Botulinum Toxin: From Poison to Possible Treatment for Spasticity in Spinal Cord Injury.

Botulism has been known for about three centuries, and since its discovery, botulinum toxin has been considered one of the most powerful toxins. However, throughout the 20th century, several medical applications have been discovered, among which the treatment of spasticity stands out. Botulinum toxin is the only pharmacological treatment recommended for spasticity of strokes and cerebral palsy. Although its use as an adjuvant treatment against spasticity in spinal cord injuries is not even approved, botulinum toxin is being used against such injuries. This article describes the advances that have been made throughout history leading to the therapeutic use of botulinum toxin and, in particular, its application to the treatment of spasticity in spinal cord injury.

Emergency response to a cluster of suspected food-borne botulism in Abuja, Nigeria: challenges with diagnosis and treatment in a resource-poor setting.

Food-borne botulism is a rare, acute and potentially fatal neurologic disorder that results from ingestion of food contaminated by botulinum toxin released from the anaerobic, spore-forming, gram-positive bacterium Clostridium botulinum. We reported an unusual cluster of botulism outbreak with high case fatality affecting a family following ingestion of home-made fish. A suspected outbreak of botulism affecting three patients in a family of six was reported to the Nigeria Centre for Disease Control. A rapid response team investigated by line-listing all the family members, interviewed extended family members, caregivers, clinicians, and nurses to collect socio-demographic and clinico epidemiological information using a semi-structured questionnaires. We collected blood from patients and food samples and locally made drink from the family home for laboratory testing. All family members ingested the same home-made food within the 48hrs before onset of symptoms in the index case. The clinical presentation of the three affected cases (AR=50.0%) was consistent with botulinum poisoning. Two of the affected cases died (CFR=66.7%) within 48hrs of admission, before antitoxin was made available. The third case had a milder presentation and survived, after administration of appropriate antitoxin. The remaining three children developed no symptoms. None of the samples cultured Clostridium botulinum. The blood samples were negative for mouse lethality test. Our report describes the challenges of diagnosis and management of rare emerging infectious disease outbreaks in resource-constrained settings.

Botulinum Toxin as a Biological Warfare Agent: Poisoning, Diagnosis and Countermeasures.

Botulinum toxin is a neurotoxin produced by Clostridium botulinum and some other relative species. It causes a lethal disease called botulism. It can enter the body via infections by Clostridium (e.g. wound and children botulism) or by direct contact with the toxin or eating contaminated food (food-borne botulism). Botulinum toxin is also considered as a relevant biological warfare agent with an expected high number of causalities when misused for bioterrorist or military purposes. The current paper surveys the actual knowledge about botulinum toxin pathogenesis, the manifestation of poisoning, and current trends in diagnostics and therapeutics. Relevant and recent literature is summarized in this paper.

[Foodbourne Botulism: A Forgotten Disease]. / Botulismo Alimentar: Uma Doença Esquecida.

Botulism is a serious illness caused by exposure to botulinum toxin. It is manifested by flaccid, paralysis, symmetric and in descending pattern affecting cranial and peripheral nerves. Given the frequent need for invasive mechanical ventilation, these patients should be approached in an intensive care setting. Treatment with anti-botulinum toxin is the only effective treatment. The authors present the case of a 64-year-old patient, with vomiting and vertigo, evolution to diplopia, dysphagia and flaccid, muscle paralysis, installation after ingestion of canning homemade. From the etiologica, we highlight the electroneuromyogram study with a pre-synaptic lesion compatible with the botulism hypothesis. Progressive improvement of the deficits after administration of anti-botulinum toxin. A brief theoretical review is made of a serious, potentially fatal and infrequent pathology in our country.

