Therapeutic uses of the botulinum toxins

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1 Therapeutic uses of the botulinum toxins

Andrew Blitzer

Summary and Key Features

• Botulinum toxins exzymatically affect the SNARE proteins in neural endings

• Botulinum toxins will reduce and prevent the release of substances exocytosed by SNARE proteins

• Reduction of SNARE function may have therapeutic implications for autonomic, sensory and motor parts of the nervous system

• Reduction of acetyl choline neurotransmitter can reduce the hyperfunction of muscles in various dystonias

• Reduction of acetyl choline neurotransmitter can reduce autonomic nervous system hyperfunction such as hyperhidrosis and sialorrhea

• Reduction of SNARE function can also reduce the release of inflammatory mediators such as substance P, CGRP, glutamate and others

• Reduction of inflammatory mediators can have an affect on pain syndromes

• Pain syndromes such as post-herpetic neuralgia, migraine headaches, TMD can be improved with botulinum toxin

• Inflammatory conditions such as rheumatoid arthritis may be improved with intra-articular injections of botulinum toxin

• Bioengineered toxins may allow precise localization and decrease of exocytosed proteins such as hormones

Introduction

Since the 1970s, when Alan Scott introduced botulinum neurotoxin A as a therapeutic agent, the number of different uses for this drug has increased exponentially. In the 1950s, Arnold Burgen and Vernon Brooks, at McGill, discovered that botulinum toxin presynaptically blocked the release of acetylcholine from motor nerve terminals, thus weakening muscle strength by chemical denervation. Brooks also reported the fact that botulinum toxin could possibly be used therapeutically. The observation that tetanus and botulinum toxins blocked the exocytosis of acetylcholine was further refined with the discovery that these toxins enzymatically degraded different portions of the soluble N-ethyl maleimide-sensitive factor attachment protein receptor (SNARE) proteins. Alan Scott’s original work using botulinum toxin to weaken muscle for the correction of strabismus, and then blepharospasm, led others to begin to investigate the toxins for use with other dystonias and hyperfunctional muscular disorders.

The original observations of Kerner that patients with botulism had dry mouth and eyes suggested that the toxin might be used to control hypersecretory states. With the knowledge that the autonomic nervous system also depended on acetylcholine as the neurotransmitter, it seemed even more likely that botulinum toxin could be used to control disorders of this system. Clinical trials have shown efficacy in autonomic disorders such as hyperhidrosis, sialorrhea, and Frey syndrome.

A number of trials for hyperfunctional muscular disorders such as cervical dystonia and spasticity showed a dramatic reduction of pain, even greater than the reduction of muscle function. Our trials of toxin use for cosmetic indications revealed a number of individuals whose migraine headaches disappeared. These and other studies revealed a pattern that seemed to indicate that the toxin had a role in pain syndromes. Other studies then showed that, even in cases of post-herpetic neuralgia, pain could be decreased or eliminated. This clinical information led to the discovery that inflammatory mediators such as calcitonin gene-related peptide (CGRP), substance P, glutamate and others are also released by SNARE proteins. The toxin will reduce or eliminate the release locally of inflammatory mediators that have the effect of lowering central nervous system pain thresholds and thereby causing central sensitization. Botulinum toxin was found to reverse this effect. Many pain studies are in progress. Toxin treatment of chronic migraine headaches was recently EU and FDA approved after extensive clinical trials.

The newest change to potential toxin treatment has been the ability to change the molecule. The binding site of the molecule has been altered chemically to add specific ligands. This allows a toxin to be created that has an affinity for sensory, but not motor neurons, autonomic neurons, and even certain excretory glands. Keith Foster, of Syntaxin, recently described making a specific ligand for growth hormone secretory cells in the pituitary gland. Growth hormone is also secreted with a SNARE-related exocytosis, and therefore can be modulated with targeted specific botulinum toxin. This treatment could be used for patients with acromegaly. Other glandular secretions should be studied in this new paradigm for hypersecretory control.

