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 Table of Contents  
Year : 2015  |  Volume : 108  |  Issue : 3  |  Page : 110-116

Evaluation of the therapeutic use of botulinum toxin A in the periorbital region

Department of Ophthalmology, Faculty of Medicine, Zagazig University, Zagazig, Egypt

Date of Submission03-Oct-2014
Date of Acceptance29-Oct-2014
Date of Web Publication30-Oct-2015

Correspondence Address:
Hala K Mattout
Ophthalmology Department, Faculty of Medicine, Zagazig University, 44111, Zagazig
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/2090-0686.168680

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Botulinum toxin blocks acetylcholine release at the neuromuscular junction causing paralysis that is reversed within 4 months. The toxin was well known for its lethal effect when ingested with food (botulism); however, it was found to be highly effective in various disorders, both cosmetic and noncosmetic. The therapeutic uses in ophthalmology include treatment of strabismus, spastic focal facial dystonias, induction of temporary ptosis in cases of lagophthalmos (chemotarsorrhaphy), temporary correction of dysthyroid upper eyelid retraction, suppression of lacrimal gland secretion to temporarily control gustatory lacrimation, some cases of obstructive epiphora and primary hyperlacrimation, and temporary correction of lower lid entropion. In this prospective study, we evaluate the results of using botulinum toxin A (botox) injection in some periorbital pathologies namely, focal facial dystonias, lower lid entropion, lagophthalmos, and epiphora. Fifty patients were treated with botox (20 patients with focal facial dystonias, nine with lagophthalmos, eight with lower lid entropion, and 13 with epiphora), different techniques were used according to the pre-existing pathology, and the following data were recorded: age and sex, total dose for each injection, onset and duration of effect, degree of improvement, and the occurrence of any adverse effects. The study results supported the high efficacy of botulinum toxin for treatment of blepharospasm, hemifacial spasm, lagophthalmos, lower lid entropion, and epiphora, with marked to moderate improvement in 99, 87.5, 55.5, 75, and 92.3% of patients, respectively. Few side effects occurred but they resolved spontaneously without residues. We concluded that botulinum toxin A is a safe and effective treatment with a temporary outcome that may be desirable in certain situations.

Keywords: Blepharospasm, botulinum toxin A, chemotarsorrhaphy, epiphora, hemifacial spasm, lower lid entropion, therapeutic uses

How to cite this article:
Tawfik A, Alshabrawy O, Almarakby MA, Mattout HK. Evaluation of the therapeutic use of botulinum toxin A in the periorbital region. J Egypt Ophthalmol Soc 2015;108:110-6

How to cite this URL:
Tawfik A, Alshabrawy O, Almarakby MA, Mattout HK. Evaluation of the therapeutic use of botulinum toxin A in the periorbital region. J Egypt Ophthalmol Soc [serial online] 2015 [cited 2022 Aug 8];108:110-6. Available from: http://www.jeos.eg.net/text.asp?2015/108/3/110/168680

  Introduction Top

Botulinum toxin is a neurotoxin produced by the bacterium Clostridium botulinum that elaborates eight antigenically distinguishable exotoxins (A, B, C1, C2, D, E, F and G). Types A, B and E are commonly associated with systemic botulism in humans [1]. The toxin acts by binding to the presynaptic membrane of cholinergic nerve terminals and prevents the release of their neurotransmitter acetylcholine through a multistep process causing paralysis of the motor unit [2],[3]. This paralysis is reversed within about 4 months when new nerve terminal sprouts emerge and extend towards the muscle surface [4],[5].

Botulinum neurotoxin A (BoNT-A) therapy for strabismus was introduced by Scheinberg [6], in the early 1980s and in 1989 the Food and Drug Administration approved BoNT-A for ophthalmologic and neurologic use in treating strabismus, blepharospasm, and hemifacial spasm (HFS) [4],[7]. Botulinum toxin injections are now frequently applied in treating spastic facial dystonias as benign essential blepharospasm (BEB) and HFS. It is also effective in the temporary treatment of thyroid dysfunction-induced upper eyelid retraction and in lower lid entropion. The temporary induction of ptosis to provide corneal protection in facial paralysis has been found to be very beneficial [3],[4],[8]. In addition, botulinum toxin injections in the lacrimal gland are effective in the treatment of hyperlacrimation due to various causes; it acts by blocking the release of acetylcholine from the postganglionic parasympathetic secretomotor fibers to the lacrimal gland [9].

