Cyclic extranasal neurostimulation for dry eye disease: a 4-week stimulation and 6-week intermission regimen based on neural adaptation dynamics
BackgroundExtranasal 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.MethodsIn 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.ResultsDistinct 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.ConclusionsBased 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 registrationChinese Clinical Trial Registry (ChiCTR2500100816). Registered on 15 April 2025 (retrospectively registered), https://www.chictr.org.cn/bin/project/edit?pid=265888.Supplementary InformationThe online version contains supplementary material available at 10.1186/s40662-025-00466-w.
- Research Article
12
- 10.3390/life12122007
- Dec 2, 2022
- Life
A decrease of the Tear Meniscus Height (TMH) has been proposed as a useful indicator for Aqueous Deficient Dry Eye (ADDE) categorization. The present study aimed to calculate a TMH cut-off criterion for the categorization or severity assessment of ADDE with the Tearscope. 200 participants with a previous Dry Eye Disease (DED) diagnosis according to TFOS DEWS-II criteria were recruited. TMH by slit-lamp illumination and Lipid Layer Pattern (LLP) with Tearscope were assessed to categorise the participants into the ADDE or the Evaporative Dry Eye (EDE) group. The ADDE group was also subdivided into Mild-moderate ADDE and Moderate-severe ADDE based on TMH with slit-lamp. Additionally, the TMH was measured by Tearscope (TMH-Tc). Receiver Operating Characteristics showed that the TMH-Tc have a diagnostic capability to differentiate between ADDE and EDE participants, and between Mild-moderate or Moderate-severe ADDE, with a cut-off value of 0.159 mm (AUC = 0.843 ± 0.035, p < 0.001; sensitivity: 86.4%; specificity: 75.4%) and 0.105 mm (AUC = 0.953 ± 0.025, p < 0.001; sensitivity: 98.1%; specificity: 80.0%), respectively. The present study proposed a cut-off criterion to differentiate between ADDE and EDE participants, or between ADDE severities through TMH assessed by Tearscope.
- Research Article
40
- 10.1097/apo.0000000000000327
- Nov 1, 2020
- Asia-Pacific Journal of Ophthalmology
Understanding the Dual Dilemma of Dry Eye and Glaucoma: An International Review.
- Research Article
24
- 10.1371/journal.pone.0230119
- Mar 12, 2020
- PLOS ONE
ObjectiveTo elucidate the relationship between lipid layer thickness (LLT), incomplete blinking rate and tear film stability in patients with different myopia degrees after small-incision lenticule extraction (SMILE) and to determine whether there is a difference in the prevalence of dry eye disease (DED) after SMILE among patients with different myopia degrees.MethodsFifty patients (100 eyes) were enrolled in this study; they were divided into 3 groups according to the degree of spherical refraction: a low-myopia group (LMG; spherical refraction ≤-3.00 D, 20 eyes), a moderate-myopia group (MMG; -3.00 D < spherical refraction <-6.00 D, 40 eyes), and a high-myopia group (HMG; spherical refraction ≧-6.00 D, 40 eyes). Testing indicators included the ocular surface disease index (OSDI), fluorescein tear film breakup time (FBUT), corneal fluorescence staining (CFS), the Schirmer test (SI), lipid layer thickness (LLT), blink rate (BR) per 20 seconds, incomplete blinking rate, noninvasive keratograph assessment of first and average tear film breakup time (NIKBUTf, NIKBUTav), and tear meniscus height (TMH). Each indicator was evaluated preoperatively and postoperatively at 1 w, 1 mo and 3 mo.ResultsThe mean age was 29.12±5.95 years. There were no significant differences among the three groups (p>0.05), except preoperative age (p = 0.006). There were significant differences in the FBUT among the three groups at postoperative 1 w and 1 mo (p<0.05). There were significant differences in the incomplete blinking rate and FBUT between the LMG and the HMG at postoperative 1 mo (p<0.05). The number of first tear film breakup points located beyond the 6 mm diameter of the cornea was higher in the HMG than in the other groups. The prevalence of DED in the LMG, the MMG, the HMG was 15%, 8% and 23%, respectively, at 1 w postoperative and 30%, 45% and 53%, respectively, at postoperative 1 mo. The change in LLT was significantly correlated with the changes in FBUT (r = 0.408, p<0.001) and incomplete blinking rate (r = -0.266, p = 0.007). The change in OSDI was negatively correlated with the change in SI (r = -0.502, p = 0.000).ConclusionsThe changes in LLT and incomplete blinking rate decreased the stability of the tear film. The changes in LLT, FBUT and incomplete blinking rate differed postoperatively with different myopia degrees. The prevalence of DED was higher in the HMG than in the other two groups.
