Botulinum toxin in otolaryngology: A review of its actions and opportunities for use.
Botulinum toxin has several important properties that make it an ideal chemical denervator. These include its high degree of specificity for the neuromuscular junction, its ability to induce temporary and reversible denervation, and its limited degree of side effects and complications. Botulinum toxin is being used safely in a wide variety of clinical settings by many different specialists. In otolaryngologic practice, it is being administered for the treatment of at least a dozen conditions, including various dysphonias, dystonias, and spasms as well as torticollis, facial nerve paralysis, and hyperkinetic facial lines. Studies have shown that botulinum toxin injections have a high rate of success in temporarily relieving symptoms.
Botulinum toxin is of interest to otolaryngologists for several reasons. First, it is becoming increasingly popular as a treatment for several otolaryngologic disorders, including spasmodic dysphonias, hemifacial spasms, facial wrinkles, and cricopharyngeal spasms. Second, although its neurotoxic properties have been known for about 100 years, it is only in the past 15 years or so that we have begun to understand its structure and mechanism of action.
Still, there is much we do not know about this substance, and we are in the infancy phase of its use as a diagnostic and therapeutic agent. Ongoing research is helping to clarify some of the less well understood biochemical aspects of botulinum toxin, as well as addressing the problems we face in using it as a chemical denervator. Areas of investigation include long-term effects, optimal treatment regimens, and reasons for treatment failure. In this article, we review the development of this interesting biologic agent in order to clarify its current importance in otolaryngology and its potential for future clinical uses.
History and epidemiology
Botulism is caused by the consumption of contaminated foods, and it can lead to muscle paralysis, suffocation, and death. The disease was first described in the late 1700s, but the toxin itself was not purified until the 1940s.  Interest in botulinum toxin was high during World War II, when reports were circulated that Axis countries had developed the capability to use certain toxins against humans. This spurred the United States Army to study botulinum toxin and other biologic toxins. Research continued until 1972, when the United States and several other nations signed the Biological and Toxin Weapons Convention agreement, which called for the termination of research on biologic agents that could be used in warfare. The study of botulinum toxin for therapeutic purposes was carried on by Schantz at the University of Wisconsin and by Scott at the Smith-Kettlewell Eye Research Institute in San Francisco. 
In the United States alone, more than 100,000 persons experience some form of involuntary muscle spasm.  Botulinum toxin has been used successfully for more than 25 years to treat the pain, disfigurement, and embarrassment that result from dystonias. In 1978, Scott received approval from the U.S. Food and Drug Administration to use botulinum toxin to treat patients with strabismus. In 1989, the FDA approved the substance for use in patients with blepharospasm and hemifacial spasm. To date, these are the only FDA-approved indications. 
Botulinum toxin is a neurotoxin produced primarily by Clostridium botulinum, an anaerobic bacterium. There are seven immunologic types of botulinum toxin--types A through 0. Type A is the most useful clinically, but types B, E, and F are being studied as potential alternatives. [3-5] The gene that encodes the toxin has been isolated and sequenced.  The toxin is synthesized as a weakly active, single-chain polypeptide. When it is exposed to a protease, it becomes fully active in the form of a dichain molecule. The dichain is made up of a heavy chain that is responsible for binding to the end-terminal at the neuro-muscular junction and a light chain that is responsible for blocking transmitter release.
Purified toxin is unstable and loses biologic activity overtime.  Therefore, hemagglutinin must be added to form the mixture that is intended for human therapeutic use.
Sites of action
Botulinum toxin binds with high affinity to cholinergic nerve endings, including the motor and autonomic nerves. Motor nerves are the most sensitive to the toxin. Small quantities of botulinum toxin can undergo retrograde axonal transport to the central nervous system, but there is no evidence that this has any effect on humans.  To exert its effect when injected into muscle, the toxin relies on cell surface receptors to become internalized. In the laboratory, however, botulinum toxin can be injected directly into cells, including non-neural cells, to block acetylcholine release.
Because different serotypes of botulinum toxin do not share the same receptor, they can have slightly different actions inside cells. These differences can be advantageous for clinical medicine. The possibility exists that some patients will respond better to one serotype than another, and a combination of serotypes (chimeras) might be more efficacious than any single one. A combination of serotypes might also permit us to use smaller doses and thus lessen the likelihood of antibody production. 
Mechanism of action
Botulinum toxin blocks the release of acetylcholine from cholinergic nerve endings. Three steps are involved in this neuromuscular blockade. First, binding is mediated by the toxin's heavy chain. The receptors are unique and localized to the neuromuscular junction. By itself, this step does not result in transmission blockade. The toxin is internalized by receptor-mediated endocytosis where it resides in an endosome. In the second step, the toxin is released into the cytosol. In step three, the light chain enzymatically blocks exocytosis and the release of acetylcholine at the neuromuscular junction. The toxin does not morphologically change the nerve ending, and it does not cause cell death. 
