Botulism had mortality rates >60% before the 1950s. We reviewed confirmed botulism cases in the USA during 1975-2009 including infant, foodborne, wound, and other/unknown acquisition categories, and calculated mortality ratios. We created a multivariate logistic regression model for non-infant cases (foodborne, wound, and other/unknown). Overall mortality was 3.0% with 109 botulism-related deaths among 3,618 botulism cases [18 (<1%) deaths among 2,352 infant botulism cases, 61 (7.1%) deaths among 854 foodborne botulism cases, 18 (5.0%) deaths among 359 wound botulism cases, and 12 (22.6%) deaths among 53 other/unknown botulism cases]. Mortality among all cases increased with age; it was lowest among infants (0.8%) and highest among persons ≥80 years old (34.4%). Toxin type F had higher mortality (13.8%) than types A, B, or E (range, 1.4% to 4.1%). Efforts to reduce botulism mortality should target non-infant transmission categories and older adults.
Clostridium botulinum toxin is one of the potent and classic molecules known to this modern scientific research field. It has dualistic characters: on one hand it causes botulism by blocking release of acetylcholine at the cholinergic nerve endings and on the other hand the same toxin molecule when administered locally at sub-lethal dose relieves various neuromuscular disorders. If the toxin is used intentionally as an act of terrorism, FDA approved therapeutic agents would be needed to recover from the illness. In addition, to prevent from such situations in the future and to protect public from botulism, there is a strong need for a mucosal vaccine. Creating a multivalent mucosal vaccine delivery system would ease the burden at the time of delivery and reduce the cost.
Botulinum neurotoxins (BoNTs) are potent toxins, which block the neurotransmitter release at neuromuscular junctions and are responsible for a severe disease, the botulism. In the natural disease, BoNTs are the most frequently acquired by the oral route. BoNT associates to non-toxic proteins (ANTPs), which have a main role in toxin protection against acidic pH and proteases, especially in the gastrointestinal tract. BoNTs which transit through the digestive tract, have first to cross the epithelial barrier. BoNTs are able to undergo a receptor-mediated transcytosis, which delivers the whole and active toxin at the basolateral side of epithelial cells. ANTPs containing hemagglutinins have an additional role in altering the intercellular junctions and facilitating a toxin passage through the paracellular way. Then, BoNT disseminates locally and at distance via the blood/lymph circulation and possibly via a retrograde axonal transport to the target motoneuron endings, where the toxin uses an endocytic pathway permitting the release of the light chain into the cytosol and its subsequent proteolytic activity towards the SNARE proteins involved in the neurotransmitter exocytosis.
Botulinum neurotoxins (BoNTs) are the most toxic substances to mankind, and yet, there are no therapeutics available to reverse the paralysis, the deadly symptom of botulism caused by BoNTs. Here we report that RNA aptamer, selected through in vitro process against light chain of botulinum neurotoxin type A (BoNT/A) showed in vivo protection efficacy against botulism. Our results showed that RNA aptamer not only accelerated the recovery of local paralysis induced by BoNT/A through mouse exercise wheel assay, but also significantly delayed the time-to-death through mouse protection assay, and rescued one mouse (out of six) completely intoxicated by BoNT/A. Our results demonstrated the potential using RNA aptamer as antidote against deadly botulism.
The highly toxic nature of botulinum neurotoxins and their placement in category A biothreat agents list under tier 1 biosecurity regulations always attract public attention about any possibility of a new form of this agent. Last time, a new type of botulinum neurotoxin (type G) was discovered was over 40 years ago, and that was not even known to cause human botulism epidemiologically. Therefore, when a novel botulinum neurotoxin was isolated from an infant botulism case in California, it became a major concern for the public health and biothreat agencies. There has been controversy among the scientists about its nomenclature. The scientific debate has been robust, and although the novel neurotoxin is now confirmed to be a hybrid of types A and F botulinum neurotoxins, the issue of calling it a new serotype (H) remains unsettled.
