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), <a href="https://www.chictr.org.cn/bin/project/edit?pid=265888">https://www.chictr.org.cn/bin/project/edit?pid=265888</a>.

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

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2025年12月2日

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Xirenayi Zhuoruo,
Yike Li,
Yiting Sun,
Chongyang Mu,
Hongjing Sun,
Tao Jiang,
Chunyang Wang,
Ning Wang,
Xiuming Jin

摘要

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.