Fundamental Science
Mechanism of Action
All serotypes of BoNT interfere with neural transmission by blocking the release of acetylcholine, the principal neurotransmitter at the neuromuscular junction, producing temporary chemodenervation and atrophy of targeted skeletal muscles. BoNT is also capable of inhibiting the release of other neurotransmitters, interfering with transmission in the cholinergic autonomic parasympathetic and postganglionic sympathetic nervous system.17 The commercially available subtypes – BoNT-A and type B (BoNT-B) – are both 150 kD dichain polypeptides comprising heavy and light chains linked by relatively weak disulfide bonds.18 The light chain of BoNT-A cleaves to a 25-kD synaptosomal associated protein (SNAP-25), a protein integral to the successful docking and release of acetylcholine from vesicles situated within nerve endings, whereas the light chain of BoNT-B cleaves to vesicle-associated membrane protein (VAMP).
When injected intramuscularly at therapeutic doses, BoNT produces temporary chemical denervation of the muscle, resulting in a localized reduction of muscle activity. Effects become apparent 2 to 4 days after injection for an average duration of 3 to 6 months, with atrophy of the target muscle and changes to individual muscle fibers within the first 2 weeks.19 Although initial recovery of muscle contraction is accompanied by collateral sprouting of active terminal buds near the parent terminal, these new sprouts are only transitory; neurotransmission is eventually restored at the original nerve ending, accompanied by the elimination of the dispensable sprouts, which suggests that treatment with BoNT does not permanently alter the neuromuscular junction.20
Subtypes and Formulations
Two subtypes of neurotoxin – types A and B – are commercially available for cosmetic and therapeutic uses. All preparations differ in terms of purification procedures, potency, and clinical effect and may not be used interchangeably, even within the same subtype. In the United States, the FDA has approved three formulations of BoNT-A, differentiated by specific names to avoid confusion and possible dosing errors: onabotulinumtoxinA (onaA; BOTOX/BOTOX Cosmetic; Allergan, Inc., Irvine, CA), abobotulinumtoxinA (aboA; Dysport; Ipsen Ltd., United Kingdom/Medicis, Scottsdale, AZ; Azzalure; Galderma, France), and incobotulinumtoxinA (incoA; Xeomin/Bocouture; Merz Pharmaceuticals, Frankfurt, Germany), the first formulation free from complexing proteins. Only one formulation of BoNT-B, rimabotulinumtoxinB (rimaB; Myobloc/NeuroBloc; Solstice Neurosciences, Inc., San Francisco, CA), has been developed and approved for use in North America.
AboA seems to be associated with greater diffusion and migration, compared with onaA, although a lack of clear dosing guidelines has resulted in conflicting study results.21,22 Current guidelines recommend a dose ratio of 1 : 2.5 or less than 1 : 3 (onaA/aboA).23,24 By contrast, studies have shown incoA to be similar to onaA in efficacy and safety, with comparable dosing, a rapid onset of effect, and a long duration of up to 5 months or more.25–27 When used for the treatment of hyperkinetic lines in the face, there are key differences between onaA and rimaB, which was FDA approved in 2000 for cervical dystonia but is used off label to treat facial rhytides. RimaB tends to diffuse more widely than onaA and is associated with a faster onset of action, a shorter, dose-dependent duration of effect, and greater pain on injection,28 although a more recent analysis found several doses to be safe and effective for cosmetic applications.29
Use in Ophthalmology
BoNT-A is used to treat a variety of ophthalmologic conditions and cosmetic periocular concerns, but not all patients are good candidates. Therapy is contraindicated in patients with peripheral motor neuropathic disease or those taking aminoglycoside antibiotics or other agents that may interfere with neuromuscular transmission. The medicine should also be avoided in cases of inflammatory or infective skin conditions.30 Moreover, caution should prevail in patients with a history of lower eyelid blepharoplasty and injections avoided in patients with lower lid laxity because of the risk of scleral show; pre-existing conditions that could be worsened by treatment, such as midfacial paresis or symptomatic dry eyes; stable or progressive muscular dystrophic conditions causing blepharoptosis; or already compromised function of the orbicularis oculi. The overall appearance of the face can be improved not only by the amelioration of superficial and more dynamic wrinkles but also by correcting primary malpositional changes, functional abnormalities, or postoperative asymmetries.31
Lid Malposition and Asymmetry
BoNT may a viable alternative to surgical correction in cases of upper and lower lid ptosis, malposition, and asymmetry. For the ptotic upper lid, low-dose subdermal onaA (0.5–1.5 units) into the extreme medial and lateral aspects of the pretarsal region of the orbicularis just above the lash line allows unopposed activity of the levator palpebrae and the Müller muscle. In the lower eyelid, symmetry can be restored by weakening the lower lid elevators on the nonaffected side. One injection is placed in the extreme lateral aspect of the lower eyelid, and the other targets the middle aspect of the lower eyelid pretarsal region.
