ORLANDO—Over the past decade, botulinum toxin has undergone a striking clinical transformation, moving from the therapeutic fringe to center stage as a potential treatment for a large and growing number of neuromuscular disorders characterized by muscular overactivity. Approved by the Food and Drug Administration in 1989 for the treatment of strabismus, blepharospasm, and hemifacial spasm-and still approved only for those indications in the United States—injection of botulinum toxin is now considered a treatment of choice for most forms of focal dystonia and is rapidly becoming a prime therapy for focal spasticity in both children and adults. In the last several years, suggested indications have grown to include tremor, migraine, tension headache, gastrointestinal disorders, and cosmetic complaints. This explosion in clinical applications was the focus of the recent International Conference 1999: Basic and Therapeutic Aspects of Botulinum and Tetanus Toxins.

A POWERFUL POISON

Botulinum toxin exerts its paralytic effect at the neuromuscular junction by cleaving one or more of the proteins responsible for fusion of synaptic vesicles with the axon terminal membrane, thereby preventing acetylcholine release. The seven serotypes of botulinum toxin, designated A through G, have different targets and different durations of action; only one, botulinum toxin type A, is currently marketed in the United States, under the trade name Botox® (it is also available overseas). Another brand of botulinum toxin type A, Dysport®, is marketed in Europe. Botulinum toxin type B, tested under the trade name NeuroBloc™, is expected to reach the market in the United States later this year.

The toxin, which is purified from bacterial cultures of Clostridium botulinum, is the most poisonous known biological substance—so potent, in fact, that a single batch of toxin, prepared in 1979, provided the entire worldwide supply of Botox until last year, when a new batch was prepared. In addition to the active molecule itself, purified toxin contains associated proteins that aid its passage through the gastrointestinal tract, its normal mode of (nontherapeutic) entry.

In research settings, toxin activity is measured in "mouse units," each defined as the amount of toxin required to kill 50% of experimental mice by intraperitoneal injection (LD50). In clinical settings, dosage ranges vary substantially between the three botulinum toxin preparations; a typical dose for treatment of cervical dystonia is 150 to 250 units of Botox, 500 to 1,000 units of Dysport, and approximately 10,000 units of botulinum toxin type B. The basis for these widely differing dosage ranges has long puzzled researchers; it is thought that interspecies differences in sensitivity to the different toxin types or to the effects of the associated proteins plays some part, and that slight variations in the lethality assays used by different manufacturers may also be important. Because of the differences in unit potency, conference presenters highlighted the importance of clarifying the specific product in question in any discussion of doses.

HEAD-TO-HEAD COMPARISONS?

Differences in autonomic actions of botulinum toxin type A versus type B might also warrant clinical attention. In phase III trials of type B for cervical dystonia, discussed at the conference by Stewart Factor, DO, dry mouth was reported by 34% of patients, and dysphagia by 25% of patients (although no patients dropped out because of these side effects). Dr. Factor is Director of the Parkinson's Disease and Movement Disorders Center at Albany Medical College. However, rates of dysphagia at clinically effective doses were comparable in treatment and placebo groups in recent controlled trials of Dysport, reported by Dr. Werner Poewe of the University of Innsbruck, and in trials of Botox, presented by Cynthia Comella, MD, of Rush Medical College in Chicago. But Dr. Comella noted that drawing valid conclusions would require head-to-head comparisons of the three botulinum toxin preparations, as well as a better understanding of their exact dosage equivalencies. Moreover, as one audience member who had used all three preparations observed, "They all work for cervical dystonia."

The antigenicity of botulinum toxin has been another cause for clinical concern; approximately 5% of patients treated with botulinum toxin type A for cervical dystonia eventually develop antibody-mediated resistance to therapy. Retrospective data presented by Dirk Dressler, MD, of the University of Rostock, Germany, suggest that resistance is most likely to develop when an individual dose is high and the interval between injections is short; however, age at onset of dystonia, duration of treatment, and cumulative dose were not important predictors. The data presented by Dr. Factor suggest that botulinum toxin type B may be effective in patients resistant to type A.

A SPASTICITY INDICATION?

The use of botulinum toxin for spasticity has grown dramatically in recent years. While spasticity is still an off-label use both in the United States and abroad, Reiner Benecke, MD, of the University of Rostock, predicted that "Should we have another meeting in perhaps four years, I have little doubt that use for spasticity will be one of the most important topics under discussion."

In the meantime, several new studies presented at the conference helped define the current role of botulinum toxin type A in the management of spasticity secondary to cerebral palsy. Dr. Bipin Bhakta, of the University of Leeds, UK, reported results from a double-blind study in which botulinum toxin type A was injected into the calf muscles of 40 children with cerebral palsy; subjects showed significant increases in foot contact, ankle range of motion, standing ability, and walking unaided with splints, but not in energy expenditure. Dr. Magdid Bakheit, from the University of Plymouth, UK, reported retrospective data from 758 children with cerebral palsy; 82% had a "good" overall response to botulinum toxin type A therapy, with 44% achieving moderate improvement in a wide variety of functional goals, including mobility and ease of care. Finally, Dr. James MacLean, from the Perth Royal Infirmary, UK, reported a retrospective analysis of 25 patients followed for several years. While most will eventually require surgery to treat muscle contractures, Dr. MacLean said, botulinum toxin delayed the need for surgery, especially when initiated in relatively young children; it can also help refine the surgical targets, he added.