O botulismo é uma doença grave causada pela exposição a toxina botulínica. Manifesta-se por paralisia flácida, simétrica e em padrão descendente que afeta nervos cranianos e periféricos. Dada a frequente necessidade de ventilação mecânica invasiva, estes doentes devem ser abordados em ambiente de cuidados intensivos. O tratamento com soro anti-toxina botulínica é o único eficaz. Os autores apresentam o caso de uma doente de 64 anos, com quadro de vómitos e vertigem, com evolução para diplopia, disfagia e parésia muscular flácida, simétrica e descendente, com instalação após ingestão de conserva alimentar de fabrico caseiro. Do estudo etiológico salienta-se eletroneuromiograma com lesão pré sináptica compatível com hipótese de botulismo. Melhoria progressiva dos défices após administração de soro anti-toxina botulínica. Faz-se uma breve revisão teórica de uma patologia grave, potencialmente fatal e pouco frequente no nosso país.

Long lasting dysautonomia due to botulinum toxin B poisoning: clinical-laboratory follow up and difficulties in initial diagnosis.

BACKGROUND: Botulism is an acute form of poisoning caused by one of four types (A, B, E, F) toxins produced by Clostridium botulinum, ananaerobic, spore forming bacillus. Usually diagnosis of botulism is considered in patients with predominant motor symptoms: muscle weakness with intact sensation and preserved mental function. CASE PRESENTATION: We report a case of 56-year-old Caucasian female with a history of arterial hypertension, who presented with acute respiratory failure and bilateral ptosis misdiagnosed as brainstem ischemia. She had severe external and internal ophtalmoplegia, and autonomic dysfunction with neither motor nor sensory symptoms from upper and lower limbs. Diagnosis of botulinum toxin poisoning was made and confirmed by serum antibody testing in the mouse inoculation test. CONCLUSIONS: Ophtalmoplegia, autonomic dysfunction and respiratory failure can be caused by botulism. Early treatment and intensive care is essential for survival and recovery. The electrophysiological tests are crucial to correct and rapid diagnosis. Botulism (especially type B) should be considered in any case of acute or predominant isolated autonomic dysfunction.

[Botulinum toxin as a biological weapon]. / Botulinumtoksiini biouhka-agenssina.

Botulism is caused by botulinum neurotoxin produced by the bacterium Clostridium botulinum. It is a flaccid paralysis in which consciousness and nociception are preserved. Natural botulism typically results from ingestion of inadequately heated or unheated vacuum-packed foods. In addition, botulinum toxin is one of the most feared biological weapons. In the diagnosis and treatment of botulism early suspicion is essential. Several coinciding or local clusters without a typical connecting source, or an uncommon type of toxin may indicate an intentionally caused epidemic.

Analysis of the mechanisms that underlie absorption of botulinum toxin by the inhalation route.

Botulinum toxin is a highly potent oral and inhalation poison, which means that the toxin must have an efficient mechanism for penetration of epithelial barriers. To date, three models for toxin passage across epithelial barriers have been proposed: (i) the toxin itself undergoes binding and transcytosis; (ii) an auxiliary protein, HA35, transports toxin from the apical to the basal side of epithelial cells; and (iii) an auxiliary protein, HA35, acts on the basal side of epithelial cells to disrupt tight junctions, and this permits paracellular flux of toxin. These models were evaluated by studying toxin absorption following inhalation exposure in mice. Three types of experiments were conducted. In the first, the potency of pure neurotoxin was compared with that of progenitor toxin complex, which contains HA35. The results showed that the rate and extent of toxin absorption, as well as the potency of absorbed toxin, did not depend upon, nor were they enhanced by, the presence of HA35. In the second type of experiment, the potencies of pure neurotoxin and progenitor toxin complex were compared in the absence or presence of antibodies on the apical side of epithelial cells. Antibodies directed against the neurotoxin protected against challenge, but antibodies against HA35 did not. In the final type of experiment, the potency of pure neurotoxin and toxin complex was compared in animals pretreated to deliver antibodies to the basal side of epithelial cells. Once again, antibodies directed against the neurotoxin provided resistance to challenge, but antibodies directed against HA35 did not. Taken collectively, the data indicate that the toxin by itself is capable of crossing epithelial barriers. The data do not support any hypothesis in which HA35 is essential for toxin penetration of epithelial barriers.

