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  » Botox  »   Botulism Toxin Review

Overview

The introduction of botulinum toxin as a therapeutic tool in the late1980s revolutionized the treatment of dystonia by offering significant relief of symptoms to many people with dystonia. Botulinum toxin, a biological product, is injected into specific muscles where it acts to reduce the involuntary contractions characteristic of dystonia. The injections weaken muscle activity sufficiently to reduce a spasm but not enough to cause paralysis.

Botulinum toxin is a complex protein produced by the bacterium Clostridium botulinum. It is a nerve "blocker" that binds to the nerves that lead to the muscle and prevents the release of acetylcholine, a neurotransmitter that activates muscle contractions. If the message is blocked, muscle spasms are significantly reduced or eliminated.

Dystonia is a disorder characterized by involuntary sustained muscle contractions resulting in repetitive movements or abnormal postures. Despite an incomplete understanding of the neurological mechanisms underlying dystonia, relief of dystonic posturing and associated pain and discomfort has improved markedly since the introduction of botulinum toxin (BTX) therapy in the late 1980s.

BTX is one of the most potent biologic substances known. The 7 distinct serotypes, A, B, C, D, E, F, and G, are of similar sizes and structures. However, the serotypes differ in their potency, duration of action, and cellular target sites. Types A and B have been shown to be safe and effective in double-blind clinical trials for the treatment of dystonia. One formulation of BTX-A is marketed worldwide under the name Botox (Allergan Inc.) and another in Europe as Dysport (Speywood, UK). Botox was approved in December 1989 by the US Food and Drug Administration (FDA) for "the treatment of strabismus, blepharospasm, and focal spasms including hemifacial spasm" and more recently for the treatment of cervical dystonia. A formulation of BTX-B was approved in December 2000 by the FDA for treatment of cervical dystonia, and will be marketed under the name Myobloc in the United States and Neurobloc in Europe (Elan Pharmaceuticals).

The clinician must recognize that the various commercial formulations of BTX differ in the dosages used clinically owing to differences in potency and diffusion (see next 2 sections).

Structure

BTX is synthesized as a single-chain peptide with a molecular mass of 150 kilodaltons. This form has relatively little potency as a neuromuscular blocking agent, and activation requires a 2-step modification in the tertiary structure of the protein. This process converts the single-chain neurotoxin to a di-chain neurotoxin comprising a 100,000-dalton heavy chain (HC) linked by a disulfide bond to a 50,000-dalton light chain (LC). BTX acts at the neuromuscular junction where it exerts its effect by inhibiting the release of ACH from the presynaptic nerve terminal.

ACH is contained in vesicles, and several proteins (VAMP, SNAP-25, and syntaxin) are required to mediate fusion of these vesicles with the axon terminal membrane. BTX binds to the presynaptic terminal via the HC. The toxin is then internalized and the HC and LC are separated. The LC from BTX-A cleaves SNAP-25, the LCs from serotypes B and F cleave VAMP, and that from serotype C cleaves syntaxin. This disrupts ACH release and subsequent neuromuscular transmission, resulting in weakness of the injected muscle.

Preparation

The toxin is produced by the gram-negative anaerobic bacterium Clostridium botulinum . It is harvested from a culture medium after fermentation of a toxin-producing strain of C botulinum, which lyses and liberates the toxin into the culture. The toxin is then extracted, precipitated, purified, and finally crystallized with ammonium sulfate. BTX-A should be diluted with preservative-free saline and the preparation used within 4 hours of reconstitution. Conditions for stability of the toxin in solution include ph 4.2-6.8 and temperature less than 20 degrees Celsius. Crystallized toxin is inactivated easily in solution by shaking.

Biological activity of BTX-A distributed by Allergan Inc. (Botox) is different from that of the BTX-A produced by Speywood Pharmaceuticals in England (Dysport) or Japan. The potency of BTX is expressed as mouse units, with 1 mouse unit equivalent to the median lethal dose (LD 50) for mice. Botox is dispensed in small vials containing 100 units (U), while a vial of Dysport contains 500 U. The relative potency of Botox units to Dysport units is approximately 1:4. Botox units are used throughout this article. Most physicians dilute the vial of Botox with 1-4 mL of saline, for a concentration of 2.5-10 U/0.1 mL.