Recovery of function
Botulinum toxin's blockade of transmission is reversible. Recovery from the neurotoxin's effects is partly mediated by the cell body's ability to synthesize and transport material to the nerve ending.  Two well-documented effects of paralysis are the sprouting of new nerve terminals and an increase in the number of postjunctional receptors. Experimental evidence in soleus and gastrocnemius muscles indicates that nerve sprouts begin to appear approximately 10 days after neuromuscular blockade and that most nerve terminals demonstrate sprouting after 3 weeks. [6,7] At first, the sprouting is not functional, although some sprouts do make contact over an area outside the neuromuscular junction and do become functional. Abnormalities in the pattern of reinnervation are not uniform and can be prolonged. Evidence also indicates that there is an increase in the number of postjunctional receptors. [4,8] Muscle atrophy occurs during the initial period of denervation, stabilizes, and then dissipates over several mont hs, although microscopic abnormalities might still be seen.  Studies confirming the long-term microscopic changes in muscles injected with botulinum toxin are lacking in humans.
There are other reasons for the variability in treatment responses. Muscle fibers can be affected differently by the same dose of toxin. Experimental evidence suggests that fast-twitch muscle fibers remained functionally denervated longer than slow-twitch fibers.  This is in contrast to other evidence that suggests that fast-twitch fibers in the thyroarytenoid and lateral cricoarytenoid muscles are reinnervated more rapidly and to a greater degree than slow-twitch fibers.  The thyroarytenoid and lateral cricoarytenoid muscles have a high proportion of fast-twitch fibers that are involved in glottic sphincteric action and a low proportion of slow-twitch fibers that are involved in phonation. This might partially explain why the side effects of breathiness and aspiration following botulinum toxin injections are transient while the relief from spasticity is long lasting. Finally, we do not know what effect muscle activity has on the duration of muscle paralysis.
Wong et al demonstrated that responses to b otulinum toxin treatment for spasmodic dysphonia were superior and longer lasting when patients underwent a period of postinjection voice rest.  The relationships between botulinum toxin response and muscle type and activity are only now being elucidated.
There are also differences in the duration and degree of response to botulinum toxin that cannot be explained by the aforementioned observations. Some patients who have a good initial response might need larger doses over the duration of treatment. Others experience a reduction in relief from spasm and a shorter duration of response over time. One possible explanation for these diminished responses might be the formation of antibodies to botulinum toxin. However, Biglan et al were unable to identify any antibody response to small doses of botulinum toxin A.  Perhaps larger doses--in the range of 300 mouse units (MU) during a 30-day period--might lead to an antibody response. The total cumulative dose might also be a factor in antibody production. Finally, some drugs (e.g., aminoglycoside antibiotics) can potentiate and prolong the effect of botulinum toxin, whereas others (e.g., guanidine and aminopyridines) can limit its effect.  The roles of antibody formation and drug potentiation have not been pro ven either clinically or in the laboratory, and they remain incompletely understood.
Types of preparations
There are two commercially available forms of botulinum toxin: Botox and Dysport. Botox is supplied in the United States by Allergan (Irvine, Calif.). A new batch prepared in 1998 contains less albumin than the original batch, which was prepared in 1979. Botox is packaged in vials of 100 MU. Dysport is supplied by Speywood (Wrexham, Wales). It is packaged in vials of 500 MU. The two formulations are not equivalent. Furthermore, either brand's potency can vary among the individual vials in each package, which must be kept in mind when reading the literature and treating patients. The dose required to kill 50% of a batch of mice is 1 MU. The lethal dose for humans has been extrapolated from monkey experiments and is thought to be 2,500 to 3,000 MU, which is well above the common doses used in otolaryngology (usually 1.25 to 75 MU).
The toxin is marketed in a lyophilized form, which must be diluted with normal saline to obtain the desired concentration. For example, a 100-MU vial that is diluted with 2 ml of saline yields 5 MU/0.1 ml. Different concentrations and different volumes are used for various purposes. For example, because the concentrations are different, a smaller volume can be used for injecting 10 MU into a thyroarytenoid muscle than for injecting 10 MU into the orbicularis oculi.
The FDA recommends that the toxin be used within 4 hours of reconstitution, and it suggests that refreezing leads to a loss of activity. Among the valid concerns about storing toxin for later use are the alteration of its molecular structure, the development of antibodies, inconsistent responses, and irregular dosing patterns.  Even so, one study of forearm injections showed that there was no difference in paralysis between patients who had received fresh toxin and those who received toxin that had been refrozen or refrigerated for 2 weeks. 
Uses in otolaryngology
Botulinum toxin is being administered for the treatment of at least a dozen conditions in otolaryngologic practice. Among them are two types of spasmodic dysphonia, adductor laryngeal breathing dystonia, blepharospasm, hemifacial spasm, oromandibular dystonia, torticollis, facial nerve paresis with synkinesis, hyperkinetic facial lines, and cricopharyngeal spasm.
Spasmodic dysphonia is probably the most well-known use for botulinum toxin in otolaryngology. Much work in this area has been done by Blitzer and Brin, [14,15] Woodson and colleagues, [16,17] Ford and colleagues, [18,19] and Ludlow and colleagues.  Spasmodic dysphonia is believed to be a disorder of central motor processing. It is a focal dystonia, and it is classified as one of two main types. The more common adductor type is characterized by involuntary spasms of the thyroarytenoid and other adductor muscles, which cause a strained or strangled voice. The abductor type is characterized by intermittent hyper-abduction of the vocal folds, which gives the patient a breathy, whispery voice. Although speech therapy might be helpful and should be attempted, most noninvasive therapies are ineffective in controlling symptoms.
