Clinical use of botulinum toxins in oral and maxillofacial surgery

Botulinum toxin (BTX) is a bacterial toxin that could be used as a medicine. Clinical applications of BTX have been expanding over the last 30 years and novel applications reported. Its mechanism of inhibiting acetylcholine release at neuromuscular junctions following local injection is unique for the treatment of facial wrinkles. Other dose-dependent anti-neuroinflammatory effects and vascular modulating properties have extended its spectrum of applications. Conditions such as temporomandibular joint disorders, sialorrhea, headache and neuropathic facial pain, muscle movement disorders, and facial nerve palsy could also be treated with this drug. Further applications of BTX are likely to be developed. This paper reviews the established and emerging applications of BTX in the field of oral and maxillofacial surgery. An overview of the pharmacology, toxicity and preparations of the agent is given.

Purified botulinum toxin (BTX) was the first bacterial toxin used as a medicine. Since its introduction into clinical use, over 30 years ago, it has become a versatile drug in various fields of medicine. The clinical applications of BTX have been expanding and novel applications developed.

BTX is widely used in cosmetic applications for the treatment of facial wrinkles after local injection, but conditions such as temporomandibular joint disorders, sialorrhea, headache and neuropathic facial pain, muscle movement disorders, and facial nerve palsy could be treated with this drug. Many other indications are under investigation, and further applications for BTX are likely to be developed . In the maxillofacial region, most studies on the use of BTX are of low quality (noncomparative, non-randomized trials), but the overall results were promising.

In this review, established and emerging applications of BTX in the field of oral and maxillofacial surgery are discussed. Emphasis is placed on the mechanism of action and outcome of treatment in different clinical situations. An overview of the pharmacology, toxicity and different preparations of the agent is given.

History

The idea of a possible therapeutic use for botulinum toxin (BTX) was first developed by the German physician and poet Justinus Kerner (1786–1862); he called it ‘sausage poison’. In 1870, Muller, another German physician, coined the name botulism. The Latin form is botulus , which means sausage .

In 1897, Emile van Ermengem investigated an epidemic of botulism in Ellezelles, Belgium, after the consumption of raw ham. He isolated the bacteria from the ham and produced the disease in laboratory animals by injecting the toxin produced by the organism .

BTX was developed as a biological weapon by many countries in the twentieth century . Although many countries stopped research related to biological weaponry after signing the Biological and Toxin Weapons Convention, purification of BTX for medical use continued .

A therapeutic use for botulinum toxin type-A (BTX-A) was first studied in primates by Scott et al in 1973 . In the late 1970s, the toxin was introduced as a therapeutic agent for the treatment of strabismus . Since then, its therapeutic applications have expanded into many different fields, often with innovative treatments and surprising results.

BTX was first used for treating facial wrinkles and aging skin in 1988, but its widespread cosmetic use did not occur until the mid-1990s . There was much speculation about the storage, dilution, delivery methods and treatment doses. In maxillofacial surgical practice, Niamtu reported on the cosmetic use of BTX for facial rhytids and dynamic lines in 1999 and 2000 . During the mid- and late-1990s, BTX was used for lateral canthal lines (crow’s feet), platysmal banding, orbicularis oris injection, masseter muscle injection and the treatment of temporomandibular disorders (TMDs). Later, there were many attempts to use BTX for different clinical situations in oral and maxillofacial surgery.

Bacteriology

Clostridium species bacteria are sporulating, obligate anaerobic, Gram-positive bacilli. The spores of C. botulinum are ubiquitous, distributed widely in soil and marine sediments worldwide and often found in the intestinal tract of domestic grazing animals .

Under appropriate environmental or laboratory conditions, spores can germinate into vegetative cells that will produce toxin. C. botulinum grows and produces neurotoxin in the anaerobic conditions frequently encountered in the canning or preservation of foods .

Seven different strains of Clostridium have been described (designated A, B, C (1 and 2), D, E, F and G), and each produces a distinct neurotoxin identified by the corresponding letter of the bacterial strain producing it, so, there are 7 distinct neurotoxins (BTX-A, -B, -C, -D, -E, -F, -G) . Humans can be affected by the toxins of 5 strains (A, B, E, F and G) and are not affected by the toxins of strains C and D . All 7 toxins may potentially cause botulism in humans given a high enough exposure . All 7 neurotoxins are structurally similar but immunologically distinct . There is some serum cross-reactivity among the serotypes because they share some sequence homology with one another as well as with tetanus toxin .

