanisms for monitoring and maintaining the integrity of the optical corneal tear film was essential for maintaining uninterrupted, useful vision needed to sustain life when our ancient ancestors transitioned from water to land. The key monitors of the tear film integrity are TRPM8 sensors known as the transient receptor potential channel membranes located in many terminals of the superficial corneal nerves. Being highly sensitive to dramatic drops in temperature such as occurs during tear evaporation. Moreover, the rate of cooling of the corneal surface and the nerves’ terminals increases as the evaporating corneal tear film becomes thinner until it reaches a trigger point which activates corneal-lacrimal gland loop activity thereby inducing reflex tearing. Moreover, I propose that chronic dry eye symptoms of 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. I further argue that this neuropathic theory can fully explain for the first time the common and often striking disparity between signs and symptoms in these eyes.

My second topic is oculofacial pain the name I have given to a previously unrecognized general syndrome in which symptoms are perceived as originating primarily in and around the eyes and orbit and are often accompanied by headaches and may also be perceived as originating in the jaws, face, ears and even teeth.

The disparity between signs and symptoms is especially striking in this group of disorders despite the apparent anomaly that most of these eyes are healthy. How can this be explained? Work by one group suggests that this pain syndrome originates in the pain circuitry of the trigeminal brainstem from where it is projected to peripheral structures which can be normal. Although it can include severe dry eye symptoms in some cases, oculofacial pain is more typically described as burning, needle-like, sharp-cutting and/or pins and needles, and other descriptive terms. In this context it is predictable that most of these patients would feel abandoned by their doctors which, in my opinion, is an important factor in nurturing thoughts of suicide commonly experienced in 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, (Ophthalmic Consultants of Long Island) Perry Henry and an associate 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 people. 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’s 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].

Or, 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 it’s important because it’s treatable.

Dr. Rosenthal: Individual differences are common and may be significant. We shouldn’t paint them all with the same brush. I agree with Professor Kaufman that lagophthalmos could be a factor in some. However, I would expect there to be signs of corneal surface desiccation in these cases.

Dr. Kaufman: I’m sure Dr. Rosenthal is correct, that in some of these it might be worth a try just to give a sticky ointment at night, or an occlusive patch for a week or so

just to see if perhaps lagophthalmos might be 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, 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 that are normally balanced by disinhibition in order to avoid excessive pain. The mechanisms are complex and at this point are 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 believe that the activated microglia in the central nervous system are the prime target. If so, they need to be down-regulated with systemic drugs that can penetrate the blood-brain barrier. However, in my experience these analgesics are only modestly effective, typically disappointing and limited by their side-effects.

Dr. Forstot: Is there anything that is effective?

Dr. Rosenthal: Not that I know of. Furthermore, this should 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 the trigeminal brain stem in some patients.

Dr. Kaufman: One of the most exciting things in 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 our office staff for the inflammatory component that is called InflammaDry (RPS). It detects MMP9, 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 under-used 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 MMP9 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 Sjo¨gren’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 and especially in Stevens-Johnson syndrome, toxic epidermolysis and pemphigoid. But, for some dry eye patients, especially those with Sjo¨gren’s syndrome, it might really be worth trying bandage contact lenses because they are cheap, simple and readily available. Although not too thin, low-water content, oxygen-permeable lenses seem most effective, others can work as well. OM

Participant information

S. Lance Forstot, MD, founding partner, Corneal Consultants of Colorado and is clinical professor of ophthalmology, University of Colorado Medical School; Marguerite McDonald, MD, OCLI on Long Island, NY, clinical professor of ophthalmology, NYU Langone Medical Center, NY, NY and clinical professor of ophthalmology, Tulane University Health Sciences Center, New Orleans, LA.

Dr. Kaufman is emeritus Boyd Professor of Ophthalmology and Pharmacology & Experimental Therapeutics at LSU.

Perry Rosenthal, M.D. is a world-renowned ophthalmologist who pioneered the development of rigid gas permeable contact lenses. He founded the nonprofit Boston Foundation for Sight to research the causes of inadequately explained severe eye pain, and now continues his research through the nonprofit Boston EyePain Foundation.