The following material will in greater depth describe the use of botulinum toxins for the management of disorders of efferent nerves and muscular hyperfunction; afferent nerves, pain disorders, and inflammatory conditions; autonomic nervous system disorders; and glandular hypersecretion. (See Box 1.1.)

Box 1.1

Therapeutic uses of botulinum toxins

I. Hyperfunctional muscular use:

1. Dystonia
a. Cervical dystonia
b. Blepharospasm
c. Oromandibular dystonia
d. Spasmodic dysphonia
e. Occupational writer’s cramp
f. Foot dystonia
g. Musician’s dystonia
h. Facial dystonia
i. Meige syndrome
j. Tic disorders and stuttering
2. Hyperfunctional facial lines (cosmetic)
3. Hemifacial spasm / facial synkinesis
4. Strabismus
5. Esotropia / exotropia
6. Nystagmus
7. Post-stroke and cerebral palsy spasticity
8. Tremor disorders: limb, neck, vocal
9. Myoclonus
10. Other laryngeal disorders: puberophonia, vocalis process granulomas

II. Autonomic nervous system use

1. Hyperhidrosis: axillary, palmar, plantar, and facial
2. Benign prostatic hypertrophy
3. Sialorrhea / sialocele / drooling
4. Rhinitis
5. UES / LES achalasia
6. Neurogenic hyperactive bladder
7. Frey syndrome
8. Anal fissures
9. Vaginismus / anismus

III. Afferent nervous system / pain syndromes / anti-inflammatory:

1. Tension headaches
2. Migraine headaches
3. Temporomandibular disorders / bruxism
4. Myofascial pain
5. Post-herpetic neuralgia
6. Arthritis
7. Trigeminal neuralgia
8. Low back pain

IV. Glandular and secretory cell modulation

1. Growth hormone / acromegaly

Hyperfunctional muscular uses

Cervical dystonia (spasmodic torticollis)

Dystonia is a group of neurological disorders characterized by muscular hyperfunction with abnormal movements and / or postures often accompanied by pain. Cervical dystonia, the most common of the dystonias (most often lateral colli, but also retrocollis and anterocollis) comprises disorders with abnormal neck postures and pain. Results of injecting the hyperfunctioning and painful muscles with botulinum toxin in several randomized, placebo-controlled or open-label studies have shown that 50–90% of patients receive benefit (improved function and / or reduced pain).The results may vary with dose and choice of muscles to be injected. The dosage range for CD is 200–400 units of Botox®. Xeomin®, botulinum toxin A (Merz Pharm.) has also been approved by the FDA for CD. Myobloc®, botulinum toxin B (Solstice) has been FDA approved for CD, particularly in patients who have a resistance to type A toxin.

Blepharospasm is a focal dystonia affecting the orbicularis oculi muscle producing excessive blinking or eye closure. This was one of Alan Scott’s original studies, and led to toxin use in other dystonias. Using botulinum toxin A for management of blepharospasm has been shown in several studies to produce significant improvement in 70–100% of patients. Toxin injections have become the treatment of choice for this disorder. Scott’s original work comprised studies of toxin use for eye muscle balancing in cases of strabismus, and later esotropia, exotropia, and nystagmus.

Scott extended the use of toxin to patients with hemifacial spasm. This is a condition in which the anterior inferior cerebellar artery beats on and compresses the facial nerve (VII), causing irritability and facial twitching. The treatment can be a neurosurgical decompression of the nerve, or injections of botulinum toxin into orbicularis oculi, and may include the zygomaticus and levator labii muscles to diminish the twitching and hyperfunctional activity. The same approach may be used for patients with post-traumatic or post-Bell’s palsy facial synkinesis. Aside from treating the synkinetic side of the face, often toxin is given to the contralateral face to balance the weakness for symmetry. These facial studies led to a number of investigators realizing the cosmetic benefit for functional facial lines and opened the door for injections of toxin for cosmesis.

