https://orcid.org/0000-0002-2307-2141
Abstract
Mild ptosis can be aesthetically displeasing for patients, especially in unilateral cases. However, some patients do not desire to undergo a surgical repair. Botulinum toxin injection might be an option in these cases.
The authors sought to objectively examine the effects of botulinum neurotoxin A (BoNT-A) injection into the orbicularis oculi muscle in the management of blepharoptosis.
In this prospective study, 8 patients with mild to moderate ptosis received application of BoNT-A in the pretarsal orbicularis oculi muscle. Standardized photographs were obtained at baseline and 2, 4, and 24 weeks. Digital image analysis software (Image J) was employed for objective analysis. Primary outcomes were the margin reflex distance-1 and qualitative changes on a 4-point scale.
A significant increase in the margin reflex distance-1 on the treated side (baseline: 2.00 ± 1.13 mm; week 2: 2.52 ± 1.13 mm; P = 0.003) and a significant reduction (baseline: 3.23 ± 0.92 mm, week 2: 3.07 ± 0.96; P = 0.0268) on the contralateral eyelid were observed at week 2. After 24 weeks, the effect of BoNT-A diminished, and no significant difference from baseline was observed in either eyelid. Subjectively, 87.5% of patients reported improvement in their eyelid ptosis.
Botulinum toxin injection in the pretarsal orbicularis oculi muscle can be an option to temporarily manage ptosis in patients who do not desire to undergo a surgical procedure. This alternative treatment can also be employed to manage temporary ptosis induced by botulinum toxin diffusion to the levator aponeurosis.
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Traditionally, eyelid ptosis is managed surgically, and several techniques can be employed, such as the anterior approach through the advancement or resection of the levator palpebrae superioris aponeurosis, the Muller muscle approach with Muller muscle-conjunctival resection, or, in more severe cases, with frontalis sling or flap approaches.1-4
Variable degrees of ptosis ranging from mild to severe can be observed. Although it rarely causes functional impairment, in a proportion of patients with mild ptosis in which the compensatory mechanisms that accompany it, such as the utilization of the frontalis muscle, ptosis can, in turn, lead to a noticeable and uncomfortable asymmetry, motivating the search for a treatment.5 In mild blepharoptosis, surgical repair can be indicated for aesthetic purposes. However, many patients do not desire to undergo a surgical procedure. A minimally invasive approach becomes desirable in these situations, and botulinum toxin emerges as a temporary option.6
Botulinum toxin injections are the first-line treatment for hemifacial spasm and blepharospasm, and this medication has also shown remarkable efficacy in managing aberrant regeneration after facial paralysis.7-10 In these cases, an improvement in the vertical palpebral fissure and eyelid symmetry has been demonstrated utilizing botulinum toxin.10,11 Theoretically, the physiological mechanism by which symmetry of the palpebral fissure is achieved in patients with hemifacial spasm and aberrant regeneration is by reducing the effect of the agonist muscle (orbicularis oculi muscle), allowing the antagonists (levator superior palpebrae and Muller muscle) to act more freely. Thus, in addition to reducing eyelid spasms in patients with hemifacial spasm, the application of botulinum toxin in the orbicularis oculi muscle leads to an increase in the palpebral fissure.11
Although the utilization of botulinum toxin has been reported to temporarily manage eyelid ptosis, to the best of our knowledge no previous study assessed patients prospectively in a standardized manner, comparing the treated and the contralateral eyelids.6,12 The present study aims to objectively assess the utilization of botulinum neurotoxin type A (BoNT-A) in treating patients with mild to moderate ptosis.
METHODS
This prospective study was approved by the Federal University of São Paulo Review Board (São Paulo, Brazil) and was conducted between April 2020 and December 2021. All patients signed an informed consent form to participate, and the study was carried out according to the Declaration of Helsinki principles.
Patients with unilateral or asymmetric mild to moderate blepharoptosis were included in this study. Only 1 eyelid underwent the intervention (the eyelid in which the patient reported the most complaints).
The exclusion criteria included prior eyelid surgeries, utilization of botulinum toxin type A in the periorbital region fewer than 5 months prior to the study, allergy to any of the components of the drug, presence of neuropathic diseases, pregnancy, breastfeeding, and patients who did not wish to undergo this minimally invasive approach to manage their eyelid ptosis.
