| 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. Clinical Applications of Botulinum Toxins It has often been said that mother is the necessity of invention. Conversely, war is considered the father of all things and certainly, in the development of botulinum toxin as a therapeutic modality, war played a critical role. Initially, the Napoleonic wars between 1795 and 1813 created widespread poverty in Europe, resulting in a decrease in hygiene, especially in Germany. In particular, there was increased consumption of foods that weren’t necessarily pure or fresh and there was an increase in fatal food poisonings. The departments of health and ministries of health began to investigate this matter and epidemiological evidence pointed towards sausage as the culprit. Wilheim Godenfrey was the first to suspect that it wasn’t necessarily the sausage but something growing in the sausage that caused the illness. Justinice Kerner was the first to accurately describe botulism. He published the first monograph in 1822 entitled “The fat poison and its affect on the animal organism.” He studied the cases of 155 patients with the disorder with postmortems and he was able to deduce that the poison blocked nerve conduction and that motor as well as autonomic nervous system function was affected, while sensate and mental faculties were not affected. He conducted experiments on himself as well as animals and interestingly, believing in the principle that medicines are just poisons at a smaller dose, he believed that the toxin applied in minimal doses could indeed be therapeutic. Mueller in 1870 coined a term “botulism” from the Latin word for sausage and Emergium in 1895 was the first to isolate the bacterium. Interesting, the development of botulinum toxin sort of fell by the wayside until another major conflict came about, in this case, World War II. In this instance it was not to be used as a therapeutic modality, but rather as a weapon of war. Why? Because botulinum toxin is considered by many people to be the most lethal substance produced. One gram, evenly distributed in the atmosphere, inhaled could easily kill one million people. During World War II, the Axis forces, in particular Germany, were developing biological weapons of war, particularly botulinum toxin. As a result, U.S. scientists at Fort Dietrich, Maryland, purified botulinum toxin and developed a vaccine. Development continued along those lines until 1969, when President Richard Nixon signed an executive order that purportedly halted all biological research. Because of what is happening currently, we know today that biological weapons research still exists in the United States, but at that time it was scaled down to the point that scientists began looking at other ways of using this toxin. In particular, Dr. Edward Shane, who was a toxicologist working Fort Dietrich and who was familiar with botulinum toxin came into contact with Dr. Alan Scott, who was an ophthalmologist and who wanted to find an alternative to oral adjacent therapy for strabismus surgery. Throughout the 70s they conducted animal studies that showed very promising results. In the early 80s they began human studies and published numerous papers that showed that this treatment was extremely efficacious. These led, in 1989, to full FDA approval for a botulinum toxin to be used with strabismus, blepharospasm and cranial nerve VII disorders. The structure of botulinum toxin is produced by the bacterium clostridium botulinum. It is a polypeptide consisting of a light and heavy chain bridged by a single disulfide bond. There are eight serial types: A, B, C1, C1 and D through G. Each one has a different site of action. In the United States the most commonly used is botulinum toxin A under the trade name Botox. Recently, botulinum toxin B, which goes under the trade name Myobloc, has found FDA approval for the treatment of cervical dystonias. By inhibiting the release of acetylcholine from nerve terminals, Botox causes a flaccid paralysis. It binds irreversibly to peripheral cholinergic nerve terminals and this is mediated by the toxin’s heavy chain. Once attached, the receptor goes under endocytosis; the light chain breaks off and then serves as a protease. It then cleaves the synaptic fusion complex. This complex is intricate. It is composed of three things: Synapse 25, Synaptobrevin and Syntaxin. These help to release acetylcholine onto the neuromuscular junction Botulinum Toxin A acts on Synapse 25 and botulinum toxin B acts on Synaptobrevin. In the normal structure, the synaptofusion complex releases acetylcholine into the neuromuscular junction. Botox inhibits that reaction. Recovery occurs by first by sprouting of accessory terminals off of the presynaptic neuron, which occurs in around 10 to 28 days. Starting around 28 days, there is