After the extraordinary success of botulinum toxin serotype A in the 1980s to treat a wide range of spasmodic muscular conditions and movement disorders, a significant number of patients were found to stop responding to their treatments with time. When investigated, they were found to have become immune ('resistant') to the products. This second article in a series looks at the next botulinum toxin serotype used clinically after serotype A to overcome this resistance and how that choice was made.
To collect specific information about the genetic mechanisms that Clostridium botulinum strains utilise when adapting to changing environments, 16 C. botulinum genomes were analysed with comparative genome sequence analysis. Particular attention was paid to low temperature adaptation and the presence of cold shock protein coding genes in these genomes was evaluated. Surprisingly, unlike any other studied strains, the type E neurotoxin-producing strains lacked these extremely conserved genes. This finding suggests unique mechanisms for the cold tolerance of these strains and offers a new perspective into the investigations concerning this subject. The sizes of the pangenome and core genome of a certain bacterial species are considered to reflect the versatility of the species. While the pangenome of C. botulinum was very large, the core genome appeared strikingly small, both findings highlighting the great diversity of C. botulinum strains.
Botulism risk information is available on government websites such as USFDA, USDA, CDC, Canadian Food Inspection Agency (Canadian CFIA), European Centre for Disease Prevention and Control (ECDC), and Health Canada. State health departments and university websites contain consumer-based information about botulism. Outbreaks of botulism are quickly investigated, and appropriate measures are coordinated among public health and regulatory agencies. Here, we compiled a list of publically reported botulism outbreaks. The data includes published reports from all countries but reports were mostly from USA. The database focuses initially on the 17-year period from 1994 to 2010 throughout the world, but has been and will be updated and expanded. The data will be publically accessible for viewing and analysis. This botulism web-based data source representing a tool for scientists and epidemiologists is both feasible and practical and is a step toward improving the understanding and knowing the occurrence of foodborne botulism worldwide.
No AccessABSTRACTSPublished Online:August 5, 2013pp 208-361https://doi.org/10.1504/TBJ.2013.055660PDFView Full Text ToolsAdd to FavouritesDownload CitationsTrack Citations Share this article on social mediaShareShare onFacebookTwitterLinkedInReddit AboutAbstractObjective: To develop a webpage as a platform to facilitate flow of information amongst patients, therapists, and others for improvement of interdisciplinary therapy in movement disorders (MD).Methods: A webpage was created by Interdisciplinary Working Group for Movement Disorders (IAB – Interdisziplinärer Arbeitskreis Bewegungsstörungen) to support IAB’s mission: communication, education, and information for registered members and the public.Results: IAB’s webpage contains information about the following topics: 1) mission statement of IAB; 2) scientific board; 3) CME points and certificates for health professionals; 4) partners and mutual links; 5) IAB regional groups, their organisation, their meetings, their special interests and protocols of their sessions; 6) IAB communication and education tools such as the communication form to facilitate flow of information about treated patients amongst different MD therapists and the communication calendar for botulinum toxin therapy of spasticity; 7) special events such as a Parkinson café for patients; 8) publications, presentations, projects and job advertisements of IAB and IAB members; 9) news box; 10) IAB contact for applications for membership and partnership, registration for meetings, purchase of products; 11) database of members and their professions, specialties and contact data open to members only or to the public.Conclusions: IAB’s webpage improves communication amongst MD therapists, patients and the public. It provides education and information for all concerned with MD.Keywordsmultidisciplinary approachwebpagecommunicationeducationinformationAbstractObjective: To assess the effectiveness of rimabotulinumtoxin B (rbtxB) in treating sialorrhea associated with Parkinson disease (PD).Background: Sialorrhea is a common non-motor symptom of PD that disrupts the quality of