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Studies, Reports Say Botulinum Toxins May Have Effects Beyond Injection Site

Studies, Reports Say Botulinum Toxins May Have Effects Beyond Injection Site Scientists and investigators are probing the possibility that botulinum toxins may migrate from the site of injection and may cause unintended effects including weakening adjacent muscles. As the myriad clinical uses for botulinum toxins continue to expand, scientists examining their mechanism of action in animal models have demonstrated that these neurotoxins may have a measurable effect on muscles adjacent to the injection site. They also have identified pathways by which the toxins may travel in the nervous system and cause distant neurological effects. The findings have emerged as the US Food and Drug Administration (FDA) investigates reports of adverse reactions in patients treated with botulinum toxin that suggest spread of toxin beyond the injection site. (Credit: Molecule Data Source: Drugbank Accession No. DB00083) Scientists have documented that the poisonous light chain (purple) of botulinum toxin type A can move from one synapse to the next. Botulinum toxins are the most powerful poisons known, according to Daniel B. Drachman, MD, professor of neurology and neuroscience at the Johns Hopkins School of Medicine in Baltimore. He explained that when ingested, even a tiny amount of the toxins will highly specifically bind to nerve endings. A key effect of the toxin is blocking the release of neurotransmitters, which causes muscle weakening or paralysis. Scientists have learned to harness the ability of some botulinum toxins to silence neurotransmission and reduce muscle activity. Although the public is most familiar with the cosmetic use of botulinum toxin to weaken facial muscles that contribute to the appearance of wrinkles, these neurotoxins are useful for dystonias and other conditions in which muscles are overactive. Researchers also are studying their use for a host of other conditions, including migraine and other types of pain. Migration documented Studies of new potential uses of botulinum toxins have led to a greater understanding of the precise mechanisms of the toxins' actions. One such study, published in April by Italian researchers investigating potential effects of botulinum toxin type A, has described an unexpected pathway by which the poison may travel through the nervous system and cause neurological changes at a distance from the injection site. Matteo Caleo, PhD, of Italy's National Research Council in Pisa, and colleagues injected botulinum toxin in rats' whisker-controlling muscles and explored whether toxin traveled from the injection site (Antonucci F et al. J Neurosci. 2008;28[14]:3689-3696). Studies dating back to the 1970s had suggested that the botulinum toxins might migrate from the site of injection; however, it was believed that the poisonous subunit of the toxin remained in the motor neuron terminal. But Caleo and his colleagues demonstrated that in fact the poisonous subunit may move not only up the nerve that is connected to the injected muscle, but may even cross to the next synapse in the spinal cord and/or central nervous system and possibly cause neurological changes distant from the site of injection. The study indicates that the functional part of the botulinum toxin is carried by retrograde axonal transport away from the muscle toward the brain and spinal cord and can affect cells further upstream in the pathway, explained Drachman, who was not involved in the research. Caleo was cautious in his assessment of the potential clinical implications of his findings. He noted that the spread of the toxin in his study was limited to the cells that project from the targeted muscle. Toxin activity in these adjacent cells may actually improve the desired therapeutic effect, he explained, “if the aim of the therapy is to shut down the activity of the motor neuron in dystonia, cerebral palsy, and also to eliminate the wrinkles in the face . . . this will add some beneficial effect.” Clinicians also might one day take advantage of this means of transport to deliver therapeutic doses of the toxin in hard-to-inject sites, such as the brain. But if the spread of the toxin blocks the action of other nerve circuits, that could be a concern, he said. “We need to know [about the drug's migration] to avoid negative side effects and, maybe in the near future, to take advantage of ability of the toxin to move for treatment of other pathologies that could be treated by peripheral administration,” Caleo said. Another team of scientists, using botulinum toxin type A in a study of the effects of muscle weakness on joint degeneration, found that the toxin can affect not only the targeted muscle but also another nearby muscles and cause measurable weakness. The scientists injected the toxin (using doses similar to those used to selectively diminish muscle function in human patients) into the soleus muscle of a cat's hind limb and measured the strength of the soleus and the neighboring plantaris muscle before and after injection (Yaraskavitch M et al. J Biomech. 2008;41[4]:897-902). They found significant reductions after injection in the strength of both muscles (about 30% reduction in the soleus and about 11%-15% in the plantaris). Drachman noted that if the goal of treatment is to weaken the soleus, some collateral weakening of the plantaris is unlikely to be clinically harmful. He also noted a previous human study in which botulinum toxins that were injected into the abductor digiti minimi muscle produced virtually no weakening of adjacent muscles (Eleopra R et al. Mov Disord. 