General complications of botulinum toxin injection include ecchymosis, rash, hematoma, headache, flu-like symptoms, nausea, and dizziness. Most common ocular complications are undercorrection, asymmetrical features, change in and/or loss of facial expression (overcorrection), lower eyelid laxity, dermatochalasis, ectropion, epiphora, eyebrow and eyelid ptosis, lagophthalmos due to orbicularis muscle weakness, keratitis sicca, and diplopia [3],[4].

BEB is a focal cranial dystonia involving the eyelid and forehead muscles. It manifests as involuntary orbicularis muscle contraction resulting in increased frequency and forcefulness of blinking [10]. The majority of blepharospasm patients display other involuntary movements in the face, mouth or jaw consistent with a form of segmental dystonia called 'Meige syndrome' [11]. Blepharospasm affects about 32/100 000 people, typically beginning in the fifth or sixth decade of life, affecting women more frequently than men (3: 1) [11]. The vast majority of cases are idiopathic. Rarely, lesions in the basal ganglia and upper midbrain (e.g. with stroke, multiple sclerosis, Wilson's and Parkinson's diseases) have been associated with blepharospasm [12].

HFS, a form of segmental myoclonus, is characterized typically by involuntary unilateral tonic and clonic contractions of the face. It occurs more commonly in women (2: 1) with an overall prevalence of about 10/100 000, but in some populations, such as the Asians, the prevalence is much higher [13]. Some patients may be genetically predisposed to developing HFS but most cases are sporadic [14]. The anatomical basis for the spasms is usually a mechanical irritation of the facial nerve at its exit root by a sagging arterial vascular branch which can be demonstrated radiographically in 85-90% of cases [10]. Microsurgical decompression can be done at the brain stem but it carries a recurrence rate of up to 25% over the next 2 years and some patients may have complications [15]. Elston [16] was the first to try botulinum toxin type A for HFS. Botulinum toxin type A received approval in the USA and Europe for HFS treatment in the early 1990s and since then it becomes the gold standard in the treatment of HFS [12].

Producing a temporary ptosis using BoNT-A is of use for those patients with corneal exposure (lagophthalmos) and who either have or are at risk of developing serious microbial keratitis as a consequence. This obviously applies to patients with lid retraction as a part of their dysthyroid eye disease [4],[17], which is of particular value during the active phase of the disease, when surgery is typically not an option [5]. Temporary protection of the cornea is also desirable in patients with exposure keratopathy owing to Bell's palsy, persistent epithelial defects, and indolent corneal ulcers [1].

Although surgical treatment remains the treatment of choice for entropion, BoNT-A is a safe and effective procedure for correction of senile, spastic and some cases of congenital entropion [18]. It plays a role for patients unable or unwilling to have an operation and in the few cases where transient relief of the entropion is all that is required [19].

Injection of botulinum toxin into the lacrimal gland has been described for the treatment of primary lacrimal gland hypersecretion, and secondary causes such as functional epiphora [1] and for patients with lacrimal obstruction who either refuse or are unfit for surgery. For those patients with gustatory tearing, botulinum toxin injection may be preferable to the other surgical alternatives [20].

The aim of this study was to evaluate the effectiveness and safety of botulinum toxin A injection in patients with focal facial dystonia (namely HFS and blepharospasm), lagophthalmos, lower lid entropion, and epiphora.

  Patients and methods Top

This study is a prospective descriptive study that was conducted at the ophthalmology outpatient clinic of Zagazig University Hospital. The study sample consisted of 50 patients who were treated with botulinum toxin A (botox) injections between October 2011 and October 2012, and were followed up for at least 18 months, that is, till April 2014. An informed consent was obtained from each patient before injection and photography and the study was approved by the ethics committee of the Faculty of Medicine, Zagazig University. Pregnant females, patients with previous hypersensitivity to the toxin or human albumin, patients with neuromuscular pathology, patients with ocular motility defects, and patients with active infections were excluded from the study.