life of patients affected, including social embarrassment and increased risk for aspiration. Oral medications may be effective, but have unwanted adverse effects, primarily anticholinergic, limiting their tolerability. Directed injections of botulinum toxin into salivary glands can provide similar or improved relief of sialorrhea compared to oral medications, without the associated adverse effects.Methods: Case series. Thirteen PD patients (12 male, 1 female) with severe sialorrhea were surveyed using a seven-point Patients’ Global Impression of Change (PGIC) scale to assess the change in sialorrhea following rbtxB injections. All PD patients had received two to four cycles of intraparotid rbtxB injections repeated every three months with total dose range 2,500–5,000 units. All were on oral medications to control their motor symptoms. Patient spouses (N = 12) also completed the PGIC survey to provide their assessment of clinical change observed.Results: PGIC scores of 1–4 were considered no significant change, and 5–7 a significant favourable response. PD patients’ PGIC scores ranged from 2–7; 9 (69%) scored 5–7. Spouse PGIC scores ranged from 3–7; 10 (77%) scored 5–7. Two patients with no improvement are now on oral or transdermal medications to treat sialorrhea. No adverse effects to rbtxB were reported.Discussion: Intraparotid rbtxB injections can produce significant improvement in sialorrhea associated with PD.Keywordsrimabotulinumtoxin BsialorrheaParkinson diseaseAbstractBackground: Clinically, spasticity has proven hard to measure. Current measures are categorical, show poor sensitivity, and have questionable reliability. Dynamic computerised dynamometry (DCD) has been proposed as a means of overcoming some of these limitations. This paper explores whether DCD can identify patterns of botulinum toxin A (BTX) response in subjects with acquired brain injuries (ABI).Methods: Assessments were completed on 27 healthy controls and 38 subjects with ABI using published DCD paradigms. 2/3 of ABI subjects were assessed pre/post-BTX. Ten cycles of maximum force and speed grasp/release cycles were collected and the sequential minimum between-cycle force analysed for each participant. Data were then grouped according to response pattern.Results: The mean minimum between-cycle force was significantly lower for controls than ABI subjects (0.5 kg vs. 2.9 kg, Z = –4.6, P < .05). Controls showed an average 3% reduction of minimum force from each cycle to the next. ABI participants showed two response patterns; 12 subjects (32%) followed an equivalent pattern, averaging a 5% force reduction across cycles. Conversely, 26 subjects (68%) showed an average 12% increased effort across each cycle (see Figure 1). Group responses were different following BTX.Conclusions: ABI participants had higher between-cycle minima than controls, evidence of muscle over-activity. However, two response patterns were seen; one equivalent to healthy controls (where force decreases as the person learns the task) and one where muscle activity increases with ongoing use. While BTX marginally reduced force in the initial cycle, it prevented the movement-inducible component of spasticity. The clinical usefulness of this effect is yet to be explored.Keywordsbotulinum toxindynamic computerised dynamometryDCDspasticityAbstractIntroduction: Although the functional imbalance in cervical dystonia has traditionally been regarded as a basal ganglia dysfunction, recently there has been provoking evidence of cerebellar involvement in pathophysiology of this focal dystonia. Even in absence of traditional ‘cerebellar signs’ in most dystonia patients, there are more subtle indications of cerebellum dysfunction. This project tries to provide more information about such dysfunction pointing towards considerable cerebellar involvement in etiopathogenesis of this disease – concretely disrupted ability to precise time movements (Jinnah and Hess, 2006).Methods: Thirty patients with cervical dystonia treated with botulinum toxin-A (BTX-A) and 30 healthy controls of comparable age and sex structure, performed series of simple computer tasks (Bares et al., 2011). The duration of cervical dystonia symptoms was 4.3 ± 1.2 years, the duration of BTX-A treatment 2.3 ± 1.4 years. The software pseudorandomly generated parameters (speed, acceleration, partially the movement direction) of a moving object – a green ball. As it moved on the computer screen from left to right, the participant had to press a button in an optimal time window to launch a projectile from the bottom of the screen that was supposed