Disclaimer: The information contained within the Grand Rounds Archive is intended for use by doctors and other health care professionals. These documents were prepared by resident physicians for presentation and discussion at a conference held at Baylor College of Medicine in Houston, Texas. No guarantees are made with respect to accuracy or timeliness of this material. This material should not be used as a basis for treatment decisions, and is not a substitute for professional consultation and/or peer-reviewed medical literature. Botulinum Toxin Applications in the Head and Neck I will be talking about applications of botulinum toxin within the head and neck. We will discuss the pathogenecity of Clostridium botulinum and then the uses of botulinum toxins in the head and neck concentrating on some diseases such as spasmodic dysphonia, tracheoesophageal function failure, cosmetic and reconstructive uses and finally our conclusions. The history of botulinum toxin began with a German physician and poet, Justinus Kerner, who first discussed the idea of a biological poison interfering with nerve conduction when patients had eaten under-cooked sausages and suffered from what is now known as botulism. He called this disease “sausage poison.” In 1895, Professor van Ermengem first isolated the bacteria Clostridium botulinum. During World War II, the US Government received threats from other countries regarding biological weapons and Dr. Schantz was appointed to lead scientists to develop protection against such applications. These investigations led to the purification of the toxin in 1946. By 1950, Dr. Brooks discovered that the toxins blocked the release of acetylcholine from motor nerve endings. Dr. Scott, in 1976, first used the toxin in a mock experiment, but it was not until 1980 that it was used for the first time in humans to treat strabismus. By 1989, the FDA first approved its use in patients with strabismus, blepharospasm, and facial nerve disorders. Clostridium botulinum is a gram-positive, obligate anaerobe, spore-forming bacillus. It comes from the Latin term botulus, which means sausage. The bacteria can be found in soil and marine sediment, while the spores are detected in fruits, vegetables and seafood. The neurotoxin is botulinum toxin that inhibits the release of acetylcholine. The disease is caused by the consumption of food contaminated with spores of Clostridium botulinum. Symptoms include autonomic dysfunction such as dryness of mouth and postural hypertension as well as muscle paralysis that leads to suffocation and sudden death. There are four groups of botulinum toxin, which include seven different serotypes. Only types A and B have clinical application. The serotypes have similar weight and structure and efficacy. The active molecule is a di-chain molecule. They all differ in their target proteins, as we will see shortly. This is a picture of the botulinum toxin that undergoes proteolytic cleavage to produce the active toxin, which is composed of a light chain and a heavy chain. The light chain is the one involved in blocking the release of acetylcholine at the neuromuscular junction. In a normal neuromuscular junction, acetylcholine is packaged in presynaptic vesicle that travels through the cell membrane. The SNARE complex proteins, which are these proteins over here, are a family of proteins that facilitate the docking of the neurotransmitter vesicle to the presynaptic membrane. As the vesicle approaches the presynaptic membrane, this SNARE complex binds and the vesicle releases the neurotransmitter. The Ach then binds its receptor in the postsynaptic membrane triggering an action potential. In the presence of botulinum toxin, the neurotransmitter is not released. The mechanism of BTX in the neuromuscular junction involves three steps. It first binds irreversibly to motor endplates and is internalized by endocytosis. Once inside of the cell, it cleaves the SNARE protein complex, blocking exoytosis of ACH. This results in flaccid paralysis of the corresponding muscle fiber. Paralysis is seen 24-48 hours after injection, once the presynaptic vesicles are depleted. Recovery involves two phases. During the first phase, new axons appear and allow for limited acetylcholine release. In the second phase, new synthesis of the SNARE complex proteins occurs. After a little more than 90 days, recovery is essentially complete. Duration of neurotransmitter inhi bition varies