The study sample was divided into four groups:

Group A: Twenty patients with focal facial dystonias namely, BEB and HFS. It was divided into two subgroups. Subgroup A1: it included 12 patients with HFS. Subgroup A2: it included eight patients with BEB.

Group B: Nine patients with lagophthalmos due to either dysthyroid upper eyelid retraction or facial nerve palsy.

Group C: Eight patients with lower lid entropion.

Group D: Thirteen patients with epiphora or hyperlacrimation.

Patients were subjected to full history taking and ophthalmic examination and regular follow-up examinations 2 weeks postinjection then every 4-6 weeks for 18 months. Photographic and video documentation of the condition was done initially and in each follow-up visit.

The toxin (botox; Allergan Corporation, Westport, Mayo, Ireland) was supplied by the agent office in Egypt (Allergan, Cairo office) in a vial contained 100 U of freeze-dried botulinum toxin A, 0.5 mg human albumin, and 0.9 mg sodium chloride. It was reconstituted and diluted with 4 ml of normal saline, resulting in a concentration of 25 U/ml (2.5 U/0.1 ml).After reconstitution the vial was stored at 2-8°C to be used within 4 h after reconstitution.

Patients with blepharospasm and HFS (group A) were injected subcutaneously with a 28-G insulin syringe, when lying in a semisetting position with eyes closed. The injection sites were in the pretarsal orbicularis above and below the eyelashes (2.5 U of botox per injection site). In some patients with severe spasm, injection lateral to the lateral canthus and into the frontalis muscle, laterally and/or medially, were also used. In the HFS group, extra sites in the upper cheek and around the mouth (zygomaticus major and depressor angularis oris) were injected. The subjective efficacy of the BoNT-A treatment was measured using a patient self-evaluation scale.

Group B (nine patients) included seven patients with lagophthalmos secondary to facial palsy and two patients with lagophthalmos secondary to dysthyroid eye disease. Transcutaneous approach was used in seven patients with severe exposure keratitis using a half-inch 26-G needle for injection procedure. The skin was penetrated immediately below the central part of the superior orbital rim with the bevel of the needle facing the globe and it was advanced posteriorly along the orbital roof for its full length in the midpupillary plane and the toxin (7.5 U) was then injected. Transconjunctival route was used in two patients with mild exposure keratitis: a small dose (2.5-5 U) of botulinum toxin type A was injected to Muller muscle under topical anesthesia. The upper eyelid was everted and the chemodenervative agent was injected using a 28-G needle above the tarsal plate aiming to induce mild ptosis. The level of induced ptosis was classified as complete (referred to as marked improvement); efficient partial (referred to as moderate improvement) and inefficient partial when there was no occlusion of the corneal defect (referred to as mild improvement).

Group C (eight patients) included seven patients with senile lower lid entropion and one infant with congenital lower lid entropion. The reconstituted toxin was injected subcutaneously over the orbicularis oculi muscle about 3-4 mm below the eyelash margin of lower lid at three sites with a 28-G needle attached to a 1-ml syringe with 2.5 U of the toxin injected in each site. However, half of the dose was injected in the child.

Group D (13 patients) included five patients with lacrimal pump failure, six patients with lacrimal obstruction, and two patients with gustatory lacrimation. Each patient received a drop of topical anesthesia, then the lateral upper eyelid was everted over a Desmarre retractor to expose the palpebral lobe of the lacrimal gland. This was followed by injection of 2.5 U of botulinum toxin (botox) with a 28-G needle on a tuberculin syringe directly in the palpebral lobe. The patients were asked to subjectively rate their response to the treatment as mild moderate and marked improvement.

The following data were collected in all groups: demographic data of the patients (age and sex), total dose for each injection, onset and duration of effect, degree of improvement, and the occurrence of adverse effects. Patients were injected with botox three times and the data were recorded for each injection time.