to hit the moving target. The speed of the projectile was constant (as was the trajectory) and much higher than the speed of the green ball. However, it was not sufficient to ignore the launch-interception time and therefore the subject had to anticipate the precise launch time to hit the green ball, taking into account not only the constant parameters, but the changing ones as well.We evaluated the overall hit ratio, percentage of early and late errors, the hit ratio in specific parameter sets (acceleration vs. deceleration or constant speed of the green ball, high vs. low speeds of the green ball, etc.) and many others.Results: The overall hit ratio in the healthy subjects was significantly higher than in the cervical dystonia group (42.07% ± 9.18% versus 34.91% ± 8.23%). Cervical dystonia patients encountered difficulties in dealing with acceleration/deceleration of the target and could not benefit from lower speeds of the flying target as much as the control group.Conclusions: The data suggest that cervical dystonia patients treated with BTX-A have a substantial problem with predictive motor timing (Husárová et al., 2011). The results imply that cerebellum and basal ganglia participate in the integration of visual information with motor output. We plan to test subgroup of cervical dystonia patients before the initiation of BTX-A treatment.This work was supported by the ‘CEITEC – Central European Institute of Technology’ project (CZ.1.05/1.1.00/02.0068) from the European Regional Development Fund and by Ministry of Health of the Czech Republic/Ministry of Health’s Departmental Research and Development Programme III (2010–2015) NT/13437.Keywordsbotulinum toxin Acervical dystoniamotor timingmovement controlAbstractStudy objective: To report the effect of botulinum toxin injection (BTI) type A (XEOMIN®) into pelvic floor muscle on symptoms of patients presenting perineal pain associated with pelvic floor muscle overcontraction and myalgia at clinical examination.Patients: 420 patients (294 women and 126 men) identified with levator ani and/or obturator internus and/or perineal superficial muscles (bulbocavernosus, ischiocavernosus) overcontraction and myalgia with trigger points along the muscles. All of them presented with symptoms of perineal, vulval, vaginal, urethral, testicular, anal and/or inguinal pain. Pain was most of the time described as burning sensation or spasm. Dysfunction associated with the pain ranged from dysuria, terminal constipation, dyspareunia to painful ejaculation in men. Criteria of pudendal neuralgia were also examined according to the Aix-en-Provence criteria.Intervention: Patients were injected with 100 to 400 IU of XEOMIN®, over a period of three years from December 2008 to December 2011, into one or both levator ani and/or obturator internus muscles and/or perineal superficial muscles. The maximum injected was 400 IU in total. Muscle injections were performed under electro-myo-stimulation and/or ultrasound control.Results: All the patients had a physical therapy muscle relaxation programme before and after the BTI. Patients were evaluated on their pain level (VAS), muscle relaxation and trigger point. There were very few adverse events: five women had a worsening of their vaginal prolapse and eight women out of 294 experienced a short period of urinary or fecal incontinence (2.7%). Of 397 patients who came back, 370 (93%) patients had an improvement of their muscle overcontraction and myalgia. 308 patients (78%) had their pain improved going from slight improvement to no pain. 119 patients had their pain starting after a physical trauma (sport trauma, fall, or traumatic delivery) and 108 (91%) of them had an improvement of their pain. Of 58 women who had associated provoked vulvodynia, 47 (82%) were improved. 178 patients had also a diagnosis of pudendal neuralgia. The neuropathic pudendal pain was improved in 57%. 76 had no change after injection (43%) and 70 patients needed pudendal nerve releasing surgery for nerve entrapment. Dysuria was improved in 92%, obstructed defaecation syndrome in 72%, painful ejaculation in 96%, erectile dysfunction in 70%.Keywordsbotulinum toxin injectionmyalgiaperineal painAbstractIncobotulinumtoxinA, a botulinum neurotoxin free of complexing proteins, has proven efficacious and safe in the treatment of focal dystonias. Using a 1U:1U dosing ratio, equivalent efficacy of incobotulinumtoxinA to onabotulinumtoxinA was demonstrated in a multicentre, double-blind, randomised study in cervical dystonia. The protocol prespecified the two-sided 95% confidence interval (CI) method