Cyclic extranasal neurostimulation for dry eye disease: a 4-week stimulation and 6-week intermission regimen based on neural adaptation dynamics.

Abstract

Background: Extranasal neurostimulation is a promising therapy for aqueous-deficient dry eye (ADDE), but neural adaptation and optimal treatment duration remain poorly characterized. This study investigated duration-dependent neural sensitivity dynamics to formulate an optimized cyclic treatment regimen.

Methods: In this prospective, randomized, open-label trial, 50 ADDE patients (Schirmer test: 2-5 mm) were assigned to 2-week or 4-week bilateral extranasal neurostimulation (twice daily). Participants were followed for 6 weeks post-treatment. The primary outcomes were neural sensitivity changes (Δ Schirmer) and short-term recovery (6 weeks after stimulation cessation). Secondary endpoints included subjective symptoms and objective signs.

Results: Distinct neural adaptation patterns were observed. The 4-week group exhibited reversible neural adaptation, with an attenuated stimulation response at treatment completion (Δ Schirmer: 1.18 ± 4.17 mm, P = 0.051, Cohen's d = 0.28) that fully recovered after the 6-week intermission (post-stimulation Schirmer: 10.90 ± 7.29 mm vs. initial 12.42 ± 6.67 mm, P = 0.90, η²p = 0.092). This reversible adaptation was associated with sustained improvements in tear film stability [fluorescent tear film break-up time (FBUT): 6.27 ± 2.49 s vs. baseline 3.18 ± 1.36 s, P < 0.001, η²p = 0.235] and tear volume [tear meniscus height (TMH): 0.25 ± 0.05 mm vs. 0.19 ± 0.02 mm, P < 0.001, η²p = 0.26]. Critically, this reversible adaptation pattern was exclusive to the 4-week protocol. The 2-week protocol showed preserved stimulation responses during treatment (Δ Schirmer: 3.22 ± 6.54 mm, P < 0.001, Cohen's d = 0.49) but developed persistent neural hyposensitivity (8.76 ± 5.95 mm vs. initial 14.88 ± 8.69 mm, P < 0.001, η²p = 0.24). Its clinical benefits, though significant for FBUT (5.20 ± 2.81 s vs. baseline 2.86 ± 1.01 s, P < 0.001, η²p = 0.109), were less pronounced than in the 4-week group, and TMH showed no sustained increase (0.21 ± 0.04 mm vs. baseline 0.19 ± 0.03 mm, P = 0.11, η²p = 0.112). Both protocols demonstrated excellent safety and high patient satisfaction.

Conclusions: Based on neural adaptation and recovery characteristics, a cyclic regimen of 4-week extranasal neurostimulation followed by a 6-week intermission is proposed as a potentially effective and sustainable clinical strategy for managing ADDE. This approach synchronizes treatment with the nervous system's intrinsic recovery cycles, addressing limitations of continuous stimulation paradigms.

Trial registration: Chinese Clinical Trial Registry (ChiCTR2500100816). Registered on 15 April 2025 (retrospectively registered), https://www.chictr.org.cn/bin/project/edit?pid=265888 .