A correct diagnosis is essential in the management of patients with laryngeal dystonias. Spasmodic dysphonia must be differentiated from other neurologic disorders that cause voice dysfunction. [17,21] An incorrect diagnosis can result in treatment without effect, worsening symptoms, or even life-threatening complications. Moreover, treatment of a misdiagnosed patient with psychogenic dysphonia might result in a placebo effect that could incorrectly support the inaccurate diagnosis and delay proper treatment.
Adductor spasmodic dysphonia. Injection of botulinum toxin into the thyroarytenoid muscle has been used since 1984 to treat adductor spasmodic dysphonia, and it is considered the treatment of choice. Injections can be administered percutaneously or perorally. Most authorities--including Sataloff,  Blitzer and Brin,  Woodson,  and Adams --use the percutaneous technique. A hollow, Teflon-coated, 27-gauge electromyographic (EMG) needle is used to penetrate the cricothyroid membrane. The needle is then directed superiorly and laterally toward the thyroarytenoid muscle, and the laryngeal lumen is avoided. Confirmation that the proper position has been reached occurs when EMG shows a sharp increase in electrical activity as the patient phonates. The disadvantage of this technique is that it requires an EMG machine and a person who is familiar with the performance and interpretation of laryngeal EMG.
Other authors prefer the peroral technique. [18,23] Because motor endplates are thought to be distributed throughout the muscle, the proponents of peroral injections argue that this technique allows them to more easily diffuse toxin over the entire muscle.  Prior to injection, the larynx is anesthetized topically and visualized by indirect laryngoscopy or flexible nasolaryngoscopy. A syringe fitted to a curved laryngeal injection needle is used to deliver botulinum toxin to two sites through the superior surface of the true vocal folds. This technique yields a high rate of success, and patients tolerate it well. Furthermore, Ford suggests that the peroral approach requires smaller doses than the percutaneous technique because localization is more precise, although this ideals controversial. [18,19] The peroral approach also has the advantage of being a technique with which otolaryngologists are already familiar. Finally, it does not require EMG guidance. Its disadvantages are the need for special needles , the greater amount of time needed to deliver the toxin, the need for an assistant, and the waste of toxin that occurs because some of it remains unused in the catheter. 
The size of the dose varies among patients and physicians. Blitzer and Brin first began injecting 2.5 MU unilaterally in patients with adductor spasmodic dysphonia, but they eventually came to believe that this amount had little effect.  Once they began injecting an additional 7.5 MU, they noted the onset of vocal fold paresis and prolonged breathiness and a 90% improvement in function. They also attained successful results with bilateral injections of 3.75 MU. Blitzer and Brin have since modified their technique and now start with 1.25 MU bilaterally and titrate the dose upward until optimal function is achieved. They note that complete paralysis is not required to achieve a good outcome. We have reported similar findings. 
One of the most useful aspects of botulinum toxin is that it can be titrated to achieve the best possible result in each individual. Doses can range from as low as 1.25 MU to as high as 30 MU, depending on the response, degree of side effects, and technique. Larger doses can lead to greater improvement in vocal function but, of course, they are also associated with a greater degree of side effects. George et al reported that dose-related responses were seen with doses up to 7.5 MU, and complete paralysis was achieved with 10 MU.  They concluded that doses smaller than 10 MU are sufficient for clinical paralysis.
In general, patients with adductor spasmodic dysphonia who receive botulinum toxin for the first time should be given a low dose--approximately 1.25 to 2.5 MU bilaterally or 10 to 20 MU unilaterally. They should be followed up within 2 weeks, and the dose should be adjusted as needed. Patients with a paralyzed vocal fold and those who have undergone a nerve section might also benefit from low-dose injections, although their improvement might not be as dramatic. Clinically, results vary among patients, and treatment patterns must be individualized. Results also vary from treatment to treatment in the same patient.
Injections can be administered unilaterally or bilaterally in patients with adductor spasmodic dysphonia, although there is some controversy over the efficacy and degree of side effects with the two techniques. [15,22,25-27] Nevertheless, both techniques result in significant improvements in voice quality and normally cause only minimal and transient side effects. The most common side effects are a short period, usually 1 to 2 weeks, of breathiness or hypophonia, dysphagia, choking, pain at the injection site, and edema of the vocal folds if too much volume is injected. Excessive weakness or more severe side effects can occur if the toxin spreads to other adductor muscles, such as the lateral cricoarytenoid.  No significant or long-term side effects have been reported. Microscopic changes in motor units and a prolonged disorganization of motor units have been described, and the process of reinnervation can take as long as 3 years.  Longer followup studies are needed to understand the long-term effect s of botulinum toxin.
Bilateral injections are usually administered because weakening or paralyzing only one vocal fold theoretically stresses the other fold and can exaggerate dystonic symptoms.  Also, bilateral injections expose the patient to less botulinum toxin because they can be given in a smaller cumulative dose than unilateral injections.
