Newer areas of research providing updated tools to treat dry eye disease
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Neuromodulation and neurostimulation are close cousins, but they are not the same thing.
Wikipedia defines neuromodulation as the application of an electrical, mechanical or chemical stimulus to a nerve, nerve complex or the brain to moderate activity and return it to a more normal state. For example, neuromodulation could be used to treat epilepsy and reduce the number or severity of seizures. In ophthalmology, we might use neuromodulation to treat hemifacial muscle spasms, severe symptomatic blepharospasm or trigeminal neuralgia. The goal would be to downregulate the afferent and/or efferent arc of the trigeminal nerve.
In neurostimulation, we do the opposite and generate an increase in a nerve or the brain’s activity, resulting in increased activity of a functional unit using electrical, mechanical or chemical stimulation. In eye care, the use of neurostimulation to increase reflex tearing is a growing indication. We and our patients are all familiar with the tearing associated with a punch in the nose, which is a mechanical neurostimulation of tearing effected by the trigeminal nerve. The tearing that occurs while cutting an onion, caused by irritation of the nasal mucosa and ocular surface by propanethial-S oxide gas, is an example of chemical neurostimulation.
As I apply these definitions to the treatment of dry eye disease, neuromodulation would be an appropriate description for a therapy that normalizes basal tear secretion, whether hyposecretion or hypersecretion. Neurostimulation would describe a treatment that activates reflex tearing.
I was involved as a member of the medical advisory board during the development of both the Oculeve mechanical intranasal tear neurostimulator, later acquired and marketed by Allergan under the brand name TrueTear, and the currently available chemical intranasal tear stimulant sold by Oyster Point as Tyrvaya. I will share a few personal thoughts.
The original purpose of the Oculeve mechanical intranasal tear stimulator was to serve as a diagnostic device to determine if stimulation of the trigeminal nerve in the nose would generate meaningful reflex tearing. This would confirm that stimulation of the lacrimal gland could be an effective treatment, and the first business plan was to stimulate the lacrimal gland with electricity using an implanted electrode. As is often the case in research and development, the diagnostic appeared to be a quite effective therapeutic. We learned that significant reflex tearing could be produced with intranasal mechanical stimulation of the trigeminal nerve. We also learned, to the surprise of many of us, that mechanical stimulation of the trigeminal nerve caused the meibomian glands and goblet cells to release their contents as well, allowing the production of all three components of a natural human tear, aqueous, lipid and mucin, along with the hundreds of virtuous hormones, proteins, cytokines and antimicrobial agents present in normal tears.
Early testing by enthusiastic dry eye expert investigators and their patients was positive. The device received FDA approval after appropriate clinical trials and was launched into the market. Despite excellent safety and efficacy, eye care professionals, whether ophthalmologist or optometrist, and their patients were not impressed, and the device failed commercially. However, a powerful learning was that neurostimulation could be an effective treatment for dry eye disease.
Oyster Point chose to utilize chemical stimulation of the trigeminal nerve with varenicline, a nicotinic receptor agonist already on the market as Chantix, used as an adjunct to cease smoking. Varenicline was applied into the nose using a nasal spray application and again proved to be a safe and effective neurostimulator of natural reflex tear production. The now FDA-approved and commercial Tyrvaya is generating better eye care professional and patient acceptance than mechanical stimulation and promises to be a sustainable and useful addition to our therapeutic options for treating dry eye disease.
Another method of trigeminal nerve stimulation is the application of mechanical energy over the external perinasal trigeminal nerve branch, and an FDA-approved device is currently available from Olympic Ophthalmics and marketed as iTear100.
Neurostimulation as a therapy to treat dry eye disease is here to stay, and we can expect further research and development in this area. Neuromodulation to normalize basal tear secretion in patients with hyposecretion or hypersecretion is also under investigation. We are fortunate that our field supports innovation, allowing these and other new and useful treatments to be developed, FDA approved and made available to our patients.
Editor's note: This article was updated on March 16, 2023, to change a product name.
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