All patients were followed-up for 6 months, with returns at weeks 2, 4, and 24, when standardized photographs were obtained with a digital camera (Powershot SX 40, Canon, Tokyo, Japan). The primary outcome measure was the margin reflex distance-1 (MRD-1), which is defined as the distance from the upper eyelid margin to the corneal light reflex in the primary position, measured in both eyes.
Photo processing and analysis were performed with Image J digital image processing software, version 1.34, available on the NIH website (http://rsb.info.nih.gov/ij/). A circular patch was placed on the patient forehead with a known diameter of 17 mm to serve as a parameter for the digital imaging software analysis. A 4-point subjective scale was also applied, and adverse events were recorded.
The patients were treated with an application of onabotulinumtoxinA (Botox, Allergan, Irvine, CA). A single investigator performed all the applications based on a standardized protocol: immediately before injection, each vial was reconstituted with normal saline without preservatives to obtain a final concentration of 50 U/mL. Topical proparacaine was administered in both eyes for comfort. An insulin syringe and a 30-gauge needle were employed to inject 2U of the drug into the lateral and medial pretarsal orbicularis muscle of the selected upper eyelid, 2 mm above the lash line. The patient was instructed not to press the region right after application.
In the postprocedure weeks 2, 4, and 24, standardized photos were taken for MRD-1 analysis, and patients were assessed regarding adverse effects. At the 2-week follow-up, a qualitative questionnaire with 4 levels of patient satisfaction was conducted on paper and distributed by the first author, asking “How would you describe your eyelid ptosis today when compared with the baseline? [a] ptosis is the same or worse; [b] some improvement, but with moderate inconvenience; [c] improvement with only mild inconvenience; [d] complete improvement.”
All statistical analyses was performed using the GraphPad Prism version 9.3.1 for Mac (GraphPad software, San Diego, CA). Dunn’s multiple comparison post hoc analysis was employed to compare measurements with the baseline. P < 0.05 was considered significant.
RESULTS
Eight eyelids from 8 patients were included. The mean age of the patients was 52.38 ± 15.26 years (range, 33-74 years). All patients were followed-up for 6 months. Most patients who underwent the procedure were female (75%), and the laterality was similar between right and left, with 4 eyelids for each side.
Table 1 shows the mean and standard deviation of MRD-1 for both the treated eyelid and the contralateral side at the following periods: baseline (pre-application), 2 weeks, 4 weeks, and 24 weeks. In the eyelid that underwent the intervention, a significant increase in MRD-1 between baseline and 2 weeks postprocedure (P = 0.003) was observed, whereas on the contralateral side, a significant reduction (P = 0.0268) was noted. Table 1 shows MRD-1 measurements in all time points and comparisons between baseline and 2, 4, and 24-week measurements in both treated and contralateral eyelids.
MRD-1 Measurements in the Treated and Contralateral Eyelids
| MRD-1 | Baseline, mm | Post BoNT-A, mm | Baseline vs post BoNT-A, adjusted Pa | ||||
|---|---|---|---|---|---|---|---|
| 2 wk | 4 wk | 24 wk | 2 wk | 4 wk | 24 wk | ||
| Treated | 2.00 ± 1.13 | 2.52 ± 1.13 | 2.50 ± 1.10 | 2.39 ± 1.14 | 0.0030* | 0.0007* | 0.06 |
| Contralateral | 3.23 ± 0.92 | 3.07 ± 0.96 | 3.16 ± 1.01 | 3.17 ± 0.95 | 0.0268* | >0.99 | >0.99 |
| MRD-1 | Baseline, mm | Post BoNT-A, mm | Baseline vs post BoNT-A, adjusted Pa | ||||
|---|---|---|---|---|---|---|---|
| 2 wk | 4 wk | 24 wk | 2 wk | 4 wk | 24 wk | ||
| Treated | 2.00 ± 1.13 | 2.52 ± 1.13 | 2.50 ± 1.10 | 2.39 ± 1.14 | 0.0030* | 0.0007* | 0.06 |
| Contralateral | 3.23 ± 0.92 | 3.07 ± 0.96 | 3.16 ± 1.01 | 3.17 ± 0.95 | 0.0268* | >0.99 | >0.99 |
BoNT-A, botulinum neurotoxin A; MRD-1, margin reflex distance-1.
aDunn’s multiple comparisons, values in mean ± standard deviation. *P < 0.05.
