Botulism

Opinion statement Botulinum toxin is the most potent toxin known to humans and as little as 100 ng can be lethal. The toxin blocks peripheral cholinergic neurotransmission at the neuromuscular junction and cholinergic autonomic nervous system by introducing an endopeptadase enzyme into the presynaptic side of the synapse. The endopeptadase cleaves acetylcholine vesicle docking proteins that are required for the synapse to release acetylcholine into the synaptic cleft. Botulism occurs from consumption or inhalation of preformed botulinum toxin or growth of Clostridium botulinum bacteria in the infant gastrointestinal tract or within a wound. Growth of C. botulinum in the immature gut or wound will release botulinum toxin that reaches the circulation. All forms of botulism cause progressive weakness, bulbar signs (blurred vision, diplopia, mydriasis, dysphagia, and dysarthria), and respiratory failure with normal sensation and mentation. Treatment is aimed at 1) maintaining respiration via intubation and mechanical ventilation, 2) stopping progression of weakness by administration of botulinum antitoxin (equine trivalent botulinum antitoxin for adults and botulism immune-globulin intravenous-human for infant botulism), and 3) preventing complications from weeks of paralysis with good supportive care. The source of the botulinum toxin should be identified to prevent additional cases. Patients can recover normal muscle strength within weeks to months, but usually complain of fatigue for years.     

Botulism, a clinical diagnosis

Foodborne botulism results from the effect of a neurotoxin produced by a sporulated anaerobic bacillus called Clostridium botulinum. The mode of contamination occurs through the consumption of foodstuff, already contaminated by the neurotoxin. Following an incubation period that varies from 2 hours to 8 days, the symptoms start with intestinal problems. Then paralysis of the cranial nerve pairs sets in, classically manifested by diplopia, dysphagia, dysphonia, areactive mydriasis and ptosis. The onset of motor disorders occurs in descending order with possible involvement of the respiratory muscles, hence requiring reanimation measures and sometimes mechanical ventilation. The diagnosis of botulism is clinical. Identification of the botulinum toxin in the blood or faeces of the patients or in the contaminating food stuff confirms the diagnosis.     

Acute paralysis following “a bad potato”: A case of botulism

PURPOSE: Intensivists often encounter patients with respiratory failure as a result of neuromuscular disease, however, acute neuro-muscular syndromes are less common. We present a case of food borne Clostridium botulism and discuss the diagnostic and therapeutic considerations. CLINICAL FINDINGS: A 35-yr-old healthy male presented with abdominal pain and blurred vision 12 hr after ingesting a "bad" potato. During the next 17 hr, the patient demonstrated a gradual descending paralysis which ultimately resulted in no cranial nerve function and 0/5 strength in all extremities. Sensation was intact. The patient required intubation and mechanical ventilation. His blood count, biochemical profile, computerized tomography and magnetic resonance imaging of the head were normal. A lumbar puncture revealed no abnormalities. Due to the rapid deterioration and presentation of 'descending' paralysis, botulism was suspected. The patient was treated empirically with botulinum anti-toxin. Samples of blood, stool and gastric contents were cultured for the presence of Clostridium botulinum and its toxin and these tests were positive for botulinum toxin A 12 days later. The patient's neuromuscular function gradually improved over a prolonged period of time. Six and one-half months after his initial presentation, the patient was discharged home after completing an aggressive rehabilitation program. CONCLUSIONS: Botulism is a rare syndrome and presents as an acute, afebrile, descending paralysis beginning with the cranial nerves. If suspected, botulinum anti-toxin should be considered, particularly within the first 24 hr of onset of symptoms. Confirmation of the presence of botulinum requires days therefore the diagnosis and management rely on history and physical examination.     

Botulinum toxin type A for the treatment of lower urinary tract disorders

Many papers report the clinical success of botulinum toxin A as a method of management of various bladder dysfunctions. The rationale was that botulinum toxin A was able to block the presynaptic release of acetylcholine from the parasympathetic efferent nerve. The efficacy might result not only from an inhibitory effect on detrusor muscle, but also some effects might be mediated by altering the afferent nerve input. This systematic literature review discusses the efficacy and safety of botulinum toxin A therapy for idiopathic detrusor overactivity, neurogenic detrusor overactivity, interstitial cystitis/painful bladder syndrome and benign prostatic hyperplasia. The information was gathered from a PubMed literature research for abstracts from recent urological meetings. Injection of botulinum toxin A appears to have a positive therapeutic effect in multiple urological conditions, such as refractory idiopathic detrusor overactivity, neurogenic detrusor overactivity, interstitial cystitis/painful bladder syndrome and benign prostatic hyperplasia. Because the United States Food and Drug Administration has approved botulinum toxin A (Botox) for injection for the treatment of urinary incontinence as a result of neurogenic detrusor overactivity (e.g. spinal cord injury, multiple sclerosis) in adults who have an inadequate response to or are intolerant of an ant cholinergic medication, the use of botulinum toxin A will spread and be a more familiar therapy in the urological arena. However, further robust evidence should be awaited. We will discuss the current use of this agent within the urological field.     