for testing the hypothesis of equivalence of incobotulinumtoxinA to onabotulinumtoxinA expressed by the change from baseline in the TWSTRS severity score four weeks after intramuscular injections of either neurotoxin. The difference between treatment groups was determined in the per-protocol population (n = 240) using least square means and corresponding two-sided 95% CIs. The clinically irrelevant difference was set to Δ = 1.3 points predefining the therapeutic equivalence range as (–1.3, 1.3). An analysis of covariance model included baseline TWSTRS severity score, country, gender and age as factors for the confirmatory analysis. Both treatments significantly (P < .0001) reduced the TWSTRS severity score: –6.6 ± 4.1 (incobotulinumtoxinA) and –6.4 ± 3.9 (onabotulinumtoxinA). The LS mean difference between the treatments was –0.33, slightly in favour of incobotulinumtoxinA. The 95% CI (–1.05, 0.38) was below the irrelevant difference and thus demonstrates statistically that incobotulinumtoxinA is equivalent to onabotulinumtoxinA. The prespecification of a two-sided 95% CI and an irrelevant difference and a statistical argument based on the closed test procedure allow the conclusion of therapeutic equivalence since the CI is fully contained in the equivalence range. Therefore, the study shows therapeutic equivalence in efficacy in the treatment of cervical dystonia in the administered dose range when used with a 1U:1U conversion ratio.Keywordsbotulinum neurotoxinincobotulinumtoxinAonabotulinumtoxinAcervical dystoniaAbstractBackground: Little data exist regarding patient satisfaction with botulinum toxin treatment in patients with poststroke spasticity. To address this question, a structured patient survey was conducted in Germany, France, the USA, and Canada.Methods: Patients with poststroke spasticity treated with at least two injection cycles of either onabotulinumtoxinA or abobotulinumtoxinA were included in this cross-sectional survey. Specific information was collected on the patients’ current and prior botulinum toxin treatment cycles and their overall quality of life.Results: Seventy-six patients with poststroke spasticity participated. Only 42.1% of patients were very satisfied with their current treatment, 46.1% were somewhat satisfied, and 11.8% were not at all satisfied. Patient satisfaction was lowest just prior to injection and highest at the time of peak effect. A total of 45.2% of patients reported that they would prefer a treatment cycle of < 12 weeks. The mean patient rating of current state of health was 53.5 (±22.4 standard deviation) on a visual analogue scale from 0 (low) to 100 (high).Conclusions: The results from the patient survey indicate that patient satisfaction typically declines prior to reinjection with botulinum toxin, and many patients may prefer an injection interval of less than the standard 12 weeks.Keywordsbotulinum toxinpoststroke spasticitycross-sectional surveyAbstractBackground: Little data exist regarding physician satisfaction with botulinum toxin treatment in patients with poststroke spasticity. To address this question, a structured physician survey was conducted in Germany, France, the USA, and Canada.Methods: Physicians who treated patients with poststroke spasticity with botulinum toxins were included in this cross-sectional survey. Specific information regarding their satisfaction with botulinum toxin treatment was collected.Results: One hundred and five physicians participated. Most physicians were moderately (58%) or very satisfied (37%) with botulinum toxins. However, physicians felt that 16.2% of poststroke patients could benefit from shorter injection intervals and 24.6% could benefit from higher maximum doses than current treatment restrictions permit.Conclusions: The results from this physician survey indicate that most physicians are generally satisfied with botulinum toxin treatment; however, many physicians feel that there is still a proportion of patients who could likely be more effectively treated if shorter treatment intervals and higher doses were used.Keywordsbotulinum toxinpoststroke spasticitycross-sectional surveyAbstractDeficiency of intracortical inhibition is the keystone of pathophysiology in dystonia. In the Brunel and Wang realistic cortical network model of interneurons and excitatory pyramidal cells that are interconnected in reentrant loops, the dominant neuronal oscillation frequency is gamma in the frequency of 30–100 Hz [J. Neurophysiol., (2003), Vol. 90, p.415]. Gamma band fluctuations in magnetoencephalography (MEG) have been shown to be positively