Bacteriology

Clostridium species bacteria are sporulating, obligate anaerobic, Gram-positive bacilli. The spores of C. botulinum are ubiquitous, distributed widely in soil and marine sediments worldwide and often found in the intestinal tract of domestic grazing animals .

Under appropriate environmental or laboratory conditions, spores can germinate into vegetative cells that will produce toxin. C. botulinum grows and produces neurotoxin in the anaerobic conditions frequently encountered in the canning or preservation of foods .

Seven different strains of Clostridium have been described (designated A, B, C (1 and 2), D, E, F and G), and each produces a distinct neurotoxin identified by the corresponding letter of the bacterial strain producing it, so, there are 7 distinct neurotoxins (BTX-A, -B, -C, -D, -E, -F, -G) . Humans can be affected by the toxins of 5 strains (A, B, E, F and G) and are not affected by the toxins of strains C and D . All 7 toxins may potentially cause botulism in humans given a high enough exposure . All 7 neurotoxins are structurally similar but immunologically distinct . There is some serum cross-reactivity among the serotypes because they share some sequence homology with one another as well as with tetanus toxin .

Structure and Toxicity

Toxins produced by clostridial bacteria are high-molecular-weight protein complexes that include 3 key proteins: a 150-kDa toxin, a non-toxin hemagglutinin protein, and a non-toxin non-hemagglutinin protein. The 150-kDa toxin is composed of a 100-kDa heavy chain and a 50-kDa light chain. Disulfide and noncovalent bonds link the heavy and light chains, and both chains are required for neurotoxicity .

BTX is the most toxic material known. It is 4 times more lethal in mice than tetanus toxin, 1 × 10 more lethal than curare, and 100 × 10 more lethal than sodium cyanide . The estimated human dose (assuming a weight of 70 kg) of type A toxin lethal to 50% of an exposed population (the LD50) is estimated, based on animal studies, to be approximately 0.09–0.15 μg by intravenous administration, 0.7–0.9 μg by inhalation and 70 μg by oral administration . Based on findings from primate studies, human LD50 for intramuscular BTX injection is estimated at 2500–3000 U for a 70-kg adult (35–40 U/kg).

Mechanism of Action

BTX is a protease that causes temporary chemical denervation of skeletal muscle by blocking the Ca +2 -mediated release of acetylcholine from nerve endings of alpha and gamma motor neurons (myoneural junction), producing a transient dose-dependent weakening of the muscle activity rendering it nonfunctional without systemic effects . This inhibition of muscular contraction is believed to be followed by the sprouting of new axon terminals, which results in synaptic regeneration and the reestablishment of neuromuscular transmission .

The 7 neurotoxins have different specific toxicities, different durations of persistence in nerve cells , and different potencies . All BTX serotypes, ultimately, inhibit acetylcholine release.

The area of flaccidity produced may be larger than the area of muscle denervated as a result of postulated paralysis of gamma motor neurones, so the output of the muscle spindles is reduced leading to reduced muscular contraction at adjacent sites within the injected muscle . Weakening of surrounding muscles not injected may also occur because of toxin diffusion. Animal studies have demonstrated that BTX-A diffuses across fascial planes to surrounding muscles .

Clinical effect occurs within approximately 3–7 days (typically seen after 1–3 days) after administration, followed by 1–2 weeks of maximum effect, which then levels off to a moderate plateau until full nerve recovery within 3–6 months (typically at approximately 3 months) .

Preparations

A number of BTX preparations have been approved in different countries. Currently, there are 6 different BTXs available on the market, 5 contain BTX-A (Botox, Dysport, Xeomin, Prosigne and PurTox) and the other contains BTX-B (Myoblocs/NeuroBlocs). Approval procedures are complex and vary between preparations and countries, but, in general, Botox has garnered the most approvals worldwide, followed by Dysport .

Treatment doses of BTX vary depending on the brand of toxin used. The dose given for any toxin refers only to that particular preparation and does not readily transfer to doses of other products, even if they are of the same toxin serotype. These ratios should be applied with extreme caution because different preparations may have different efficacy in different parts of the body .

