Clinical Use of Botulinum Toxin. NIH Consens Statement 1990 Nov 12-14;8(8):1-20.
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Clinical Use of Botulinum Toxin. NIH Consens Statement Online 1990 Nov 12-14 [cited year month day];8(8):1-20.
Botulinum toxin is a complex protein produced by the anaerobic bacterium Clostridium botulinum. Previously known only as a cause of a serious and often fatal paralysis acquired through ingestion of contaminated food, the toxin causes paralysis by blocking the presynaptic release of acetylcholine at the neuromuscular junction. Advantage can be taken of this neuromuscular blocking effect to alleviate muscle spasm due to excessive neural activity of central origin or to weaken a muscle for therapeutic purposes. In therapeutic applications, minute quantities of botulinum neurotoxin type A are injected directly into selected muscles.
Local injections of botulinum toxin are effective in the treatment of strabismus, essential blepharospasm, and hemifacial spasm. The U.S. Food and Drug Administration recently has approved botulinum toxin for these indications. Clinical studies indicate that botulinum toxin injections also can provide useful symptomatic relief in a variety of other conditions characterized by involuntary spasms of certain muscle groups, notably in focal or segmental dystonia including spasmodic torticollis, oromandibular dystonia (orofacial dyskinesia, Meige syndrome), and spasmodic dysphonia. A few studies suggest that it also may be useful in treating writer's cramp and related occupational cramps of the hand, limb dystonia, anismus, and urinary detrusor-sphincter dyssynergia. The value of the toxin in treating other conditions such as spasticity due to brain or spinal cord lesions is under investigation.
For most patients with these conditions, botulinum toxin injection provides significant but variable relief of symptoms that lasts for weeks to months. Repeated injections are required to sustain benefit over long periods of time. Conventional therapy for many of these conditions depends on minimally effective drugs or surgical procedures designed to denervate or destroy the involved muscles and has been generally unsatisfactory. Reports of the benefits of botulinum toxin have thus aroused great interest and hope among physicians, biomedical scientists, and patients.
This new therapeutic agent has been used principally by highly specialized physicians in academic medical centers. Many of the data are recent. Controversies persist regarding the indications, contraindications, optimal methods of use, and the nature of the side effects. Long-term effects of chronic botulinum toxin therapy are unknown. Long-term followup of treated patients is necessary. Additional research appears needed to clarify the metabolism and pharmacology of the toxin, assess new indications, and define optimal techniques of administration.
To evaluate the developing experience with botulinum toxin in the treatment of various clinical disorders characterized by muscle hyperactivity, the National Institute of Neurological Disorders and Stroke and the Office of Medical Applications of Research of the National Institutes of Health convened a Consensus Development Conference on November 12-14, 1990. The conference was cosponsored by the National Institute on Deafness and Other Communication Disorders of the National Institutes of Health and the Food and Drug Administration. After a day and a half of presentations by experts from all over the world and discussion by the audience, a consensus panel drawn from specialists in relevant fields, clinical investigators, and public representatives considered the evidence relative to the following questions:
There are several serologically distinct botulinum neurotoxins, which have slightly different specific effects. Only botulinum neurotoxin type A has been used in clinical studies at present. There are three steps in the neurotoxic action. First the toxic protein attaches to the presynaptic nerve membrane. Then the toxin crosses the presynaptic plasma membrane, following which the toxin inhibits release of vesicle-bound acetylcholine. The specific mechanism of intracellular action in blocking the release of acetylcholine and the subsequent fate of the toxin are not known at present. Although botulinum toxin has been shown to enter the central nervous system in animals by retrograde axonal transport, the therapeutic effects in humans are due primarily to the blockade of peripheral neuromuscular transmission.
Botulinum toxin produces its therapeutic effect by a long-term blockade that leads to changes very similar to those produced by surgical denervation. These changes include muscle paralysis, atrophy, and electromyographic abnormalities. In most situations, the clinical effects of botulinum toxin are of limited duration. In experimental animals and humans, recovery is accompanied by sprouting of new nerve terminals. The formation of new neuromuscular junctions adjacent to these sprouts parallels the effective return of neuromuscular activity.
Botulinum toxin therapy is invasive. Its use should be reserved for patients in whom a diagnosis has been established with reasonable certainty. Botulinum toxin is safe and effective for the symptomatic treatment of blepharospasm, strabismus, hemifacial spasm, adductor spasmodic dysphonia, cervical dystonia (spasmodic torticollis), and jaw-closing oromandibular dystonia. Botulinum toxin is promising in the management of other conditions, including other oromandibular dystonias, focal and segmental limb dystonias, abductor spasmodic dysphonia, stuttering, and vocal and other tremors. Preliminary studies suggest that botulinum toxin injection may be useful in urinary and anal sphincter dysfunction, spasticity, and dynamic deformities in selected cases of cerebral palsy.
