Musings on pterodactyl eggs and dry eye

What if inflammation is not the cause of dry eye disease?

Issue: November 25, 2016

ByDarrell E. White, MD

What if we are wrong about the cause of dry eye disease?

It is not very likely, I know, but what if we are? What if inflammation is not the primary event in the pathophysiology of DED, but is rather no higher than second on the cascade? For some 15 years now we have been discussing whether inflammation or dryness itself is the chicken or the egg. Just for the sake of discussion, what if the root cause of DED is neither?

What if DED is actually a primary neurological disorder?

It is a little wacky, but bear with me here. At the very least, we will get a chance to talk about a couple of new concepts and two new treatments, and remember two really tough clinical problems that definitely involve neuropathology, dry eye and inflammation.

In the rightfully famous Restasis (cyclosporine ophthalmic emulsion 0.05%) slide deck that each of us is so familiar with, Allergan reintroduced the concept of a neural feedback loop that begins on the surface of the eye and circles through the central nervous system by way of the trigeminal nerve. We are shown an example in which this loop is adversely affected by dryness and inflammation on the surface of the eye, and this in turn leads to a diminution of normal tear production. Inflammation is involved in the process on the surface of the eye, and the postulate is that treating the inflammation contributes to the restoration of the normal feedback loop.

There are several examples of neural diseases that produce signs and symptoms that are similar to what we see on the surface of the eye in DED. Let us look at two challenging clinical problems: herpes zoster ophthalmicus and denervation keratitis. Both involve the interruption or disruption of normal trigeminal nerve activity. Surface inflammation is associated with poor tear function, and at various times in the course of both diseases, we see corneas that look for all the world like really bad dry eye. In some way, the affected nerves are unable to participate in the normal feedback arc between the eye and central nervous system. It is almost always necessary to use some sort of anti-inflammatory therapy to successfully treat these problems. Sounds familiar, and all because of a primary neurological problem in both instances.

Neuropathic dry eye

The concept of “neuropathic” DED is starting to get a bit of traction in academic dry eye circles (As an aside, do you have any idea how startling it is to type the words “academic dry eye?!”). Faint whispers about adding a third type of dry eye are filtering out of the DEWS II meetings. Neuropathic dry eye could join our established aqueous deficient and evaporative dry eye mainstays. Articles with titles such as “Is dry eye all in our patient’s head” refer to this (hat tip to Whitney Hauser, OD, for the find). The essential question before us, if there is indeed a neuronal component to DED, is whether this is more cause or more effect.

In Cleveland I have a rather brilliant young colleague, Rony Sayegh, who practices at University Hospital. Rony is what we at Williams College used to call “stupid smart.” Along with neurosurgical colleagues, he is exploring the treatment of one kind of neuropathic pain from dry eye that persists in the absence of the initiating insult. Some patients have devastating, life-altering corneal pain that is present despite what appears to be a totally normal ocular surface both by exam and point-of-care testing criteria. To treat them, Rony and his team insert an electrode to electrically stimulate the trigeminal pain pathway of the cornea. Despite the quite obvious technical challenges involved, they have had several successes.

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Of course, neuropathic DED could certainly be nothing more than a consequence or effect of incompletely treated aqueous deficient or evaporative DED, right? Rony and his colleagues could have simply identified the neural pathway that explains those patients who come to our office with pain that is wholly and totally out of proportion when compared with the signs we uncover in the office. The nerve damage would be the consequence of the inflammation in that case. If so, not only is my hypothesis totally blown up, but really, so might be the concept of a separate type of DED. I do not think that is the case, though, because of a soon-to-be on the market device from Allergan called TrueTear (formerly Oculeve).

Stimulation of trigeminal nerve

TrueTear is an ingenious little gadget that stimulates the trigeminal nerve inside the nose. Remember that little twig of V1, the first division of the trigeminal nerve that goes to the tip of the nose and sports a vesicle in herpes zoster ophthalmicus? Hutchinson’s sign! That is the nerve you are juicing with TrueTear. Now I know what you are thinking, that the best part about TrueTear is going to be all of the great jokes (“It’s a pulse, not a pick!”), but it turns out that this thing really works. A single application of a mild electric current results in secretion of complete, natural tears. In addition, it appears that increased production and secretion are maintained for a period of time after the stimulation. There are quite obvious clinical applications that arise from this observation, and we will doubtless hear more than a bit about this once TrueTear is fully FDA approved.

What interests me in the context of this discussion is what this means in relation to the ultimate cause of DED. The fact that mild stimulation of the trigeminal nerve results in the increased production of complete tears makes me wonder if the “original sin” of DED is actually neuronal in nature. If we consider some of the DED associations we are all so familiar with, there are a couple of things that could fit. Once upon a time DED was a disease mostly seen in the elderly. Certainly age has an effect on multiple neuronal pathways. Of late we have seen an exponential increase in DED in all age groups associated with the so-called “multiple screen lifestyle” of computer and smartphone use. Might there be a sort of downregulation of trigeminal nerve conduction from the eye caused by the decreased frequency and amplitude of blinking associated with computer use?

In the end, no one really knows if neuropathic DED is a thing, and if it is, if it is a primary cause of DED that precedes inflammation in the cascade of bad things that cause DED. We have spent many an hour over the last 15 years or so ruminating on whether inflammation or dryness is the chicken or the egg. I do not think that a discussion of whether a primary neuropathy is the pterodactyl or the pterodactyl egg is going to change our treatment paradigm in the foreseeable future; we can still expect to see two pharmaceutical options to treat inflammation utilized very frequently for a very long time.

All I know is that the discussion of the neuronal component of DED not only let me show off that I (kinda) understand what Rony is talking about, but I also get credit for the first official joke on TrueTear in print.

For more information:
Darrell E. White, MD, can be reached at SkyVision Centers, 2237 Crocker Road, Suite 100, Westlake, OH 44145; email: dwhite@healio.com.

Disclosure: White reports he is a consultant for Bausch + Lomb, Allergan, Shire and Eyemaginations; is on the speakers board for Bausch + Lomb, Allergan and Shire; and has a financial interest in TearScience.