PROMISING FOR PAIN

Several studies from the meeting addressed another promising application for botulinum toxin—relief of myofascial pain. Mike Royal, MD, Adjunct Professor, Oklahoma University College of Medicine, and Medical Director of the Pain Evaluation and Treatment Center in Tulsa, reported retrospective data on 76 patients who received botulinum toxin type A injections into trigger points and surrounding muscle for refractory myofascial pain. Good to excellent relief, lasting approximately three months, was reported by 70% of the patients. "During the response phase, these patients were also able to tolerate a more aggressive therapeutic exercise program," Dr. Royal noted.

Drs. Brian Freund and Marvin Schwartz, of the Institute for Head and Neck Therapy, Ontario, described a double-blind study of botulinum toxin type A for whiplash-associated chronic neck pain. The treatment group had significantly less pain and increased range of motion at four weeks compared to the placebo group, but there was only a trend toward subjective functional improvement.

Dr. Mauro Porta, from the Policlinico San Marco in Zingonia, Italy, injected botulinum toxin or methylprednisone into patients' back muscles in single-blind fashion, followed by a period of rehabilitation. At 30 days, the reduction in pain with botulinum toxin type A treatment was greater than that with methylprednisone, although the difference fell just short of statistical significance; at 60 days the relative benefits of botulinum toxin type A were much greater, as the effects of the steroid had begun to wane.

"TANTALIZING" RESULTS IN MIGRAINE

Headache is another experimental arena in which botulinum toxin is increasingly used. Two double-blind trials reported at the conference suggest that botulinum toxin type A may be an effective therapy for tension-type headache in patients resistant to other medications, including antidepressants. Botulinum toxin treatment led to significantly more headache-free days, as well as a decline in pain intensity. One researcher noted that 15 of the original 16 patients in his study have chosen to continue open-label botulinum toxin type A for more than one year after the study's double-blind interval ended.

Migraine also appears susceptible to botulinum toxin treatment. Mitchell Brin, MD, of Mount Sinai School of Medicine, New York City, reported data from an open-label study of 77 patients; nearly 90% had a partial or complete response, typically lasting for about two and a half months. Thomas Ward, MD, of the Dartmouth-Hitchcock Medical Center, New Hampshire, reported a placebo-controlled trial of botulinum toxin type A for migraine prophylaxis. A total of 123 patients received injections of placebo, 25 units of Botox, or 75 units of Botox into the glabellar, frontalis, and temporalis muscles. Low-dose treatment led to significant reductions in migraine frequency, with 60% of patients reporting at least two fewer migraines per month. This group also required less analgesic medication during most of the treatment period, and had less migraine-associated vomiting. Paradoxically, lower efficacy was demonstrated with the higher dose, perhaps because patients randomized to this group had fewer initial migraines, as well as a higher incidence of adverse effects (including ptosis) that may have affected perceptions of benefits.

Nonetheless, "these results are very tantalizing," Dr. Ward said. He added, however, that he is "not yet a true believer," and that he is awaiting results of a newer and larger study currently under way, with results expected in the spring of 2000.

Why migraine should be amenable to botulinum toxin treatment remains unclear. According to Dr. Brin, some substantial new evidence supports a role for the toxin in the inhibition of afferent signals, as well as motor commands. With this in mind, he suggested that botulinum toxin may be suppressing pain afferents that would otherwise trigger the release of inflammatory peptides. "The observation that botulinum toxin can help migraine may force us to reconsider the mechanism of action of pain relief," he said, with nonmotor effects coming into play. "We may learn more in the next couple of years," he added, citing the number of new clinical trials ongoing in this area.

"ON TO SOMETHING INTERESTING"?

Findings from the conference also suggested a host of other possible therapeutic settings, including Parkinson's disease and amyotrophic lateral sclerosis (ALS). In both of these diseases, sialorrhea has been treated with injections to the parotids and submandibular glands. Dr. Marcus Naumann of the University of Wurzburg, Germany, noted that while ALS is normally an exclusion criterion, botulinum toxin may be appropriate in selected patients when sialorrhea is a significant symptom. One neurologist in the audience reported using botulinum toxin to treat painful jaw spasms in late-stage ALS patients, easing oral hygiene and allowing the patients to talk more easily with family members.

Another potential application was discussed by Dr. Nir Giladi of the Tel Aviv Medical Center, who treated 10 patients with Parkinson's disease for freezing of gait; injection of botulinum toxin to the calf muscles led to an average of six weeks of improvement in six patients. One went on to receive a single-blind injection, with saline as the placebo in the other calf, and had significant improvement on the toxin-treated side only. "At the end of this preliminary, open trial," Dr. Giladi said, "we can say we think we are on to something interesting. It's too early to say more than that for now."

—Richard Robinson
Contributing Writer

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