2004;19[suppl 8]:S53-S59). “It's important to realize that injecting botulinum in one muscle may conceivably weaken others in the neighborhood,” he said. This collateral weakening may be clinically relevant in some conditions but not in others, he added. But Walter Herzog, PhD, professor of kinesiology at the University of Calgary, who led the research team, said in a statement that the findings suggest more study of botulinum toxin is needed. “Many people believe that when Botox is injected into a single muscle it stays there,” Herzog said. “This research shows that is not that easy to control. As therapeutic applications of botulinum toxin type A in humans increase, it is important that we understand more about the functional effects of this product, which, at the end of the day, is a toxin.” Botulism-like symptoms The findings come on the heels of an FDA announcement in February that 3 botulinum toxin products, Botox and Botox Cosmetic (botulinum toxin type A) and Myobloc (botulinum toxin type B), have been linked to adverse reactions, including respiratory failure and death, in patients treated with the drugs for a variety of conditions and at a range of doses. The adverse reactions “appear to be related to the spread of the toxin to areas distant from the site of injection, and mimic symptoms of botulism, which may include difficulty swallowing, weakness, and breathing problems,” the agency noted in a statement. These drugs are approved for treatment of such disorders as muscle spasms of the eyelids (Botox) or neck (Botox and Myobloc), for excessive sweating (Botox), and for the temporary lessening of moderate to severe facial frown lines (Botox Cosmetic). However, botulinum toxin products are also commonly used off-label to treat a range of other conditions. There have been warnings since at least 2005 that botulinum products may cause adverse events distant from the site of injection. In 2005, the European Medicines Agency (EMA), the FDA's European counterpart, updated the packaging of Neurobloc (botulinum toxin type B) to note possible systemic effects among serious adverse events reported for the drug, including dry mouth, dysphagia, and blurred vision. In 2006, the EMA expressed concern that botulinum toxin products were associated with dysphagia and fatal outcomes (17 deaths were noted by the agency in 2005). Finally, the agency updated the labeling in 2007 to note that distant reactions, including muscle weakness, dysphagia, and aspiration, “represent a significant proportion of all reported serious events associated with botulinum-containing products.” According to the agency's Web site, the effects were typically temporary and cleared up within a few weeks. In some fatal cases the toxin may have contributed, although most involved patients with underlying medical conditions such as neurological disorders and prior history of dysphagia or aspiration. In an e-mailed response to questions, officials from the FDA's Division of Neurology Products noted that the labels for FDA-approved botulinum products already warn about the potential for spread of the toxin near the injection site. However, reports of systemic adverse events in pediatric patients treated with the products prompted the agency to review its Adverse Events Reporting System for other such cases. The most serious adverse events have occurred in children treated with botulinum toxins for cerebral palsy–associated limb spasticity, the FDA said. Data from a preliminary review of adverse event reports to the agency, which was completed in November, and cases described in the literature revealed that pediatric patients who developed botulism following treatment had symptoms that included dysphagia and respiratory insufficiency, requiring gastric feeding tubes and ventilator support. Reported adverse effects in adult patients included difficulty holding up the head, dysphagia, ptosis and, in some cases, weakness or numbness in the lower extremities. There were no deaths among adults; although some were hospitalized, none required intubation or ventilator support. There have been reports of these sort of distant effects with cosmetic use, “but they are extremely rare and it's not even really clear whether or not those events could be attributed to the treatment,” Katz said during a press briefing in February. Public Citizen, a consumer advocacy organization, petitioned the FDA to force the companies that market botulinum toxins in the United States to issue warning letters to physicians about the reported complications. The organization reviewed the FDA's adverse event reports between November 1, 1997, and December 31, 2006, for botulinum toxin products and found 180 cases involving dysphagia, aspiration, or pneumonia in which botulinum toxins were suspected; 16 were fatalities, 4 of them in children. As of April, the FDA had not released data on the numbers of cases involved. The agency said some of the adverse events reported may have involved overdosing, and have posted advice on the agency's Web site for clinicians using medicinal botulinum toxins (http://www.fda.gov/cder/drug/early_comm/botulinium_toxins.htm). Whether the animal studies provide any insight on these events remains unclear. “It is too early, based on these animal studies, to extrapolate to activity of the drug in humans,” according to the FDA officials. The agency continues to investigate the safety of the drug and will report its conclusions when the investigation is complete, they said. US Food and Drug Administration (FDA) Recommends Caution While the FDA investigates the cause of adverse events in patients treated with medicinal botulinum toxins, physicians are advised to Understand that the potency determinations expressed in units or U vary among these products and clinical doses expressed in units are not comparable from one product to the next Be vigilant for signs of systemic effects following administration such as dysphagia, dysphonia, weakness, dyspnea, or respiratory distress Be aware that such adverse events have been reported after as early as 1 day after treatment or as late as several weeks after administration Provide patients and caregivers information that will help them to identify the signs and symptoms of systemic effects Instruct patients to seek immediate medical attention if they have worsening or unexpected difficulty swallowing or talking, trouble breathing, or muscle weakness http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png JAMA American Medical Association