BTX-A

Botox (Allergan Inc, USA): BTX-A (originally called ‘Oculinum’) was first used in humans in 1968 to treat strabismus . In 1991, Allergan Inc. purchased several batches of this purified BTX-A, and the agent was given the name Botox .

Botox is the only available BTX product approved for cosmetic use in North America. It is specifically approved for the therapeutic treatment of strabismus, blepharospasm, cervical dystonia and axillary hyperhidrosis. There are reports of Botox specifically improving patient self-perception .

Each vial of Botox contains 5 ng (100 U) of air-dried toxin, with 1 unit (U) equal to the median amount necessary to kill 50% of female Swiss-Webster mice weighing 18–20 g each after intraperitoneal injection (LD50) . Each vial contains 500 μg of albumin and 900 μg of sodium chloride .

Dysport (Ipsen Limited, UK) is another BTX-A product approved for cosmetic use, which is marketed and sold in many European countries as well as Russia, New Zealand, Mexico, Brazil, Argentina and Vietnam . Each vial contains 12.5 ng (500 U) of air-dried toxin, 125 μg of albumin, and 2.5 mg of lactose . Dysport comes from a different type A strain of bacteria than Botox and doses are not equivalent. Direct comparisons of Botox and Dysport in animal studies suggest that the equivalence doses are 1 U Botox to 2.5–5 U Dysport, though in humans, this conversion is largely an estimate .

Xeomin (NT-201; Merz Pharmaceuticals GmBH, Germany), packaged as a freeze-dried powder, is a purified BTX-A that is free of the accessory complexing proteins (hemagglutinin and nonhemagglutinin) found in the other BTX-A products . It is reported to be less immunogenic than other BTX-A products, making it useful when large amounts of toxin are required for extended periods . Animal studies support this, but reliable human immunogenicity data are not available .

Many studies have found that Botox and Xeomin have similar dose-dependent paralytic effects and minimal diffusion effects on surrounding musculature . It has been suggested that conversion of Botox and Xeomin doses can be performed in a 1:1 ratio allowing exchange of both BTX drugs in a therapeutic setting.

Prosigne (Lanzhou Biological Products Institute, China) is a BTX-A that is only approved in China; it has been available for clinical use there since October 1993 . Preliminary studies suggest that Prosigne may have therapeutic actions comparable with Botox for some therapeutic purposes . Trials specifically examining Prosigne for cosmetic uses are lacking .

PurTox (Mentor Corp, Santa Barbara, CA, USA) is a purified BTX-A that is undergoing trials to approve its efficacy in some therapeutic uses .

BTX-B

BTX-B is available as Myobloc (Solstice Pharmaceuticals, South San Francisco, CA, USA) and is marketed as Neurobloc (Elan Pharmaceuticals, Shannon, County Clare, Ireland) . Myobloc has shown efficacy in clinical trials for the treatment of various movement disorders since 1995 and was approved by the FDA for the treatment of cervical dystonia and hemifacial spasm in 2001 . Myobloc has not received cosmetic approval in any country, but there are reports of its efficacy in the treatment of lateral canthal, glabellar and forehead rhytides. It appears to offer versatility in cosmetic neuroblockade by exhibiting action in patients resistant to BTX-A products .

Myobloc is preconstituted in vials containing 25 ng (2500 U)/0.5 cc, 50 ng (5000 U)/1.0 cc and 100 ng (10,000 U)/2.0 cc of product in solution with 0.05% albumin . Treatment of patients with cervical dystonia with Botox and Myobloc led to attempts at equivalency doses in many cosmetic studies (1 U Botox equals approximately 50–100 U Myobloc), but the optimal ratio has not been established .

Studies comparing the cosmetic efficacies of BTX-A and BTX-B report that the latter causes more pain during injection, has shorter action and probably a less predictable diffusion pattern . BTX-B could be useful in situations in which rapid onset is desirable or in which there are concerns about antibody production to BTX-A .

Cosmetic Uses

Intramuscular injection of BTX to reduce facial wrinkles is the most common cosmetic procedure performed in many countries. In conjunction with fillers, BTXs allow the practitioner to sculpt the face through alterations in the dynamics of the facial muscles. The limited on-label uses of these drugs for hyperkinetic forehead wrinkles and brow furrows belie its range of cosmetic applications.

