Neurostimulation for Tear Production

Ji Kwan Park; Sandra Cremers; Andrea Lora Kossler

Curr Opin Ophthalmol. 2019;30(5):386-394.

Abstract and Introduction

Abstract

Purpose of review: Dry eye disease (DED) is a chronic multifactorial disease that affects millions of people worldwide. Despite ongoing research, treatment for DED remains a challenge. Neurostimulation for tear production is a rapidly evolving field that culminated in the development of the intranasal tear neurostimulator (ITN). In this article, we review the neuroanatomy and pathophysiology of tear production and the evolution of neurostimulation for the treatment of DED.

Recent findings: The ITN was approved for commercial use in April 2017. This innovation stemmed from the success of lacrimal nerve and anterior ethmoid nerve stimulation animal studies. Since then, numerous pilot studies and multicenter randomized controlled trials demonstrate increased aqueous tear production, improved DED-related symptoms, and device safety. Recent studies also report the positive effects of intranasal stimulation on mucin and lipid secretion.

Summary: Neurostimulation for enhanced tear production is a promising new treatment option for DED. Stimulation of the lacrimal nerve and anterior ethmoid nerve both effectively increase tear volume. The ITN is a noninvasive device that effectively increases aqueous tear volume and may improve tear composition, including mucin and lipid concentrations. Further studies are needed to determine proper patient selection and the long-term efficacy of neurostimulation for DED.

Introduction

Dry eye disease (DED), also known as keratoconjunctivitis sicca, is a multifactorial condition with a global prevalence ranging between 5 and 50% among the adult population. In the United States, 3.2 million women and 1.7 million men over the age of 50 years have been estimated to have moderate-to-severe DED.^[1,2,3] The disease is increasing among the younger population between 18 and 34 years of age because of the frequent use of contact lenses, computer, smartphones, and tablets.^[4,5]

A vicious cycle of aqueous tear deficiency and excessive tear evaporation from inflammation and somatosensory abnormalities can result in visual disturbances, ocular irritation, pain, photophobia, excessive tearing, and decreased quality of life.^[2,5] Previous modalities focused on lubricating the ocular surface with artificial tears, ointments, and punctal plugs, and inhibiting the inflammatory response with agents, such as cyclosporine and lifitegrast.^[2,3,6,7] Advances in understanding the neural control of the tear film and the dynamic interplay between the nasolacrimal reflex (NLR) and lacrimal functional unit (LFU) has led to a paradigm shift in the treatment of DED.^[3,5] Neurostimulation utilizes the NLR to stimulate tear production via the afferent or efferent branches of the neural reflex arc.^[8,9–11] This article aims to review the neural pathways involved in tear production and the evolution of neurostimulation for the treatment of DED.

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Abstract and Introduction
Nasolacrimal Reflex
Lacrimal Functional Unit
Neurostimulation
Early Animal Studies
Intranasal Tear Neurostimulator
Effects on Aqueous Tear Production
Effects on Mucin, Protein, and Lipid Tear Production
Safety
Future Directions
Conclusion
References
Sidebar

