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Botulinum Toxin: Oculofacial Clinical Applications
Adam J. Cohen, MD · Michael Mercandetti, MD, MBA, FACS
Botulinum A Toxin, which is commercially available as Botox (Allergan), is one of seven toxins produced by Clostridium botulinum, a gram-positive anaerobic bacterium. After the clinical trials conducted by Alan B. Scott, MD, the U.S. Food and Drug Administration (FDA) in 1989 approved Botox for treatment of strabismus and facial spasms. Since initial approval, its clinical indications have widened to treat muscle spasms involving the larynx, upper1 and lower extremities and neck. Gustatory sweating, also known as Frey’s syndrome, involves sweating of the cheek while eating and has been treated with Botox.2 Aberrant seventh nerve regeneration associated with Bell’s palsy, with resultant crocodile tears, has been successfully managed with Botox as has hyperhidrosis.2
Although this article focuses on the Botox brand of botulinum toxin A, other labels include Dysport and CS-Bot (Speywood-Vaccine and Research Labortories-Porton Down, Salisbury, UK). In addition, botulinum toxin B is marketed in the United States as Myobloc (Elan, Dublin, Ireland), which needs no reconstitution and can be stored for 21 months if refrigerated.
Mechanism of Action / Pharmacology
Botox inhibits acetylcholine release effecting a resultant paralysis.3 Acting at the neuromuscular junction, cellular uptake is believed to occur through an active cell surface receptor-mediated process.4 This three-step chemical denervation is initiated by the toxin’s selectively binding to sites on the surface membrane of cholinergic nerve endings.4 An energy-dependent endocytotic process ensues internalizing the cell membrane with bound protein.4 The final step is presumed to act on calcium-mediated exocytosis, preventing the release of acetylcholine into the synaptic cleft.4 It is also believed that Botox acts as a zinc-dependent metalloendoprotease to inhibit exocytosis.5
Chemically induced paralysis usually commences within 24 to 72 hours after injection, with a maximal effect noted at 1 to 2 weeks. One review found the mean duration of orbicularis oculi weakening to be 13.4 weeks.4 A longer duration of effect has been noted and may be explained by Holds and colleagues6 who found unmyelinated axonal sprouts at motor endplates in histological specimens of orbicularis oculi that were previously treated with Botox. De Paiva and colleagues also support this endplate remodeling theory by elucidating limited activity of the regenerated motor endplates, which are subsequently purged after sprouting.7
Antibody production in humans has been described and may play a role in some persons who become resistant to Botox after recurrent treatment.8
Botox is commercially available in 100-unit (U) vials of sterile, lyophilized powder. This heat-sensitive crystalline complex must be stored at –5°C prior to reconstitution with sterile, nonpreserved normal saline. A unit is measured as the amount necessary to kill 50% of Swiss-Webster mice injected with that dose.9
Allergan recommends using reconstituted Botox within 4 hours, although it has been used up to 1 week after reconstituting without problems or apparent loss of efficacy.10
Before treating patients with Botox, as with any medication, a thorough history is mandatory with special attention to previous facial surgery or chemodenervation, and current medications. Contraindications include pregnant or lactating patients, patients younger than 12 years of age, previous allergic reactions to botulinum toxin, and a history of myasthenia gravis or other neuromuscular disorder. The physician should also exercise caution if a patient must maintain a high level of facial expression (e.g., comedian).
As with any procedure, all risks, benefits, and alternatives should be clearly explained to the patient and documented before obtaining consent. The authors routinely obtain pre-injection photographs for further documentation.
Botox is reconstituted in a gentle fashion to avoid agitation and disruption of the toxin. A typical dilution for the treatment of blepharospasm and hemifacial spasm is to dilute the Botox to a concentration of 2.5 U per 0.1 mL. This is achieved by adding 4 mL of the saline to one vial of Botox (100 U/4 mL = 25 U/mL; 25 U/10 = 2.5 U/0.1mL). This solution is drawn into 1-mL (Tuberculin) syringes with a wide bore needle, which is able to reach the bottom of the vial and then replaced with a 30-gauge, 0.5-inch needle. A topical anesthetic agent such as EMLA (lidocaine 2.5% and prilocaine 2.5%, Astra Zeneca), ELA-Max11 (lidocaine, 4%, Ferndale Laboratories) (if not contraindicated), or ice can be used to reduce the pain of injections. The patient’s skin overlying the muscles to be treated is cleansed with alcohol or povodine wipes. Muscle localization can be aided by the use of electromyography, but is not routinely implemented by the authors. The injections are given in a subcutaneous or intramuscular fashion directly over or into the muscles to be paralyzed. Pressure is applied for several minutes following the injection to quell any bleeding and prevent ecchymosis, which occurs rarely.