Facial Wrinkles

Glabellar lines, also called frown lines, occur naturally with facial animation, as a result of the pulling of the skin by the underlying musculature, predominantly the procerus muscle and the corrugator supercilii. With aging and chronic activity of the facial muscles, these lines become more prominent . The cosmetic potential of BTX-A was first explored in the mid 1980s in the treatment of hyperfunctional facial lines. Since then, BTX-A has been used to temporarily treat glabellar lines and other hyperfunctional facial lines such as horizontal forehead lines, lateral canthal lines ‘crow’s feet’, platysma bands and perioral lines . The evidence for the effect of BTX in the treatment of facial wrinkles is level 2 evidence (evidence from randomized controlled trials).

The technique for injecting BTX is generally simple and most patients tolerate injections without anesthesia quite well, although topical anesthetics are used by some practitioners. Some have used acid mantle cream mixed with lidocaine (4%) and Lidoderm patches (lidocaine 5%) . Many patients treated with topical anesthesia elected not to use it for subsequent treatments .

Multiple injection techniques have been described. Some authors describe a method based on brow position . Others describe a method based on needle angulation and measurement . All injections are now made perpendicular to the skin surface and are tailored to the specific anatomy, but they must be 10 mm away from the bony orbit because the apparent diffusion of BTA is approximately 10 mm .

Botox has only been approved officially for the treatment of glabellar lines, but other uses have shown the same degree of improvement for frontalis and lateral canthal regions. Botox has also been used for the reduction of platysmal bands . Several patients with mentalis wrinkling and lower eyelid orbicularis hypertrophy were treated successfully with Botox injections . Other sites treated include the vertical lip rhytids (lipstick lines) with minimal improvement and good patient satisfaction but perioral muscular palsy was reported in some cases . Some have described an improvement in patients with excessive gingival exposure. By weakening the lip elevators, the amount of movement decreases and the patient shows less gingiva on smiling .

Masseteric and temporalis muscle hypertrophy

Masseteric hypertrophy usually results from anatomical asymmetry of the jaw, habitual asymmetric use of the jaw, clenching during exercise or sleep, excessive chewing of gum or congenital malformations. It may be unilateral or bilateral. The early results of treatment with intramasseter injections of BTX have been encouraging and satisfying to patients, but the effect has not been well quantified .

Temporalis muscle hypertrophy is less common but has been managed successfully using BTX injection; there were no appreciable side effects .

Therapeutic Uses

BTX has evolved from a poison to a versatile clinical tool for a growing list of conditions resulting from muscular hyperfunction. In the head and neck, this list includes focal dystonias, vocal tics and stuttering, cricopharyngeal achalasia, various manifestations of tremor, hemifacial spasm, temporomandibular joint dysfunction, bruxism, masticatory myalgias, sialorrhea, hyperhidrosis and headache . Recently, it has been reported for clinical use in dental implantology for the prophylactic reduction of masseter and temporalis muscle strength after implantation in immediate load protocols .

Temporomandibular joint (TMJ)

Many reports on BTX-A treatment for TMJ disorders have dealt with TMJ and masticatory muscle pain , reduced jaw opening capacity , recurrent TMJ dislocations , and masticatory hyperactivity . Most of these studies were case series (level 4 evidence).

Temporomandibular disorders (TMDs) are subgroups of musculoskeletal and rheumatologic disorders, and are considered the major cause of pain in the orofacial region . TMDs may be divided into those related to the muscles acting on the joint (myofascial) and those related to the joint itself (arthrogenic). Joint noise, pain and a restricted range of mandibular motion are the most frequent symptoms of TMD . Directing treatment at the muscular component of TMD, which in some patients can be identified as non-spastic clenching or bruxism, could yield important therapeutic gains. BTX-A has been effective in the treatment of some patients with TMD with high specificity as well as tolerable side-effects . Injections are usually performed under electromyographic or ultrasonic control .

The source of chronic myofascial pain is not clear . There is some consensus that peripheral and central mechanisms are variably involved in the propagation of pain in TMD . The injection of BTX-A into the masseter and temporalis muscles of patients with TMD reduced subjective pain and tenderness in some patients coincident with the objective and subjective weakening of the masticatory muscles and not before . This observation was attributed to the presumed action of BTX on nociceptors and the inhibitory effect of specific protein-receptor binding within the intracellular compartment on the release of neuropeptides and inflammatory molecules, such as calcitonin gene-related peptide, substance P, and glutamate .