Pearl 1

Botulinum toxins may be used for management of lines and wrinkles of the face that are related to pleating of the skin overlying the facial muscles of expression.

Pearl 2

Botulinum toxin may be used to control hyperfunctional muscular conditions such as dystonia, tremor, spasticity, and synkinesis.

Oromandibular dystonia is a focal dystonia affecting the muscles of the jaw and may present most commonly with closing spasms, making opening of the mouth for eating and chewing very difficult. It may also present with opening spasms, making closing of the mouth difficult, or with lateral or protrusive spasms of the jaw. Some patients may have writhing movements of the jaw making speaking and eating difficult. In a number of cases the tongue is also involved, producing not only a jaw opening but also uncontrolled tongue protrusion. When this is combined with other cranial dystonias (usually blepharospasm) it has been termed ‘Meige syndrome’.

Our group successfully treated the first oromandibular dystonia (OMD) with botulinum toxin in 1983. We reported our series in a publication in 1989. Treatment of the tongue with toxin is often ill advised in many of these patients, since the production of a hypofunctional tongue causes dysarthria and significant dysphagia. The successful treatment of OMD led to the management of other hyperfunctional disorders of the jaw including temporomandibular disorders (TMD) and bruxism. The usual muscles injected are the masseter, temporalis, and external pterygoids.

Spasmodic dysphonia is a focal dystonia of the larynx. Most patients have the adductor or closing type producing a strain-strangled voice type. We performed the first injection of botulinum toxin injections of the larynx for this condition in 1984. The other types are the abductor or opening type that produces a whispering voice or voice with breathy breaks. There are also patients with adductor respiratory spasms and a singer’s dystonia. All of these can be managed with botulinum toxin injections, and this has become the standard treatment for these disorders. Laryngeal injections were extended to include management of vocal tremor, vocalis process granulomas, puberophonia, stuttering with glottal block, and other hyperfunctional vocal disorders.

Occupational writer’s cramp (focal dystonia of the hand) was also found to be a disorder in which toxin can reduce spasm and return normal function. These injections are usually given with EMG guidance into the muscle causing the abnormal postures or contractures. This treatment also is for other functionally specific hand dystonias including stenographer’s dystonia and musician’s dystonia. This treatment was extended to include dystonias of the feet. In cases of more generalized dystonia, the abnormal limb postures can also be reduced and function increased with toxin injections of the affected muscles. Treatment has also been extended to patients with post-stroke spasticity and cerebral palsy spasticity. Toxin treatment has reduced the contractures and pain.

Extending the concept of reducing hyperfunctional muscle activity with toxin injections, patients with tremor disorders and myoclonus have been successfully treated. This includes treatment of the limbs, neck, palate, and vocal cords. Although the toxin doesn’t prevent the tremulous activity it can decrease it, thereby decreasing the patient’s symptoms.

Autonomic nervous system use

Based on observations of patients with botulism, many have autonomic symptoms such as dry eyes and dry mouth. Since the sweat glands are cholinergic, it became obvious that toxin injections should be able to decrease their function. Numerous studies have shown this and led to FDA approval for axillary hyperhidrosis. Studies have also shown efficacy on palmar, facial, and plantar hyperhidrosis. The effects on these glands last longer than in muscle perhaps owing to glandular atrophy. Frey syndrome or gustatory sweating is from aberrant regeneration of the autonomic nerve supply of the salivary glands to the sweat glands of the skin after trauma. Injecting the facial skin with toxin can prevent the gustatory sweating for 6–24 months. The salivary glands themselves can be injected to decrease salivary production in patients who have drooling, sialorrhea, and sialoceles. Recent studies are extending the use of botulinum toxin to treat rhinitis with rhinorrhea (also cholinergically induced).

Pearl 3

Acetylcholine release is also the neurotransmitter for the parasympathetic nervous system, and blockade can therapeutically improve conditions such as hyperhidrosis, sialorrhea, sphincter spasms, and rhinitis.