correlated with GABA concentration [Pro. Natl. Acad. USA, (2009), Vol. 106, p.8356]. The aim of the present MEG study was to determine whether treatment with botulinum toxin would affect the gamma band brain activity in torticollis patients.Methods: In seven torticollis patients, whole head magnetoencephalography (MEG) was recorded in a resting-state condition before and after treatment with botulinum toxin. Coherence was calculated in the gamma frequency band. Discriminant analysis was used to determine if gamma locations were altered after treatment.Results: After treatment with botulinum toxin, torticollis patients demonstrated decreased gamma band coherence in the right middle temporal and right inferior temporal gyrus together with an increase in gamma band coherence in the left middle frontal gyrus, left pre- and post-central gyri. Discriminant analysis was used to identify group differences with P < .01 based on 86 out of 4,168 locations in the brain.Conclusions: Treatment with botulinum toxin increases gamma activity in the pre- and post-central gyrus restoring cortical inhibition, which in turn reduces the symptoms of torticollis. Gamma band increases may reflect a direct increase in GABA concentration in this region.Keywordsbotulinum toxintorticollismagnetoencephalographyMEGgamma bandAbstractObjective: To compare the distal spread of onabotulinumtoxin A (obtxA) and rimabotulinumtoxin B (rbtxB) in humans using single-fibre electromyography (SFEMG).Background: Botulinum toxin (btx) is an effective therapy for a variety of neurologic conditions. Distal spread of btx to non-injected muscles is an undesirable side effect. Prior studies have compared spread effects of different toxin serotypes using CMAP amplitude variation. SFEMG is a more sensitive measure of neuromuscular junction blockade. Comparing the spread of different btx serotypes using SFEMG may assist clinicians in choosing between serotypes for use.Methods: Twelve patients with migraine headaches were studied; six received obtxA (120 units) and six received rbtxB (6,000 units) distributed over 15 sites of the face and neck. SFEMG was performed on a distal muscle (extensor digitorum communis) prior to, and 30-days following, injections. The patients and electromyographer were blinded to serotype used. The jitter [mean consecutive discharge (MCD)], percentage of abnormal muscle fibre pairs, and percentage of pairs demonstrating blocking were compared between groups.Results: Baseline average MCD for each group was similar: obtxA 31.8 mcs; rbtxB 30.2 mcs. Average MCD 30 days following treatment was: obtxA –0.2 mcs; rbtxB 4.0 mcs (P = .75). The average change in percentage of abnormal pairs was: obtxA +4.2%; rbtxB +7.5% (P = .83). There was no difference in blocking for either group. No patient reported muscle weakness.Conclusions: Our study demonstrated no significant remote SFEMG differences between obtxA and rbtxB. Small absolute differences were seen between baseline and 30-day follow-up for each group. No weakness was reported by any patient regardless of SFEMG change.Keywordsbotulinum toxinonabotulinumtoxin Arimabotulinumtoxin Bsingle-fibre electromyographySFEMGAbstractIn the literature, few reports exist about peripheral myoclonus involving the injury of different nerves. Involuntary movements of pectoralis muscles in patients who had mastectomy for breast cancer are extremely rare. We describe a case of a 60-year-old woman who underwent left mastectomy and implantation of a breast prosthesis; six months later she began feeling pain and movement disorder in the pectoralis region on the left and she had to remove the prosthesis. She complained of very high distress.A surface poly EMG of the pectoralis area and a needle EMG showed at rest or during voluntary movement bursts of 500 msec to 4 sec, amplitude 200–500 micron volt with asynchronous repetition in particular in the sternocostal region of pectoralis muscles. As a symptomatic therapy of the painful and distressing movement disorder she underwent, with US/EMG guide, a treatment with OnabotulinumtoxinA 100 U diluted in 1 ml of physiological solution in six points, three in the major and three in the minor left pectoralis muscle.After two weeks the patient described reduced pain in the pectoralis left region (VAS 2), less global discomfort and an EMG needle recording showed a reduced amplitude and duration, of the involuntary movement with lower frequency of myoclonus. After four weeks there was a nearly complete resolution of the JB and np pathological activity at the EMG.Botulinum toxin A could be a useful