resynthesis of synapse 25. Over the next three months, the neuromuscular junction completely recovers and function returns. Again, recovery occurs in two phases. You have the accessory terminal sprout, which begins to stimulate the muscle. The main terminal starts recovering around day 28, with synthesis of new Synapse 25. Clinically you see a maximum effect in about two weeks, a plateau phase for about three months, and usually complete recovery within 90 days. Botulinum Toxin A is available as a crystalline complex. It’s purified and vacuum dried. It is measured in units - one unit equals the medium lethal intraperitoneal dose. This simply means that if you take experimental mice, and inject 100 of them, the dose that kills 50% of the mice would be considered one unit. There can be differences in potencies from vial to vial. The current batch of Botox contains 4.8 nanograms of toxin per 100 units and the toxin does require rehydration with preservative-free saline since preservatives, agitation and freezing will all destroy the toxin. It is impossible to determine the dose for individual patients in. The range can be several orders of magnitude. For example, speaking with Dr. Donovan, his dose range for adductor spasmodic dystonia is anywhere from one unit to 30 units. He typically starts with 15 units, follows the patient and as he measures and documents the effect, he tries to go with the lowest possible dose. Most papers recommend that further toxin should only be added after the drug reaches its maximum effect, which is usually about two weeks. You should probably follow the patient for a full 90 days to get the complete picture. Additional therapy should only be added after you have documented both the beneficial and adverse effects of the therapy. Delivery mechanisms for the drug can vary, depending on the site injected. Keep in mind that the drug's adverse effects are related to the diffusion away from the intended site. Most experts recommend many smaller volume injections as opposed to fewer larger volume injections. Although anatomic landmarks can be used alone, it can be somewhat difficult to localize smaller muscles. Brin in 2000, in his review, suggested that EMG would reduce the variability of injection site as well as maximize the effect of each treatment. For muscles of the forehead and glabella, EMG is probably not required. But for the smaller muscles in the larynx most everyone recommends using EMG. Long-term use causes reversible denervation atrophy in the muscles injected but interestingly enough there are changes in muscles distant from the site as well. The clinical significance of that is unknown. There are only two reports of botulism-like syndromes. Safety in pregnancy as well as safety to the fetus is not well established at this point. However, in terms of outcomes, it does seem to be safe for use in children. It has been used successfully in patents with neuromuscular diseases such as ALS, but there is one reported systemic weakness as well as report of severe dysphasia in a patient with myasthenia. Avoid concurrent use with aminoglycosides because that can potentate the toxin. There have been no human fatalities in the last 23 years of use. In case of accidental overdose, there is an antibody available and this needs to be administered within the first 24 hours. Clinically, it is well recognized that the most important adverse reaction is that some patients acquire tolerance. It is presumed to result mostly from a blocking antibody that develops. However, the presence of the antibody does not always correspond with actions of effect. Again, speaking with Dr. Donovan, he likes to use a clinical assay of effect. If a patient fails to respond after three injections including modifications, which could either be an increase in dose or perhaps bilateral injections, then the patient is deemed resistant and a different strategy should be used, including perhaps testing for antibodies. Dr. Jankovic who is also here at Baylor and who has done a tremendous amount of work on the use of botulinum toxin, says that it is generally the development of antibodies is generally associated with patients treated with larger doses with shorter intervals. The Empirics, Greek philosophers, believed that people learned in three ways. The first is by direct experience: if you touch fire and get burned, you don’t touch fire anymore. Another way that people learn is by seeing someone else: you see someone touch fire and you realize that maybe you should not touch fire. The third way is by applying the best case scenario for something you’ve never seen before: this looks hot, it’s red, it’s giving off heat, and perhaps I shouldn’t touch it. Botulinum toxin entered otolaryngology as a treatment for dystonia in much that same manner. Dystonia is a chronic neurological