Electromyographic (EMG) guidance of injections is generally advised with the exception of injections of muscles around the eye and some facial muscles. The dose of Botox injected intramuscularly depends on the muscle size. Small muscles such as the vocal cords receive 0.75 U, whereas larger neck muscles may require 100-150 U and lower limb muscles may require 200-300 U to exert a desirable effect. After injection, BTX starts to weaken the muscle within 24-72 hours, and maximal effect occurs after about 14 days; benefit can last for 3-6

History

In the late sixties, Alan B. Scott, MD, of the Smith-Kettlewell Eye Research Foundation and Edward J. Schantz, PhD, Director of Food Microbiology and Toxicology at the University of Wisconsin were researching a substance to relax certain eye muscles causing strabismus (cross-eye). Botulinum toxin type-A was developed as a therapeutic agent for this disorder along with blepharospasm, hemifacial spasm, and other disorders characterized by inappropriate muscle spasms.

Forms

Seven serotypes or forms of botulinum toxin have been isolated, and they are A, B, C, D, E, F, and G. Each one has different properties and actions. No two are exactly alike. Of these subtypes, botulinum toxin type-A and type-B are commercially available. Botulinum toxin type-F is also being investigated.

Although the overall effect is similar, the specific mechanism by which each toxin achieves this effect is different. For example, both type-A and type-B block the neurotransmitter acetylcholine, but they do so by breaking up different proteins within the nerve cell.

Botulinum toxin type-A is commercially available as BOTOX® from Allergan, Inc. and as Dysport® from Ipsen, Ltd. in England. The trade name in the U.S. for botulinum type-B is MYOBLOC™.

In 1989 the U.S. Food and Drug Administration (FDA) approved botulinum toxin-which at that time was only available in the form of BOTOX®-for the treatment of blepharospasm. In 2000, the FDA approved the use of both BOTOX® (botulinum toxin type-A) and MYOBLOC™ (type-B) for the treatment of cervical dystonia. Botulinum toxin is used extensively to treat the various forms of dystonia. The regulations of the FDA permit physicians to use approved medications for conditions other than the specified indications. This is called "off-label" use.

Methods

Injections of botulinum toxin should only be performed by a physician who is trained to administer this treatment. The physician needs to know the clinical features and study the involuntary movements of the person being treated. The physician doing the treatment may palpate the muscles carefully, trying to ascertain which muscles are over-contracting and which muscles may be compensating. In some instances, such as in the treatment of laryngeal dystonia, a team approach including other specialists may be required.

For selected areas of the body, and particularly when injecting muscles that are difficult or impossible to palpate, guidance using an electromyograph (EMG) may be necessary. For instance, when injecting the deep muscles of the jaw, neck, or vocal cords, an EMG-guided injection may improve precision since these muscles cannot be readily palpated. An EMG measures and records muscle activity and may help the physician locate overactive muscles.

Injections into the overactive muscle are done with a small needle, with one to three injections per muscle. Discomfort at the site of injections is usually temporary, and a local anesthetic may be used to minimize any discomfort associated with the injection.

The success of injection rests largely with muscle selection, dosage, and preparation of the botulinum toxin serotypes. The onset of effect usually begins within days of the injection, peaking in approximately four weeks and lasting three to four months.

BOTOX®, distributed by Allergan, is a sterile, vacuum dried preparation of botulinum toxin type-A. BOTOX® is stored in the freezer and reconstituted at the time of use. MYOBLOC™, distributed by Elan Pharmaceuticals, is a liquid formulation of type-B that is stored in the refrigerator.

A distinct difference between BOTOX® and MYOBLOC™ is the number of units needed for treatment. The units vary among the commercially produced toxins along with different amounts of protein per effective dose and different duration of action.

Whether one serotype offers a distinct advantage over the other has not been determined. The Dystonia Study Group is conducting a clinical trial that will assess a "head-to-head" comparison between type-A and type-B.

Optimizing Benefit

In general, the possible side-effects associated with botulinum toxin are temporary and clear up on their own. Depending on the part of the body treated, some side-effects include muscle weakness, difficulty swallowing, flu-like symptoms, and soreness at the site of the injection. Patients treated with botulinum toxin type-B may also be more susceptible to dry mouth. If a patient experiences side-effects, adjusting the dosage or site of injection for future treatments may help avoid these effects.