treatment of rare cases of spinal myoclonus. A very precise clinical and neurophysiological evaluation is mandatory and it is useful to use US and EMG techniques to perform a good targeting of the muscles involved in the movement disorder.Keywordsbotulinum toxinmastectomybreast prosthesismovement disordermyoclonusAbstractWe are presenting the results of our 12 years of experience using BtA (Dysport®) as a part of the comprehensive rehabilitation programme for children with various forms of cerebral palsy (CP) in Kazakhstan.Methods: In total, more than 3,000 children had the injections. According to the type of CP, 38.2% of children had the double hemiplegic type, 31.6% had the spastic diplegic type, 23.8% had hemiparetic type, 11.1% had the mixed type, and 7.5% astatic-atonic type. To assess the programme effectiveness the subjective scale of physical and psycho-emotional wellbeing (0–100%), gross motor function classification system (GMFCS) and Ashwart scale were used.Results: The treatment group (n = 40) also received Dysport® injections while the control group (n = 40) did not.Table 1 Ashwart scale in intervention and control groups on admission and on dischargeCP typeTreatment group, n = 40Control group, n = 40On admissionOn dischargeOn admissionOn dischargeDouble hemiplegia (n = 8)3.42.12.61.7Spastic diplegia (n = 10)3.62.61.91.5Mixed diplegia (n = 10)3.22.41.71.2Hemiparetic (n = 12)3.42.532M ± m3.4 ± 0.12.4 ± 0.152.1 ± 0.51.6 ± 0.25t5.55.50.84P< 0.001>0.05Table 2 GMFCS in intervention and control groups on admission and on dischargeCP typeTreatment group, n = 40Control group, n = 40On admissionOn dischargeOn admissionOn dischargeDouble hemiplegia (n = 8)4.13.23.63Spastic diplegia (n = 10)3.62.62.11.6Mixed diplegia (n = 10)3.43.21.61.5Hemiparetic (n = 12)3.32.52.51.6M ± m3.6 ± 0.252.87 ± 0.322.45 ± 0.61.9 ± 0.54t4.30.81p< 0.001> 0.05Conclusions: Our experience showed that injections of BtA (Dysport®) are effective in all types of CP manifesting by increased muscle tone, spasticity, dystonia, and hyperkinesia. In cases of hyperkinetic syndromes the severity decreased as well so children could sit better and gained better voluntary motor control. In our experience the best results were obtained if the BtA injections were initiated in the early childhood when the first signs of muscle hypertonicity and spasticity start to appear.Keywordsbotulinum A toxinDysport®cerebral palsyhyperkinetic syndromeAbstractObjective: To review the evidence for the use of abobotulinumtoxinA (ABO) in upper and lower limb spasticity, blepharospasm, hemifacial spasm, sialorrhea, writer’s cramp and truncal dystonia.Methods: A systematic literature search (PubMed, Cochrane Library, EMBASE) was performed to identify randomised controlled trials and other comparative clinical studies of ABO published between 1991 and January 2012. Study methodology, patient, and treatment-level data were extracted and summarised using descriptive statistics. Each included study underwent quality assessment for bias based on Cochrane metrics.Results: A total of 28 studies met the data extraction eligibility criteria. All included studies were randomised clinical trials with the exception of one study (observational comparative) for hemifacial spasm. Of the 28 studies, 20 focused on adult spasticity (12 upper limb, eight lower limb) of various origins (17 post-stroke, three others). The other studies were: two each in blepharospasm, hemifacial spasm, and sialorrhea; one each in truncal dystonia and writer’s cramp. Overall, ABO demonstrated clinically or statistically significant efficacy for each disorder. The majority of studies fulfilled criteria for low risk of reporting bias. Total ABO doses ranged between 500–1,500 U for upper limb spasticity; 50–2,000 U for lower limb spasticity; 100–182 U for blepharospasm; 51–70 U for hemifacial spasm; 37.5–450 U for sialorrhea; 500 U for truncal dystonia and 178 U for writer’s cramp.Conclusions: Based on data extracted from 20 randomised clinical studies, a strong evidence base exists for the use of ABO in limb spasticity. Based on data from eight studies, ABO appears efficacious for blepharospasm, hemifacial spasm, sialorrhea, truncal dystonia, and writer’s cramp.KeywordsabobotulinumtoxinAbotulinum toxinblepharospasmhemifacial spasmspasticitysialorrheadystoniawriter’s crampsystematic reviewAbstractBackground: The usefulness of electromyography (EMG) for botulinum neurotoxin (BoNT) injections for cervical dystonia (CD) is controversial. Frequency of EMG utilisation has not been previously described from a large, prospectively ascertained