Responses can be minimal or quite dramatic. Studies have shown that success rates are high. [15,16,21,22,28] It has been postulated that by paralyzing the laryngeal muscles and possibly altering a feedback loop, botulinum toxin might modify the inappropriate timing of phonatory muscles in the speech-motor loop, [16,29] but the significance of this action has not been fully studied. Although botulinum toxin therapy might not always result in normal speech, it is a safe and reasonable treatment to restore fluency. Its effect usually becomes evident in 24 to 72 hours; maximum effectiveness is seen in about 2 weeks, and it lasts on average 3 to 6 months, occasionally longer. Some patients have gone into remission. The reasons for this are not clear, but such instances raise questions about the accuracy of the diagnosis.
Abductor spasmodic dysphonia. For patients with abductor spasmodic dysphonia, injections are delivered to the posterior cricoarytenoid muscle, although cricothyroid injections have also been used. [15,30] These injections usually require EMG guidance. When one is injecting the posterior cricoarytenoid muscle, the larynx is rotated away from the side of the injection and the needle is placed percutaneously into the skin over the lateral aspect of the thyroid ala below its midpoint. EMG confirmation can be achieved by having the patient sniff. The posterior cricoarytenoid muscle can also be reached through the cricothyroid membrane, especially in females and some young men. Peroral injections can also be performed; the cricothyroid is approached through the midline in a lateral and superficial direction. Confirmation of proper needle position is obtained by having the patient sing an ascending scale or slide (glissando) and observing an increase in EMG activity as the pitch increases.
The posterior cricoarytenoid is injected with an initial dose of 3.75 MU, and this amount can be titrated as necessary.  If symptoms persist and the posterior cricoarytenoid has already been completely paralyzed, the contralateral posterior cricoarytenoid can be injected cautiously with very small increments of toxin. However, the patient must be willing to accept the risk of airway compromise. In patients who fail this technique, injections into the cricothyroid can be performed. [30,31]
Blitzer et al studied 32 patients with abductor spasmodic dysphonia and found that after subjective pre- and postoperative evaluations by patients, physicians, and speech pathologists, the patients' percentage of normal function improved on average from 31 to 70%.  Most of these patients received bilateral posterior cricoarytenoid injections. The authors did not comment on the duration of response. In another study, Ludlow et al treated 10 patients who had abductor spasmodic dysphonia and cricothyroid hyperactivity.  They found that six of the 10 patients responded to cricothyroid injections and experienced an increase in sentence duration (the length of time a patient is able to speak without breaks or breaths) and in their proportion of voiced speech. Patients returned for reinjection at 4- to 6-month intervals.
As is the case with patients who have adductor spasmodic dysphonia, results in patients with abductor spasmodic dysphonia vary, but many do obtain benefit from botulinum toxin injections. The most worrisome adverse effects seen with posterior cricoarytenoid injections, especially bilateral injections, are stridor and airway compromise, but they are not common. When stridor does occur, it usually manifests during exertion. Two other fairly common side effects are transient dysphagia and aspiration of fluids.
Special laryngeal applications
Botulinum toxin has been used by one of the authors (R.T.S.) and by others--Andrew Blitzer, MD (oral communication, 1996), Michael Rontal, MD (oral communication, 1997), and Steven Zeitels, MD (oral communication, 1998)--for a variety of special laryngeal problems. The toxin can be used for the treatment of recurrent laryngeal granulomata, as an adjunctive treatment for arytenoid dislocation, and for the management of laryngeal synkinesis associated with reinnervation after recurrent nerve paralysis. We have also considered its use in selected cases of bilateral vocal fold paralysis.
Adductor laryngeal breathing dystonia
The treatment of adductor laryngeal breathing dystonia (respiratory dystonia) with botulinum toxin was described by Grillone et al in 1994,  This condition is characterized by a paradoxical adduction of the vocal folds during inspiration, which leads to stridor. The stridor usually disappears during sleep and worsens with exertion. The voice is normal. Many patients experience a respiratory dysrhythmia, and many complain of severe fatigue that can interfere with work. These patients can be treated with botulinum toxin injections into each thyroarytenoid muscle, usually with up to 3.75 MU, depending on the severity of the condition. Treatment can significantly alleviate stridor and fatigue for up to 3 or 4 months. The most common complications are a transient breathy voice and a mild aspiration of liquids.
Blepharospasm is a disabling condition that can cause functional blindness. It involves the involuntary activity of the orbicularis oculi, procerus, and corrugator supercilii muscles. Its symptoms include lower facial spasms and oromandibular spasms. Blepharospasm can occur in isolation or as part of other conditions, such as Meige's syndrome.
Botulinum toxin has been used to successfully treat blepharospasm since 1982, and it is now the treatment of choice. [33-35] The injections can be given with or without EMG guidance. Without EMG guidance, injection sites are determined by palpating the affected muscle groups. A 30-gauge needle is used to inject small doses at several sites laterally, medially, and inferiorly. Patients who do not respond might benefit from brow injections. Injections delivered outside the orbital rim have the shortest duration of action and the least effect, but they also cause the fewest side effects. [36,37] Initial doses range from 2.5 to 5.0 MU per site and are titrated upward to 12.5 to 30 MU per eye. Effects are seen in 2 or 3 days and generally last 3 or 4 months.