Formulating a new basis for the treatment against botulinum neurotoxin intoxication: 3,4-Diaminopyridine prodrug design and characterization.

Botulism is a disease characterized by neuromuscular paralysis and is produced from botulinum neurotoxins (BoNTs) found within the Gram positive bacterium Clostridium botulinum. This bacteria produces the most deadliest toxin known, with lethal doses as low as 1 ng/kg. Due to the relative ease of production and transport, the use of these agents as potential bioterrorist weapons has become of utmost concern. No small molecule therapies against BoNT intoxication have been approved to date. However, 3,4-diaminopyridine (3,4-DAP), a potent reversible inhibitor of voltage-gated potassium channels, is an effective cholinergic agonist used in the treatment of neuromuscular degenerative disorders that require cholinergic enhancement. 3,4-DAP has also been shown to facilitate recovery of neuromuscular action potential post botulinum intoxication by blocking K(+) channels. Unfortunately, 3,4-DAP displays toxicity largely due to blood-brain-barrier (BBB) penetration. As a dual-action prodrug approach to cholinergic enhancement we have designed carbamate and amide conjugates of 3,4-DAP. The carbamate prodrug is intended to be a slowly reversible inhibitor of acetylcholinesterase (AChE) along the lines of the stigmines thereby allowing increased persistence of released acetylcholine within the synaptic cleft. As a secondary activity, cleavage of the carbamate prodrug by AChE will afford the localized release of 3,4-DAP, which in turn, will enhance the pre-synaptic release of additional acetylcholine. Being a competitive inhibitor with respect to acetylcholine, the activity of the prodrug will be greatest at the synaptic junctions most depleted of acetylcholine. Here we report upon the synthesis and biochemical characterization of three new classes of prodrugs intended to limit previously reported stability and toxicity issues. Of the prodrugs examined, compound 32, demonstrated the most clinically relevant half-life of 2.76 h, while selectively inhibiting AChE over butyrylcholinesterase--a plasma-based high activity esterase. Future in vivo studies could provide validation of prodrug 32 as a potential treatment against BoNT intoxication as well as other neuromuscular disorders.

Foodborne botulinum type E intoxication associated with dried bean curd: first case report in Taiwan.

PURPOSE: Botulism type E intoxication is a rare condition among human botulism. We aim to describe a first case of botulism type E intoxication in Taiwan. CASE REPORT: We report a 36-year-old young man with foodborne botulism type E associated with commercially vacuum packaged dried bean curd. He developed bilateral ptosis, diplopia and dysphagia 4 days after taking the dried bean curd. Electrophysiologic findings demonstrated waxing responses to 3 Hz repetitive nerve stimulation and decreased compound muscle action potentials on peripheral nerve conduction study. A bioassay for botulism in mice demonstrated that the patient had botulism caused by type E botulinum toxin. Antibodeis to C. botulinum type E were identified from his serum, confirming the diagnosis. CONCLUSIONS: This is the first known case of foodborne type E botulism in Taiwan. The potential source of this foodborne botulism should consider contaminated food made of soy beans.

Autopsy findings in botulinum toxin poisoning.

In the United States, foodborne botulism is most commonly associated with home-canned food products. Between 1950 and 2005, 405 separate outbreaks of botulism were reported to the Centers for Disease Control and Prevention (CDC). Approximately 8% of these outbreaks were attributed to commercially produced canned food products. Overall, 5-10% of persons ingesting botulinum toxin die. Few reports exist pertaining to autopsy findings in cases of foodborne botulism. Here, we report the autopsy findings of a man who died after a prolonged illness caused by botulinum toxin exposure likely attributable to a commercially prepared food source. Despite extensive testing, our histopathologic findings were nonspecific. We therefore conclude that the forensic pathologist must become familiar with the neurotoxicity syndrome associated with this illness. Maintaining vigilance for botulism by carefully reviewing the decedent's clinical history will aid in the early identification and control of outbreaks, either foodborne or terrorism-related.