- Research Article
1
- 10.13703/j.0255-2930.20230407-k0006
- Sep 19, 2023
- Zhongguo zhen jiu = Chinese acupuncture & moxibustion
To compare the clinical efficacy and safety of acupuncture and sodium hyaluronate eye drop in the treatment of aqueous deficiency dry eye. A total of 60 patients (120 eyes) with aqueous deficiency dry eye were randomly divided into an observation group (30 cases, 1 case dropped out) and a control group (30 cases, 1 case dropped out). In the control group, sodium hyaluronate eye drop were used, one drop at a time, 4 times a day, for 14 consecutive days. In the observation group, acupuncture was applied at bilateral Shangjingming (Extra), Cuanzhu (BL 2), Sizhukong (TE 23), Taiyang (EX-HN 5), and Tongziliao (GB 1) , once a day, treatment for 6 days with the interval of 1 day was required, for 14 consecutive days. The tear meniscus height (TMH), Schirmer Ⅰ test (SⅠT), ocular surface disease index (OSDI) score, non-invasive tear break-up time (NIBUT), and corneal fluorescein sodium staining (FLS) score were compared between the two groups before and after treatment, and the safety of the treatment of the two groups was observed. Compared with those before treatment, after treatment, TMH, SⅠT and NIBUT were increased (P<0.01, P<0.05), and FLS scores were decreased (P<0.01) in the two groups; the score of OSDI was reduced (P<0.01) in the observation group. After treatment, in the observation group, TMH and SⅠT were higher than those in the control group (P<0.01), and the score of OSDI was lower than that in the control group (P<0.01). No adverse reactions and adverse events were observed in the two groups. Acupuncture and sodium hyaluronate eye drop can both effectively treat aqueous deficiency dry eye, acupuncture has obvious advantages in improving TMH and basic tear secretion, and reducing the subjective symptoms of patients. Acupuncture for dry eye is safe.
- Research Article
109
- 10.1046/j.1475-1313.2003.00081.x
- Jan 1, 2003
- Ophthalmic and Physiological Optics
To evaluate the effects of dissolvable collagen punctal plugs on the symptoms, tear stability and volume in aqueous deficient dry eyes. Sixty-two aqueous deficient dry eye patients of mixed aetiology underwent lacrimal punctal occlusion with dissolvable collagen plugs. The subjects were randomly allocated to one of two treatment groups: group I (n = 36) had their lower puncta occluded and group II (n = 26) had both their upper and lower puncta occluded. The effectiveness of this treatment was clinically assessed by (1). scoring subject symptoms and (2). measuring the tear parameters of tear thinning time (TTT) and tear meniscus height (TMH) as indicators of tear stability and volume, respectively. Following baseline measurements, patients were reviewed at time intervals of 5 and 12 days post-occlusion. A group of age- and gender-matched normals (n = 45) was recruited for comparison (group III). Tear volume and stability were significantly higher in group III compared with I and II at baseline. In the treated groups on both days 5 and 12: (1). symptom score reduced significantly from a median value of 7 to 3 (p = <0.001); (2). tear stability increased significantly from a median value of 3 to 5 s by day 5 (p <or= 0.001); reduced between days 5 and 12 (p < 0.05) and remained below the stability in group III at all times; (c). tear volume increased significantly by day 5 in both treatment groups from a median value of 0.13 to 0.20 mm (p<or=0.001), remained stable by day 12 in group II but reduced in group I (p < 0.05); (d). the increase in tear volume was negatively correlated with pre-treatment tear volume; (e). symptom score correlated with both baseline tear volume and stability. Collagen plugs improved tear status in the aqueous deficient dry eyes. Occluding both upper and lower puncta with temporary collagen plugs offers no practical beneficial gain compared with occluding just the lower punctum.