Most patients with restricted mouth opening experienced some degree of improvement in the maximal range of vertical motion after BTX therapy. Muscular relaxation, reduction of inflammation in the muscle and the TMJ, and the guarding response to pain may contribute to this finding .

Earlier studies suggest that displacement of the articular disc may be caused, precipitated or maintained by lateral pterygoid activity or friction between the articular surfaces of the disc and condyle causing clicking . BTX injection into the lateral pterygoid muscle has reduced the clicking associated with TMD . Clicking was permanently eliminated in some cases with a small but distinctive positional improvement in the disc–condyle relationship .

The term ‘bruxism’ is derived from the Greek word brychein , which means ‘to grind or gnash the teeth’ . When severe, this rhythmic grinding is associated with headache, masseter hypertrophy, dysarthria, TMJ destruction and dental wear . Several studies have described the treatment of bruxism with BTX . Some authors have found that BTX-A injection into the flexor muscles of the mandible produced subjective and objective reductions in the power of muscular voluntary contraction in most subjects . There have been no double-blind studies to assess the effectiveness of BTX therapy in bruxism.

Arthrocentesis is a less invasive surgical intervention than open arthrotomy to relieve the discomfort and dysfunction associated with chronic cases of internal derangement of TMJ . Intramuscular injection of BTX as an adjunct to arthrocentesis of the TMJ gave encouraging results regarding duration of improvement, suggesting that there may be synergy between the two procedures .

Dislocation of the TMJ occurs when the mandibular condyle is displaced anteriorly beyond the articular eminence. It represents 3% of all reported dislocated joints . There have been several anecdotal reports of the use of BTX-A as treatment for TMJ dislocation , but a controlled clinical trial is needed to prove evidence of its efficacy. BTX-A was first used to treat surgical failures and then used as initial treatment . The muscle selected varies with each case, but the lateral pterygoid is that most commonly reported. Treating only the lateral pterygoid muscle appears to be sufficient to prevent temporarily recurrent dislocation of the TMJ , but, in some reports, the superficial part of the masseter at the angle of the mandible was also injected .

BTX injection is invasive, but it is a relatively conservative option. It is specifically indicated in patients for whom conservative treatment of recurrent dislocation of the TMJ has failed and for whom surgery carries major risks. BTX injection therapy is also an option in patients who suffer recurrent dislocation of the TMJ as a result of impaired muscle coordination secondary to oromandibular dystonia, neuroleptically induced early and late dyskinesias, epilepsy and brain-stem syndromes .

BTX treatment of protracted TMJ dislocation after medical conditions such as anoxic encephalopathy and stroke or cerebrovascular event has also been reported, which could lead to an increase in verbalization, mastication and improved quality of life.

Salivary secretory disorders

Xerostomia is one of the first manifestations of botulism, which led to investigations of its application for sialorrhea and drooling. Topical injection of BTX-A as a minimally invasive option for the treatment of drooling has been used for many years in neurological diseases . Its greatest limitation in this indication is its transient effectiveness (3–4 months), requiring multiple and expensive administrations . The therapeutic effect is based on the inhibitory action of the toxin at the cholinergic receptors of the salivary gland cells, shown in animal experiments . An initial animal model showed a significant reduction in saliva production without direct toxicity to the acinar cells .

Only pilot studies with relatively small groups of patients are available with a brief follow-up (level 4 evidence), although here are some studies on sialorrhea associated with Parkinson’s disease [level 2 evidence (randomized clinical trials)]. The outcome of using BTX-A in the treatment of drooling appears to be uniformly favorable; the preliminary results are promising, with rare reports of serious complications. Up to two-thirds of patients experienced a marked or moderate improvement in drooling after the treatment of both parotid glands or parotid and submandibular glands combined . Treatment is mostly focused on the parotid gland and to a lesser extent on the submandibular gland. The sublingual gland is seldom injected .