Other autonomic indication began to evolve with the success found with hyperhidrosis and salivary conditions. Upper and lower esophageal sphincter achalasia or hyperactivity and gastroparesis can be diminished with intramuscular injections of botulinum toxin. These are usually performed endoscopically. Recently, the FDA has approved Botox® for neurogenic hyperactive bladder function. There are also several trials for the use of botulinum toxin for benign prostatic hypertrophy. The initial data has shown gland reduction for about 6 months with apoptosis and sphincter weakness. Patients with painful, non-healing anal fissures had been treated with surgical sphincterotomy. Not all of the patients had healing with this procedure and some had permanent fecal incontinence. With toxin injection, there is a temporary chemical sphincterotomy, improved blood flow with near-100% healing of the fissures, and dramatic pain reduction. Anismus and vaginismus management with toxin have also been reported.

Afferent nervous system / pain syndromes / anti-inflammatory

A number of hyperfunctional muscular conditions had pain associated with them, and it was thought that pain reduction was related only to the reduced muscle contracture. Our group’s work with cosmetic injections led Bill Binder to observe that several patients with a migraine headache history ceased to have headaches. Patients with post-herpetic neuralgia also could be injected with toxin and have resolution of pain. These clinical observations led basic scientists to discover that SNARE proteins also release inflammatory mediators from afferent nerves. The toxin can bind to C fibers and A-delta fibers, and reduce or prevent release of the inflammatory mediators, thereby reducing pain and allowing central thresholds to rise. The management of chronic migraine headaches with Botox® has recently been FDA approved. Numbers of other studies of toxin in pain disorders have included trigeminal neuralgia, myofascial pain, tension headaches, temporomandibular disorders with pain, and low back pain. The anti-inflammatory effects have also been studied in a small series of patients with rheumatoid arthritis.

Pearl 4

It has been found that botulinum toxin can bind and blockade to the unmyelinated C-fibers and partially myelinated A-delta fibers of the sensory nervous system.

Pearl 5

Botulinum toxin has been found to also block the release of inflammatory mediators such as CGRP, substance P, glutamate, and others from its effect on SNARE proteins.

Pearl 6

Pain syndromes such as chronic migraine, post-herpetic neuralgia, temporomandibular disorders and others can be treated with botulinum toxins.

Glandular and secretory cell modulation

Foster and his group have shown that SNARE proteins are also responsible for the exocytosis and release of many hormones. Therefore, if ligands can be made to allow selective binding of the toxin to specific glandular cell proteins, toxin can be released in these cells to cleave the SNARE proteins and therefore prevent exocytosis of the hormone. Foster reported reduction of growth hormone with a bioengineered toxin in animals. Much more work needs to be done in this arena, but this exciting development opens up brand new ways of managing many disorders.

Further reading

Aoki KR. Evidence for antinociceptive activity of botulinum toxin type A in pain management. Headache. 2003;43(suppl 1):S9–S15.

Arad-Cohen A, Blitzer A. Botulinum toxin treatment for symptomatic Frey’s syndrome. Otolaryngology, Head and Neck Surgery. 2000;122:237–240.

Binder WJ, Brin MF, Blitzer A, et al. Botulinum toxin type A (Botox) for the treatment of migraine headaches; an open-label study. Otolaryngology, Head and Neck Surgery. 2000;123:669–676.

Blasi J, Chapman ER, Link E, et al. Botulinum neurotoxin A selectively cleaves the synaptic protein SNAP-25. Nature. 1993;365:160–163.

Blitzer A, Brin MF. Use of botulinum toxin for diagnosis and management of cricopharyngeal achalasia. Otolaryngology, Head and Neck Surgery. 1997;116:328–330.

Blitzer A, Brin MF, Greene PE, et al. Botulinum toxin injections for the treatment of oromandibular dystonia. Annals of Otolaryngology, Rhinology and Laryngology. 1989;98(2):93–97.