- Research Article
113
- 10.1016/j.ajo.2010.07.019
- Oct 22, 2010
- American Journal of Ophthalmology
Interferometry in the Evaluation of Precorneal Tear Film Thickness in Dry Eye
- Research Article
4
- 10.1007/s00417-022-05880-7
- Nov 15, 2022
- Graefe's Archive for Clinical and Experimental Ophthalmology
This study aimed to observe the changes in the ocular surface after phacoemulsification in patients with age-related cataracts with respect to the addition of varying concentrations of hyaluronate. Patients with dry eye syndrome were treated with 0.3% and 0.1% sodium hyaluronate eye drops to evaluate the clinical improvement in each treatment group. A total of 73 patients (91 eyes) with age-related cataracts suffering from dry eye syndrome after phacoemulsification were divided into treatment group A (30 eyes), undergoing conventional therapy and treatment with 0.3% sodium hyaluronate; treatment group B (31 eyes), undergoing conventional therapy and treatment with 0.1% sodium hyaluronate; and the control group (group C; 30 eyes), undergoing conventional therapy only. Two groups were given different concentrations of sodium hyaluronate eye drops four times a day (should be completed between 8 AM and 8 PM), one drop at a time. Seven days, 2weeks, 1month, and 2months postoperatively, there were significant differences in the Schirmer I test (SIt), first noninvasive tear film break-up time (NIBUTf), average noninvasive tear film break-up time (NIBUTav), tear meniscus height (TMH), and irregularity (when the refractive force of different parts of different meridians on the same meridian is different. The main manifestation is that the two meridians on the anterior surface of the cornea do not show a 90-degree vertical distribution, which cannot be corrected by conventional astigmatism lenses) between the three groups (p < 0.05). When compared with group C, there were significant differences in the SIt, NIBUTf, NIBUTav, TMH, and irregularity of group A and group B (p < 0.05). When compared with group B, there were significant improvements in the SIt, NIBUTf, NIBUTav, and TMH in group A (p < 0.05). In the early stage after phacoemulsification, the stability of the tear film is reduced. Adding sodium hyaluronate eye drops can restore tear film structure and improve corneal surface regularity, and a 0.3% solution of sodium hyaluronate eye drops is more effective than a 0.1% solution.
- Research Article
37
- 10.1111/j.1755-3768.2012.02485.x
- Dec 24, 2012
- Acta Ophthalmologica
To evaluate the efficacy and safety of new moist cool air device (MCAD) for ocular symptoms, tear film stability and ocular surface status in office workers with dry eye disease (DED). In this prospective single-centre clinical trial, 40 eyes of 20 patients with DED were recruited and randomly divided into two groups (group with MCAD exposure and group without MCAD). All subjects are visual display terminals (VDTs) workers spending at least 4 h/day in front of VDTs. Patients using MCAD underwent moist air applications for 4 h/day for a total of five working weekdays during VDT works at their offices. The other group of patients performed their VDT work without moist cool air device exposure. The change in symptoms of ocular surface (OS) dryness, fatigue and discomfort was evaluated using visual analogue scale (VAS) scores. Changes in visual function, tear functions and ocular surface status were evaluated using best-corrected visual acuity (BCVA), the functional visual acuity (FVA) test, blink rate, BUT measurements, strip meniscometry (SM), tear evaporation rate, fluorescein staining and rose bengal staining scores. Tear film lipid layer interferometry was also performed to assess the status of the lipid layer over the tear film. In addition, adverse events were recorded. In group with MCAD, symptoms of OS dryness during VDTs work, and FVA and BUT were significantly improved. SM and tear evaporation rate were significantly improved. There were no statistically significant differences on lipid layer stability and corneal staining scores in both groups. Blink rate was significantly increased in group without MCAD. No adverse events were reported during this trial. Moist cool air device use provided symptomatic relief of ocular dryness and improvement on tear stability in office workers with DED. This new device seems to be a safe and promising alternative in the treatment of DED.