MRD-1 Measurements in the Treated and Contralateral Eyelids
| MRD-1 | Baseline, mm | Post BoNT-A, mm | Baseline vs post BoNT-A, adjusted Pa | ||||
|---|---|---|---|---|---|---|---|
| 2 wk | 4 wk | 24 wk | 2 wk | 4 wk | 24 wk | ||
| Treated | 2.00 ± 1.13 | 2.52 ± 1.13 | 2.50 ± 1.10 | 2.39 ± 1.14 | 0.0030* | 0.0007* | 0.06 |
| Contralateral | 3.23 ± 0.92 | 3.07 ± 0.96 | 3.16 ± 1.01 | 3.17 ± 0.95 | 0.0268* | >0.99 | >0.99 |
| MRD-1 | Baseline, mm | Post BoNT-A, mm | Baseline vs post BoNT-A, adjusted Pa | ||||
|---|---|---|---|---|---|---|---|
| 2 wk | 4 wk | 24 wk | 2 wk | 4 wk | 24 wk | ||
| Treated | 2.00 ± 1.13 | 2.52 ± 1.13 | 2.50 ± 1.10 | 2.39 ± 1.14 | 0.0030* | 0.0007* | 0.06 |
| Contralateral | 3.23 ± 0.92 | 3.07 ± 0.96 | 3.16 ± 1.01 | 3.17 ± 0.95 | 0.0268* | >0.99 | >0.99 |
BoNT-A, botulinum neurotoxin A; MRD-1, margin reflex distance-1.
aDunn’s multiple comparisons, values in mean ± standard deviation. *P < 0.05.
Figures 1 and 2 show before and after photographs of patients who underwent the procedure. Figure 3 shows the variation in MRD-1 over the weeks, with P < 0.05 at weeks 2 and 4 in the treated eyelid and at week 2 in the contralateral eyelid.
This 62-year-old female patient presented with mild eyelid ptosis in the left eye. She underwent botulinum toxin injection in the pretarsal area of the left upper eyelid. Photographs show the patient (A) before and (B) 2 weeks after the procedure.
This 74-year-old male patient presented with moderate eyelid ptosis in the right eye. He underwent botulinum toxin injection in the pretarsal area of the right upper eyelid. Photographs show the patient (A) before and (B) 2 weeks after the procedure.
Evolution of the margin reflex distance-1 (MRD-1) measurements over 6 months in the treated and contralateral eyelids.
Regarding the subjective improvement questionnaire, 1 patient reported a complete improvement in ptosis (12.5%), and 3 (37.5%) reported a significant improvement; however, they continued to experience mild discomfort. Three patients reported a partial improvement with moderate discomfort (37.5%), and 1 patient reported no improvement (12.5%).
No serious adverse events were reported during follow-up. One patient presented temporary mild punctate keratitis due to minimal lagophthalmos, which resolved after 1 week utilizing lubricating eye drops.
DISCUSSION
Botulinum toxin is a neurotoxin produced by the bacterium Clostridium botulinum. It weakens the target muscle by inhibiting the release of acetylcholine from the presynaptic terminal of the neuromuscular junction.6 Although the pathophysiology of ptosis is complex and cannot be entirely explained by a simple model of agonist and antagonist muscles, in the present study, botulinum toxin injections were employed to weaken the pre-tarsal orbicularis oculi muscle in an attempt to reach a balance of forces favoring palpebral opening, with a more unimpeded action of the Muller’s muscle and the levator palpebrae superioris. Our results showed that this minimally invasive approach could be an option to elevate the eyelid position and thus decrease eyelid asymmetry in patients with mild eyelid ptosis.
The present study shows a significant improvement in MRD-1 after a single session of BoNT-A in the pretarsal orbicularis muscle. The MRD-1 of the eyelids that underwent the procedure increased from 2.0 ± 1.13 mm to 2.52 ± 1.13 mm in week 2 (P = 0.003) and 2.50 ± 1.10 in week 4 (P = 0.0007). Our results are more conservative than those reported by Mustak et al., in which an average improvement of 0.914 mm was observed in a case series of 3 patients.12 However, in that small case series, BoNT-A injection was not standardized, other sites received BoNT, and the dose applied in the pretarsal area was higher (3 U on average), which could have interfered in a more pronounced effect of elevation. In the current study, we aimed to isolate the effect in the pretarsal orbicularis oculi muscle to exclusively assess its effect on the composition of the eyelid ptosis. Furthermore, in this preliminary study by our group, a lower BoNT dose was utilized to minimize the risk of lagophthalmos.