Blitzer A, Brin MF, Stewart C. Botulinum toxin management of spasmodic dysphonia (laryngeal dystonia): a 12 year experience in more than 900 patients. Laryngoscope. 1998;108:1435–1441.

Blitzer A, Zalvan C, Gonzales-Yanes O, et al. Botulinum toxin injections for the management of the hyperfunctional larynx. In: Brin MF, Jankovic J, Hallett M. Scientific and therapeutic aspects of botulinum toxin. Philadelphia: Lippincott Williams & Wilkins; 2002:207–217.

Carruthers JDA. The treatment of congenital nystagmus with Botox. Journal of Pediatric Ophthalmology and Strabismus. 1995;32:306–308.

DeFazio G, Abbruzzese G, Girlanda P, et al. Botulinum toxin A treatment for primary hemifacial spasm: a 10 year multicenter study. Archives of Neurology. 2002;59:418–420.

Diener HC, Dodick DW, Aurora SK, et al. PREEMPT 2 Chronic Migraine Study Group. OnabotulinumtoxinA for treatment of chronic migraine: results from the double-blind, randomized, placebo-controlled phase of the PREEMPT 2 trial. Cephalalgia. 2010;30(7):804–814. Epub 17 Mar

Freund B, Schwartz M, Symington JM. Botulinum toxin: new treatment for temporomandibular disorders. British Journal of Oral and Maxillofacial Surgery. 2000;38:466–471.

Frucht SJ. Focal task-specific dystonia in musicians. Advances in Neurology. 2004;94:225–230.

Gless R, Nauman M, Werner B, et al. Injections of botulinum toxin A into the salivary glands improve sialorrhea in amytropic lateral sclerosis. Journal of Neurology, Neurosurgery, and Psychiatry. 2000;69:121–123.

Glogau RG. Botulinum A neurotoxin for axillary hyperhidrosis. Dermatologic Surgery. 1998;24:817–819.

Gui D, Cassetta E, Anastasio G, et al. Botulinum toxin for chronic anal fissure. The Lancet. 1994;344(8930):1127–1128.

Laskawi R, Damanez W, Roggenkamper P. Botulinum toxin treatment in patients with facial synkinesis. Archives of Otolaryngology. 1994;4:S195–S199.

Liu HT, Tsai SK, Kao MC, et al. Botulinum toxin A relieved neuropathic pain in a case of post-herpetic neuralgia. Pain Medicine. 2006;7(1):89–91.

Maria G, Brisinda G, Civello IM, et al. Relief by botulinum toxin of voiding dysfunction due to benign prostatic hyperplasia: results of a randomized, placebo-controlled study. Urology. 2003;62:259–264.

Meng J, Wang J, Lawrence G, et al. Synatorbrevin I mediates exocytosis of CGRP from sensory neurons and inhibition by Botulinum toxin reflects their anti-nociceptive potential. Journal of Cell Science. 2007;120:2864–2874.

Pasricha P, Ravich W, Kalloo A. Botulinum toxin for achalasia. The Lancet. 1993;341:244–245.

Phelan MW, Franks M, Somogyi GT, et al. Botulinum toxin urethral sphincter injection to restore bladder emptying in men and women with voiding dysfunction. Journal of Urology. 2001;165:1107–1110.

Scott AB. Botulinum toxin injection of the eye muscles to correct strabismus. Transactions of the American Ophthalmologic Society. 1981;79:734–770.

Shaari CM, Sanders I, Wu BL, et al. Rhinorrhea is decreased in dogs after nasal application of botulinum toxin. Otolaryngology, Head and Neck Surgery. 1995;112:566–571.

Smith SJ, Ellis E, White S, et al. A double-blind, placebo controlled study of botulinum toxin in upper limb spasticity after stroke or head injury. Clinical Rehabilitation. 2000;14:5–13.

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