Botulinum toxin and quality of life in patients with facial paralysis

OBJECTIVES: To examine the effect botulinum toxin, a potent neurotoxin that causes temporary paralysis of hyperkinetic musculature, has on the quality of life (QOL) in the patient with facial paralysis. We surveyed patients with facial paralysis, using the previously validated Facial Clinimetric Evaluation QOL instrument, before and then again after therapeutic administration of botulinum toxin for the management of their facial hyperkinesis, and performed pair-wise comparisons to determine the effect on patient QOL. DESIGN: Prospective clinical study at an outpatient facial nerve center. RESULTS: The overall Facial Clinimetric Evaluation score improved from a mean (SD) of 51.7 (20.9) in the pretreatment group to 63.7 (17.8) in the posttreatment group (P < .05). Statistically significant improvements were noted in all subdomain scores, including Facial Movement, Facial Comfort, Oral Function, Eye Comfort, Lacrimal Control, and Social Function (P < .05 for all comparisons). CONCLUSIONS: Botulinum toxin has a well-established objective benefit in the control of facial hyperkinesis in patients with facial nerve disorders. This study establishes the associated QOL benefit and reaffirms its important role in the multimodality management of patients with facial nerve disorders.     

Botulism toxin,bioterrorist weapon

BOTULISM AND BIOWARFARE: Botulism is a severe neuro-paralysing infection due to a toxin produced by Clostridium botulinum. The use of the botulinum toxin for terrorist aims in the form of aerosols is a perfectly credible eventuality. The botulinum toxin is the most potent toxin known; it is easy to produce and can lead to massive destruction. DEPENDING ON THE CONTAMINATION: The clinical forms of botulism depend on the mode of contamination. Botulism through inhalation can only be the result of a deliberate act using an aerosol. The clinical symptomatology is identical to that of the other forms. PREVENTION: In the case of a bio-terrorist attack with an aerosol of botulinum toxin, the subjects exposed should be vaccinated as a prophylactic measure with trivalent antitoxin vaccine (types A, B and E). This vaccine must be administered as rapidly as possible in symptomatic patients. A single case of botulism acquired by inhalation corresponds to an act of terrorism.     

Anwendung von Botulinumtoxin beim Blepharospasmus, Spasmus facialis und bei Synkinesien nach Fazialisdefektheilung

Involuntary facial movements are caused by various diseases. This article describes three of these diseases: blepharospasm, hemifacial spasm and facial synkinesis following facial nerve paralysis. The different etiologies, clinical symptoms and diagnosis are discussed. A common therapeutic approach for these three diseases is presented. Involuntary facial movements can be reduced or even completely suppressed by local injections of botulinum toxin.     

Botulinum toxin treatment of urethral and bladder dysfunction

There has been tremendous excitement with the use of botulinum toxin for the treatment of various urethral and bladder dysfunction over the past several years. Botulinum toxin is the most lethal naturally occurring toxin known to humankind. Why, then, would an urologist want to use this agent to poison the bladder or urethral sphincter? In this article, we will review the mechanisms underlying the effects of botulinum toxin treatment. We will discuss the current usage of this agent within the urologic community and will provide perspectives on future targets of botulinum toxin.     

Mechanisms of action of intravesical botulinum treatment in refractory detrusor overactivity

Urinary retention is one of a multitude of autonomic deficits resulting from acute botulism (oral botulinum intoxication). The powerful influence of botulinum-A neurotoxin (BoNT-A) on autonomic function has now been harnessed to the benefit of patients with detrusor overactivity (DO), by injecting the agent intramurally, with consequent improvement in urodynamic and clinical variables. Nonetheless, the complexity of bladder cellular physiology and putative mechanisms underlying the pathophysiological basis of DO even now render the precise mechanisms of clinical response to intravesical BoNT-A uncertain. In this review, the processes by which BoNT-A affects nerve function and the state-of-the-art in the physiological understanding of bladder dysfunction are discussed together, conveying how much must be reckoned when attempting to understand the mechanisms by which this powerful agent can improve refractory and bothersome DO.     