Regardless of technique, the central part of the upper eyelid should not be injected in order to avoid paralysis of the levator palpebrae superioris and subsequent ptosis. Diplopia can occur if the toxin enters the extra-ocular muscles. Other side effects include epiphora, ocular irritation, lagophthalmos, and exposure keratitis. On rare occasions, ectropion, entropion, or blurred vision occur. [33,35,36,38] Side effects can occur as a result of the diffusion of toxin, but they can be minimized by injecting smaller volumes and avoiding massage of the region.
Hemifacial spasm usually begins in the orbicularis oculi, and it can spread to involve the muscles of the brow, lower face, and neck. Patients with hemifacial spasm (like those with blepharospasm) might have an underlying neurologic disorder or other condition that is causing their spasm. For example, hemifacial spasm can be caused by a vascular loop compression of the facial nerve, or it might be associated with parkinsonism or another neurologic disorder characterized by involuntary muscle spasms. Regardless of the etiology, botulinum toxin provides temporary relief of symptoms.
Before considering botulinum toxin therapy, it is necessary to conduct a complete evaluation, which can include magnetic resonance imaging, EMG, angiography, neurologic consultation, selected blood tests, and other studies.
Injections can be guided by EMG, but many experienced physicians feel comfortable without it. Patients usually receive 12 to 30 MU distributed in 2.5- to 5.0-MU doses. The toxin is typically injected into the zygomaticus major and minor, the levator anguli oris, and the risorius. Improvement has been reported to occur in 92 to 100% of patients. [35,37-39] The duration of symptom relief extends beyond 4 months on average, but some patients require a reinjection after 10 weeks, sometimes sooner. A few patients have gone into remission.  Over time, some patients require larger doses, some can get by with smaller loses, and some are maintained on the same doses. The reasons for this variability are not known.
Side effects include those seen with blepharospasm. substantial facial weakness is noted occasionally. Facial asymmetry, drooling, and chewing problems can also occur. [33,35,36,38] But for many patients, these side effects are inconsequential when compared with the disabling spasms of their disease.
Oromandibular dystonia can occur alone or with other focal or generalized dystonias. Spasms of the muscles of mastication can lead to pain, abnormal jaw positioning, temporomandibular joint dysfunction, and trismus. The diagnosis can be difficult. In addition to botulinum toxin, treatments include anticholinergics and benzodiazepines. 
Botulinum toxin injections are delivered to those muscles that appear to be the most spasmodic, usually the temporalis, masseter, and medial and lateral pterygoids. Injections into the pterygoids must be made with EMG guidance. Toxin is delivered in one or more injections of 10 MU distributed over the muscle. Doses range from 10 to 40 MU and can be titrated as necessary.  The effects of botulinum toxin in oromandibular dystonia are seen in 24 to 72 hours and generally last 10 weeks to 4 months.  Patients show significant improvement and are able to return to normal eating and speaking habits without pain.
Botulinum toxin has been used to treat torticollis caused by sternocleidomastoid spasm. Large doses are usually needed, sometimes 100 to 300 MU per sternocleidomastoid muscle. Local complications include dysphagia and neck weakness, and systemic complications include pruritus, nausea, flu-like symptoms, fatigue, generalized weakness, and distant, unrelated muscle weakness. [41,42]
Dysphagia is thought to be caused by toxin diffusion into the constrictor muscles. Toxin diffusion has been shown to be dose-related. The toxin can spread over a large area and even cross fascial planes. Symptom relief lasts 11 weeks on average. The physician should keep in mind concerns over the long-term effects of such large doses, particularly the risk of developing antibodies against botulinum toxin. These doses are also high enough to raise concerns about the development of antibodies to botulinum toxin. 
Facial nerve paralysis
The management of patients with facial nerve paresis can be very difficult. Involuntary eyelid closure and other facial movements associated with facial nerve paralysis can be disfiguring. These signs are associated with an aberrant regeneration of the facial nerve. Among the other treatments for facial nerve paralysis are ptosis repair, selective myectomy, and selective neurectomy. But these procedures have their drawbacks, including the weakening of an already denervated muscle, their irreversibility, and the difficulty encountered in achieving optimal results.
Borodic et al studied 12 patients with synkinesis following facial nerve paralysis who received a mean dose of 22 MU of botulinum toxin and found that improvement lasted about 5 months.  The authors noted significant improvement in synkinetic movements, but periocular injections increased facial dyssymmetry. Minimizing the dose can limit diffusion.
Patients with facial nerve paralysis often do not regain complete function. Techniques to reanimate the face often improve facial symmetry, but they fail to do anything about the pull of the normal contralateral face, which can be very deforming. In these patients, botulinum toxin can be injected into the contralateral zygomaticus major and the risorius to improve symmetry at the nasolabial fold and oral commissure. For patients with facial nerve paralysis, the uses of botulinum toxin in rehabilitation, surgical reanimation, and temporary relief of spasm, synkinesis, and asymmetry are evolving. 
Hyperkinetic facial lines
Botulinum toxin has been helpful in treating the aging face. Glabellar lines, crow's feet, deep forehead lines, and deep nasolabial folds have all been treated successfully. Hyperkinetic lines are a result of pull on the skin by underlying muscles. The procerus and corrugator supercilii create deep lines in the glabella during frowning. Crow's feet are created by the lateral orbicularis oculi during squinting. In the forehead, lines are made by the frontalis muscle. Nasolabial folds are created by the zygomaticus minor, levator labii superioris, orbicularis oris, and levator labii superioris alaeque nasi.