according to serotype. Type A is of long duration and may last approx 90 days or longer, while type B is of moderate duration and lasts approximately 2 months This is a table showing the botulinum toxin available for commercial use. There are two sorts of botulinum toxin A: Botox® and Dysport®. Botox® is more commonly used in the United States, while Dysport® is used more commonly in Europe. Botox® is nearly four times more effective than Dysport® in similar doses, and therefore it is available in 100 MU vials as opposed to 500 MU Dysport®. Botulinum toxin B is known as Myobloc® and is far less potent than the Botulinum toxin A and thus comes in higher vial doses. They are all contraindicated in pregnant and nursing women and in patients with neuromuscular diseases or those taking aminoglycosides. Botulinum toxin A is indicated for blepharospasm, hemifacial spasm and glabellar rhytids. Botulinum toxin B has been FDA approved for cervical dystonia. The toxin initially should be diluted with normal saline and 1 MU is equivalent to the lethal dose of Botulinum toxin at 50% in tested mice. The lethal dose for a 70 kg human is estimated to be approximately 2800 MU, and the common doses in our practice ranges from 1.25 MU to 75 MU. The FDA recommends that the toxin should be used about four hours after the normal saline was added, and re-freezing, violent agitation and preservatives should be avoided. Botulinum toxin is being administered for the treatment of at least a dozen conditions in otolaryngologic practice. Among theses are ophthalmologic disorders, voice disorders, muscle spasm disorders, as well as cosmetic and reconstructive purposes. Today, we will concentrate on spasmodic dysphonia, cricopharyngeus muscle spasm, tracheoesophageal speech failure, aging, and wound healing. Laryngeal dystonia is probably the best known use for Botox ® in otolaryngology. Laryngeal dystonia results in slurred speech, and is most common in the third decade of life and in women. There are two types: abductor dysphonia and adductor dysphonia. Diagnosis is usually based on careful history and physical examination of the larynx during phonation. Eighty percent of the patients with spasmodic dysphonia suffer from adductor type, which is caused by inappropriate glottic closure and hyperactivity of the thyroarytenoid muscle, causing harshness and strangled breaks in speech. The abductor subtype is less common, which is caused by hyperactivity of the posterior cricoarytenoid muscle, and results in hypophonia and breathy breaks in speech. This is a picture of the thyroarytenoid muscles and this is the posterior cricoarytenoid muscle. In both conditions, Botox® has been considered the treatment of choice. This video shows a patient with spasmodic dysphonia of adductor type, and we notice the straining of her voice. Here you can see her laryngeal phonation with intermittent adduction of her vocal folds. This patient is an example of abductor dysphonia and we can hear the breaking of her voice while she speaks. The patient received Botox® injections with very good results. As you can see, there is improvement of the sound quality of voice. There are different approaches for injecting the larynx with Botox® for spasmodic dysphonia. In the percutaneous technique, a hollow Teflon-coated, 27 gauge electromyographic 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 abductor dysphonia also has percutaneous techniques and parallel techniques, and this video shows a patient receiving a perioral injection at the posterior cricoarytenoid muscle, and, as you see here, the needle is posterior to its targeted muscle. Doses vary from patient to patient. In 1992, Blitzer and Brin started to inject the larynx with 2.5 MU, which showed very little effect on the patient. They increased the dose to 7.5 MU and had significant improvement; however, there were many side effects. They decided to lower the dose and inject it bilaterally and they titrate the dose upward until optimal function is achieved. Currently, the recommended starting dose for adductor spasmodic dysphonia ranges between 1.75 to 2.5 MU unilaterally and 10 to 20 MU unilaterally. The recommended dose for abductor spasmodic dysphonia is 6 to 75 MU unilaterally and these doses should be adapted as needed. Unilateral versus bilateral vocal fold injections has been a controversy for years. Bielomowicz in 2001 performed Botox® injections for abductor dysphonia