Table 1. Recent studies on neurostimulation in treating dry eye disease.
Study title	Author	Year	Type of study	Primary outcome	Secondary outcomes	Sample size (N)	Follow-up period	Conclusions	Limitations
Neurostimulation of the lacrimal nerve for enhanced tear production	Kossler et al. [3]	2015	Animal study	ATV after LNS.	Histologic examination of LG after chronic LNS.	6 rabbits	1 month	LNS increases ATV without histologic damage.	Co-stimulation of lacrimal gland. Small animal study.
Chronic electrical stimulation for tear secretion: lacrimal vs. anterior ethmoid nerve	Kossler et al. [18]	2017	Animal study	ATP and after LNS and AENS.	Histologic examination of LG and nasal septum after stimulation.	6 rabbits (AENS); 5 rabbits (LNS)	3 weeks (AEN); 4–7 months (LNS)	AENS is more effective than LNS at enhancing ATP. The LG implant is well tolerated, the nasal implant needs modification.	Curved shaped implant design in nasal mucosa resulted in suboptimal placement and mucosal erosion.
Enhanced tearing by electrical stimulation of the anterior ethmoid nerve	Brinton et al. [17]	2017	Animal study	Aqueous, lipid and protein contents after AENS.	Modulation of pulse frequency and duty cycles.	13 rabbits	3 weeks	AENS increases ATV, increases lipid and protein contents and, reduces osmolarity.	Short follow-up because of nasal implant erosion.
A nonrandomized, open-label study to evaluate the effect of nasal stimulation on tear production in patients with dry eye disease	Friedman et al. [25]	2016	Prospective, open-label, single arm, nonrandomized pilot study	ATP, symptoms of DED after ITN, safety of ITN.	Subject satisfaction.	40 patients	40 patients	ITN increases ATP, decreases the conjunctival but not corneal staining and improves DED symptoms.	No evaluation of other tear film layers. Peristimulation TBUT not measured.
Randomized controlled crossover trial comparing the impact of sham or intranasal tear neurostimulation on conjunctival goblet cell degranulation	Gumus et al. [26]	2017	Prospective, randomized, controlled, cross-over, multicenter clinical trial	GC degranulation and mucous secretion after ITN. TMH and area after ITN	OSDI and VAS scores, CDVA, TBUT, corneal and conjunctival staining, tear production.	10 dry eyes, 5 normal patients	2 visits, at least 1 week	ITN stimulates degranulation of conjunctival GC. TMH increases more in normal than dry eye patients.	Limited accuracy in MUC5AC measurement. Technique difficult to replicate in another study.
Effect of intranasal neurostimulation on tear protein content in patients with dry eye	Woodward et al. [27]	2017	Single-center, open-label single arm study	Tear protein contents with ITN.		55 patients	1 visit	ITN promotes protein release from LG (not significant).	A single treatment study.
In-vivo confocal microscopy demonstrates intranasal neurostimulation-induced goblet cell alterations in patients with dry eye disease	Dieckmann et al. [28]	2017	Single-center, open-label single arm study	Morphological GC changes after ITN.		15 patients	1 visit	GC area and perimeter decrease demonstrating a direct effect on GC.	A single treatment study.
Tear total lipid concentration in patients with dry eye following intranasal neurostimulation	Green et al. [29]	2017	Single-center, open-label single arm study	Tear lipid concentration with the use of ITN.	ATV after ITN.	55 patients	1 visit	ITN improves ATV with equivalent change in total lipid concentrations.	A single treatment study.
Quantitation of tear production by tear meniscus height following acute use of the intranasal tear neurostimulator	Orrick et al. [30]	2017	Crossover, open-label Study	TMH changes in ITN compared with ETN.		25 patients	4 visits, 3 treatment	ITN improves TMH and Schirmer scores.	No evaluation of other tear film layers.
Intranasal neurostimulator induces morphological changes in meibomian glands in patients with dry eye disease	Pondelis et al. [31]	2017	Single-center, open-label single arm study	MG morphology with the use of ITN.		12 patients	1 visit	Reduction in MG area and perimeter suggests release of meibum.	A single treatment study.
Effect of the intranasal tear neurostimulator on meibomian glands	Watson et al. [32]	2017	Crossover, open-label study	Activity of MG after ITN.		25 patients	4 visits, 2 treatments	ITN increases both LG and MG secretion.	No evaluation of other tear film layers.
Characterization of tear production in patients with dry eye disease during intranasal tear neurostimulation: results from two pivotal clinical trials	Sheppard et al. [8]	2019	A. Prospective two-visit, randomized, double-masked, dual control, cross over study	ATP after ITN compared with ETN or sham device.	Safety outcomes measures, CDVA, corneal staining, biomicroscopy and nasal speculum findings.	48 patients	1 day	ITN is superior to ETN or sham ITN in ATP less than 10% of patients reported mild AE.	Short-term testing. High-intensity testing completed in 1 day.
			B. Prospective, six-visit, single-arm, open-label study	ATP after ITN.	Corneal staining, DED symptoms, satisfaction, AE.	89 patients	6 months	ITN improves ATP, corneal staining, and DED symptoms.	Limited racial heterogeneity (primarily Caucasians).
Randomized, controlled, double-masked, multicenter, pilot study evaluating safety and efficacy of intranasal neurostimulation for dry eye disease	Cohn et al. [33]	2019	Multicenter, randomized, controlled, double-masked pilot study	ATP, DED symptoms and safety of ITN.	Corneal and conjunctival staining, TBUT changes.	56 patients	3 months	ITN is superior to sham ITN in ATP. Nosebleed is the most common AE. No improvement in corneal or conjunctival staining. Improves dry eye category scores but not OSDI or VAS scores.	No evaluation of other tear film layers.

AE, adverse effect(s); AENS, anterior ethmoid nerve stimulation; ATP, aqueous tear production; ATV, aqueous tear volume; CDVA, corrected distance visual acuity; DED, dry eye disease; ETN, extranasal neurostimulation; GC, goblet cells; ITN, intranasal nerve stimulator; LG, lacrimal gland; LNS, lacrimal nerve stimulation; MG, meibomian gland; MUC5AC, mucin 5AC oligomeric mucus/gel-forming; OSDI, ocular surface disease index; TBUT, tear break up times; TMH, tear meniscus height; VAS, visual analog scale.

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Neurostimulation for Tear Production

Abstract and Introduction

Abstract

Introduction

Tables

References

Authors and Disclosures

Authors and Disclosures

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