  Results Top

Demographic results

Age : The range of age for all cases was extended from 1 year of age to 80 years. The peak incidence of age distribution in group A was between 60 and 79 years (65%), in group B it was between 40 and 59 years (55.6%), in group C it was between 60 and 79 (87.5%) and in group D it was between 21-39 years and 60-79 years (five cases in each age group; 38.5% each). [Table 1] shows age range and mean age in each group.
Table 1: Age range, mean and SD of age in each group

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Sex: As regards the total number of patients, 29 patients were males (58%) and 21 patients were females (42%).The females were more predominant in groups A (60%), whereas the males were more predominant in groups B (77.8%) and D (76.9%). There was no sex difference in group C. Graph 1 [Additional file 1] shows age distribution in each group.

Injected dose

The mean dose injected in the first injection time in group A1 (HFS group) was 17.1 ± 4.6 U and in group A2 (blepharospasm group) was 31.8 ± 6.00 U. In the remaining groups the mean doses were 8 ± 5.9 U for group B (lagophthalmos group), 11.1 ± 4.7 U for group C (lower lid entropion group), and 3.6 ± 1.3 U for group D (epiphora and hyperlacrimation group).

Graph 2 [Additional file 2] shows the mean injected dose in different groups.

There was a decrease in the mean dose injected each time for groups A, B and C with the lowest values in the third injection time, whereas group D shows a trivial increase in the mean injected dose each time with the highest value in the third injection time.

Onset of action

The mean onset of action in the first injection time was 2.5 ± 0.5 days for group A1, 2.4 ± 0.7 days for group A2, 3 ± 1 days for group B, 2 ± 0 days for group C, and 2.9 ± 0.6 days for group D. The onset of action in the third injection time was shorter than in the first time for groups A1, B, the same for group C, and longer for groups A2 and D (Graph 3 [Additional file 3]).

There was a statistically significant difference in the mean onset of action among groups mainly seen in the first and second injection times with the shortest onset in group C.

Duration of effect

The mean duration of effect in the first injection time was 4.1 ± 0.9 months for group A1, 3.8 ± 0.7 months for group A2, 3.3 ± 9.9 months for group B, 3.7 ± 0.5 months for group C, and 3.5 ± 0.9 months for group D. The longest duration of action was for group A1 and the shortest duration was for group D. [Figure 2] shows the duration of botulinum toxin effect in different groups for each injection time.

Graph 4 [Additional file 4] shows the duration of effect in each injection time for different groups.

Effect of treatment

In group A1, 91.7% of patients show marked improvement and in group A2 62.5% of patients show marked improvement [Figure 1]. Group B showed marked improvement in 22.2% and moderate improvement in 33.3% of patients [Figure 2]. In group C 50% of patients show marked improvement and 25% show moderate improvement [Figure 3]. In group D 23.1% of patients show marked improvement and 69.2% show moderate improvement. The most marked improvement among all groups was in group A1 followed by A2 group (focal dystonia group) and the least improvement was in group B (lagophthalmos group).
Figure 1: Right hemifacial spasm (HFS) before (a) and after (b) injection.

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Figure 2: Left lagophthalmos before (a) and after (b) injection.

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Figure 3: Right lower lid entropion before (a) and after (b) inject ion.

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The improvement level was the same for each injection time.

[Table 2] shows the effect of botulinum toxin treatment in each group.
Table 2: Effect of treatment in different groups

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The adverse effects

The adverse effects were more in group A1 (HFS) in which five patients (of 12) developed adverse effects in the form of: upper lid ecchymosis (one patient), lagophthalmos (two patients), and mild facial asymmetry (two patients). In group A2 (blepharospasm) no adverse effects were noticed in seven patients, whereas in the remaining one patient adverse effects were noticed in the form of allergic conjunctivitis. In group D (epiphora) no adverse effects were noticed in 11 patients, whereas in the remaining two patients adverse effects were noticed in the form of: subconjunctival hemorrhage (one patient) and moderate ptosis (one patient). Adverse effects were absent in groups B and C. There was a highly significant difference in the adverse effects incidence among various groups.