Carruthers et al first noted that patients who were treated for blepharospasm, hemifacial spasm, and Bell's palsy all displayed a loss of wrinkles.  Since then, botulinum toxin has been used to lessen or eliminate the degree of hyperfunctional lines of the face. [46-49]
EMG can be used to guide the placement of the needle in the treatment of glabellar lines, but once a physician becomes familiar with the technique, EMG can be dispensed with. As is the case in the treatment of other types of muscle spasms, the advantage of using EMG is that if a patient does not respond to the initial injection, specific sites of persistent activity can be identified and subsequent injections can be made with greater precision. If there is an absence of activity, injections can be placed in the orbicularis oculi, corrugator supercilii, and frontalis muscles. It is important to remember that the injections must be placed into the muscles, not the wrinkles. Treatment usually begins with 10 MU into each corrugator supercilli and can be repeated as necessary. 
Crow's feet are treated in a similar fashion, usually with EMG guidance. Smaller doses (5 MU) are used to treat each eye. Forehead lines and nasolabial folds are treated with various amounts of botulinum toxin. In each region, treatment can render a graded weakening of the underlying musculature and a partial or complete resolution of the hyperkinetic lines. When treating these areas, small doses are delivered to several sites. Results can be seen in 5 to 7 days, and the treatment effects last from 2 to 6 months. [48,49] Patients are generally satisfied with their outcomes and return for further therapy.  Complications include temporary ptosis, upper lip droop, mild swelling, ecchymosis, and local discomfort.
Botulinum toxin can be an excellent alternative or adjunctive treatment to topical agents, chemical peel, laser resurfacing, soft tissue augmentation, or surgery. No major or long-term complications have been reported following cosmetic botulinum toxin injections. The maximum degree of expected improvement can be simulated by spreading apart the wrinkle to be treated with two fingers.  But because improvement is only temporary, some patients opt to discontinue botulinum toxin injection treatment and undergo a permanent but more invasive procedure. However, these approaches are often ineffective and can leave visible incision scars.
Patients who are most likely to fail botulinum toxin injection therapy are those who have thick, sebaceous skin, deep dermal scarring, extraordinarily deep lines, excess skin laxity as a result of aging, incomplete denervation, and accessory muscle function that contributes to the wrinkling. [46,47]
Botulinum toxin can be used to correct voice failure following tracheoesophageal puncture and dysphagia secondary to cricopharyngeal spasm. Cricopharyngeal spasm has been reported to be a cause of failure of voice restoration following tracheoesophageal puncture in as many as 12% of laryngectomy patients.  It is sometimes difficult to make this diagnosis, but a barium swallow, esophageal manometry, and EMG showing persistent spasm on swallow can be helpful. Injection of botulinum toxin into the cricopharyngeus can be used diagnostically and therapeutically in patients who have voice failure or dysphagia secondary to cricopharyngeal hyperactivity, [50,51] Under EMG guidance, the cricopharyngeus is injected at two or three sites on each side, superior and lateral to the laryngectomy stoma. The cricopharyngeus is identified by electrical activity at rest that diminishes or stops when the patient swallows. The cricopharyngeus can also be injected endoscopically. Blitzer et al studied six patients who had voic e failure secondary to cricopharyngeal spasm and found that all six benefited from botulinum toxin injections, including two who had already undergone myotomies.  We have also found temporary benefits in a small number of patients (unpublished data, 1997 to present). Doses average 30 to 40 MU, and effects last about 3 months.
This technique is also useful for patients who have dysphagia secondary to cricopharyngeal spasm as a result of a neurologic impairment such as stroke, for those who have discoordinated swallowing, and for those who have undergone a laryngectomy. Blitzer and Brin reported improvement in six of six patients with 10 MU spread over four injection sites.  In another study, Annese et al compared pneumatic dilation with botulinum toxin injection in 16 patients with achalasia and elevated lower esophageal sphincter tone and found that the toxin was comparable to dilation with regard to symptom scores, even though dilation led to a significantly lower sphincter pressure.  There are no published studies comparing dilation and botulinum toxin in cricopharyngeal spasm.
Typically, treatment effects become evident after a few days and can last up to 5 months. No major side effects have been reported. Some patients prefer botulinum toxin injections as an alternative to myotomy or dilation. Patient selection is important and clinical trials are lacking, but this might become an indication for which botulinum toxin might prove to be very beneficial.
In conclusion, additional research--including careful documentation and the reporting of results of otolaryngologic applications of botulinum toxin--should be encouraged to help answer the remaining questions and clarify the roles of botulinum toxin in otolaryngology.
From the Department of Otolaryngology--Head and Neck Surgery, Thomas Jefferson University (Dr. Neuenschwander, Dr. Pribitkin, and Dr. Sataloff), and the Department of Otolaryngology-Head and Neck Surgery, Graduate Hospital (Dr. Sataloff), Philadelphia.
(1.) Schantz EJ, Johnson EA. Botulinum toxin: The story of its development for the treatment of human disease. Perspect Biol Med 1997;40:317-27.
(2.) NIH Consensus Development Panel on Clinical Use of Botulinum Toxin. Botulinum toxin. J Voice 1992;6:394-400.