disorder seen as processing and includes task-specific, action-induced muscular spasms, which can be focal or generalized. Focal examples include blepharospasm and torticollis. Spasmodic dystonia is a dystonia of the larynx of which there are two types: adductor and abductor, depending on whether there is glottic opening or closing. Because botulinum toxin had such great efficacy in the treatment of blepharospasm, which is a focal dystonia, doctors here at Baylor realized that perhaps it could be used for other focal dystonias including spasmodic dystonia. Drs. Jankovic, Woodson and Miller were first to report the use of botulinum toxin for spasmodic dystonia. They looked at two patients treated and noticed that within the first 24 hours there was marked improvement in symptoms. The maximum effect was seen in two weeks, which was followed by a plateau at three months. The side effects, which were uncommon, were related to the diffusion away from the adjacent muscles or overdosing of the target site. So they saw dysphagia and breathy dystonia for adductor dystonia and dyspnea for abductor. Since breathy dystonia is going to be somewhat characteristic in all patients who receive botulinum toxin, some consider that it is not so much a side effect as just a part of the natural therapy. However, it can be severe enough to cause problems and you have to try and find a balance. After using botulinum toxin, the pathophysiology of dystonias was better understood. Spasmodic dystonia is considered a bilateral disease. However, unilateral injections are efficacious and remember, dystonias are thought to originate in the brain. However, injecting the periphery as well as using sensory tricks -which are techniques used by patients, for example who stutter, such as clenching down or coughing in order to fool the CNS and then able to do things naturally or normally. However, these things do begin to lose their effectiveness and some people feel that the CNS eventually overrides the input. This is also true for surgical interventions with recurrent laryngeal nerve resections, which were once used for spasmodic dystonia. Botox is felt to affect both pathways and in fact, it may even change intercortical circuits so dystonias are starting to be felt as diseases not only of the CNS but diseases that require feedback in order to perpetuate. This was shown in patients with writer’s cramp, which is a dystonia of the wrist muscles. They treated them with Botox. In PET scans done before and after treatment, they found that the motor cortex underwent pronounced changes after treatment with botulinum toxin. They felt that because denervation is not constant, the CNS couldn’t adapt, which is why it remains efficacious over time as compared to surgery or other treatments. Once again, people recognized that because botulinum toxin works so well for spasmodic dystonia and other dystonias, perhaps it could be used for other conditions that also affected the voice. It has been shown to have some efficacy in stuttering, which are action-induced, task-specific movement abnormalities that can involve respiration formation as well as articulation. If the glottis is affected, botulinum toxin has been particularly successful. Essential voice tremor is like a central tremor of the hand. It can be hereditary and can cause pronounced troubles with voice. In 2000, Hertegard reported that over 50% of his patients benefited from botulinum toxin. Speaking with Dr. Donovan, he felt his experience has been similar. Vocal tics are common in Tourette’s and schizophrenia. Sometimes there is inappropriate use of profanities, and interestingly, Dr. Donovan and Dr. Jankovic here at Baylor showed that botulinum toxin was actually successful in reducing the occurrence of tics, which also points to possible effects on efferent pathways. In terms of other disorders of the larynx, Rontal and Rontal introduced the concept of laryngo rebalancing. By changing the sensory input by chemodenervation, you can perhaps change the outcome of such disorders as vocal cord granuloma and dystonia, and plica ventricularis. These disorders are believed to be due not only to reflux, but also to inappropriate compensation to some underlying disease. There is some evidence that by changing or rebalancing the larynx and the way it works, the severity of theses diseases can perhaps be reduced, or the diseases even cured. Botulinum toxin is the non-surgical treatment of choice for cricopharyngeal spasm. It can be injected percutaneously or endoscopically. Studies show that 7% to 100% of patients can benefit, and this is especially powerful if it is the only cause of the dysphasia. Botulinum toxin has also been helpful in patients with TEP. For any patient with a TEP that’s not functioning correctly, where you suspect hypopharyngeal