Appropriate concentration of botulinum toxin type A for dry eye disease treatment by injection into the medial lower eyelid. A randomized comparative study

doi:10.21203/rs.3.rs-2083374/v1

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Appropriate concentration of botulinum toxin type A for dry eye disease treatment by injection into the medial lower eyelid. A randomized comparative study

https://doi.org/10.21203/rs.3.rs-2083374/v1

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This prospective, double-blind, randomized, comparative eye-to-eye interventional study aimed to determine the appropriate concentration of botulinum toxin type A for dry eye disease treatment in terms of effectiveness, complications, and cost-effectiveness.

Patients with dry eye having a similar degree in both eyes treated with non-preservative artificial tears for at least 1 month and persistent dry eye symptoms were enrolled. In each patient, a subcutaneous injection of 3.3 U of botulinum toxin type A was administered in the medial part of the randomly selected lower eyelid and 2.5 U of the same was administered to the second lower eyelid. Complete subjective and objective evaluations were performed at baseline and 2, 8, 12, and 16 weeks after intervention.

Eleven patients (mean age 64.63 ± 14.81 years) were included. Dry eye symptoms assessed by the Ocular Surface Disease Index (OSDI) score improved significantly after treatment in both the 3.3 and 2.5 U groups. Comparison of post-treatment OSDI scores, tear film break-up time (TBUT), Schirmer’s test, and modified Oxford grading scheme between the 3.3 and 2.5 U groups showed no significant difference at any time point of the study.

Conclusions: Both 3.3 and 2.5 U botulinum toxin injections improved dry eye symptoms.

Health sciences/Diseases

Health sciences/Neurology

Health sciences/Signs and symptoms

botulinum toxin

dry eye

ocular surface disease

The prevalence of dry eye disease, with and without symptoms, ranges from 5–50%, reaching 75% in some populations. Asian ethnicity appears to be a risk factor. The most severe economic impact of dry eye disease likely results from the costs related to decreased work productivity [1].

Several medications and methods are available for treating dry eye disease. Tear conservation therapy is a treatment for tear insufficiency [2]. Several studies reported that the injection of botulinum toxin type A in the medial part of the lower eyelid decreases the tear volume ejected at each blink and the ability to drain tears, favoring the maintenance of the teardrop, which may benefit patients with dry eye [3–8]. This effect is due to paralysis of the lacrimal part of the orbicularis oculi muscle and Horner’s muscle, which is closely related to the components of the lacrimal drainage system, and decreases the effect of the lacrimal pump as well as tear drainage [9].

There are few publications about botulinum toxin use for dry eye treatment, all of which demonstrated that botulinum toxin injection into the medial lower eyelid can improve signs and symptoms of dry eye [3–8]. Nevertheless, the concentration of botulinum toxin used varies among studies.

Sahlin et al. [5] reported that a botulinum toxin concentration of 3.75 international units (U) can reduce the mean blink output to 70% of the baseline values and improve eye comfort in six of nine cases.

Bukhari [7] concluded that the 3.3 U/0.1 mL botulinum toxin A injections can be an alternative to punctal plugs in improving the clinical manifestations of dry eye disease and is associated with the development of fewer and milder complications as well as higher levels of patient satisfaction. He also indicated that 8/24 (33.3%) patients who received botulinum toxin A reported getting shampoo in their eyes while showering, which implies that one-third of the patients had some degree of lagophthalmos due to botulinum toxin injection [7].

Although a high complication rate was reported in Bukhari’s study [7], Serna-Ojeda and Nava-Castaneda [8] reported effective treatment without any adverse events while using 4 U/0.1 mL botulinum toxin injection.

This study aimed to determine the appropriate concentration of botulinum toxin type A for the treatment of dry eye disease in terms of effectiveness, complications, and cost-effectiveness.

This prospective, double-blind, randomized, comparative, eye-to-eye interventional study was conducted at the Department of Ophthalmology, Naresuan University Hospital, Thailand from January 2020 to April 2021. Inclusion criteria were patients with dry eye older than 20 years who had a similar degree of dry eye in both eyes, received treatment with non-preservative artificial tears for at least 1 month, and dry eye symptoms persisted with positive corneal fluorescein staining. Patients with dry eye attributable to eyelid abnormalities, nasolacrimal duct obstruction, active corneal infection, or a history of botulinum toxin hypersensitivity were excluded. Active inflammatory dry eye cases and severe dry eye cases that required autologous serum were also excluded because retention of proinflammatory tear components could occur and enhance damage to the ocular surface after botulinum toxin injection [10].

Subjective evaluation was achieved using the ocular surface disease index (OSDI) questionnaire to assess the symptoms of dry eye for each eye. Objective evaluation included best-corrected visual acuity (BCVA), margin reflex distance 2 (MRD-2), tear film break-up time (TBUT), Schirmer’s test, and a modification of the Oxford grading scheme for corneal and conjunctival staining. A double-blind technique was used. All objective data were assessed by an ophthalmologist (J. Sawatdiwithayayong) who was blinded to the treatment received.