The duration of botulinum toxin effect is variable, depending on the dose and muscle strength, among other factors, and usually does not surpass 4 to 6 months.13 We decided to carry out the subjective questionnaire (Appendix, available online at www.aestheticsurgeryjournal.com) at week 2 of follow-up when the BoNT-A effect was supposed to be maximum. As expected, we observed a loss of botulinum toxin effect at the 24-week assessment, with no statistically significant difference in MRD-1 between preprocedure and postprocedure at 24 weeks (P = 0.06). We found that 87.5% of the patients reported at least some improvement in ptosis, with 50% reporting a significant or complete improvement.
It is also interesting to observe the effect on the contralateral eyelid. There was a significant reduction in the mean MRD-1 from 3.23 ± 0.92 to 3.07 ± 0.96 (P = 0.0268) at week 2 of follow-up. This significant difference likely reflects Hering’s law of equal innervation. Walsh14 was the first to describe Hering’s law for eyelids, which is the compensatory retraction of the contralateral upper eyelid in unilateral or asymmetric ptosis cases. Clinically, according to Hering’s law, a patient’s attempt to overcome ptosis in 1 eye will induce an increase in innervation in both levators, resulting in contralateral lid retraction. After improving the ptosis in the treated eye, there is no more attempt to overcome ptosis, reducing then innervation in both levators and resulting in a contralateral reduction in MRD-1, as observed in the present study. Hering’s law effect is frequently observed after surgical procedures to correct ptosis.15 However, to the best of our knowledge, Hering’s law effect was not previously demonstrated after BoNT injections to manage eyelid ptosis.
Care must be taken to avoid possible complications arising from the application of BoNT-A in the periocular region. Complications described include lagophthalmos and, consequently, exposure keratitis, or even worsening of eyelid ptosis due to diffusion of the toxin to the levator palpebrae aponeurosis.16 In the present study, only 1 patient presented mild exposure keratitis caused by minimal lagophthalmos, which was resolved with the utilization of lubricating eye drops for 1 week. Nestor et al reviewed causes and treatment for eyelid ptosis after botulinum toxin injection.17 They reported an incidence of BoNT-A induced blepharoptosis of 5.4% among inexperienced injectors and <1% among experienced injectors. The injection site, however, was mainly the glabellar and brow area, with a proposed mechanism that involves the toxin spreading through the orbital septal. Botulinum toxin injection in the pretarsal orbicularis oculi muscle can be an option to temporarily manage BoNT-induced ptosis.17
Other possibilities of non-surgical interventions for eyelid ptosis correction have been reported.18-20 The utilization of eyelid makeup and octyl-2-cyanoacrylate liquid bandage has immediate effect and is an alternative for temporarily correcting ptosis induced by BoNT-A and in myopathic blepharoptosis cases.18,19 The utilization of naphazoline eye drops at 0.05% showed a significant effect on MRD-1 without causing mydriasis. However, the effect is more ephemeral, tending to reduce after 120 minutes, and the study was carried out in patients without ptosis.20
Limitations of this study include the sample size. However, even the small sample size was sufficient to show a significant increase in MRD-1 in the treated eyelid and a significant reduction on the contralateral side, demonstrating Hering’s law. Dissemination of this alternative approach and the safety shown in the present study can allow further studies with a larger number of patients.
CONCLUSIONS
The present study objectively shows that the application of BoNT-A in the pre-tarsal region of the orbicularis oculi muscle improves eyelid ptosis without clinically relevant adverse events. This minimally invasive procedure may be an alternative to improve eyelid asymmetry in patients with mild ptosis who do not wish to undergo a surgical procedure and for those who present with BoNT-induced blepharoptosis.
Supplemental Material
This article contains supplemental material located online at www.asjopenforum.com.
Disclosures
Drs T. Osaki and M. Osaki receive book royalties from Elsevier (Amsterdam, the Netherlands). The present study has no relationship with the book. The other authors declared no potential conflicts of interest with respect to the research, authorship, and publication of this article.
Funding
The authors received no financial support for the research, authorship, and publication of this article.