Based on over a decade of clinical experience, patients who respond well to botulinum toxin may continue treatment over the course of many years without side-effects from long-term use.

No studies have been done to examine the effects of botulinum toxin during pregnancy.

The effectiveness and duration of benefit following a botulinum toxin treatment may vary from injection to injection and from serotype to serotype. Especially when first beginning treatment with botulinum toxin, there may be a short "trial" phase during which the physician and patient work together to find the right combination of location and dosage for that person. It is recommended that physicians use one serotype at a time rather than alternate or mix type-A and type-B.

In some cases, a patient who has previously been successfully treated with botulinum toxin begins to experience a loss in benefit. Several factors could be responsible for this change. The nature and pattern of muscle contractions may change over time, thus necessitating an adjustment in the site of injection and dosage. If deep muscles become involved, it may be difficult to access those muscles.

It is also possible that a person who has been treated with botulinum toxin may develop antibodies that "neutralize" the injected toxin. It is possible to test for antibodies by injecting a small amount of botulinum toxin into the muscles over the eyebrow that cause wrinkling. If the wrinkles disappear within two weeks, it is apparent that the patient still responds to the treatment. If the wrinkles remain unchanged, the patient is immune to the toxin.

There is currently no data to indicate if people receiving injections of botulinum toxin type-A will be either more or less likely to develop antibodies than botulinum toxin type-B or vice versa.

FAQ

How does BTX prevent spasticity?
A solution of BTX is injected directly into several sites in the spastic muscle near the nerve terminals. BTX works inside the nerve terminals to block release of acetylcholine , the chemical that actually stimulates muscle contraction. Some nerve terminals remain unaffected by BTX, so that the injected muscle can still contract, but with less force. One important benefit of BTX is that the dose may be adjusted to provide the precise degree of weakness needed to overcome spasticity, while preserving some strength for normal function.

Is BTX safe?
Yes. The amount of BTX injected for treatment of spasticity is many times lower than the dose that would be needed to cause botulism poisoning, and accidental overdose would require injecting many more vials than are necessary for treatment. In addition, when properly injected, the drug does not travel more than a few centimeters from the injection site, so it does not affect the muscles used for respiration (the major risk from botulism poisoning).

What benefits can I expect from BTX treatment?
BTX temporarily weakens spastic muscle, allowing more normal limb positioning and function. When used as part of an integrated antispasticity program, BTX may allow improvements in mobility, positioning, sitting, toileting, hygiene, and other activities of daily living. The benefits BTX can offer any particular patient depend on the location and degree of spasticity being treated. In general, BTX cannot be used to treat widespread, severe spasticity, since the amount of drug required to bring about meaningful functional improvements would likely lead to antibody formation, resistance to BTX, and eventual loss of response.

Is BTX useful in treating pain?
Many patients with painful spasms or contracture report a reduction in pain after injection with BTX.

Is BTX a permanent treatment?
No. The effects of BTX are usually greatest for 2-6 weeks following treatment, and usually fade completely after 3-6 months. Reinjection is possible at that time, if the clinical team, the patient, and the caregiver agree that retreatment is likely to be beneficial. In most situations, reinjections are not given any sooner than 3 months after the last injection to decrease the possibility of antibody formation.

What are antibodies, and why are they a problem with BTX-A therapy?
Antibodies are proteins produced by the immune system to fight foreign invaders. Antibodies bind to and inactivate BTX, rendering it useless for spasticity reduction. Once a person forms antibodies to a particular type of BTX (A or B), further injections with that type are ineffective. Antibodies against BTX-A have been found in about 5% of patients who receive it regularly in high doses, as in treatment for cervical dystonia. The incidence of antibodies to type B in cervical dystonia patients is also in this range or higher. The incidence of antibodies to either type in the spasticity population is unknown, but antibody resistance has been reported in spasticity patients.
A patient who has developed antibody resistance to one type may obtain benefit by switching to the other type.