spasm, you should test with Botox. It’s showing tremendous applicability. Botulinum toxin is also beginning to be used for palatal myoclonus. Palatal cyclones can cause a clicking tinnitus and it seems that chemodenervation of the tensor velum palatinum alleviates the symptoms. Mandibular dystonias are characterized by jaw opening and closing, tongue protrusion or combinations thereof and botulinum toxin has shown to be most successful for some of those dystonias, especially those involved by the sternocleidomastoid, temporalis, and external pterygoid. This was done quite extensively by Dr. Jankovic in his clinic and has been shown to be less successful in other muscle groups secondary to side effects such as dysarthria, labial incontinence and dysphasia. Botulinum toxin is now becoming more useful in TMJ disorders as well. Of course blepharospasm, a focal dystonia of the orbicularis occuli muscle was the first therapy for which botulinum toxin was FDA approved. Published studies show that two-thirds of patients benefit. It decreased foreign body sensations as well as photophobia. Some of the side effects seen include dry eye, ptosis, epiphora and diplopia. Hemifacial spasm, the result of cranial nerve VII irritation intracranially, is another application. Surgically, one can decompress the nerve root through retrosigmoid craniotomy. However, Botox has been shown to be a non-surgical alternative that approaches 100% efficacy. It does require chronic therapy but, looking at the alternatives, that seems reasonable. There are other face and neck applications. Facial nerve synkinesis often accompanies facial nerve paralysis. It’s esthetically not pleasing and Botox has been shown to be efficacious in that regard. Cervical dystonia has been extensively studied, particularly by Dr. Jankovic. He has published numerous articles on treatment with Botox, and has shown it to be extremely effective. Treatment does require a thorough understanding of the anatomy and muscle physiology since multiple muscles within the neck, sternocleidomastoid, trapezius, etc must be injected. In the course of treating hemifacial spasm and blepharospasm, patients began to notice that they looked younger and that the hyperfunctional facial lines were less pronounced. Hyperfunctional facial lines or facial lines that run perpendicular to underlying muscles, can cause skin pleating with muscle contractions which are often misrepresented as anger or fatigue. A double blind placebo controlled trial was done, which showed that botulinum toxin does indeed eliminate or reduce these hyperfunctional lines. As a result, the use of botulinum toxin has begun to expand to other areas of the face and neck with respect to facial plastics: forehead, glabella, lateral orbits, and nasal lateral region. People are using it in combination with other modalities such as facelifts. Since botulinum toxin works for hyperactive motor disorders, and since we know that the autonomic nervous system shares acetylcholine as a principle neurotransmitter, perhaps botulinum toxin can have some effect in those hyperactive disorders as well. It has been tried in Frey’s Syndrome, which results from central motor neurons innervating sweat glands after parotidectomy. Injection into affected areas appears to be curative for some patients. The mechanism of action is unknown but it may be related to chronic denervation. Other areas of active research include drooling, which is often a troublesome symptom of cerebral palsy, ALS as well as Parkinson’s disease, and also interestingly for the treatment of rhinorrhea. There has been some success in animal models but no data on humans just yet. Once again, we see that patients receiving the therapy for one reason began to notice improvement in other problems they were having. In this case, patients receiving botulinum toxin for cosmetic reasons also reported improvement in their migraine headaches. This has now been confirmed in both retrospective as well as placebo controlled trials. The exact mechanism is unknown, but perhaps reducing the tension in the muscles of the forehead affects an afferent pathway that reduces migraines. Botulinum toxin has also shown promise in the treatment of chronic tension headaches perhaps by reducing the amount of muscle spasms that occur. In conclusion, botulinum toxin acts by inhibiting acetylcholine release from nerve terminals. The effects are transient and non-destructive. Therapy has been tailored to individual patient’s needs. It is extremely safe when used appropriately. The primary use is in the treatment of hyperfunctional motor disorders. However, future developments include further applications of the autonomic nervous system as well as for headache and pain disorders. Case Presentation: The laryngeal component of the physical examination was significant