Contraindications to the use of botulinum toxin are allergy to the drug and infection or inflammation at the proposed injection site(s). Safety for use during pregnancy or lactation has not been established. Therefore, it is prudent to avoid botulinum toxin therapy for elective procedures in women of childbearing age until absence of pregnancy or adequate contraception is assured. Relative contraindications include diseases of neuromuscular transmission, coagulopathy (including therapeutic anticoagulation), and inability of the patient to cooperate. In the more complex disorders, botulinum toxin therapy should not be used unless a skilled interdisciplinary team and sophisticated instrumentation are available to ensure valid diagnosis, state-of-the-art treatment, and appropriate followup. The physician administering this drug should be trained in its use and qualified to manage any complications.
Strabismus is a misalignment of the eyes that may result in diplopia (double vision), suppression and amblyopia (lazy eye), deficient depth perception, and an undesirable appearance. Botulinum toxin is effective as an alternative to surgery to realign the eyes of selected patients with congenital or acquired strabismus. The toxin appears to be more effective in esotropia (in-turning of the eyes) of small to moderate angles than in exotropia (out-turning), vertical deviations, or large angle deviations. Botulinum toxin may be indicated in certain ocular conditions where surgery is inappropriate such as acute thyroid ophthalmopathy. Controlled studies comparing botulinum toxin treatment and surgical treatment of strabismus have not been done.
Botulinum toxin may prevent contracture of antagonist muscles in cases of extraocular muscle palsy from which some recovery is expected. In these cases, single binocular vision may be enabled or enhanced during the recovery phase, and late contractures that would require surgery may be prevented. The drug also may be used as an adjunct to surgery intraoperatively and postoperatively.
Disadvantages of botulinum toxin in the extraocular muscles include the need for more than one injection, unstable ocular alignment for several weeks, diplopia, and blepharoptosis. Other complications may occur, such as perforation of the globe and orbital hemorrhage. Administration of the toxin requires electromyographic control and injection by a physician trained in the technique.
Essential blepharospasm is a variable, progressive, bilateral, involuntary, focal dyskinesia characterized by spasmodic, forceful eyelid closure resulting in visual disability. The disorder may be associated with cranial-cervical dystonia (Meige syndrome).
Botulinum toxin is effective in the long-term management of patients with essential blepharospasm, and it has become the treatment of choice. Symptoms are controlled in most patients by injection of the toxin in multiple sites in the periocular and facial muscles. Duration of control is variable but averages between 3 and 4 months. Timing for repeat injections is determined by the patient's sense of need and the physician's estimation of recovery of muscle function. Injection sites and dosages vary widely in published reports, but treatment results seem to be similar. Injections in these areas are given without electromyography control in most cases.
Botulinum toxin treatment of neurological conditions requires proper identification of the pathologically hyperactive muscles, either by inspection and palpation or by electromyography. Not all patients respond to botulinum toxin injection. In focal dystonias, most of which respond poorly to conventional therapy, botulinum toxin injection may be the treatment of choice. In more generalized dystonias, however, oral medication may be tried before botulinum toxin. In generalized disorders, botulinum toxin injection is indicated only for the treatment of particularly severe focal abnormalities, because injection of multiple muscle groups would require unacceptably high doses of toxin.
Hemifacial spasm is characterized by sudden, unilateral, synchronous contractions of muscles innervated by the facial nerve. These may subside immediately or persist as a tonic contraction of several seconds' duration and may occur many times a day. Eyelid closure may interfere with vision on the involved side. Hemifacial spasm may cause discomfort, cosmetic deformity, and social embarrassment. In most cases, it is due to mechanical irritation of the facial nerve in the posterior fossa or distally. Palliation with repeated injections of botulinum toxin may be appropriate and effective. Oral medications and surgical decompression are therapeutic alternatives.
Cervical dystonia (spasmodic torticollis) is characterized by asymmetric muscle spasms in the neck, which cause turning or tilting movements and sustained abnormal postures of the head. Mild to moderate head tremor and musculoskeletal pain are frequently present. The spasms often subside briefly in response to a variety of stimuli. Spontaneous remission may occur. Some patients respond to a limited extent to various medications, but many do not. Botulinum toxin is an accepted therapy.