All these adverse effects had occurred in the first injection time and they were not noticed either in the second or third injection times. [Table 3] shows the occurrence of adverse effects in different groups.
Table 3: Adverse effects in different groups

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  Discussion Top

BoNT-A blocks neuromuscular conduction by inhibiting the release of acetylcholine from motor or autonomic nerve terminals. Injected intramuscularly, it produces a localized chemical denervation of the muscle, resulting in localized muscle weakness or paralysis. The denervation is reversible and nerve endings recover over 3 or 4 months during which muscle tone increases and glandular secretion recommences [6]. Its clinical use was spearheaded in ophthalmology where its potential applications have expanded to cover a broad range of visually related disorders. These include strabismus, nystagmus, entropion, headache syndromes such as migraine, BEB, myokymia, lacrimal hypersecretion syndromes, eyelid retraction, aberrant regeneration of facial nerve, corneal exposure, compressive optic neuropathy, and, more recently, periorbital esthetic uses [3],[8].

Although botulinum toxin A has been used to treat these disorders for several years, most available studies describe its use in one or maximally two indications with little work comparing its use in multiple periorbital pathologies [7],[21],[22],[23]. There are three commercially available botulinum toxin preparations: botox (Allergan Corporation, Irvine, California, USA) and Dysport (Speywood Pharmaceuticals, Maidenhead, Berkshire, United Kingdom), both are serotype-A, and Myobloc (Elan Pharmaceuticals, San Diego, California, USA) which is a serotype-B preparation [2]. The current work evaluated the botulinum toxin A treatment in patients with focal facial dystonia [namely HFS and blepharospasm (BEB)], lagophthalmos, lower lid entropion and epiphora. The study data support the high efficacy for treatment of BEB, HFS, entropion, and epiphora with significant improvement in 99, 87.5, 75, and 92.3% of patients, respectively. In patients with lagophthalmos the marked to moderate improvement rate was lower (55.5%).

In the HFS group, the demographic data were well comparable with other studies [24],[25]. It was found the there is a decrease in the mean dosage of botulinum toxin and increased duration of relief over the injection times which was against the finding of Cillino et al. [7] in 2010 who stated that there was an increase in mean dosages for HFS patients in every injection time with no statistically significant change in duration of relief during the follow-up period.

Incidence of adverse effects in HFS group was 41.7% that compares well with other studies [7],[24],[26]. However, in other studies ptosis was the main side effect encountered after injection which was not the case in this study where no cases of ptosis were met after injection which can be attributed to the pretarsal injection technique that keeps the toxin effect remoter from the levator than in the preseptal injection technique.

In BEB group, the mean dose and duration of the effect compared well with other studies [7],[27]. The effect of injection (87.5% significant improvement) was well comparable with other studies [7],[28]. The incidence of adverse effects was 12.5% (one patient) in the form of severe allergic conjunctivitis. This incidence was lower than in other studies [7],[24],[26] with no ptosis encountered as a side effect for probably the same explanation in HFS group.

In lagophthalmos group, efficient ptosis occurred in 55.5% of patients with improvement of the corneal pathology which is lower than the efficient ptosis rate in other studies [29],[30]. No adverse effects were observed for all the nine patients in this group unlike other studies [29],[30],[31] in which temporary superior rectus underaction was the main side effect of injection. This can be attributed to the technique of injection used in this study that was aimed at the anterior most part of the levator muscle, using a half-inch needle where the anterior placement of the toxin prevented superior rectus underaction.

In the lower lid entropion group, significant improvement was encountered by 75% of patients, which is lower than other studies [7],[18] in which 100% of patients experienced significant relief of symptoms. No adverse effects were noticed in this group, which is consistent with earlier studies [18].

In the epiphora group, 92.3% of patients showed moderate to marked improvement which is consistent with the study conducted by Wojno [9] in 2011, in which 91% of his patients showed marked to moderate improvement. The most marked improvement was in the patients suffering from lacrimal pump failure and gustatory lacrimation confirming the results presented by Whittaker et al. [32]. However, this result differs from the finding presented by Wojno who stated that there was no significance in the favorable response rate between the two groups. Incidence of adverse effects was 15.4% in the form of moderate ptosis and subconjunctival hemorrhage, which compares well with other studies [20].

  Conclusion Top

Botulinum toxin A provides a safe, simple, rapid and effective alternative of surgery for many conditions and its temporary outcome may be desirable in certain situations.

  Acknowledgements Top

Conflicts of interest

There are no conflicts of interest.

  References Top

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  [Figure 1], [Figure 2], [Figure 3]

  [Table 1], [Table 2], [Table 3]

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