BTX has found application for sialorrhea in Parkinson’s disease , amyotrophic lateral sclerosis , cerebral palsy , and carcinoma of the upper digestive tract. It has also been used for accumulated saliva and drooling caused by swallowing disorders after tumor operations of the upper aerodigestive tract and for diseases of the glandular tissue such as posttraumatic and iatrogenic salivary sialoceles and cysts or salivary fistulas after sialadenectomy or oropharyngeal cancer surgery where the temporary stopping of glandular secretory action is needed to promote healing. It has also been used successfully to treat auriculotemporal (Frey’s) syndrome as it reduces the skin area affected by gustatory sweating by inhibiting the sweat glands abnormally re-innervated by the cholinergic pathway . BTX-A also has advantages in temporarily drooling states because its effect is only temporary . In patients with recurrent and chronic parotitis, BTX injection resulted in a reduction in the number of episodes of parotid swelling . BTX-B has also been successful in some cases .

With the exception of those with Frey’s syndrome who are treated intracutaneously, all of the injections are performed percutaneously, either intraparenchymal or perilesional. In the case of sialoceles, the extravasation fluid should be drained beforehand . Some authors still use BTX injections under EMG control when treating salivary secretory disorders. According to others, ultrasonographic-assisted intraparenchymal infiltration is preferable and improves efficacy and safety . Others have found no difference in undesired effects associated with the method of drug application .

Facial pain (other than myofascial origin)

Chronic facial pain often presents difficult management problems requiring interdisciplinary consultations and multiple attempts with different therapies. BTX injections showed some advantages over existing therapies regarding safety and efficacy . The evidence provided by the literature in this area lies in level 2 (randomized clinical trials).

Facial pain relief has been reported after treatment by BTX for other reasons; such conditions include regional dystonias , facial wrinkles , and skull base surgery . These observations led to the study of non-dystonic pain syndromes, such as myofascial pain and tension headache, these produced beneficial results and were then studied in larger controlled trials . Several studies have been conducted on the use of BTX-A in pain conditions such as tension headache, myofascial pain, migraine, trigeminal neuralgia, bruxism and hemifacial contracture after seventh cranial nerve injury . BTX-A was found promising in postoperative wound pain including reconstructive facial and oral surgery, traditional and endoscopic sinus surgery, TMJ surgery and blowout fracture repair . Chronic facial pain following post-dental procedures was associated with a poor results .

Similar benefits have been reported with the use of BTX-B . The ultimate efficacy of BTX in pain is difficult to assess and the data available do not permit definitive conclusions. Other studies did not show a beneficial effect of BTX-A .

Facial nerve palsy (FNP)

FNP is a disfiguring condition, different aspects of which have been treated successfully using BTX. Most studies were case series (level 4 evidence).

BTX injection, through an orbital route or a skin crease, provides a good means of inducing a protective ptosis by temporarily paralyzing the levator palpebrae superioris . This intentionally induced ptosis may be useful in intensive care patients to prevent desiccation of the cornea .

Synkinesis is an involuntary uncoordinated muscle movement associated with voluntary movement of the muscle. It is secondary to aberrant regeneration . BTX-A is commonly used to relieve the symptoms of synkinesis with marked improvement .

In patients with facial asymmetry, chemo-denervation of the normal side with BTX has been reported to be an effective disguising tool. In this setting, BTX reduces the relative hyperkinesis of the contralateral side to the paralysis, resulting in a more symmetrical function of the face.

An aberrant connection of the salivary sceromotor fibres to the fibres of the lacrimal gland may develop after a facial palsy, causing a hyperlacrimation whenever the patient salivates (crocodile tears). Injection of BTX into the lacrimal gland is a successful treatment for hyperlacrimation in these cases .

Other nerve palsies

Trauma is a common cause of acquired third-nerve palsy in adults and children . Such patients are less likely to recover than those with palsies of other causes . There are few reports (level 4 evidence) of BTX injection to the lateral rectus muscle for treatment of third-nerve palsy . BTX injection decreases the likelihood of contracture of the lateral rectus muscle, thereby allowing return of medial rectus muscle function .

The abducens nerve can be injured during a severe orbital trauma . In such cases, BTX injection of the medial rectus muscle has been studied with variable improvements .

Muscle movement disorders

BTX has been used since 1977 as a therapeutic agent in the treatment of numerous neuromuscular disorders . BTX-A injections are considered a safe and efficient local treatment for focal dystonia and muscle spasms . Other serotypes have been used with comparable effects .