Effect of botulinum toxin A on the autonomic nervous system of the rat lower urinary tract

PURPOSE: The magnitude and duration of the effects of botulinum toxin A on acetylcholine (ACh) and norepinephrine release from the bladder and urethra of rats were measured using a radiochemical method. MATERIALS AND METHODS: Saline (sham treatment) or botulinum toxin A was injected into the bladder (50 microl.) or urethra (30 microl.) in separate groups of animals. The release of 3H-norepinephrine or 14C-choline was measured at 2 time points after injection (5 or 30 days). RESULTS: The fractional release of ACh in botulinum toxin A treated animals was significantly inhibited at higher frequencies of electrical field stimulation (20 Hz.) but not at lower frequencies (2 Hz.) 5 days after injection. However, ACh release recovered to sham injected values 30 days after toxin injection. No significant differences in the fractional release of norepinephrine from sham injected or botulinum toxin A bladders were observed. In contrast, norepinephrine release from the urethra was inhibited by botulinum toxin A for at least 30 days after injection. Similar to its effect on transmitter release in the bladder, botulinum toxin A inhibited norepinephrine release in the urethra at high (20 Hz.) but not at low (4 Hz.) electrical stimulation frequencies. CONCLUSIONS: These data indicate that the clinical effects of botulinum toxin A on the lower urinary tract may vary depending on the site of injection and level of nerve activity.     

Simplified bladder botulinum-toxin delivery technique using flexible cystoscope and 10 sites of injection

Recently, the use of botulinum toxin A has been extended to patients with non-neurogenic urologic disorders such as refractory idiopathic overactive bladder. We describe a modification of our original injection technique that allows one to deliver botulinum toxin into the bladder quickly and efficiently in an office setting with reliable results and no local or systemic side effects.     

The basic science of botulinum toxin

Understanding the basic science of botulinum toxin should serve as a fundamental first step for clinical therapy. This article endeavors to cover many aspects of basic research that also have clinical import. The two principal toxins of the clostridial family, Clostridium tetani and C botulinum, are described in detail. The five clinical manifestations of botulism poisoning are also outlined, and structural aspects and the mechanism of action of botulinum toxin are then presented. Finally, the immunologic and pharmacologic principles that define the various serotypes of botulinum toxin are set forth.     

A型肉毒毒素膀胱内不同部位注射治疗女性膀胱疼痛综合征/间质性膀胱炎的临床研究

目的 比较A型肉毒毒素膀胱内逼尿肌注射以及逼尿肌联合三角区注射两种不同注射方法治疗女性膀胱疼痛综合征/间质性膀胱炎的疗效以及安全性.方法 60例入选病例,随机分为两组:逼尿肌注射组(A组)、逼尿肌联合三角区注射组(B组),评估两组患者治疗前及治疗后8周的平均每日排尿次数、最大排尿量、残余尿量、PUF评分、QOL评分.结果 A组及B组治疗后平均每日排尿次数减少,最大排尿量增加,PUF及QOL评分降低,残余尿量无明显增加,B组治疗后与A组治疗后相比,平均每日排尿次数、最大排尿量及PUF评分改善更明显,残余尿量与QOL评分无明显区别.结论 A型肉毒毒素膀胱内注射治疗女性膀胱疼痛综合征/间质性膀胱炎疗效好,生活质量提高,采用逼尿肌联合三角区部位的注射,症状缓解更为明显,副作用无明显增加,值得进一步研究及推广.     

Botulinum toxin urethral sphincter injection to restore bladder emptying in men and women with voiding dysfunction