Can the risk of antibody formation be reduced?
Yes. Repeated, high dose injections are more likely to cause antibody formation than less frequently repeated, low dose injections. Physicians should, therefore, use the smallest amount of BTX necessary to achieve therapeutic benefit and extend the interval between treatment sessions as long as possible. Patients need to understand this important limitation on BTX therapy.

CLINICAL APPLICATIONS OF BOTULISM TOXIN:

  • Blepharospasm

Blepharospasm is characterized by involuntary, intermittent, forced eyelid closure. BTX is considered the treatment of choice for blepharospasm and has been used for this disorder since 1983. It has been used effectively in the treatment of blepharospasm induced by drugs such as L-dopa or neuroleptics, dystonic eyelid and facial tics in patients with Tourette syndrome, and "apraxia of eyelid opening.”

Injection technique

Treatment may be started with 10 U of Botox per eyelid, injecting a total of 20 U per patient. The most common effective dose is 25 U per eye. Diluting the Botox with 4 mL of isotonic saline is recommended. As the orbicularis oculi muscle lies superficially, intradermal injection with a 27- to 30-gauge needle is recommended. Typically 3-5 points around each eye are injected. The principle is to avoid the mid portion of the upper eyelid to avoid inadvertent diffusion into the levator palpebrae superiores, which would lead to undesirable ptosis. Injection into the medial lower lid also is avoided.

Therapeutic efficacy

Onset of improvement is seen in 4-7 days and benefit can last for up to 4 months.

Risks and adverse effects

Ten percent of patients develop ptosis, which improves spontaneously in less than 2 weeks. Other complications include blurring of vision, tearing, and local hemorrhage.

•  Focal hand dystonia

This condition typically presents with loss of speed and fluency of movement during a specific task. Neurologic evaluation is required to rule out radiculopathy or peripheral nerve entrapment for which specific treatment might be available. Nerve conduction studies may be required to exclude ulnar neuropathy or median entrapment neuropathy at the wrist. Examination of the forearm muscles should be performed during the specific task to determine which muscles are involved in the dystonia. Observations should be made at rest and during the provoking activity. The patient should be instructed to avoid compensating for the dystonia. The selection of muscles for injection depends on clinical examination, patient report of local pain or tightness, and/or EMG evidence of excessive activity.

Injection technique

BTX is injected into the muscle belly; localizing muscles for injection in the forearm may be difficult, as many of the muscles are deep and overlapping. EMG is recommended to help identify the target dystonic muscle. Once proper needle location is confirmed, BTX can be injected.

Common initial doses of Botox for writer's cramp are 5 U for small muscles and 10-20 U for muscles in the forearm. Large doses into a single muscle are best given in multiple sites to aid diffusion of the toxin to a greater number of end plates. The dose of BTX is titrated over several injection sessions to the dose that maximizes relief from dystonia while minimizing muscle weakness. Subsequent injections should be given at 2- to 4-month intervals. At each subsequent session, the patient should be examined for weakness that might indicate postponing treatment or reducing the dose. As the pattern of muscle contraction can change, the dystonia should be reevaluated at each session.

Therapeutic efficacy

Treatment may lead to an improvement in abnormal posture and pain and/or restoration of normal function. Benefit has been reported in as many as 80-90% patients and is usually apparent 5-7 days after injection. Symptomatic relief peaks about 2 weeks after treatment and may last for 3-4 months.

•  Cervical dystonia

Cervical dystonia (CD) is the most common form of focal dystonia and is characterized by sustained postures or contractions of the neck muscles. Deviation of the head can occur in multiple directions; turning of head (torticollis) is the most common subtype of cervical dystonia. Laterocollis (tilting) bends the head laterally, moving the ear toward the ipsilateral shoulder; anterocollis (forward flexion) deviates the chin downward toward the chest; and retrocollis (extension) produces upward extension of the chin. Cervical dystonia can involve any combination of these deviations.

Examination of patient

CD is usually idiopathic but in some cases it follows trauma. A study including 300 patients at Baylor College of Medicine revealed that as many as 11% of patients had significant neck injury less than 1 year prior to the onset of CD. Exposure to neuroleptic drugs accounted for 6% of the cases of CD in the Baylor series. Neurologic examination is essential to rule out radicular processes or ophthalmologic disorders, which can present with abnormal posture of the head.