- Research Article
45
- 10.1016/s0275-5408(98)00005-2
- Nov 1, 1998
- Ophthalmic and Physiological Optics
The value of a phenol red impregnated thread for differentiating between the aqueous and non-aqueous deficient dry eye
- Research Article
6
- 10.3390/jcm13030659
- Jan 23, 2024
- Journal of Clinical Medicine
(1) Background: Dry eye disease (DED) is a chronic ocular surface condition that requires precise diagnostic tools. The present study aimed to investigate the diagnostic potential of the absolute inter-eye difference (|OD-OS|) in tear meniscus height (TMH) for the detection of the presence of aqueous deficient dry eye (ADDE). (2) Methods: A sample of 260 participants with dry eye complaints underwent ocular surface examinations thorough diagnostic assessments based on the Tear Film and Ocular Surface Society guidelines (TFOS DEWS II). Participants were subsequently categorized as No ADDE and ADDE based on TMH. Statistical analyses to determine the optimal TMH|OD-OS| cut-off value in a randomly selected study group (200 participants) were performed, while a separate validation analysis of the cut-off value obtained in a random cross-validation group (60 participants) was also performed. (3) Results: The significant diagnostic capability of TMH|OD-OS| (area under the curve = 0.719 ± 0.036, p < 0.001) was found. The identified cut-off value of 0.033 mm demonstrated reliable specificity (77.6%) and moderate sensitivity (59.1%). Cross-validation confirmed the cut-off value’s association with the TFOS DEWS II diagnostic criterion (Cramer’s V = 0.354, p = 0.006). (4) Conclusions: The present study provides evidence for the diagnostic potential of TMH|OD-OS| in identifying ADDE. The identified cut-off value enhances the specificity and offers moderate sensitivity, providing an objective tool for clinical decision making.
- Research Article
177
- 10.1016/j.ophtha.2010.01.057
- Jun 3, 2010
- Ophthalmology
Application of Visante Optical Coherence Tomography Tear Meniscus Height Measurement in the Diagnosis of Dry Eye Disease
- Research Article
18
- 10.1016/j.clae.2020.03.014
- Apr 20, 2020
- Contact Lens and Anterior Eye
Provocation of the ocular surface to investigate the evaporative pathophysiology of dry eye disease
- Research Article
21
- 10.1111/j.1755-3768.2012.02538.x
- Sep 20, 2012
- Acta Ophthalmologica
To investigate the efficacy of umbilical cord serum eyedrops after laser epithelial keratomileusis (LASEK). Sixty patients (120 eyes) with myopia who underwent LASEK were studied. Thirty-two patients (64 eyes) were treated with 20% umbilical cord serum eyedrops in combination with conventional treatment (group A), and 28 patients (56 eyes) received conventional treatment only (group B). Epithelial healing time was analysed. Visual acuity, refraction, haze score (0-4) and tear film and ocular surface parameters were evaluated at 1, 2, 4 and 12 weeks after LASEK. The concentration of transforming growth factor (TGF)-β1 in tears was measured with ELISA at 1 week after LASEK. No significant differences in visual acuity and refraction were found between groups. The mean time to epithelial healing was 3.53 ± 1.19 days in group A and 3.91 ± 1.41 days in group B (p = 0.18). The mean haze scores at 2 and 4 weeks were 0.59 ± 0.80 and 0.31 ± 0.54 in group A and 1.06 ± 0.91 (p = 0.02) and 0.69 ± 0.78 (p = 0.03) in group B. Four and 12 weeks after LASEK, tear film break-up time was longer and keratoepitheliopathy score was lower in group A compared with group B. The mean concentration of TGF-β1 was lower in group A compared with group B (p = 0.01). Application of 20% umbilical cord serum eyedrops in addition to conventional treatment after LASEK can reduce early postoperative corneal haze and improve tear film and ocular surface parameters.