Benign Essential Blepharospasm
Benign essential blepharospasm is an involuntary contraction of the periorbital musculature including the pretarsal and preseptal orbicularis oculi, the corrugator supercilii, and the procerus. Usually unilateral at first, bilateral involvement occurs within weeks to months and can range from increased blinking to severe orbicularis spasms. This dystonic, idiopathic condition is hypothesized to stem from dysfunction of the supranuclear blink circuitry.12 It is important to exclude conditions such as tear film abnormalities, corneal pathology, supranuclear disorders, and apraxia of eyelid opening or lagophthalmos before arriving at a diagnosis of essential blepharospasm. Meige syndrome is the moniker for essential blepharospasm when coupled with dystonia of the mandibular and neck region (oromandibular dystonia).
Involuntary, unilateral contractures of the facial musculature are the usual clinical manifestation of hemifacial spasm (HFS), although a bilateral scenario may occur rarely. Hemifacial spasm usually begins with the orbicularis oculi muscle contracture, spreading inferiorly to include other facial regions and the platysma. The authors strongly suggest and routinely obtain a magnetic resonsance angiogram of the cerebral vasculature and a magnetic resonance image with gadolinium of the brain with particular attention to the facial nerve and posterior fossa. Structural lesions of the skull base such as cerebellopontine angle tumefactions must be excluded before a diagnosis of HFS can be made. Several etiologic scenarios have been reported in the literature including facial nerve impingement as it exits the brainstem by a tortuous or dolichoectatic anterior cerebellar artery or increased excitation of the facial nerve nucleus.
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Treatment of HFS includes a similar but unilateral periocular pattern (Slide 1) with additional injections in the midfacial area. Injecting proximal to the oral commissure should be avoided to reduce the occurrence of oral commissure drooping. If spasms involve the platysma, this region may be targeted, as well.
Epiphora, ocular irritation, ptosis, and diplopia were the major complications most commonly noted by Price and colleagues.13
Other functional applications of Botox include treatment of lid retraction secondary to thyroid eye disease14 and spastic entropion of the lower lid.15
Activity of the facial muscles results in rhytids; weakening these muslces attains temporary reduction of dynamic skin wrinkles. Optimal outcomes were found in patients who possessed thin skin and fine rhytids that increased with muscle contraction and were able to be reduced by finger spreading.16, 17 Lines resulting from loss of dermal elasticity, static rhytids, are not amenable to Botox and should be treated with other rejuvenative modalities.
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The corrugator supercilii muscles are responsible for the vertical hyperfunctional lines of the glabella. Commonly, overactivity of the muscles leads to the appearance of an angry or frowning patient. Patient frowning facilitates localization of these muscles. The physician should be cognizant of the nearby supraorbital and supratrochlear neurovascular bundles while carefully injecting directly into the muscle belly. We routinely inject the medial and lateral portions of the muscles with 5 U per site. We prefer to spread the injection throughout the muscle instead of giving a single bolus. Patient sensitivity may be increased in this region due to the proximity of the supraorbital and supratrochlear nerves.
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Some have successfully targeted the levator labii superioris alaeque nasi for reduction of the nasolabial fold. The possibility of upper lid paresis does exist and the authors do not currently employ this technique.
Rhytids of the upper labial region can be treated with 1 U of Botox injected adjacent to the wrinkle. The lateral lip and oral commissure are sidestepped to avoid a transient palsy.
Identification of platysmal bands allows for reduction of these telltale signs of aging. A 5-U dose of Botox can be injected in horizontal fashion along the rhytids of interest. Kane and colleagues have reported improvement in all patients treated with Botox.19 Side effects include dysphagia and airway obstruction.
Botulinum toxin continues to be used for aesthetic and functional purposes. This modality has a long history of safety and efficacy in selective muscle paralysis for treatment functions.