The anatomy of the neck is complex; a basic familiarity with anatomic landmarks, muscle origins and insertions, and vital structures in that region is necessary to use BTX injections effectively to treat these patients. The abnormal postures of CD usually result from abnormal activity of multiple muscles. Postures are complex, with combinations of turning, tilting, head flexion or extension, and shoulder elevation.

Proper selection of the involved muscles is the most important determinant of response to BTX treatment. Thus, careful examination of the patient in different positions is indicated; instruct the patient to position the head in a comfortable upright posture. Passively adjust the head and observe for additional extension, flexion, and rotation that may be compensated for by the patient and note any contractures. Palpate for contracting muscles and hypertrophy and any point tenderness. The patient should then be asked to walk and the head position observed and recorded. The head position that is most abnormal is used to select the muscles for injection. EMG is recommended to localize involved muscles.

Injection techniques

The most commonly injected muscles include sternocleidomastoid, trapezius, splenius capitis, levator scapulae, and scalene complex. Muscles involved in the abnormal posturing are isolated using standard anatomic landmarks. EMG guidance is recommended for injection purposes. Once the EMG electrode is inserted, the patient is instructed to activate the muscle evoking a full recruitment pattern. The needle is held in position and the patient resumes a relaxed position. The syringe is aspirated to ensure that the tip is not within a blood vessel and the appropriate amount of BTX is then injected directly through the electrode into the muscle. Botox treatment doses range from 10-600 U, with 200-300 U most commonly used. Usually 2-6 muscles are injected at multiple sites; the BTX should be injected along the belly of the muscle to allow for adequate diffusion.

Therapeutic efficacy

Ninety percent of patients report some improvement in the postural deviation. In published reports 76-93% of patients experienced pain relief following treatment with BTX. In some studies, subjective pain relief is frequently more impressive than objective improvement in head posture. Latency between injections and onset of clinical benefit is around 7 days. Duration of effect is 3-4 months.

Risks and adverse effects

The most common adverse effects include neck weakness (20-30%), dysphagia (10-20%), and local pain. The occurrence of dysphagia appears to be related to the dose and the muscles injected. Adverse effects are transient and usually resolve spontaneously within 2-3 weeks.

•  Oromandibular dystonia

Oromandibular dystonia (OMD) is characterized by abnormal involuntary movements or spasms of lower face, jaw, and tongue muscles. Patients present with spasms of these muscles and jaw deviation.

Injection technique

Treatment of this condition with BTX requires a detailed knowledge of the local anatomy. Evaluation by both a neurologist and otolaryngologist is recommended. OMD can involve different combinations of muscles including the masseter, lateral and medial pterygoids, and temporalis. The recommended dose of BTX is 20 U in each muscle.

Therapeutic efficacy

Seventy to eighty percent of patients with OMD benefit from local injections of BTX into the inappropriately contracting muscles. Improvement is observed within the first week after BTX and the benefit can last for 3-4 months.

Risks and adverse effects

Adverse effects are uncommon and include dysphagia and pain at the injection site.

•  Laryngeal dystonia

Laryngeal dystonia, also called spasmodic dysphonia, is characterized by abnormal involuntary spasms of vocal muscles resulting in an abnormal voice pattern.

Injection technique

Before a patient can be considered as a potential candidate for BTX injections, the diagnosis of laryngeal dysphonia must be confirmed by neurologic, otolaryngologic, and voice assessment. Clinical findings should be documented by video and voice recording with fiberoptic laryngoscopy. The thyroarytenoid muscles are located with EMG guidance, and percutaneous injections of BTX are administered through the cricothyroid membrane. BTX dose ranges from 1.5-3 U. Currently, a bilateral injection approach is the most frequently used technique.

Therapeutic efficacy

Seventy-five percent of patients note improvement in voice symptoms. Relief after BTX injection begins within 24-72 hours and lasts for an average of 4 months.

Risks and adverse effects

Swallowing difficulties, which can last for 3-7 days, occur in 60% of patients. Transient hypophonia and stridor also have been reported.

•  Hemifacial spasm

Hemifacial spasm (HFS) is one of the more common craniofacial movement disorders. It is characterized by unilateral muscle contractions of the face. HFS may involve any combination of orbicularis oculi, frontalis, risorius, zygomaticus major, and platysmas muscles. This is not a form of focal dystonia but rather is caused most probably by irritation of cranial nerve VII by an artery compressing the nerve as it exits the brain stem.