BCVA was assessed using the Early Treatment of Diabetic Retinopathy Study chart. TBUT was defined as the time required for dry spots to appear on the corneal surface after blinking following fluorescein staining, and the mean value of three measurements was recorded. Schirmer’s test was performed without instillation of topical anesthetic; sterile paper strips were inserted into the inferotemporal aspect of the conjunctival sac for 5 minutes to measure tear production in millimeters (mm). The modified Oxford grading scheme for corneal and conjunctival staining was used after fluorescein staining, to grade according to severity from 0 (absent) to 5 (severe) [11].

Using the randomization list generated by www.randomization.com, one eyelid was randomly administered a subcutaneous injection of 3.3 U of botulinum toxin type A (Botox; Allergan, Irvine, CA, USA) in the medial part of the lower eyelid, 2 mm inferior to the lid margin, and 5 mm medial to the lower punctum. The other eye underwent a similar procedure with 2.5 U of botulinum toxin type A. Complete subjective and objective evaluations were performed at baseline and 2, 8, 12, and 16 weeks after the intervention.

Statistical analyses were performed using STATA statistical software program (STATA version 12.0; StataCorp, College Station, TX, USA). Demographic variables were analyzed using descriptive statistics. To determine the differences in the variables among the eyes, the Mann-Whitney U-test and Wilcoxon signed-rank tests were used. Statistical significance was set at p < 0.05.

This study was approved by the Human Research Ethics Committee of the Faculty of Medicine, Naresuan University (COA No. 138/2019, IRB No. 0871/61) and conducted in accordance with the Declaration of Helsinki. Informed consents were obtained from all subjects. The study was registered on thaiclinicaltrials.org as TCTR20221004007 and posted to the Thai Clinical Trials Registry Platform on October 4, 2022.

Eleven patients were included, with a mean age of 64.63 ± 14.81 years. After randomization, the eye treated with 3.3 U of botulinum toxin type A was the right eye in five (45%) and the left eye in six (55%) patients. The baseline OSDI score, MRD-2, TBUT, Schirmer’s test, and modified Oxford grading scheme were similar in both groups

(Table 1 * significant change from baseline)

Table 1

Baseline and post-treatment dry eye characteristics
Variable	3.3 U (n = 11) Mean ± SD	2.5 U (n = 11) Mean ± SD	p-value^#
OSDI
Baseline	26.87 ± 18.85	29.10 ± 18.15	0.793
2 weeks post-treatment	11.63 ± 9.23*	13.41 ± 10.51*	0.767
8 weeks post-treatment	11.78 ± 3.55*	13.58 ± 11.42*	0.175
12 weeks post-treatment	13.74 ± 4.98	9.91 ± 7.17*	0.895
16 weeks post-treatment	11.57 ± 2.95*	11.03 ± 9.08*	0.948
TBUT
Baseline	5.06 ± 2.00	4.63 ± 1.73	0.645
2 weeks post-treatment	4.42 ± 1.79	4.70 ± 1.82	0.620
8 weeks post-treatment	4.70 ± 1.70	5.00 ± 1.79	0.792
12 weeks post-treatment	3.49 ± 1.33*	3.82 ± 1.25	0.408
16 weeks post-treatment	3.18 ± 0.87*	4.58 ± 2.49	0.177
Schirmer’s test
Baseline	9.73 ± 6.53	10.55 ± 7.63	0.869
2 weeks post-treatment	9.36 ± 5.57	10.64 ± 8.94	0.948
8 weeks post-treatment	10.0 ± 6.42	8.64 ± 6.56	0.576
12 weeks post-treatment	7.73 ± 2.19	7.86 ± 2.78	0.869
16 weeks post-treatment	5.27 ± 2.87*	7.36 ± 1.88*	0.528
modified Oxford grading scheme
Baseline	1.55 ± 0.69	1.64 ± 0.67	0.715
2 weeks post-treatment	0.91 ± 0.70*	0.82 ± 0.60*	0.765
8 weeks post-treatment	1.27 ± 0.65	1.36 ± 0.67	0.715
12 weeks post-treatment	1.18 ± 0.98	1.27 ± 0.79	0.914
16 weeks post-treatment	1.24 ± 0.74	1.18 ± 0.87	0.925
MRD2
Baseline	5.18 ± 0.60	5.09 ± 0.70	0.765
2 weeks post-treatment	5.27 ± 0.65	5.18 ± 0.75	0.800
8 weeks post-treatment	5.27 ± 0.47	5.18 ± 0.40	0.619
12 weeks post-treatment	5.18 ± 0.40	5.09 ± 0.54	0.686
16 weeks post-treatment	4.82 ± 0.60	4.82 ± 0.60	1.000

The baseline and post-treatment data were presented in Table 1. Eight of 11 eyes (72.7%) in both groups had better OSDI scores. Dry eye symptoms assessed using the OSDI score improved after treatment in both groups (Fig. 1), with significant improvements in the mean OSDI at 2, 8 and 16 weeks post-treatment in the 3.3 U injection group (p = 0.023, 0.010, and 0.016, respectively) and at all follow-up visits in the 2.5 U group (p = 0.016, 0.016, 0.013, 0.008, respectively). Although the symptoms improved, no statistical significance was reached for most objective variables. The modified Oxford grading scheme tended to improve after treatment, but statistically significant improvement was observed only at 2 weeks post-treatment in both the 3.3 and 2.5 U groups (p = 0.021 and 0.009, respectively) (Table 1, Fig. 1).