Entropion of the lower eyelid – inversion of the lid margin, resulting in irritation and discomfort – is caused by the spastic contraction of the pretarsal orbicularis oculi muscle. Five to 10 units of onaA injected into the pretarsal or preseptal orbicularis muscle (divided into two sites in each lower eyelid) provides temporary relief and may be considered as an alternative to definitive entropion surgery, particularly in older patients.11,32,33
BoNT can be used to chemically denervate the eyelids to induce ptosis for the management of thyroid eye disease (TED) and to improve eye closure for better protection of the cornea. Upper eyelid retraction associated with TED results in incomplete eye closure that may lead to corneal ulceration; in patients for whom surgery is not an option – or for patients who wish to defer surgical correction – BoNT-A can produce a significant drop in eyelid position of 2 to 3 mm in lid height for 8 to 14 weeks,34–36 with a greater duration of effect in patients with fibrotic-stage versus congestive-stage TED.37 Injection techniques and doses vary, with 1 to 10 units of onaA injected subconjunctivally at the upper border of the tarsus in the levator aponeurosis-Müller muscle complex – sometimes divided into two injections medially and laterally to avoid overcorrection and subsequent significant ptosis – or transcutaneously into the levator muscle. In patients with facial paralysis, such as those with Bell palsy, lagophthalmos may be reduced by BoNT-induced ptosis and may be a suitable alternative to surgical tarsorrhaphy in cases of corneal exposure, providing adequate corneal protection and healing.38–40 Naik et al. demonstrated that anterior injection of 10 to 15 units of onaA into the levator palpebrae superioris muscle in patients with Bell palsy with exposure keratopathy, persistent epithelial defect, or neurotrophic ulcer led to a significant reduction in palpebral fissure height of 2 to 5 mm lasting an average of 9 weeks.39
Apraxia
Eyelid apraxia, the inability to raise the upper eyelid, can occur in isolation or with other disorders such as Parkinson syndrome and progressive supranuclear palsy,41 or it may be associated with blepharospasm, when contractions of the pretarsal orbicularis oculi suppress the action of the levator muscle. Apraxia of eyelid opening may respond favorably to chemodenervation; injections of BNT-A are directed toward the junction of the preseptal and pretarsal parts of the palpebral orbicularis oculi muscle for best results,42–44 although a combined approach with surgery (including upper lid ptosis repair and possible orbicularis myectomy) may be more successful in some cases.45
Lacrimal Disorders
Gustatory epiphora (“crocodile tears”) is a troublesome, rare condition in which aberrant regeneration of the seventh cranial nerve results in excessive tearing upon salivary stimulation. A more common cause of excessive tearing, lacrimal hypersecretion, may be caused by irritation of the ocular surface via malposition of the eyelid and eyelashes. Injection of 2.5 to 5 units of onaA into the palpebral lobe of the lacrimal gland results in a clinically significant reduction in tear production and improvement in symptoms for 3 to 4 months (Fig. 33.2).46–48
Chemodenervation may also restore balance to the aqueous component of the tear film, which is produced and drained by the lacrimal gland and drainage system, respectively. Located in the medial canthal region, the lacrimal pump of the drainage system is regulated by the action of the orbicularis oculi as the eye blinks. In patients with blepharopasm and hemifacial spasm, dry eye typically – although not always – resolves when excessive blinking is treated via BoNT-A injections.49–51 In cases of isolated, chronic dry eye, BoNT-A injections into the medial portion of the upper and lower eyelids reduces activity of the lacrimal pump, allowing tears to pool in the fornix for symptomatic relief.52
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