Studies, Reports Say Botulinum Toxins May Have Effects Beyond Injection Site

Kuehn, Bridget M.
JAMA , Volume 299 (19) – May 21, 2008
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Publisher
American Medical Association
Copyright
Copyright © 2008 American Medical Association. All Rights Reserved.
ISSN
0098-7484
eISSN
1538-3598
DOI
10.1001/jama.299.19.2261
Publisher site
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Abstract

Scientists and investigators are probing the possibility that botulinum toxins may migrate from the site of injection and may cause unintended effects including weakening adjacent muscles. As the myriad clinical uses for botulinum toxins continue to expand, scientists examining their mechanism of action in animal models have demonstrated that these neurotoxins may have a measurable effect on muscles adjacent to the injection site. They also have identified pathways by which the toxins may travel in the nervous system and cause distant neurological effects. The findings have emerged as the US Food and Drug Administration (FDA) investigates reports of adverse reactions in patients treated with botulinum toxin that suggest spread of toxin beyond the injection site. (Credit: Molecule Data Source: Drugbank Accession No. DB00083) Scientists have documented that the poisonous light chain (purple) of botulinum toxin type A can move from one synapse to the next. Botulinum toxins are the most powerful poisons known, according to Daniel B. Drachman, MD, professor of neurology and neuroscience at the Johns Hopkins School of Medicine in Baltimore. He explained that when ingested, even a tiny amount of the toxins will highly specifically bind to nerve endings. A key effect of the toxin is blocking the release of neurotransmitters, which causes muscle weakening or paralysis. Scientists have learned to harness the ability of some botulinum toxins to silence neurotransmission and reduce muscle activity. Although the public is most familiar with the cosmetic use of botulinum toxin to weaken facial muscles that contribute to the appearance of wrinkles, these neurotoxins are useful for dystonias and other conditions in which muscles are overactive. Researchers also are studying their use for a host of other conditions, including migraine and other types of pain. Migration documented Studies of new potential uses of botulinum toxins have led to a greater understanding of the precise mechanisms of the toxins' actions. One such study, published in April by Italian researchers investigating potential effects of botulinum toxin type A, has described an unexpected pathway by which the poison may travel through the nervous system and cause neurological changes at a distance from the injection site. Matteo Caleo, PhD, of Italy's National Research Council in Pisa, and colleagues injected botulinum toxin in rats' whisker-controlling muscles and explored whether toxin traveled from the injection site (Antonucci F et al. J Neurosci. 2008;28[14]:3689-3696). Studies dating back to the 1970s had suggested that the botulinum toxins might migrate from the site of injection; however, it was believed that the poisonous subunit of the toxin remained in the motor neuron terminal. But Caleo and his colleagues demonstrated that in fact the poisonous subunit may move not only up the nerve that is connected to the injected muscle, but may even cross to the next synapse in the spinal cord and/or central nervous system and possibly cause neurological changes distant from the site of injection. The study indicates that the functional part of the botulinum toxin is carried by retrograde axonal transport away from the muscle toward the brain and spinal cord and can affect cells further upstream in the pathway, explained Drachman, who was not involved in the research. Caleo was cautious in his assessment of the potential clinical implications of his findings. He noted that the spread of the toxin in his study was limited to the cells that project from the targeted muscle. Toxin activity in these adjacent cells may actually improve the desired therapeutic effect, he explained, “if the aim of the therapy is to shut down the activity