Oromandibular dystonia (orofacial dyskinesia, Meige syndrome) consists of continuous, bilateral, asynchronous spasms of muscles of the face, jaw, pharynx, tongue, and, in some severe cases, neck, larynx, and respiratory system. It may respond to a modest degree to treatment with anticholinergics, baclofen, benzodiazepines, and other medication. Treatment with botulinum toxin has been shown to be effective and safe in the "jaw-closing" variant of the condition. "Jaw-opening" and other more complex variants also may respond to botulinum toxin injection. Optimal management of oromandibular dystonias requires thorough knowledge of the anatomy and pathophysiology as well as collaboration among an experienced otolaryngologist, speech-language pathologist, neurologist, and physicians skilled in regional electromyography. Because many muscles often are involved, multiple injections may be required. Side-effects, including dysphagia, dysarthria, diplopia, and weakness, may occur. Further studies of the effectiveness of botulinum toxin in these conditions are needed.
Focal and segmental limb dystonias consist of involuntary, inappropriate spasms of limited numbers of distal limb muscles. The spasms are often precipitated by voluntary contractions and include occupational dystonias such as writer's cramp and musician's cramp. These dystonias can be incapacitating and have been exceptionally resistant to treatment with oral medications. Preliminary clinical reports indicate that botulinum toxin may be an effective therapy, but further studies are necessary.
Anismus is a rare condition in which dyssynergia of the external anal sphincter and puborectalis muscles causes profound constipation. Urinary detrusor-sphincter dyssynergia following spinal injury is characterized by urinary sphincter spasm occurring simultaneously with bladder contraction. The result is urinary obstruction. Spasticity is excessive muscle tone caused by lesions of the corticospinal tract. Preliminary clinical reports suggest that botulinum toxin may be useful in these conditions.
Botulinum toxin therapy for voice and speech disorders requires the involvement of an interdisciplinary team, including an otolaryngologist, a speech-language pathologist, a neurologist, and a physician skilled in regional electromyography. A psychiatrist and/or psychologist, voice scientist, and neuroradiologist should be available. Voice laboratory facilities should be available to assure valid diagnosis and to document and quantify voice and speech function before and following treatment. In addition, the team should make available to the patient other treatment such as voice and speech therapy.
Predominantly adductor spasmodic dysphonia is characterized by forceful, involuntary approximation of the vocal folds. This interrupts the airstream and produces a strained, hoarse, choppy voice. Botulinum toxin therapy is effective in ameliorating the symptoms and restoring fluency. Because the effect is temporary, repeated injections are required.
Predominantly abductor spasmodic dysphonia is a condition characterized by forceful, involuntary separation of the vocal folds. This causes breathy interruptions in speech. Botulinum toxin therapy has been reported to be effective in selected cases, but it carries a risk of bilateral abductor paralysis with airway obstruction if the posterior cricoarytenoid muscles are injected.
Stuttering is characterized by repetitions of sounds and words, prolongations of sounds, and interruptions of the fluent flow of speech. Vocal tremor is characterized by quavering because of adductor and abductor oscillations of the vocal folds. Preliminary reports of botulinum toxin therapy for each of these conditions warrant further research.
Commercial preparations of botulinum toxin include nontoxin protein and other stabilizers, notably albumin pasteurized to kill the hepatitis and human immunodeficiency viruses. Paracrystalline stability for greater than 2 years has been established. For administration, this material is diluted to an appropriate concentration in preservative-free normal saline.
Local injection of pure toxin does not cause irritation or inflammation. The occasional complaints of pain at the site of injection may be related to factors such as the volume injected, concentration of active (or inactive) protein, or even the pH of the solution; however, no studies have investigated these variables.
The appreciation of botulinum as a potent, irreversible, and potentially lethal neurotoxin is fundamental to the safe use of this natural product. No pharmaceuticals currently are available to overcome the blockade created by botulinum toxin at the neuromuscular junction. However, coincident administration of agents known to potentiate neuromuscular blockade such as aminoglycosides, should be avoided.
Single large doses of greater than 500 mouse units (MU) of botulinum may produce acute symptoms and signs of botulism. There is no evidence of desensitization with chronic use.
In addition to diagnostic prudence, elaborate planning and precise understanding of three-dimensional anatomy of the regions of proposed injection are essential for safe administration. Physicians who attempt this therapeutic intervention must assume the joint responsibilities of knowledgeable diagnostic evaluation and diligent followup of their patients.
Even small volumes of botulinum toxin may have undesired regional effects, presumably because of diffusion. Injection of smaller volumes of more concentrated toxin may limit regional side effects. For example, injection of the sternocleidomastoid, lingual, and deep neck muscles can be associated with weakness of the pharyngeal and esophageal muscles and resultant difficulty with swallowing. Similarly, adjacent levator muscle paresis is seen in 10 to 40 percent of cases in whom the orbicularis oculi muscle is injected. Although dysphagia and blepharoptosis seem to be shorter lived than the paralysis of the target muscles, these complications are sometimes troublesome.