(3.) Tsui JK. Botulinum toxin as a therapeutic agent. Pharmacol Ther 1996;72:13-24.
(4.) Simpson LL. Clinically relevant aspects of the mechanism of action of botulinum neurotoxin. J Voice 1992;6:358-64.
(5.) Mezaki T, Kaji R, Kohara N, et al. Comparison of therapeutic efficacies of type A and F botulinum toxins for blepharospasm: A double-blind, controlled study. Neurology 1995;45:506-8.
(6.) Holland RL, Brown MC. Nerve growth in botulinum toxin poisoned muscles. Neuroscience 1981;6:1167-79.
(7.) Duchen LW. Changes in the electron microscopic structure of slow and fast skeletal muscle fibres of the mouse after the local injection of botulinum toxin. J Neurol Sci 1971;14:61-74.
(8.) Duchen LW, Strich SJ. The effects of botulinum toxin on the pattern of innervation of skeletal muscle in the mouse. Q J Exp Physiol Cogn Med Sci 1968;53:84-9.
(9.) Castellanos PF, Gates GA, Esselman G, et al. Anatomic considerations in botulinum toxin type A therapy for spasmodic dysphonia. Laryngoscope 1994;104:656-62.
(10.) Wong DL, Adams SG, Irish JC, et al. Effect of neuromuscular activity on the response to botulinum toxin injections in spasmodic dysphonia. J Otolaryngol 1995;24:209-16.
(11.) Biglan AW, Gonnering R, Lockhart LB, et al. Absence of antibody production in patients treated with botulinum A toxin. Am J Ophthalmol 1986;101:232-5.
(12.) Gartlan MG, Hoffman HT. Crystalline preparation of botulinum toxin type A (Botox): Degradation in potency with storage. Otolaryngol Head Neck Surg 1993;108:135-40.
(13.) Sloop RR, Cole BA, Escutin RO. Reconstituted botulinum toxin type A does not lose potency in humans if it is refrozen or refrigerated for 2 weeks before use. Neurology 1997;48:249-53.
(14.) Blitzer A, Brin MF. Laryngeal dystonia: A series with botulinum toxin therapy. Ann Otol Rhinol Laryngol 199l;100:85-9.
(15.) Blitzer A, Brin MF. Treatment of spasmodic dysphonia (laryngeal dystonia) with local injections of botulinum toxin. J Voice 1992;6:365-9.
(16.) Zwirner P. Murry T, Swenson M, Woodson GE. Effects of botulinum toxin therapy in patients with adductor spasmodic dysphonia: Acoustic, aerodynamic, and videoendoscopic findings. Laryngoscope 1992;102:400-6.
(17.) Woodson GE, Zwirner P, Murry T, Swenson MR. Functional assessment of patients with spasmodic dysphonia. J Voice 1992;6:338-43.
(18.) Ford CN, Bless DM, Lowery JD. Indirect laryngoscopic approach for injection of botulinum toxin in spasmodic dysphonia. Otolaryngol Head Neck Surg 1990;103:752-8.
(19.) Ford CN, Bless DM, Patel NY. Botulinum toxin treatment of spasmodic dysphonia: Techniques, indications, efficacy. J Voice 1992;6:370-6.
(20.) Davidson BJ, Ludlow CL. Long-term effects of botulinum toxin injections in spasmodic dysphonia. Ann Otol Rhinol Laryngol 1996;105:33-42.
(21.) Deems DA, Sataloff RT. Spasmodic dysphonia. In: Sataloff RT. Professional Voice: The Science and Art of Clinical Care. 2nd ed. San Diego: Singular Publishing Group, 1997:499-505.
(22.) Adams SG, Hunt EJ, Irish JC, et al. Comparison of botulinum toxin injection procedures in adductor spasmodic dysphonia. J Otolaryngol 1995;24:345-51.
(23.) Rhew K, Fiedler DA, Ludlow CL. Technique for injection of botulinum toxin through the flexible nasolaryngoscope. Otolaryngol Head Neck Surg 1994;1 11:787-94.
(24.) George EF, Zimbler M, Wu BL, et al. Quantitative mapping of the effect of botulinum toxin injections in the thyroarytenoid muscle. Ann Otol Rhinol Laryngol 1992;101:888-92.
(25.) Maloney AP, Morrison MD. A comparison of the efficacy of unilateral versus bilateral botulinum toxin injections in the treatment of adductor spasmodic dysphonia. J Otolaryngol 1994;23:160-4.
(26.) Liu TC, Irish JC, Adams SG, et al. Prospective study of patients' subjective responses to botulinum toxin injection for spasmodic dysphonia. J Otolaryngol 1996;25:66-74.
(27.) Adams SG, Hunt EJ, Charles DA, Lang AE. Unilateral versus bilateral botulinum toxin injections in spasmodic dysphonia: Acoustic and perceptual results. J Otolaryngol 1993;22:171-5.
(28.) Truong [sic; Troung is correct spelling] DD, Rontal M, Rolnick M, et al. Double-blind controlled study of botulinum toxin in adductor spasmodic dysphonia. Laryngoscope 1991;101:630-4.
(29.) Brin MF, Stewart C, Blitzer A, Diamond B. Laryngeal botulinum toxin injections for disabling stuttering in adults. Neurology 1994;44:2262-6.