of the motor neuron in dystonia, cerebral palsy, and also to eliminate the wrinkles in the face . . . this will add some beneficial effect.” Clinicians also might one day take advantage of this means of transport to deliver therapeutic doses of the toxin in hard-to-inject sites, such as the brain. But if the spread of the toxin blocks the action of other nerve circuits, that could be a concern, he said. “We need to know [about the drug's migration] to avoid negative side effects and, maybe in the near future, to take advantage of ability of the toxin to move for treatment of other pathologies that could be treated by peripheral administration,” Caleo said. Another team of scientists, using botulinum toxin type A in a study of the effects of muscle weakness on joint degeneration, found that the toxin can affect not only the targeted muscle but also another nearby muscles and cause measurable weakness. The scientists injected the toxin (using doses similar to those used to selectively diminish muscle function in human patients) into the soleus muscle of a cat's hind limb and measured the strength of the soleus and the neighboring plantaris muscle before and after injection (Yaraskavitch M et al. J Biomech. 2008;41[4]:897-902). They found significant reductions after injection in the strength of both muscles (about 30% reduction in the soleus and about 11%-15% in the plantaris). Drachman noted that if the goal of treatment is to weaken the soleus, some collateral weakening of the plantaris is unlikely to be clinically harmful. He also noted a previous human study in which botulinum toxins that were injected into the abductor digiti minimi muscle produced virtually no weakening of adjacent muscles (Eleopra R et al. Mov Disord. 2004;19[suppl 8]:S53-S59). “It's important to realize that injecting botulinum in one muscle may conceivably weaken others in the neighborhood,” he said. This collateral weakening may be clinically relevant in some conditions but not in others, he added. But Walter Herzog, PhD, professor of kinesiology at the University of Calgary, who led the research team, said in a statement that the findings suggest more study of botulinum toxin is needed. “Many people believe that when Botox is injected into a single muscle it stays there,” Herzog said. “This research shows that is not that easy to control. As therapeutic applications of botulinum toxin type A in humans increase, it is important that we understand more about the functional effects of this product, which, at the end of the day, is a toxin.” Botulism-like symptoms The findings come on the heels of an FDA announcement in February that 3 botulinum toxin products, Botox and Botox Cosmetic (botulinum toxin type A) and Myobloc (botulinum toxin type B), have been linked to adverse reactions, including respiratory failure and death, in patients treated with the drugs for a variety of conditions and at a range of doses. The adverse reactions “appear to be related to the spread of the toxin to areas distant from the site of injection, and mimic symptoms of botulism, which may include difficulty swallowing, weakness, and breathing problems,” the agency noted in a statement. These drugs are approved for treatment of such disorders as muscle spasms of the eyelids (Botox) or neck (Botox and Myobloc), for excessive sweating (Botox), and for the temporary lessening of moderate to severe facial frown lines (Botox Cosmetic). However, botulinum toxin products are also commonly used off-label to treat a range of other conditions. There have been warnings since at least 2005 that botulinum products may cause adverse events distant from the site of injection. In 2005, the European Medicines Agency (EMA), the FDA's European counterpart, updated the packaging of Neurobloc (botulinum toxin type B) to note possible systemic effects among serious adverse events reported for the drug, including dry mouth, dysphagia, and blurred vision. In 2006, the EMA expressed concern that botulinum toxin products were associated with dysphagia and fatal outcomes (17 deaths were noted by the agency in 2005). Finally, the agency updated the labeling in 2007 to note that distant