PURPOSE: Botulinum toxin injection into the external urinary sphincter in spinal cord injured men with detrusor-sphincter dyssynergia has been reported. We expand the clinical use of botulinum toxin for a variety of bladder outlet obstructions and to decrease outlet resistance in patients with acontractile detrusor but who wish to void by the Valsalva maneuver. MATERIALS AND METHODS: Prospective treatment was performed for voiding dysfunction in 8 men and 13 women 34 to 74 years old. The reasons for voiding dysfunction included neurogenic detrusor-sphincter dyssynergia in 12 cases, pelvic floor spasticity in 8 and acontractile detrusor in 1 patient with multiple sclerosis who wished to void by the Valsalva maneuver. Using a rigid cystoscope and a collagen injection needle, a total of 80 to 100 units of botulinum A toxin (Botox) were injected into the external sphincter at the 3, 6, 9 and 12 o'clock positions. RESULTS: Preoperatively 19 of 21 patients were on indwelling or intermittent catheterization. After botulinum A injection all but 1 patient were able to void without catheterization. No acute complications, such as general paralysis or respiratory depression, occurred and none of the patients had dribbling or stress urinary incontinence. Postoperative post-void residual decreased by 71% and voiding pressures decreased on average 38%. Of the 21 patients 14 (67%) reported significant subjective improvement in voiding. Followup ranges from 3 to 16 months, with a maximum of 3 botulinum A injections in some patients. CONCLUSIONS: Urethral sphincter botulinum injection should be considered for complex voiding dysfunction. Encouraging improvement without complications were seen in most of our patients. We have expanded the use of botulinum toxin to treat pelvic floor spasticity and also women.     

New indications for botulinum toxin in rheumatology

Previously known only as a deadly bacterial poison responsible for severe paralysis, botulinum toxin is now a well-recognized therapeutic agent used to relieve involuntary movements, dystonia-related functional impairments, spasticity, and autonomic disorders such as hyperhidrosis. Musculoskeletal pain in patients with rheumatic disorders is among the emerging indications for botulinum toxin therapy. Preliminary data have been obtained in patients with cervical or thoracolumbar myofascial pain syndrome, chronic low back pain, piriformis muscle syndrome, tennis elbow, and stiff person syndrome. At present, the effects of botulinum toxin and its use for pain relief remain controversial. Carefully designed prospective trials are needed to investigate the efficacy and safety of botulinum toxin in pain disorders.     

Effect of fresh and stored botulinum toxin a on muscle and nerve ultrastructure: an electron microscopic study

The aim of this study was to compare the ultrastructural alterations of the muscle and nerve that appear following injection of freshly reconstituted and stored botulinum toxin A. Fifteen New Zealand white rabbits were assigned to 6 groups, and anterior auricular muscle was used for injections. Group 1 did not receive any injection and group 2 received saline injection. Groups 3 and 5 received fresh botulinum; muscles and motor nerves were harvested at 5 days and 12 weeks, respectively. Groups 4 and 6 received stored botulinum; muscles and motor nerves were harvested at 5 days and 12 weeks, respectively. Alterations in muscle and nerve ultrastructure were evaluated with electron microscopy. Degeneration findings in muscle after botulinum toxin injection revealed no significant difference between freshly reconstituted and stored toxin in the early period. When stored toxin was used, atrophic changes in the muscle were less severe than the fresh toxin at 3 months. On nerve evaluation, fresh toxin displays significant acute changes on nerve ultrastructure; however, fresh and stored toxin shows similar degeneration at 12 weeks.     

Safety and Efficacy of Restoring Facial Symmetry Using Polydioxanone Thread Face Lift Technique in Patients with Facial Palsy

BackgroundFacial nerve palsy often leads to functional and physiological impairment in patients and they often suffer from social stigma. The use of polydiaxone (PDO) threads has long been used to treat facial furrows and age-related sagging in the face. The basic principle of the thread lift procedure is placing cogged threads in the subcutaneous plane along a planned trajectory. The efficacy and ease of this procedure compared to a traditional face lift has made PDO threads a popular option in the past three decades. MethodsWe treated 50 patients with a drooping face on one side following facial paralysis with thread lifting and botulinum injections to control contralateral hypertrophy and ipsilateral synkinesis. The Facial Grading System or the serial Sunnybrook Facial Grading System (SB scores) was used to assess at all the visits and serial photographs were recorded.ResultsFollowing the threading procedure, all 50 patients displayed improved facial symmetry. There was significant improvement in the baseline SB scores compared to the scores over following year, with all the scores having significant p value less than 0.05.Conclusion Based on our results, subdermal suspension with re-absorbable threads in conjunction with botulinum toxin constitutes an efficient and safe procedure for face lifting and rejuvenation of a drooping face as a result of long-lasting facial paralysis.     

