Neurostimulation: Does It Work on Dry Eye?

A device used under patient direction stimulates the nervous system to increase production of basal tears.

By Milton M. Hom, OD

The eye and nose share more than anatomic proximity. The first connection is a physical one, as the ocular and nasal structures share continuous epithelial surfaces and are connected via the nasolacrimal sac.1-3 The second connection is rooted in the nervous system. The nasal and ocular surface sensory systems share common innervation, prominently cranial nerve V (specifically, trigeminal branches V1 and V2), which has sensory functions in each, and cranial nerve VII (specifically, the vidian nerve to the pterygopalatine ganglion), which is contained in the parasympathetic nervous system. The innervation to the nasal and ocular surface intersect at the pterygopalatine ganglion, a parasympathetic ganglion that has axonal projection to the lacrimal glands and nasal mucosa. This structure connects it all to the nasal (nasopalatine) nerves, including the lacrimal gland, goblet cells, and meibomian glands.1

TO THE POINT

Neurostimulation may provide an alternative approach for patients with DED who do not wish to receive, or have not responded to, pharmacologic solutions.

These anatomic and functional relationships are key reasons why there is high comorbidity of allergic rhinitis and allergic conjunctivitis4; surveys suggest that both conditions may be present in more than 80% of allergy patients.5-8 Although processes of neurogenic inflammation and venous flow are also likely involved, this shared parasympathetic innervation of the tear film and nasal secretion likely induces the naso-ocular reflex common to both etiologies.

A recent innovation in the treatment of dry eye disease (DED) utilizes the relationship between the nasal cavity and the ocular structure to derive therapeutic benefit. The device (TrueTear, Allergan) is a noninvasive neurostimulation instrument inserted into the nose; it is the only such device approved by the US Food and Drug Administration to temporarily increase tear production during neurostimulation in adult patients. Two prongs on the distal end of the device contact the ophthalmic branch of the trigeminal nerve, and an electrical signal stimulates activity within the trigeminal nerve (V1), with additional activity to cranial nerve VII, which innervates the lacrimal glands.

The concept of neurostimulation has been described extensively in medical literature, notably in chronic migraine pain.9 It has also been successfully implemented in rehabilitative settings, and its investigational applications include the treatment of post-traumatic stress disorder10 and various cognitive neurologic conditions, such as Alzheimer disease.11

MEIBOMIAN GLANDS

There is evidence that neurostimulation yields morphologic changes in meibomian glands, such that they begin to contribute to tear development following neurostimulation.1 Brinton et al demonstrated that, in addition to stimulating the afferent ethmoid pathway, neurostimulation also induced activity in glands responsible for secretion of lipids and proteins that contribute to tear development.2

Further evidence that neurostimulation yields endogenous tear production is suggested in a study by Friedman et al.3 The study noted that patients reported approximately 3 hours of sustained relief of ocular discomfort secondary to DED after using the device. The authors associated the extended relief of symptoms to the plausible production of endogenous tears.

1. Pondelis JN, Dieckmann G, Kataguiri P, et al. Intranasal Neurostimulator Induces Morphological Changes in Meibomian Glands in Patients with Dry Eye Disease. Poster presented at: ARVO 2017; May 8, 2017; Baltimore, MD.

2. Brinton M, Chung JL, Kossler A, et al. Electronic enhancement of tear secretion. J Neural Eng. 2016;13(1):016006

3. Friedman NJ, Burton K, Robledo N, et al. A nonrandomized, open-label study to evaluate the effect of nasal stimulation on tear production in subjects with dry eye disease. Clin Ophthalmol. 2016;10:795-804.

The net therapeutic benefit of neurostimulation in the treatment of DED is increased production of basal tears. Arguably, there could also be long-term benefits associated with its continued use beyond the immediate stimulation of tear production. There is suggestive evidence that sustained use may result in remodeling within the local nervous network, possibly returning proper physiologic function to the lacrimal glands.12

NEUROSTIMULATION AND BASAL TEAR PRODUCTION

It is important to recognize that the function of a neurostimulation device is the production of basal tears rather than a simple tear reflex.

While it is known that stimulation of the sensory nerves initiates an afferent signaling pathway, the exact mechanism of resulting basal tear secretion is unclear as of this writing. There are two possible mechanisms at work.