Dystonia refers to the involuntary contraction of specific muscles. Numerous studies document the usefulness of BTX therapy in the treatment of oromandibular dystonia , cervical dystonia (spasmodic torticollis) , hemifacial spasm , tardive dyskinesia , and tardive tongue protrusion dystona . Many studies were double-blind randomized trials (level 2 evidence).

A specific type in this category is hyperkinesia of the platysma. In the literature, data on successful treatment of the platysma with BTX are nearly always related to its use for aesthetic indications . BTX also provides a favorable therapeutic option .

Perioperative use of botulinum toxins

In patients with movement disorders who require surgery, the presence of postoperative involuntary movements may be detrimental to healing. BTX weakens the muscle and in so doing may improve postoperative recovery and healing. Wound healing improves if the muscles involved are injected with BTX prior to surgery .

In maxillofacial surgery, patients undergoing eyelid reconstructive surgery had successful wound healing after adjunct treatment with BTX . BTX was better than placebo in the wound healing of facial lacerations requiring surgery . BTA has been used to immobilize muscles after jaw fractures (level 4 evidence) to reduce the displacing forces on the fracture ends and obtain good immobilization especially if rigid internal fixation is not available or feasible.

BTX has also been beneficial during the initial osseointegration phase for dental implants. This indication is mostly experimental, but some authors have found it to be safe and effective in the prophylactic reduction of masseter and temporalis muscle strength after implantation in immediate loading protocols .

Complications

Botox has a large margin of safety . The most important side effects reported for cosmetic use of BTX include immunogenicity, allergy and local complications.

Neutralizing antibodies to BTX-A toxins can lead to loss of treatment effect. Clinical resistance to BTX-A has been estimated as high as 7% , and BTX-B is being investigated as an alternative therapeutic agent .

In theory, because human albumin is used in the preparation of Botox, a patient could exhibit an allergic reaction, but no case has been reported.

Adverse effects such as pain, oedema, erythema, ecchymosis and short-term hypoesthesia may occur after injection of BTX-A . Other reported adverse events are headache, blepharoptosis and perioral muscular palsy .

In therapeutic applications, complications were mostly local and relatively mild, such as pain, erythema, ecchymosis of the region injected, dry eyes, mouth droop, ptosis and lid edema, facial muscle weakness, asymmetry of facial expression during dynamic facial movements, xerostomia, transient dysphagia, restricted mouth opening, nasal regurgitation and nasal speech, headache, blurred vision, dizziness, upset stomach, infection, neck weakness, voice changes, difficulties in chewing and breathing risk of aspiration, recurrent jaw dislocation, dysarthria, salivary duct calculi and local injuries of the carotid arteries or branches of the facial nerve .

Systemic side effects are rarely reported, generally not dose related, and can include transient weakness, fatigue, nausea and pruritis . Flu-like syndromes have been reported, but they are generally of brief duration .

Some adverse effects such as xerostomia and dysphagia are more frequently seen after treatment with BTX-B than BTX-A .

Contraindications

Contraindications to BTX-A are generally few. In many studies, no complaints were received about systemic problems associated with cosmetic injection. Allergan lists Botox contraindications as pregnancy and breastfeeding, disorders of the neuromuscular junction (myasthenia gravis, amyotrophic lateralizing sclerosis, myopathies) and theoretical drug interactions (aminoglycoside antibiotics, quinidine, calcium channel blockers, magnesium sulfate, succinylcholine, and polymyxin) . Other reported contraindications are Eaton–Lambert syndrome and hypersensitivity to BTX or one of its ingredients .

Potential Therapeutic Uses

Topical Formulations

Because intradermal BTX injection has been successful in treating focal hyperhidrosis of the palms, soles, axillae and facial areas , investigators have considered the potential for a topical formulation. Topical BTX has been used for axillary hyperhidrosis with promising results .

Keloid and Hypertrophic Scar

Clinical observations indicate that BTX-A can improve the appearance of hypertrophic scar and inhibit its growth . Evidence supporting this potential use arise from BTX’s ability to prevent excessive muscle contraction of the skin near keloid tissue , and its reported influence on cellular apoptosis and cellular proliferation .

Funding

None.

Competing interests

None declared.

Ethical approval

Not required.

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