and compared the groups that received unilateral injections with those receiving bilateral injection. He found that the unilateral group had benefit for three months or more and side effects of less than two weeks. He also found that successive unilateral injections at the same dose were more likely than successive bilateral injections to produce the same or longer duration of benefit. For these reasons, routine unilateral injections have a more optimal treatment effect and less side effect profile. Another interesting topic has been resistance towards Botox® injections with Botulinum toxin A. Sataloff, in 2002, reported a case report where botulinum toxin B proved to be safe and effective in a patient who had developed botulinum toxin A resistance. In 2003, Park evaluated the immune status of six spasmodic dysphonic patients and found that five of them had a significant titer of the anti-botulinum toxin A IgG antibodies and these antibodies will not cross over with the botulinum toxin B. Some of the side effects with the use of Botox® in adductor dysphonia are breathiness, hypophonia, dysphagia and aspiration. Some of side effects of the abductor dysphonia treatment include stridor and airway compromise. No significant long-term side effects have been reported. Botulinum toxin provides nonsurgical treatment of upper esophageal sphincter spasm. The cricopharyngeus muscle is the only muscle in the neck activated at rest. Ahsan in 2000 showed a 70% to 100% benefit in patients with cricopharyngeal spasm that were injected with Botox ® . He found that these patients were able to take solid food, had the feeding tubes removed, and gained weight after the Botox ® injection. The benefit was greatest when the patient had cricopharyngeal spasm as the only abnormality. However, there have been no studies that compared other modalities such as dilation of the esophagus with the outcome of botulinum toxin. Cricopharyngeal spasm is the cause of tracheoesophageal puncture failure following laryngectomy in almost 12% of cases. Hoffman in 1997 showed that the treatment of the transesophageal segment with Botox ® improved tracheoesophageal functional speech. He injected three sites in laryngectomy patients: the first site was in the junction between the base of the tongue and the middle constrictor, the second site was in the lower portion of the pharyngoesophageal segment at the tracheostomy site, and the other injection site was in between the other two. He found that these injections were as safe and effective as other proven methods of transesophageal puncture speech. The efficacy is shown in this graphic of one of the patients, who, prior to those injections had no phonation. After the injection, he started to have phonation and also had lower pressure in the tracheostomy site. After the effects of botulinum toxin wore off, the patient went back to his baseline, and after another injection, he started again to have phonation. Botulinum toxin has also been used in the head, face, and neck. It has been shown to improve the rhytids of the forehead caused by the frontalis; in the glabella, caused by the procerus and corrugator muscles; and in the periorbital region, the nasolabial region, and in perioral rhytids and their subsequent bands. The cosmetic use of the Botox® was started in 1993 when Blitzer recognized that patients treated for blepharospasms and hemifacial spasm experienced loss of wrinkles. Carruthers, in 2003, published a placebo controlled, double-blind study where he found out that 80% of the experimental group showed improvement of the glabellar lines at day #30 with some still experiencing some improvement at 120 days after injection. The FDA approved the use of Botox® for glabellar rhytids in 2002. Injections are basically straight into the muscle and not the wrinkles. The result can appear in 3 to 5 days and can last from 2 to 6 months. Some of the side effects that we can see from these injections are ptosis, upper lip droop, ecchymosis, and local discomfort. The horizontal lines in the forehead are treated by injections to the frontalis muscle. This picture shows the treatment areas of the forehead and usually 2 to 3 MU are injected in each treatment zone. To eliminate the vertical lines of the forehead, the corrugator muscles are usually injected with 6 MU of the toxin, and to eliminate hard central lines, the procerus was injected with 3 MU of the toxin. These are treatment