(30.) Ludlow CL, Naunton RF, Terada S, Anderson BJ. Successful treatment of selected cases of abductor spasmodic dysphonia using botulinum toxin injection. Otolaryngol Head Neck Surg 1991;104:849-55.
(31.) Blitzer A, Brin MF, Stewart C, et al. Abductor laryngeal dystonia: A series treated with botulinum toxin. Laryngoscope 1992; 102:163-7.
(32.) Grillone GA, Blitzer A, Brin MF, et al. Treatment of adductor laryngeal breathing dystonia with botulinum toxin type A. Laryngoscope 1994;104:30-2.
(33.) Mauriello JA Jr., Dhillon 5, Leone T, et al. Treatment selections of 239 patients with blepharospasm and Meige syndrome over 11 years. Br J Ophthalmol 1996;80:1073-6.
(34.) Jordan DR, Patrinely JR. Anderson RL, Thiese SM. Essential blepharospasm and related dystonias. Surv Ophthalmol 1989;34:123-32.
(35.) Taylor JD, Kraft SP, Kazdan MS, et al. Treatment of blepharospasm and hemifacial spasm with botulinum A toxin: A Canadian multicentre study. Can J Ophthalmol 1991;26:133-8.
(36.) Price J, Farish S, Taylor H, O'Day J. Blepharospasm and hemifacial spasm. Randomized trial so determine the most appropriate location for botulinum toxin injections. Ophthalmology 1997; 104: 865-8.
(37.) Brin MF, Fahn S, Moskowitz C, et al. Localized injections of botulinum toxin for the treatment of focal dystonia and hemifacial spasm. Mov Disord 1987;2:237-54.
(38.) Jankovic J, Schwartz K, Donovan DT. Botulinum toxin treatment of cranial-cervical dystonia, spasmodic dysphonia, other focal dystonias and hemifacial spasm. J Neurol Neurosurg Psychiatry 1990;53:633-9.
(39.) Biglan AW, May M, Bowers RA. Management of facial spasm with Clostridium botulinum toxin, type A. Arch Otolaryngol Head Neck Surg 1988;114:1407-12.
(40.) Blitzer A, Brim MF, Greene PE, Fahn S. Botulinum toxin injection for the treatment of oromandibular dystonia. Ann Otol Rhinol Laryngol 1989;98:93-7.
(41.) Borodic GE, Joseph M, Fay L, et al. Botulinum A toxin for the treatment of spasmodic torticollis: Dysphagia and regional toxin spread. Head Neck 1990; 12:392-9.
(42.) Dutton JJ. Botulinum-A toxin in the treatment of craniocervical muscle spasms: Short- and long-term, local and systemic effects. Surv Ophthalmol 1996;41:51-65.
(43.) Borodic GE, Pearce LB, Cheney M, et al. Botulinum A toxin for treatment of aberrant facial nerve regeneration. Plast Reconstr Surg 1993;91:1042-5.
(44.) May M, Croxson GR, Klein SR. Bell's palsy: Management of sequelae using EMG rehabilitation, botulinum toxin, and surgery. Am J Otol 1989;10:220-9.
(45.) Carruthers A, Kiene K, Carruthers J. Botulinum A exotoxin use in clinical dermatology. J Am Acad Dermatol 1996;34:788-97.
(46.) Keen M, Blitzer A, Aviv J, et al. Botulinum toxin A for hyperkinetic facial lines: Results of a double-blind, placebo-controlled study. Plast Reconstr Surg 1994;94:94-9.
(47.) Pribitkin EA, Greco TM, Goode RL, Keane WM. Patient selection in the treatment of glabellar wrinkles with botulinum toxin type A injection. Arch Otolaryngol Head Neck Surg 1997;123:321-6.
(48.) Blitzer A, Brin MF, Keen MS, Aviv JE. Botulinum toxin for the treatment of hyperfunctional lines of the face. Arch Otolaryngol Head Neck Surg 1993;119:1018-22.
(49.) Lowe NJ, Maxwell A, Harper H. Botulinum A exotoxin for glabellar folds: A double-blind, placebo-controlled study with an electromyographic injection technique. J Am Acad Dermatol 1996;35:569-72.
(50.) Blitzer A, Komisar A, Baredes S, et al. Voice failure after tracheoesophageal puncture: Management with botulinum toxin. Otolaryngol Head Neck Surg 1995;113:668-70.
(51.) Blitzer A, Brin MF. Use of botulinum toxin for diagnosis and management of cricopharyngeal achalasia. Otolaryngol Head Neck Surg 1997;l16:328-30.
(52.) Annese V, Basciani M, Perri F, et al. Controlled trial of botulinum toxin injection versus placebo and pneumatic dilation in achalasia. Gastroenterology 1996;111:1418-24.
|Printer friendly Cite/link Email Feedback|
|Comment:||Botulinum toxin in otolaryngology: A review of its actions and opportunities for use.|
|Author:||Sataloff, Robert T.|
|Publication:||Ear, Nose and Throat Journal|
|Date:||Oct 1, 2000|
|Previous Article:||Uncontrolled central adenoid cystic carcinoma: Case report.|
|Next Article:||Case report: Acute management of external laryngeal trauma.|