The post-treatment OSDI score, TBUT, Schirmer’s test, and modified Oxford grading scheme were not significantly different between the 3.3 and 2.5 U injection groups at any time point of the study (Table 1).

All the patients completed the 16 weeks follow-up. The minimal retraction of the lower lid was mentioned as increased MRD-2 in three of 11 eyes in both 3.3 and 2.5 U groups. One patient reported that the lower eyelid had more laxity when treated with 3.3 U botulinum toxin, but no lagophthalmos was found and no other adverse events were reported in the study.

Botulinum toxin injection into the medial part of the lower eyelid is a dry eye treatment method aimed to decrease tear drainage into the lacrimal sac. There are few publications on the use of botulinum toxin in dry eye treatment. The reported effective dose varies from 3.3 to 4 U [3–8]. To our knowledge, this is the first study to compare different dosages of botulinum toxin injections in an eye-to-eye interventional study.

Bukhari [7] reported an effective dose of 3.3 U/0.1 mL botulinum toxin. This is the lowest dosage for single-point lower eyelid injection that has been documented in literature. He also reported that 33.3% of patients reported getting shampoo in their eyes while showering. Therefore, this study compared two dosages of botulinum toxin 2.5 and 3.3 U to determine the more cost-effective dosage and the dosage associated with fewer complications.

Although a high complication rate was reported in the study by Bukhari [7], Serna-Ojeda Nava-Castaneda [8] reported effective treatment without any adverse events while using 4 U/0.1 mL botulinum toxin injection. These results imply that the effectiveness and complication rate depend on the dosage of botulinum toxin and injection technique. Injection at a more central lower eyelid increases the risk of lower lid laxity and lagophthalmos. Therefore, the injection site of this study was approximately 5 mm medial to the lower punctum to avoid complications after injection.

The results of this study demonstrated that the OSDI score improved after treatment in both groups, but no statistical significance was reached for most objective variables. These results differ from those of some previous studies that reported improvements in TBUT, Schirmer’s test, and the modified Oxford grading scheme [7–8]. This difference may be due to the difference in baseline dry eye severity of the patients enrolled in each study. Schirmer’s test has poor discriminability for milder forms of dry eye disease [12]. The baseline dry eye severity of patients in this study were better than those of the patients included in both Bukhari’s [7] and Serna-Ojeda and Nava-Castaneda’s [8] studies; therefore, the change may not reach a significant value.

Jones et al. [2] reported that eyes that received botulinum toxin had better TBUT, Schirmer’s test, modified Oxford grading scheme, and some dry eye symptoms when compared with the sham group at 3 months post-intervention, and these variables were not significantly different at 6 months [2]. In our study, at 2 weeks post-treatment, the mean OSDI score and modified Oxford grading scheme improved significantly and remained steady until the end of follow-up at 16 weeks. This may imply that the effect of botulinum toxin could last longer than 16 weeks. Further studies are needed to follow up the patients until 6 months post-intervention to determine the longest duration effect and time to repeat injection of botulinum toxin.

Limitations of this study were expected given the small sample size. The strength of this study is that it was a prospective, double-blind, randomized, comparative, eye-to-eye interventional study, which helped avoid bias.

In summary, both the 3.3 and 2.5 U botulinum toxin injections improved dry eye symptom in up to three-quarters of the patients. The symptom-improving effect of botulinum toxin could be long-lasting and exceed 16 weeks. Botulinum toxin injection can be used as an adjunctive treatment for dry eye disease.

Data availability statement:

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

Acknowledgements: -

Authors and Affiliations:

Department of Ophthalmology, Faculty of Medicine, Naresuan University, 99 Moo 9 Tambon Tha Pho, Muang Phitsanulok, 65000, Thailand

Nattapong Mekhasingharak, Nattamol Kosaiyaganonth & Jeerawat Sawatdiwithayayong

Contributions: Study conception and design: All authors. Acquisition of data: N.K., J.S. Analysis and interpretation of data: N.M., J.S. Drafting of the manuscript: N.M., J.S.

All authors read and approved the final version.

Competing interests:

The authors declare no competing interests.

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No competing interests reported.

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Appropriate concentration of botulinum toxin type A for dry eye disease treatment by injection into the medial lower eyelid. A randomized comparative study

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