Routine electromyography is not required in every patient. However, the injection of muscles that are difficult to identify such as those in the orbit, the larynx, and the pterygoid area, and any muscle in obese subjects, is best accomplished with simultaneous hollow needle electrode recordings. Direct visualization of the target, such as the extraocular muscles during surgery or the larynx by indirect laryngoscopy, may obviate the need for electromyography in selected circumstances.
Prudence and current medical practice dictate that the patient or individual responsible for legal consent should be informed of all reasonable medical and surgical alternative therapies, the possibility of limited or absent benefits, the lack of permanent response and the unpredictability of response to an individual dose, and the need for repeated administration. For specific applications, other considerations should be disclosed. For example, in ophthalmic applications, scleral perforation, orbital hemorrhage, blepharoptosis, and overcorrection due to weakness of other extraocular muscles may occur. When the larynx is injected, bleeding and laryngeal edema, hoarseness, breathiness, and even aspiration may follow. When the deep neck musculature is injected, weakness and difficulty in swallowing can occur.
Botulinum toxin is a safe therapy when administered in the appropriate doses by experienced physicians. Side effects are generally transitory, well tolerated, and amenable to treatment. Persistent complications are distinctly rare, and serious side effects are uncommon. Generalized weakness, mimicking botulism, is rare, but electromyographic abnormalities may occur in muscles distant to the site of injection without clinical signs of muscle weakness. Systemic complications are uncommon, but several studies report a flu-like syndrome, particularly after the first injection. A similar syndrome has been reported following placebo injection. Most complications are related to diffusion or, rarely, inadvertent injection of the toxin into nearby muscle groups. Some complications may be dose dependent.
Some patients develop antibodies to the toxin. It is unclear exactly what factors predispose to development of antibodies, but some studies suggest that risk is increased by the administration of more than 300 MU within a 30-day period and by low body weight of the patient. Antibodies may be one factor associated with therapeutic failure. The long-term (>5 years) effects of chronic botulinum toxin injections are unknown.
Complications of therapy for specific disorders have been reported in large clinical studies and in a few, small, placebo-controlled studies. Although the types of complications are consistent from study to study, the rates vary, reflecting differences in technique and methods of data collection. Complications are described according to site of injection and clinical disorder.
For blepharospasm, mild eyelid ptosis is the most common complication (10 to 40 percent of cases). Ptosis usually resolves within a few weeks and may be dose or site related. Severe ptosis and diplopia are estimated to occur in 3 percent and 6 percent of patients, respectively. Other infrequent local complications include ectropion and lagophthalmos leading to exposure keratopathy and tearing. Facial weakness, ecchymoses, and eyelid edema also may occur. Treatment of strabismus frequently is complicated by transient ptosis and undesirable weakness of other extraocular muscles. More severe complications, such as perforation of the globe and orbital hemorrhage, have occurred. In hemifacial spasm, the types of complications are similar to those that occur in blepharospasm. In addition, injection of muscles that elevate the lip may result in bothersome weakness.
The most common complications of toxin injection for cervical dystonias are dysphagia, local neck weakness, and local pain. These are generally short-lived, but dysphagia occasionally is severe enough to require a modified diet and monitoring for aspiration. Risk for complications is higher in women, individuals with thin necks, those with low body weight, and those receiving injections into the sternocleidomastoid muscles.
Treatment of oromandibular dystonias has similar complications. Dysphagia is common when injections are given into the pterygoid and deep tongue muscles, and aspiration may occur. Patients with spasmodic dysphonias also are subject to transient dysphagia. "Breathiness" of voice is seen in up to 50 percent of patients and occasionally is severe enough to warrant discontinuation of treatment. Hoarseness and aspiration also may occur.
Mild local weakness, a desired effect, occurs in all patients who are treated successfully with toxin for hand and limb dystonias. However, until the appropriate dose is determined for an individual patient, weakness may be excessive. Transitory tenderness at the site of injection is noted in up to 20 percent of patients.
In a small clinical series, toxin treatment for detrusor-sphincter dyssynergia in spinal cord injury patients has been uncomplicated except for mild, transitory, generalized weakness in two patients. Treatment of focal spasticity in multiple sclerosis and cerebral palsy, in small case series, has been uncomplicated. Transitory fecal incontinence has been recorded in 2 of 15 patients treated for anismus.
To study the general properties of botulinum toxin, including:
To study the indications for botulinum toxin treatment, including:
To study contraindications for botulinum toxin treatment, including:
To study the technique of injecting and handling of botulinum toxin, including:
To study the side effects and complications of botulinum toxin treatment, including: