Clinical Use of Botulinum Toxin National Institutes of Health Consensus Development Conference Statement November 12-14, 1990 This statement is more than five years old and is provided solely for historical purposes. Due to the cumulative nature of medical research, new knowledge has inevitably accumulated in this subject area in the time since the statement was initially prepared. Thus some of the material is likely to be out of date, and at worst simply wrong. For reliable, current information on this and other health topics, we recommend consulting the National Institutes of Health's MedlinePlus http://www.nlm.nih.gov/medlineplus/. This statement was originally published as: Clinical Use of Botulinum Toxin. NIH Consens Statement 1990 Nov 12-14;8(8):1-20. For making bibliographic reference to the statement in the electronic form displayed here, it is recommended that the following format be used: Clinical Use of Botulinum Toxin. NIH Consens Statement Online 1990 Nov 12-14 [cited year month day];8(8):1-20. Abstract The National Institutes of Health Consensus Development Conference on Clinical Use of Botulinum Toxin brought together neurologists, ophthalmologists, otolaryngologists, speech pathologists, and other health care professionals as well as the public to address: the mechanisms of action of botulinum toxin, the indications and contraindications for botulinum toxin treatment, the general principles of technique of injection and handling for its safe and effective use, and the short-term and long-term side effects and complications of therapy. Following 2 days of presentations by experts and discussion by the audience, a consensus panel weighed the evidence and prepared their consensus statement. Among their findings, the panel recommended that (1) botulinum toxin therapy is safe and effective for treating strabismus, blepharospasm, hemifacial spasm, adductor spasmodic dysphonia, jaw-closing oromandibular dystonia, and cervical dystonia; (2) botulinum toxin is not curative in chronic neurological disorders; (3) the safety of botulinum toxin therapy during pregnancy, breast feeding, and chronic use during childhood is unknown; (4) the long-term effects of chronic treatment with botulinum toxin remain unknown; and (5) botulinum toxin should be administered by committed interdisciplinary teams of physicians and related health care professionals with appropriate instrumentation. The full text of the consensus panel's statement follows. Introduction 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: What are the mechanisms of action of botulinum toxin? What are the indications and contraindications of botulinum toxin therapy? How should it be handled to assure safe and effective use? What are its side effects and complications? What further research on botulinum toxin therapy is needed? What Are the Mechanisms of Action of Botulinum Toxin? 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.   What Are the Indications and Contraindications for the Use of Botulinum Toxin Treatment? Introduction 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. Ophthalmic Disorders Extra-Ocular Muscle Dysfunctions 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. Blepharospasm 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.   Neurological Disorders Introduction 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 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 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 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 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, Urinary Detrusor-Sphincter Dyssynergia, and Spasticity 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.   Voice and Speech Disorders Introduction 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. Adductor Spasmodic Dysphonia 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. Abductor Spasmodic Dysphonia 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 and Vocal Tremor 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. How Should It Be Handled To Assure Safe and Effective Use? 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.     What Are Its Side Effects and Complications? 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. Blepharospasm, Strabismus, and Hemifacial Spasm 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. Cervical and Oromandibular Dystonias (Meige syndrome) and Spasmodic Dysphonias 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. Hand and Limb Dystonias 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. Other Conditions 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.   What Further Research on Botulinum Toxin Is Needed? To study the general properties of botulinum toxin, including: mechanism of action metabolism and catabolism mechanisms of recovery from paralysis the target receptors pharmacology of other serotypes antidotes and blocking techniques techniques to increase the specificity and duration of action stability and consistency of pharmaceutical preparations To study the indications for botulinum toxin treatment, including: efficacy and safety through controlled clinical trials that use reliable outcome measures optimal measures of clinical benefit long-term and remote effects dose/response relationships and dose schedules causes of primary failure causes of secondary failure pathophysiology of the diseases treated physiology of spasm reduction in regional muscles that are not directly injected To study contraindications for botulinum toxin treatment, including: pregnancy and lactation high doses or chronic maintenance in infants and children diseases of neuromuscular transmission To study the technique of injecting and handling of botulinum toxin, including: effects of location, dose, concentration, and volume on response dose selection based on objective physiologic or anthropometric parameters the value of electromyography for diagnosis, localization of the site(s) of administration, and control of dose To study the side effects and complications of botulinum toxin treatment, including: antibody formation and its implications long-term consequences of repeated injection the variability in sensitivity to injection among different patients and different muscle groups in an individual patient the mechanism of undesirable regional effects valid and reliable parameters for assessment of outcome systemic effects Conclusions and Recommendations Botulinum toxin therapy is safe and effective in the treatment of strabismus and in the symptomatic treatment of essential blepharospasm, hemifacial spasm, predominantly adductor spasmodic dysphonia, jaw-closing oromandibular dystonia and cervical dystonia. Botulinum toxin therapy appears promising in other conditions described in this report, but additional investigations, including controlled clinical trials, are needed. Botulinum toxin therapy is not curative in chronic neurological disorders. Further study of the mechanism of action of botulinum toxin and its pharmacotherapeutics is needed. International standardization of measures of biological activity of botulinum toxin is needed. For most indications, botulinum toxin should be used by committed interdisciplinary teams of physicians and related health care professionals with appropriate instrumentation. The safety of botulinum therapy during pregnancy, breast feeding, and chronic use in childhood is unknown. The long-term effects of chronic treatment with botulinum toxin remain unknown. Prolonged followup is necessary in patients on maintenance therapy. An independent national database should be established. The health care community needs additional education for the availability, benefits, risks, and special health care provider skills associated with botulinum toxin therapy. Further clinical and basic research should be encouraged to address the many unanswered questions about botulinum toxin and its therapeutic uses. Consensus Development Panel Roger C. Duvoisin, M.D., F.A.C.P. Conference and Panel Chairperson Professor and Chairman Department of Neurology University of Medicine and Dentistry of New Jersey Robert Wood Johnson Medical School New Brunswick, New Jersey Walter G. Bradley, D.M., F.R.C.P. Professor and Chairman Department of Neurology University of Miami College of Medicine Miami, Florida O.G. Bruce President Benign Essential Blepharospasm Research Foundation, Inc. Lake Quivira, Kansas Forrest D. Ellis, M.D. Professor Department of Ophthalmology Indiana University School of Medicine Indianapolis, Indiana Susan E. Folstein, M.D. Professor Department of Psychiatry Johns Hopkins University School of Medicine Baltimore, Maryland Mae E. Gordon, Ph.D. Biostatistician Division of Biostatistics Department of Ophthalmology and Visual Sciences Washington University School of Medicine St. Louis, Missouri Philip B. Gorelick, M.D., M.P.H. Associate Professor Department of Epidemiology, Biostatistics and Neurology Michael Reese Hospital and Medical Center School of Pubic Health University of Illinois at Chicago Chicago, Illinois David G. Hanson, M.D. Professor and Chairman Department of Otolaryngology/Head and Neck Surgery Northwestern University Medical School Chicago, Illinois Audrey L. Holland, Ph.D. Professor Department of Otolaryngology University of Pittsburgh School of Medicine Pittsburgh, Pennsylvania Richard Alan Lewis, M.D. Professor Departments of Ophthalmology, Medicine, and Pediatrics, and The Institute for Molecular Genetics Baylor College of Medicine Houston, Texas Manfred D. Muenter, M.D. Professor and Head of Section of Neurology Mayo Clinic Scottsdale Scottsdale, Arizona Robert T. Sataloff, M.D., D.M.A. Professor Department of Otolaryngology Thomas Jefferson University Philadelphia, Pennsylvania Roy B. Sessions, M.D. Professor and Chairman Department of Otolaryngology/Head and Neck Surgery Georgetown University Medical Center Washington, D.C. Speakers Michael J. Aminoff, M.D. "Clinical Trials for Cervical Dystonia 5" Professor Department of Neurology University of California at San Francisco School of Medicine San Francisco, California Arnold E. Aronson, Ph.D. "Background to Speech Disorders Potentially Treatable With Botulinum Toxin: Etiology, Pathophysiology, Symptomatology and Therapeutic Alternatives" Head Section of Speech Pathology Department of Neurology Mayo Clinic Mayo Medical School Rochester, Minnesota Albert W. Biglan, M.D. "Management of Hemifacial Spasm With Botulinum A Toxin" Professor of Ophthalmology University of Pittsburgh School of Medicine Pittsburgh, Pennsylvania Andrew Blitzer, M.D., "Botulinum Toxin for the Treatment of Oromandibular and Lingual Dystonia" "Botulinim Toxin for the Treatment of All Forms of Spasmodic Dysphonia" Professor and Director Department of Otolaryngology/Head and Neck Surgery Columbia University New York, New York Mitchell F. Brin, M.D. "Botulinim Toxin for the Treatment of All Forms of Spasmodic Dysphonia" "Botulinum Toxin for the Treatment of Oromandibular and Lingual Dystonia" Assistant Professor Department of Neurology Columbia Presbyterian Hospital New York, New York Leonardo G. Cohen, M.D. "Botulinum Toxin in the Treatment of Focal Dystonias of the Hand" Head, Human Corpical Physiology Unit Human Motor Control Section National Institute of Neurological Disorders and Stroke National Institutes of Health Bethesda, Maryland Bibhuti R. DasGupta, Ph.D. "Botulinum Neurotoxin: Structure and Structure-Function Relationship" Senior Scientist Department of Food Microbiology and Toxicology University of Wisconsin Madison, Wisconsin Donald T. Donovan, M.D. "Clinical Trials for Speech Disorders 5: Botulinum Toxin in the Treatment of Adductor Spasmodic Dysphonia" Assistant Professor Department of Otolaryngology and Communicative Sciences Baylor College of Medicine Houston, Texas Richard M. Dubinsky, M.D. "Electromyographic Guidance of Botulinum Toxin Treatment in Torticollis" Assistant Professor Department of Neurology Kansas University Medical Center Kansas City, Kansas Jonathan J. Dutton, M.D., Ph.D. "Botulinum Toxin in the Management of Hemifacial Spasm: Clinical Trials 1" "Botulinum Toxin in the Management of Essential Blepharospasm: Clinical Trials 2" Associate Professor Duke University Eye Center Durham, North Carolina Dennis D. Dykstra, M.D., Ph.D. "Effects of Botulinum A Toxin on Detrusor-Sphincter Dyssynergia in Spinal Cord Injury Patients" Assistant Professor Department of Physical Medicine and Rehabilitation Assistant Professor of Urologic Surgery University of Minnesota Minneapolis, Minnesota John S. Elston, M.D., B.Sc., F.R.C.S. "Botulinum Toxin for Blepharospasm: Rationale and Results" Consultant Ophthalmologist National Hospital for Neurology and Neurosurgery London ENGLAND Stanley Fahn, M.D. "Overview of Torsion Dystonia" Merritt Professor Department of Neurology Columbia University New York, New York John T. Flynn, M.D. "Strabismus: Other Therapies" Professor Department of Ophthalmology Bascom Palmer Eye Institute University of Miami Miami, Flordia Charles N. Ford, M.D., F.A.C.S. "Indirect Laryngoscopic Approach for Injection of Botulinum Toxin in Spasmodic Dysphonia" Professor of Otolaryngology Head and Neck Surgery University of Wisconsin Madison, Wisconsin Bruce George, B.Sc., F.R.C.S. "Treatment of Anismus with Botulinum A Toxin" Research Follow The Royal London Hospital London ENGLAND Paul Greene, M.D. "Clinical Trials for Cervical Dystonia 2" Assistant Professor of Neurology Columbia Presbyterian Medical Center Neurological Institute New York, New York Joseph Jankovic, M.D. "Clinical Trials for Cervical Dystonia 1" "Clinical Trials for Blepharospasm 3" "Clinical Trials for Speech Disorders 5: Botulinum Toxin in the Treatment of Adductor Spasmodic Dysphonia" Professor Neurology Director of Parkinson's Disease Center and Movement Disorders Clinic Baylor College of Medicine Houston, Texas Peter J. Jannetta, M.D. "Hemifacial Spasm" Professor and Chairman Department of Neurological Surgery University of Pittsburgh School of Medicine Pittsburgh, Pennsylvania L. Andrew Koman, M.D. "Cerebral Palsy Management by Neuromuscular Blockade With Botulinum-A Toxin" Associate Professor Orthopedic Surgery Bowman Gray School of Medicine Winston-Salem, North Carolina Anthony E. Lang, M.D., F.R.C.P. (C) "Clinical Trials of Botulinum Toxin in Cervical Dystonia" Professor and Director Department of Neurology Toronto Western Hospital Movement Disorders Clinic Toronto, Ontario CANADA Christy L. Ludlow, Ph.D. "Clinical Trials for Oromandibular Dystonia 2" "Clinical Trials for Speech Disorders 1" Head Speech and Voice Unit Division of Intramural Research National Institute on Deafness and Other Communication Disorders National Institutes of Health Bethesda, Maryland Elbert H. Magoon, M.D. "Clinical Use of Botulinum Toxin-Clinical Trials for Strabismus" Ophthalmologist Canton Eye Center, Inc. Northeast Ohio College of Medicine Canton, Ohio Seth L. Pullman, M.D., F.R.C.P. "Limb Dystonia: Treatment With Botulinum Toxin" Assistant Professor and Director Department of Neurology Clinical Motor Physiology Laboratory Columbia University College of Physicians and Surgeons New York, New York Arthur L. Rosenbaum, M.D. "The Clinical Use of Botulinum Toxin in Acute and Chronic VI Nerve Palsy" Professor and Chief Division of Pediatric Ophthalmology Jules Stein Eye Institute University of California, Los Angeles Los Angeles, California Alan B. Scott, M.D. "Botulinum Toxin Production and Immunology" "Strabismus Injection Treatment" Co-Executive Director Smith-Kettlewell Eye Research Institute San Francisco, California Kathleen M. Shannon, M.D. "Clinical Trials for Cervical Dystonia 4" Assistant Professor Department of Neurology Vanderbilt University Medical Center South Nashville, Tennessee Lance L. Simpson, Ph.D. "The Structure and Biological Activity of Botulinum Neurotoxin" Director and Professor of Medicine Division of Environmental Medicine and Toxicology Jefferson Medical College Thomas Jefferson University Hospital Philadelphia, Pennsylvania Joseph K.C. Tsui, M.B., B.S., M.R.C.P. "Clinical Trials for Cervical Dystonia 3" "Clinical Trials for Spasticity" Assistant Professor Department of Neurology University of British Columbia Vancouver, British Columbia CANADA G. Woodson, M.D. "Acoustic, Aerodynamic, and Videoendoscopic Assessment of Unilateral Thyroarytenoid Muscle Injection With Botulinum Toxin for Spasmodic Dysphonia" Staff Physician and Professor VA Medical Center University of California, San Diego Medical Center San Diego, California Planning Committee Mark Hallett, M.D. Planning Committee Chairman Clinical Director National Institute of Neurological Disorders and Stroke National Institutes of Health Bethesda, Maryland Linda Blankenbaker Program Analyst Office of Medical Applications of Research National Institutes of Health Bethesda, Maryland Stephanie E. Clipper Public Information Specialist Information Office National Institute of Neurological Disorders and Stroke National Institutes of Health Bethesda, Maryland Roger C. Duvoisin, M.D., F.A.C.P. Conference and Panel Chairman Professor and Chairman Department of Neurology University of Medicine and Dentistry of New Jersey Robert Wood Johnson Medical School New Brunswick, New Jersey Stanley Fahn, M.D. Merritt Professor Department of Neurology Columbia University New York, New York William H. Habig, Ph.D. Deputy Director Division of Bacterial Products Food and Drug Administration Bethesda, Maryland William H. Hall Director of Communications Office of Medical Applications of Research National Institutes of Health Bethesda, Maryland Joseph Jankovic, M.D. Professor of Neurology Director of Parkinson's Disease Center and Movement Disorders Clinic Baylor College of Medicine Houston, Texas Christy L. Ludlow, Ph.D. Head Speech and Voice Unit Division of Intramural Research National Institute on Deafness and Other Communication Disorders National Institutes of Health Bethesda, Maryland Arthur L. Rosenbaum, M.D. Professor and Chief Division of Pediatric Ophthalmology Jules Stein Eye Institute University of California, Los Angeles Los Angeles, California Alan B. Scott, M.D. Co-Executive Director Smith-Kettlewell Eye Research Institute San Francisco, California Lance L. Simpson, Ph.D. Director and Professor of Medicine Division of Environmental Medicine and Toxicology Jefferson Medical College Thomas Jefferson University Hospital Philadelphia, Pennsylvania Gayle Woodson, M.D. Staff Physician and Professor VA Medical Center University of California, San Diego Medical Center San Diego, California Conference Sponsors National Institute of Neurological Disorders and Stroke Murray Goldstein, M.D. Director NIH Office of Medical Applications of Research John H. Ferguson, M.D. Director National Institute on Deafness and Other Communication Disorders James B. Snow, Jr., M.D. Director Food and Drug Administration David Kessler, M.D., J.D. Commissioner

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