reactions, including muscle weakness, dysphagia, and aspiration, “represent a significant proportion of all reported serious events associated with botulinum-containing products.” According to the agency's Web site, the effects were typically temporary and cleared up within a few weeks. In some fatal cases the toxin may have contributed, although most involved patients with underlying medical conditions such as neurological disorders and prior history of dysphagia or aspiration. In an e-mailed response to questions, officials from the FDA's Division of Neurology Products noted that the labels for FDA-approved botulinum products already warn about the potential for spread of the toxin near the injection site. However, reports of systemic adverse events in pediatric patients treated with the products prompted the agency to review its Adverse Events Reporting System for other such cases. The most serious adverse events have occurred in children treated with botulinum toxins for cerebral palsy–associated limb spasticity, the FDA said. Data from a preliminary review of adverse event reports to the agency, which was completed in November, and cases described in the literature revealed that pediatric patients who developed botulism following treatment had symptoms that included dysphagia and respiratory insufficiency, requiring gastric feeding tubes and ventilator support. Reported adverse effects in adult patients included difficulty holding up the head, dysphagia, ptosis and, in some cases, weakness or numbness in the lower extremities. There were no deaths among adults; although some were hospitalized, none required intubation or ventilator support. There have been reports of these sort of distant effects with cosmetic use, “but they are extremely rare and it's not even really clear whether or not those events could be attributed to the treatment,” Katz said during a press briefing in February. Public Citizen, a consumer advocacy organization, petitioned the FDA to force the companies that market botulinum toxins in the United States to issue warning letters to physicians about the reported complications. The organization reviewed the FDA's adverse event reports between November 1, 1997, and December 31, 2006, for botulinum toxin products and found 180 cases involving dysphagia, aspiration, or pneumonia in which botulinum toxins were suspected; 16 were fatalities, 4 of them in children. As of April, the FDA had not released data on the numbers of cases involved. The agency said some of the adverse events reported may have involved overdosing, and have posted advice on the agency's Web site for clinicians using medicinal botulinum toxins (http://www.fda.gov/cder/drug/early_comm/botulinium_toxins.htm). Whether the animal studies provide any insight on these events remains unclear. “It is too early, based on these animal studies, to extrapolate to activity of the drug in humans,” according to the FDA officials. The agency continues to investigate the safety of the drug and will report its conclusions when the investigation is complete, they said. US Food and Drug Administration (FDA) Recommends Caution While the FDA investigates the cause of adverse events in patients treated with medicinal botulinum toxins, physicians are advised to Understand that the potency determinations expressed in units or U vary among these products and clinical doses expressed in units are not comparable from one product to the next Be vigilant for signs of systemic effects following administration such as dysphagia, dysphonia, weakness, dyspnea, or respiratory distress Be aware that such adverse events have been reported after as early as 1 day after treatment or as late as several weeks after administration Provide patients and caregivers information that will help them to identify the signs and symptoms of systemic effects Instruct patients to seek immediate medical attention if they have worsening or unexpected difficulty swallowing or talking, trouble breathing, or muscle weakness

Journal

JAMA – American Medical Association

Published: May 21, 2008

Keywords: botulinum toxins,toxins

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