Injections of BTX are tailored to the facial muscles in spasm; the muscles affected differ from patient to patient. Adverse effects depend on location of injection; lower face injections may result in facial weakness and asymmetry, face and mouth droop, drooling, and loss of facial expression. Forehead injections can result in brow ptosis or loss of eyebrow elevation. Most patients receive substantial benefit within 48-72 hours after an injection, and benefit peaks by 2-3 weeks; it can last for 3-4 months.

BOTULISM TOXIN TYPE - B

Myobloc (Elan Pharmaceuticals) was approved by the FDA in December 2000 for treatment of patients with cervical dystonia to reduce the severity of abnormal head position and neck pain associated with cervical dystonia. BTX-B also has received marketing authorization from the European Union's Committee for Proprietary Medicinal Products and will be marketed as Neurobloc (Elan Pharmaceuticals).

Reported clinical studies have shown Myobloc/Neurobloc to be a safe and effective treatment for cervical dystonia in patients who have responded to BTX-A and in those who developed resistance to BTX-A. As with all the botulinum toxins, BTX-B acts at the neuromuscular junction inhibiting the release of ACh at the presynaptic membrane; however, the primary mechanism of action of BTX-B differs from that of BTX-A, as BTX-B inactivates a different protein involved in the release of ACh.

FUTURE AND CONTOVERSIES:

Unresolved issues concerning BTX include the following:

  • Lack of standardization of biological activity of the different preparations
  • Poor understanding of the toxin, including its mechanism of action, potency, and long-term effects
  • Inadequate assays of BTX antigens
  • Variations in method of injection

Future directions include improving the efficacy of BTX or finding a superior neuromuscular junction–blocking agent with a prolonged duration of action. Given the potential for development of an immune response against the toxin, development of (1) alternative serotypes that can replace the ones to which patients are immune, (2) formulations that are engineered to be less immunogenic, and (3) alternative drugs with little or no probability of evoking antibody formation is necessary.

Greater clinical utility would occur with formulations that can be stored longer once partially used, that provide more prolonged benefit, and that less frequently induce antibody formation that leads to nonresponsiveness.

BIBLOGRAPHY:

  • Brin MF, Lew MF, Adler CH: Safety and efficacy of NeuroBloc (botulinum toxin type B) in type A- resistant cervical dystonia. Neurology 1999 Oct 22; 53(7): 1431-8 [Medline] .
  • Elston JS: Botulinum toxin for blepharospasm. In: Jankovic J, Hallett M, eds. Therapy with Botulinum Toxin. New York: Marcel Dekker; 1994: 299-306.
  • Hallett M: Physiology of dystonia. In: Fahn S, Marsden CD, Delong M, eds. Advances in Neurology. New York: Lippincott-Raven; 1997: 11-9.
  • Illowsky K, Hallett M: Botulinum toxin treatment of focal hand dystonia. Jankovic J, Hallett M, eds. Therapy with Botulinum Toxin. New York: Marcel Dekker; 1994: 299-306.
  • 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 Aug; 53(8): 633-9 [Medline] .
  • Jankovic J: Botulinum toxin in movement disorders. Curr Opin Neurol 1994 Aug; 7(4): 358-66 [Medline] .
  • Report of the Therapeutics and Technology Assessment Subcommittee of the America: Assessment: the clinical usefulness of botulinum toxin-A in treating neurologic disorders. Neurology 1990 Sep; 40(9): 1332-6 [Medline] .

DISCLAIMER:

Medicine is a constantly changing science and not all therapies are clearly established. New research changes drug and treatment therapies daily. The authors, editors, and publisher of this journal have used their best efforts to provide information that is up-to-date and accurate and is generally accepted within medical standards at the time of publication. However, as medical science is constantly changing and human error is always possible , the authors, editors, and publisher or any other party involved with the publication of this article do not warrant the information in this article is accurate or complete, nor are they responsible for omissions or errors in the article or for the results of using this information. The reader should confirm the information in this article from other sources prior to use. In particular, all drug doses, indications, and contraindications should be confirmed in the package insert.