areas in the glabellar areas. This is a picture of a patient that had horizontal forehead lines and used Botox® injections. This picture shows forehead lines before and after injection. The lateral orbicularis oculi muscle is targeted to decrease periorbital rhytids. Usually treatment areas use injections of about 1 to 2 MU of the toxin. The orbicularis oris muscle is targeted to reduce the vertical lines of in the mouth. The upper lip usually is separated in four treatment areas and the lower lip can be treated with 2 to 3 injections. This example shows a patient with lateral periorbital lines and effacement of both lines after injection. This picture shows a patient who was concerned about the prominence of his forehead lateral lines. He underwent Botox® injections in these areas and he had very good results. Subsequent platysma rhytids can be reduced also by Botox®. The neck should be evaluated at rest and maximal flexion and extension. There are 3 to 8 fascicular injection sites and these sites usually receive about 3 MU of botulinum toxin A. Very recently, in 2006, Dr. Gassner and Brissett from Mayo Clinic performed a perspective randomized placebo control clinical trial to determine the improvement of cosmetic appearance after trauma with trials of Botox®. Thirty-one patients with traumatic forehead lacerations in a 2-year period were evaluated. All these patients were randomized with Botox® versus placebo injections into the muscles added into the wound 24 hours after wound closure. The final cosmetic outcome was rated on a Visual Analog Scale of 0 being the worse and 10 being the ideal outcome; the Botox® group had a native score of 8.9 compared with 7.2 of the placebo groups. They concluded that the injections of Botox® in the muscles adjacent to the wound enhances healing and improved cosmesis. As we can see, this is one of the patients of the experimental group who had a forehead laceration, and, after injections of Botox®, there is basically no visible scar. In conclusion, BTX acts by blocking Ach release from nerve terminals at the neuromuscular junction. Its effects are transient and nerve recovery takes approximately 90 days. Treatment must be individualized to each patient as there is no standard injection strategy that will be effective for every individual. BTX is used primarily or in combination with other modalities for the treatment of hyperfunctional muscle disorders, dystonias and cosmetic purposes. The underlying principle is the same: manipulation of neural input to the muscle to improve healing or resolution of existing pathology. Case Presentation: B.O. is a 76-year-old female with a long history of difficulty speaking since 1988. At that time, she noted a subacute onset of trouble speaking with straining and strangling of her voice , which gradually worsened, such that was virtually unable to talk. She was evaluated for her speech disorder in the same year at the Methodist Hospital by our Otolaryngology-Head & Neck specialists. During her evaluation, she was found to have intermittent adduction of vocal folds resulting in quick glottic closure and was diagnosed with adductor spasmodic dysphonia. The rest of her physical exam was unremarkable. B.O. was referred to speech therapy without much improvement. Subsequently, she was started on unilateral botulinum toxin injections to the thyroarytenoid muscle under laryngeal EMG control shortly after her diagnosis. She started to notice significant improvement in her speech and quality of life. B.O. has received botulinum toxin injections for approximately 18 years. She is very pleased with her botulinum toxin injection results in her speech disorder and continues to follow up in our clinic every three to five months. She currently receives 15MU of BOTOX® unilaterally in the thyroarytenoid muscles and has not developed long term consequences. Bibliography: Adler CH, Bansberg SF, Hentz JG, Ramig LO, Buder EH, Witt K, Edwards BW, Krein-Jones K, Caviness JN. Botulinum toxin type A for treating voice tremor. Arch Neurol 2004;61:1416-1420. Ahsan SF, Meleca RJ, Dworkin JP. Botulinum toxin injection of the cricopharyngeus muscle for the treatment of dysphagia. Otolaryngol Head Neck Surg 2000;122:691-695. Batniji RK, Falk AN. Update on botulinum toxin use in facial plastic and head and neck surgery. Curr Opin Otolaryngol Head Neck Surg 2004;12:317-322. Bielamowicz S, Stager SV, Badillo A, Godlewski A. Unilateral