The Brain

The first mechanism that may be stimulated by use of a neurostimulation device is controlled by the brain. Friedman et al suggested that stimulation of the trigeminal afferent nerve fibers in the nasal cavity via the anterior ethmoidal nerve may initiate the nasolacrimal reflex.12 They argue that this stimulus leads to “an increase in activity in the superior salivatory nucleus region of the brain, which is responsible for control of natural lacrimation.”12

Nasal-ocular Tear Reflex

Another mechanism may responsible for basal tear production following neurostimulation: nasal-ocular tear reflex. It is plausible that, upon electrical stimulation, the nasal nerve carries the signal to the pterygopalatine ganglion. In theory, much like a passenger switching trains at a junction, the electrical signal reaching this point may shift to the parasympathetic pathway, thereby stimulating facial nerve VII, which connects to goblet cells and meibomian glands.1

THERAPEUTIC BENEFIT

Many of the therapeutic modalities used for treatment of DED are predicated on reducing inflammation. One limitation to this approach is that patients are not always receptive to continued use of pharmacologic modalities. My own experience with patients is that they are generally accepting of modalities that are drug free and natural.

Another consideration is that directing efforts to the inflammatory response in DED solves a consequence of the underlying physiologic changes caused by the condition. It is logical to seek options that facilitate the ability for patients to produce their own tears, especially healthy basal tears. Although there are no studies regarding concomitant use of neurostimulation with medical approaches at the time of this writing, it makes a sense to combine neurostimulation with other treatment strategies.

The data on neurostimulation are extremely encouraging. In a clinical trial, patients who used the device for 180 days demonstrated increased tear production over baseline at all time points (days 0, 7, 30, 90, and 180) when evaluated with Schirmer testing.13

LOOKING OUTSIDE OF THE PHARMACY

Not all patients respond adequately to the medical approach for DED. The availability of a nonpharmacologic approach to DED treatment gives eye care providers another tool to help patients find relief from ocular symptoms that affect their quality of life.

1. Hom MM, Bielory L. The anatomical and functional relationship between allergic conjunctivitis and allergic rhinitis. Allergy Rhinol (Providence). 2013;4(3):e110–e119.

2. Berger W, Chipps B, Mah FS, et al. New perspectives on allergy management: Ophthalmologists and allergists weigh in on key issues. Review of Ophthalmology. 2008;15(4).

3. Bergmanson JPG, Gierow P. Ocular and orbital circulation. In: Clinical Ocular Anatomy and Physiology. JPG Berg-manson (Ed). Houston, TX:166-172, 2008.

4. Durham SR. One airway: The link between allergic rhinitis and asthma. Advanced Stud Med. 2002;2(24):861-866.

5. Bielory L, Katelaris CH, Lightman S, Naclerio RM. Treating the ocular component of allergic rhinoconjunctivitis and related eye disorders. MedGenMed. 2007;9(3):35.

6. Wüthrich B, Brignoli R, Canevascini M, Gerber M. Epidemiological survey in hay fever patients: Symptom prevalence and severity and influence on patient management. Schweiz Med Wochenschr. 1998;128(5):139-143.

7. Bousquet J, Knani J, Hejjaoui A, et al. Heterogeneity of atopy. I. Clinical and immunologic characteristics of patients allergic to cypress pollen. Allergy. 1993;48(3):183-188.

8. Bielory L. Allergic conjunctivitis and the impact of allergic rhinitis. Curr Allergy Asthma Rep. 2010;10(2):122-134.

9. Cho SJ, Song TJ, Chu MK. Treatment update of chronic migraine. Curr Pain Headache Rep. 2017;21(6):26.

10. Sharma M, Naik V, Deogaonkar M. Emerging applications of deep brain stimulation. J Neurosurg Sci. 2016;60(2):242-255.

11. Mondragón-Rodríguez S, Perry G, Pena-Ortega F, Williams S. Tau, amyloid beta and deep brain stimulation: aiming to restore cognitive deficit in Alzheimer’s disease. Curr Alzheimer Res. 2017;14(1):40-46.

12. Friedman NJ, Burton K, Robledo N, et al. A nonrandomized, open-label study to evaluate the effect of nasal stimulation on tear production in subjects with dry eye disease. Clin Ophthalmol. 2016;10:795-804.

13. Allergan announces positive pivotal trial results for Oculeve intranasal tear neurostimulator [press release]. Allergan; May 16, 2016. https://www.allergan.com/news/news/thomson-reuters/allergan-announces-positive-pivotal-trial-results. Accessed March 15, 2017.

Milton M. Hom, OD, FAAO
• optometrist, Azusa, Calif.
• financial disclosures: consultant, Allergan, Bausch + Lomb, Shire, Sun Pharma
• 626-963-7100