Histologic features in the urinary bladder wall affected from neurogenic overactivity--a comparison of inflammation, oedema and fibrosis with and without injection of botulinum toxin type A

OBJECTIVES: To study histological features and morphological differences in bladder wall specimen from patients with and without botulinum toxin A injections and to compare those issues in responders and non-responders to the toxin therapy. MATERIAL AND METHODS: Bladder wall specimen obtained from cystectomy in 45 patients with neurogenic overactive bladders with and without injection of botulinum toxin A into the detrusor muscle for treatment of neurogenic incontinence were evaluated concerning the histological criteria inflammation, oedema and fibrosis of the bladder wall. RESULTS: Bladder wall specimen obtained from patients suffering from neurogenic detrusor overactivity showed important histological alterations. Generally, inflammatory infiltration, oedema and fibrosis of the bladder wall were frequently observed. When comparing specimen from patients who had received botulinum toxin injection to those from patients who had not, there was no difference concerning inflammation and oedema. However, patients who had received botulinum toxin injection showed significantly less fibrosis of the bladder wall than those who had not received the toxin injection (p<0.00073). When comparing specimen from responders and non-responders to the botulinum toxin therapy, there was no difference in inflammation. Although not significant, a trend was observed that responder to the toxin therapy had less fibrosis and oedema of the bladder wall than non-responder. CONCLUSION: In our study injection of botulinum toxin into the detrusor muscle did not lead to increased fibrotic activity within the bladder wall, on the contrary patients with previous botulinum toxin injection revealed significant less fibrosis than patients without toxin injection.     

Botulinum toxin for the treatment of lower urinary tract symptoms: a review

AIMS: To review the available literature on the application of botulinum toxin in the urinary tract, with particular reference to its use in treating detrusor overactivity (DO). METHODS: Botulinum toxin, overactive bladder (OAB), detrusor instability, DO, detrusor sphincter dyssynergia (DSD), and lower urinary tract dysfunction were used on Medline Services as a source of articles for the review process. RESULTS: DO poses a significant burden on patients and their quality of life. Traditionally patients have been treated with anti-cholinergic drugs if symptomatic, however, a significant number find this treatment either ineffective or intolerable due to side effects. Recent developments in this field have instigated new treatment options, including botulinum toxin, for patients' refractory to first line medication. Botulinum toxin, one of the most poisonous substances known to man, is a neurotoxin produced by the bacterium Clostridium botulinum. Botulinum toxin injections into the external urethral sphincter to treat detrusor sphincter dyssynergia has been successfully used for some years but recently its use has expanded to include voiding dysfunction. Intradetrusal injections of botulinum toxin into patients with detrusor overactivity and symptoms of the overactive bladder have resulted in significant increases in mean maximum cystometric capacity and detrusor compliance with a reduction in mean maximum detrusor pressures. Subjective and objective assessments in these patients has shown significant improvements that last for 9-12 months. Repeated injections have had the same sustained benefits. CONCLUSIONS: Application of botulinum toxin in the lower urinary tract has produced promising results in treating lower urinary tract dysfunction, which needs further evaluation with randomised, placebo-controlled trials.     

Bupivacaine-induced myotoxicity and its effect on botulinum toxin paresis

PURPOSE: To determine the effect of the coinjection of bupivacaine with botulinum toxin type A on the degree of muscular paralysis. Enhancement of paralysis could allow a decreased dose of neurotoxin treatment, thus reducing the risk for neutralizing antibody formation. METHODS: Prospective, randomized, double-blind study. Sixteen consecutive patients undergoing treatment of glabellar furrows received botulinum toxin A reconstituted with bupivacaine 0.75% to one corrugator muscle and botulinum toxin A reconstituted with nonpreserved normal saline to the contralateral muscle. Patients were evaluated on days 0 (injection day), 3, 7, 30, 60, and 90. Patients also completed a questionnaire each visit regarding their assessment of paralysis, asymmetry, and adverse effects. RESULTS: At 1 week after botulinum toxin A injection, 68.8% of the patients showed greater weakness on the bupivacaine-reconstituted side as opposed to 25.0% of patients showing greater weakness on the saline-reconstituted side. At 1 and 3 months, there was no statistical difference in weakness between the saline and the bupivacaine sides. The survey revealed that 56% of the patients had greater pain on the saline side, 31% on the bupivacaine side, and equal pain in 13%. CONCLUSIONS: Reconstituting botulinum toxin A with bupivacaine is safe, does not limit efficacy, and does not reduce the degree or relative duration of muscular paralysis. Reconstituting botulinum toxin A with bupivacaine results in faster onset of paresis, possibly due to a synergistic effect of bupivacaine induced myotoxicity. Utilizing bupivacaine may result in less pain for patients.