versus bilateral injections of botulinum toxin in patients with adductor spasmodic dysphonia. J Voice 2002;16:117-123. Blitzer A, Brin MF. Treatment of spasmodic dysphonia (laryngeal dystonia) with local injections of botulinum toxin. J Voice 1992;6:365-369. Blitzer A, Sulica L. Botulinum toxin: Basic science and clinical uses in otolaryngology. Laryngoscope 2001;111:218-226. Cantarella G, Berlusconi A, Maraschi B, Ghio A, Barbieri S. Botulinum toxin injection and airflow stability in spasmodic dysphonia. Otolaryngol Head Neck Surg 2006;134:419-423. Carruthers J, Fagien S, Matarasso SL; Botox Consensus Group. Consensus recommendations on the use of botulinum toxin type A in facial aesthetics. Plast Reconstr Surg 2004;114(6 Suppl):1S-22S. Carruthers JD, Lowe NJ, Menter MA, Gibson J, Eadie N; Botox Glabellar Lines II Study Group. Double-blind, placebo-controlled study of the safety and efficacy of botulinum toxin type A for patients with glabellar lines. Plast Reconstr Surg 2003;112:1089-1098. Damrose JF, Goldman SN, Groessl EJ, Orloff LA. The impact of long-term botulinum toxin injections on symptom severity in patients with spasmodic dysphonia. J Voice 2004;18:415-422. Eckardt A, Kuettner C. Treatment of gustatory sweating (Frey's syndrome) with botulinum toxin A. Head Neck 2003;25:624-628. Gassner HG, Brissett AE, Otley CC, Boahene DK, Boggust AJ, Weaver AL, Sherris DA. Botulinum toxin to improve facial wound healing: A prospective, blinded, placebo-controlled study. Mayo Clin Proc 2006;81:1023-1028. Hertegard S, Granqvist S, Lindestad P. Botulinum toxin injections for essential voice tremor. Ann Otol Rhinol Laryngol. 2000;109:204-220. Hoffman HT, Fischer H, VanDenmark D, Peterson KL, McCulloch TM, Karnell LH, Funk GF. Botulinum neurotoxin injection after total laryngectomy. Head Neck 1997;19:92-97. Keir J. Botulinum toxin-physiology and applications in head and neck disorders. Head Neck 2005;27:525-535. Larrabee WF Jr. Treatment of facial wounds with botulinum toxin A improves cosmetic outcome in primates. Plast Reconstr Surg 2000;105:1954-1955. Manrique D. Application of botulinum toxin to reduce the saliva in patients with amyotrophic lateral sclerosis. Rev Bras Otorhinolaryngol (Engl Ed). 2005;71:566-569. Neuenschwander MC, Pribitkin EA, Sataloff RT. Botulinum toxin in otolaryngology: A review of its actions and opportunities for use. Ear Nose Throat J 2000;79:788-789. Park JB, Simpson LL, Anderson TD, Sataloff R. Immunologic characterization of spasmodic dysphonia patients who develop resistance to botulinum toxin. J Voice 2003;17:255-264. Said S, Meshkinpour A, Carruthers A, Carruthers J. Botulinum toxin A: Its expanding role in dermatology and esthetics. Am J Clin Dermatol 2003;4:609-616. Sataloff RT, Heman-Ackah YD, Simpson LL, Park JB, Zwislewski A, Sokolow C, Mandel S. Botulinum toxin type B for treatment of spasmodic dysphonia: A case report. J Voice 2002;16:422-424. Singer MI, Blom ED. Selective myotomy for voice restoration after total laryngectomy. Arch Otolaryngol 1981;107:670-673. Stager SV, Ludlow CL. Responses of stutterers and vocal tremor patients to treatment with botulinum toxin. In: Therapy with Botulinum Toxin. New York: Marcel Dekker, Inc, 1994: 481-490. Stong BC, DelGaudio JM, Hapner ER, Johns MM 3rd. Safety of simultaneous bilateral botulinum toxin injections for abductor spasmodic dysphonia. Arch Otolaryngol Head Neck Surg 2005;131:793-795. Sulica L. Contemporary management of spasmodic dysphonia. Curr Opin Otolaryngol Head Neck Surg 2004;12:543-548. Thomas JP, Siupsinskiene N. Frozen versus fresh reconstituted botox for laryngeal dystonia. Otolaryngol Head Neck Surg 2006;135:204-208. Vartanian AJ, Dayan SH. Facial rejuvenation using botulinum toxin A: Review and updates. Facial Plast Surg 2004;20:11-19. Warrick P, Dromey C, Irish JC, et al. Botulinum toxin for essential tremor of the voice with multiple anatomic sites of tremor. Laryngoscope 2000;110:1366-1374. Watts C, Nye C, Whurr R. Botulinum toxin for treating spasmodic dysphonia (laryngeal dystonia): A systematic Cochrane review. Clin Rehabil 2006;20:112-122. Watts CC, Whurr R, Nye C. Botulinum toxin injections for the treatment of spasmodic dysphonia. Cochrane Database Syst Rev 2004;(3). Grand Rounds Archive | Department Home page BCM Public | BCM Intranet | Privacy Notices | Contact BCM | BCM Site Map | ©2001-2007 Baylor College of Medicine
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