Toxins from bacteria.

Bacterial toxins damage the host at the site of bacterial infection or distant from the site. Bacterial toxins can be single proteins or oligomeric protein complexes that are organized with distinct AB structure-function properties. The A domain encodes a catalytic activity. ADP ribosylation of host proteins is the earliest post-translational modification determined to be performed by bacterial toxins; other modifications include glucosylation and proteolysis. Bacterial toxins also catalyze the non-covalent modification of host protein function or can modify host cell properties through direct protein-protein interactions. The B domain includes two functional domains: a receptor-binding domain, which defines the tropism of a toxin for a cell and a translocation domain that delivers the A domain across a lipid bilayer, either on the plasma membrane or the endosome. Bacterial toxins are often characterized based upon the secretion mechanism that delivers the toxin out of the bacterium, termed types I-VII. This review summarizes the major families of bacterial toxins and also describes the specific structure-function properties of the botulinum neurotoxins.

Sufficiency of care in disasters: ventilation, ventilator triage, and the misconception of guideline-driven treatment.

This essay examines the management of ventilatory failure in disaster settings where clinical needs overwhelm available resources. An ethically defensible approach in such settings will adopt a "sufficiency of care" perspective that is: (1) adaptive, (2) resource-driven, and (3) responsive to the values of populations being served. Detailed, generic, antecedently written guidelines for "ventilator triage" or other management issues typically are of limited value, and may even impede ethical disaster response if they result in rescuers' clumsily interpreting events through the lens of the guideline, rather than customizing tactics to the actual context. Especially concerning is the tendency of some expert planners to mistakenly assume that medical treatment of respiratory failure: (1) always requires full-feature mechanical ventilators, (2) will always occur in hospitals, and (3) can be planned in advance without sophisticated public consultation about likely ethical dilemmas.

Botulism Questionnaire: a tactical tool for community use in a mass casualty incident.

A botulism-induced mass casualty incident has the potential to severely compromise a community's health-care infrastructure, based upon its lethality, rare occurrence, and duration of symptoms, which require extensive support and care. Although early recognition and treatment with antitoxin or botulism immunoglobulin are essential to the effective management of this type of an incident, the two major challenges in recognition and treatment are the hundreds, if not thousands, of casualties or potential casualties requiring rapid screening and the fact that most clinicians remain ignorant of the management of botulism. The purpose of this article is to present the Botulism Questionnaire, which will assist with the screening of casualties, provide educational and diagnostic cues for clinicians and the lay public, and create a layer of protection for the health-care infrastructure. The applications of this questionnaire in various formats, the numerous points of distribution, and the variety of platforms from which it can be launched will be explored.

[Botulinum toxin: from drug to poison]. / Botulinum Toxin: vom Medikament zum Toxin ...

For most of its time, the history of botulinum toxin (BT) has been the history of botulism, i. e. of an intoxication with BT. By the end of the 1960's a paradigm shift took place which in this radicalness had never occurred before in the history of mankind. At that time BT was first used therapeutically to treat strabismus. From ophthalmology BT rapidly spread into numerous medical specialties. For most of its indications BT is the therapy of choice, for some it has revolutionized their treatment altogether. The widespread therapeutic use of BT allowed detailed clinical and technical investigations of BT's action upon the human body. Applying this knowledge we diagnosed for the first time chronic botulism in adults living on a farm with chronic bovine botulism. This constitutes another radical paradigm shift. The history of BT is the history of a dual paradigm shift each time induced by a complete reversal of the viewing perspective. Knowledge gain can be a linear process. It can, however, also be a circular one. Changes of the viewing perspective are crucial. Changing the viewing perspective may facilitate knowledge gain. This might be used to develop an instrument to facilitate knowledge gain.