- Research Article
69
- 10.1111/aos.12516
- Oct 12, 2014
- Acta Ophthalmologica
To investigate the effect of non-invasive tear stability assessment with forced eye opening on the lower tear meniscus. Twenty-three eyes of 23 patients with aqueous-deficient dry eye and 23 eyes of 23 normal subjects were enrolled. All subjects underwent imaging with a Keratograph 5M equipped with a modified tear film scanning function. Lower tear meniscus images were captured, and tear meniscus height (TMH) was measured with an integrated ruler before and after non-invasive Keratograph break-up time (NIKBUT) measurements in each subject. Subjects were instructed to keep their eyes open as long as possible during NIKBUT measurements, and the recording was discontinued at the next blink. The TMH values of the normal and dry eye groups were 0.20±0.05 mm and 0.14±0.03 mm, respectively, at baseline. The TMH values of dry eyes were significantly smaller than those of normal eyes (p<0.001). Significant increases in TMH values were observed in both normal (0.10±0.12 mm) and dry eyes (0.04±0.09 mm) with the NIKBUT measurement (p<0.001, p=0.039). A moderate negative correlation was observed between increased TMH and baseline TMH in dry eyes (r=-0.44, p=0.03), whereas no correlation was observed in normal eyes (r=0.04, p=0.85). Forced eye opening required for the non-invasive tear stability assessment influences the TMH measurement possibly due to reflex tear secretion, even in patients with aqueous-deficient dry eye. TMH should be assessed before tests that require forced eye opening.
- Research Article
- 10.11606/issn.1679-9836.v99isupplp16-17
- Nov 4, 2020
- Revista de Medicina
Introduction: Dry Eye (DE) is a common, complex, and multifactorial disease of the ocular surface and tear film that results in discomfort and visual disturbance. Prevalence varies from 5 to 50%, according to criteria, age, sex, and population studied. A meta-analysis was conducted to determine the prevalence of DE for different diagnostic criteria stratified by age and sex and reported by the TFOS DEWS II (Tear Film Ocular Surface Dry Eye Workshop) epidemiology committee showing relevant higher n umber among youth. The prevalence of symptomatic and clinically diagnosed DE varied by age, and sex, but only one study included young participants. Objective: This study aims to evaluate DE among a sample of undergraduate students from 2 major universities in Brazil, to comprehend symptoms, clinical signs presentation and most associated risk factors. Methodology: Cross-sectional survey that included 2,140 students (1,649 from UNICAMP and 491 from UNIFESP). Three fields of knowledge were included:1,128 from biological; 699 from exact; and 313 from human area. All participants completed 2 self-applicable questionnaires about dry eye symptoms: Ocular Surface Disease Index (OSDI) and short questionnaire used in the Women Heath Study (WHS), both previously translated and validated to Portuguese. DE symptoms were considered positive if OSDI score >22 or reported severe symptoms and/or previous history of clinical diagnosis at WHS questionnaire. Indeed, a list of risk factors such as contact lens wear, medications, ocular surgery, and systemic disease associated to DE was presented. Participants who fulfilled criteria for DE symptoms underwent a complete clinical evaluation for signs of the disease evaporative and aqueous deficient DE: such as tear meniscus height, hyperemia, non-invasive tear break up time, ocular surface staining with fluorescein and lisamine green and Schimmer test. Results: 2,140 participants aged 23.4±5.2 years old, 56.1% female and 43.9% male were enrolled. OSDI score was 19.4±16.2; 34.4% had OSDI had >22 and according to WHS 23.5% presented severe symptoms and/or previous history of clinical diagnosis. DE prevalence showed consistent sex differences, according OSDI scores 69.29% (510/736) female and 30.71% (226/736) male and with WHS questionnaire 64.8% (326/503) were female and 35.2% (177/503) were male (p<.0001). Most common risk factors were visual display use (50.1%), less than 6 hours of sleep/day (37.0%), oral contraceptive use (21.9%), contact lens wear (16.3%) and antiallergic use (15.1%). Univariate and multivariate analysis demonstrated that female sex, contact lens wear, ocular surgery, use of electronic devices over 6 hours/day, oral contraceptive, anti-depressant, anti-allergic, sleep less than 6 hours/day as relevant related factors. Clinical evaluation demonstrated mild signs of ocular surface dysfunction, normal tear volume, tear film instability and evaporative DE, such as tear film instability: Schimer test <10mm 14.8%; TBUT <10sec 61.1%; Fluorescein >4 5.6%; and Lisamine green >3 1.9%.Conclusion: Dry eye is prevalent condition among undergraduate students. In this Brazilian youth sample, rates were higher than data recently published, that showed in the general Brazilian population over 40 years old, the overall rate was 12.8%. However, further investigation might be addressed to better understand related risk factors and clinical presentation.
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