for prominent tremor of the vocal cords and secondary spasm on words and phases. No focal masses ere noted. The patient was diagnosed with adductor spasmodic dysphonia and vocal tremor. She was started on Botulinum toxin. She noticed a significant change in her voice within 2-3 days and marked improvement over the course of three months. She has now been treated successfully with BTX for the past five years without major loss of efficacy or development of side effects. Bibliography: Ansved T, Odergren T, Brog K. Muscle fiber atrophy in leg muscles after botulinumum toxin type A treatment of cervical dystonia. Neurology 1997;48:1440-1442. Blitzer A, Binder WJ, Aviv JE, Keen MS, Brin MF. The management of hyperfunctional facial lines with botulinumum toxin. Arch Otolaryngol Head Neck Surg 1997;123:389-392. Blitzer A, Binder WJ, Brin MF. Botulinumum toxin injection for facial lines and wrinkles: Technique. In: Blitzer A, Binder WJ, Boyd JB, Carruthers A. editors. Management of Facial Line and Wrinkles. Philadlephia: Lippincott Williams & Wilkins; 2000. pp. 303-313. Blitzer A, Brin MF, Fahn S, Lange D, Lovelace RE. Botulinumum toxin (BOTOX) for the treatment of ‘spastic dysphonia’ as part of a trial of toxin injections for the treatment of other cranial dystonias. Laryngoscope 1986;96:1300-1301. Blitzer A, Brin MF, Greene PE, Fahn S. Botulinumum toxin injection for the treatment of oromandibular dystonia. Ann Otol Rhinol Laryngol 1989;98:93-97. Blitzer A, Brin MF, Stewart CF. Botulinumum toxin management of spasmodic dysphonia (laryngeal dystonia): A 12-year experience in more than 900 patients. Laryngoscope 1998;108:1434-1441. Blitzer A, Komisar A, Baredes S, Brin MF, Stewart C. Voice failure after tracheoesophageal puncture: Management with botulinumum toxin. Otolaryngol Head Neck Surg 1995;113:668-670. Binder W, Brin MF, Blitzer A, Schoenrock L, Diamond B. Botulinumum toxin type A (BTX-A) for migraine: An open label assessment. Mov Disord 1998;13:241. BOTOX (Botulinumum toxin type A) purified neurotoxin complex. Package insert, 1995. Brin MF. Botulinumum toxin: Chemistry, pharmacology, toxicity, and immunology. Muscle Nerve 1997;Suppl6:S146-168. Brin MF. Botulinumum toxin therapy: Basic science and overview of other therapeutic applications. In: Blitzer A, Binder WJ, Boyd JB, Carruthers A, editors. Management of Facial Line and Wrinkles. Philadelphia: Lippincott Williams & Wilkins; 2000. pp.279-302. Brin MF, Stewart C, Blitzer A, Diamond B. Laryngeal botulinumum toxin injections for disabling stuttering in adults. Neurology 1994;44:2262-2266. Byrnes ML, Thickbroom GW, Wilson SA, et al. The corticomotor representation of upper limb muscles in writer’s cramp and changes following botulinumum toxin injection. Brain 1998;121:977-988. Hertegard S, Granqvist S, Lindestad P. Botulinumum toxin injections for essential voice tremor. Ann Otol Rhinol Laryngol 2000;109:204-220. Jankovic J. Blepharospasm and oromandibular-laryngeal-cervical dystonia: A controlled trial of botulinumum A toxin therapy. Adv Neurol 1988;5:583-591. Jankovic J, Hallett M, editors. Therapy With Botulinumum Toxin. New York: Marcel Dekker, Inc.; 1994. Jankovic J, Schwartz K. Response and immunoresistance to botulinumum toxin injections. Neurology 1995;45:1743-1746. Miller RH, Woodson GE, Jankovic J. Botulinumum toxin injection of the vocal fold for spasmodic dysphonia. Arch Otolaryngol Head Neck Surg 1987;113:603-605. Rontal E, Rontal M. Laryngeal rebalancing for the treatment of arytenoid dislocation. J Voice 1998;12:383-388. Salloway S, Stewart CF, Israli L, et al. Botulinumum toxin for refractory vocal tics. Mov Disord 1996;11:746-748. Sanders DB, Massey EW, Buckley EG. Botulinumum toxin for blepharospasm: Single-fiber EMG studies. Neurology 1986;36:545-547. Schantz EJ. Historical perspectives. In: Jankovic J, Hallett M (eds). Therapy With Botulinumum Toxin. New York: Marcel Dekker, 1994:223-226. Scott AB. Botulinumum toxin injection into extraocular muscles as an alternative to strabismus surgery. Ophthalmology 1980;87:1044-1049. Scott AB. Foreward. In: Jankovic J, Hallett M, editors. Therapy With Botulinumum Toxin. New York: Marcel Dekker; 1994. pp. 7-9. Scott BL, Jankovic J, Donovan DT. Botulinumum toxin injection into vocal cord in the treatment of malignant coprolalia associated with Tourette’s syndrome. Mov Disord 1996;11:431-433. Scott AB, Kennedy RA, Stubbs HA. Botulinumum toxin A injection as a treatment for blepharospasm. Arch Ophthalmal 1985;103:350-374. Trimble MR, Whurr R, Brookes G, Robertson MM. Vocal ties in Gilles de la Tourette syndrome treated with botulinumum toxin injections. Mov Disord 1998;13:617-619. Whurr R, Nye C, Lorch M. Meta-analysis of botulinumum toxin treatment of spasmodic dysphonia: A review of 22 studies. 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