[Botulism in dairy cattle in 2008: symptoms, diagnosis, pathogenesis, therapy, and prevention]. / Botulisme bij melkkoeien anno 2008: symptomatologie, diagnostiek, pathogenese, therapie en preventie aan de hand van een catastrofaal verlopen casus.

Botulism affects about 20 dairy herds a year in the Netherlands. This article describes the dramatic outcome of botulism in a dairy herd. The main clinical symptoms in this herd were increased lying down, slight ataxia of the hind legs, and a high mortality (98%). The diagnosis is difficult to establish in adult cattle, and for this reason the clinical and laboratory findings, differential diagnosis, therapy, and preventive measures are discussed. On the basis of this outbreak, previous experience with botulism, and cases described in literature, it is suggested that presence of 'free-range" poultry could contaminate grazing pastures with botulism neurotoxins, causing clinical problems in cattle. If there is an increased risk of contamination of the pasture and/or silage with botulinum neurotoxins, vaccination should be considered to prevent substantial economic and emotional damage.

Clinical recovery and circulating botulinum toxin type F in adult patient.

A 56-year-old woman in Helena, Montana, USA, who showed clinical signs of paralysis, received antitoxins to botulinum toxins A, B, and E within 24 hours; nevertheless, symptoms progressed to complete quadriplegia. On day 8, she began moving spontaneously, even though blood tests later showed botulinum toxin type F remained.

An outbreak of foodborne botulism in Taiwan.

Botulism is a rare but serious paralytic disease caused by botulinum toxin. We report an outbreak of type B botulism in Taiwan in 2006. There were five cases involved in this outbreak. They present ileus and acute cranial nerve dysfunction including dysphagia and blurred vision. One of them had severe neurologic impairment and required mechanical ventilatory support. No patient received antitoxin administration because of delayed diagnosis. The food specimen revealed positive botulism toxin B. There were no fatalities. Consumption of fermented food was significantly associated with this outbreak. We also reviewed the characteristics of cases with botulism in Taiwan since 1985.

Recurrent bulbar paralysis caused by botulinum toxin type B.

Botulism is a rare, potentially lethal paralytic disease characterized by cranial nerve palsies, descending flaccid muscle paralysis, and possible involvement of the diaphragm and other respiratory muscles. Here, we report, to our knowledge, the first case of recurrent botulism type B in the United States, caused by repetitive ingestion of contaminated homemade hot chili pepper in oil from the same jar.

[Diagnostic difficulties in foodborne botulism--case reports and literature review]. / Trudnosci diagnostyczne w zatruciu jadem kielbasianym--opis przypadków i przeglad pismiennictwa.

Food borne botulism is a relatively rare clinical syndrome, which symptomatology is generally highly distinctive. The physicians of various specialties should be familiar with the symptoms of botulism because its sings concern the nervous system, the organ of sight and the gastrointestinal system. In older persons with coexisting chronic diseases some symptoms of botulism may be not distinctive or may mimic exacerbation of early existing diseases. The handbook descriptions present the food borne botulism as dramatic and often deadly disease. However in some cases this disease can have mild course and poor symptomatology. Two cases of food borne botulism with different clinical course are presented in this paper, when the correct diagnosis was established with delay. A 78-year-old man was admitted with the symptoms of pneumonia and dizziness of uncertain aetiology. The diagnosis of food borne botulism was established in 10th day of hospital stay, when the most symptoms were not present. Despite of such late diagnosis and relatively good patient's condition a therapy with antitoxin was administrated. The second case reports a 70-year-old man with chronic heart failure, diabetes and obesity, when the delay of correct diagnosis was about of 24 hours. Despite of relatively early antitoxin administration and intensive supportive care patient died in 11th day of hospital stay.