treatment cohort.Methods: The CD PROBE study is an ongoing observational study of CD treated with onabotulinumtoxinA that includes physicians with prior injection experience. Subjects were included if they had primary CD and were new to the treating physician’s practice, had not received toxin for greater than or equal to 16 weeks, or were toxin naïve. This analysis was designed to describe the use of EMG by physicians at the baseline (first) injection.Results: The CD PROBE study has enrolled 1030 CD subjects; 75% women, mean age 58.0 ± 14.6 years, duration of CD 5.0 ± 8.1 years, total TWSTRS score 38.7 ± 13.1. In this group, 47.6% had predominant torticollis, 39.3% laterocollis, 5.4% anterocollis, and 5.2% retrocollis. There were 85 treating physicians who have been using BoNT for a mean of 12.2 ± 5.4 years, 89% of whom were neurologists. 81% of the physicians used EMG for the injection. When EMG was used, a greater number of muscles was injected than when injections were done without EMG (4.1 ± 1.3 vs. 3.6 ± 1.4; P < .0001).Conclusions: This subanalysis of the CD PROBE study shows that most treating physicians in the CD PROBE study utilise EMG for CD injections, but additional analyses are needed to determine whether outcomes differ between patients injected with or without EMG.Keywordsbotulinum neurotoxinBoNTcervical dystoniaelectromyographyEMGonabotulinumtoxinAAbstractBackground: Intramuscularly administered onabotulinumtoxinA is an effective treatment for a variety of movement disorders. Severe bruxism, which can generate discomfort, pain, tongue laceration, and tooth fragmentation, is a frequent complication of anoxic brain injury. Severe bruxism is usually amenable to medical treatment. We report successful symptomatic treatment of severe bruxism with onabotulinumtoxinA in four patients with anoxic brain injury.Methods: Four patients were seen on the inpatient and/or outpatient service at Henry Ford Health System between November 2003 and August 2011. All four patients were females. Ages ranged from 23 to 63 years old.Results: All four patients received onabotulinumtoxinA injection to the bilateral masseter and/or temporalis muscles (total of 50–100 units were injected during each visit). Two of the four patients received multiple injections separated by two weeks to three months due to severity of the symptoms. All four patients responded positively to the injections. No side effects were reported in any of the studied patients.Conclusions: OnabotulinumtoxinA injections are an efficacious and valuable treatment for patients with severe bruxism post anoxic brain injury.KeywordsonabotulinumtoxinAsevere bruxismanoxic brain injuryAbstractBackground: The American Academy of Sleep Medicine defines bruxism as a stereotyped oral motor disorder characterised by clenching, grinding, bracing, and gnashing of the teeth during sleep, and American Academy of Orofacial Pain has extended the definition during wakefulness. Jaw closing dystonia refers to the co-contraction of the bilateral masseter and temporalis muscles that may result in clenching, grinding, and trismus. Like other types of focal dystonia, the spasm and muscle contraction can be constant or spasmodic. In this comparative analysis, we assess differences and similarities in etiology, pathophysiology, clinical manifestations, management, and prognosis between bruxism and jaw closing dystonia.Methods: Medline and current textbooks of sleep medicine and neurology were searched for relevant information. Search terms: bruxism, oromandibular dystonia, and jaw closing dystonia.Results: Similar pathophysiology and clinical manifestation were found in different literature regarding these two ostensibly distinct clinical entities. In both entities, the involvement of the nigrostriatal system was shown in multiple separate studies. Clinical outcome and response to the therapy by chemodenervation with botulinum toxins was similar as well.Conclusions: This comparative analysis suggests that bruxism and jaw closing dystonia follow the same pathophysiology, clinical manifestations and outcome. It seems that we are naming the same clinical entity differently in the dentistry, orofacial medicine, and neurology literature. We believe that bruxism is a spasmodic subtype of the jaw closing dystonia.Keywordsbotulinum toxinbruxismjaw closing dystoniaoromandibular dystoniaAbstractThe voltage-gated potassium channel Kv inhibitor 3,4 diaminopyridine (3,4-DAP) has been examined in the treatment of human botulism outbreaks. In a diaphragm muscle paralysed by BoNT/A, but not BoNT/E exposure, 3,4-DAP induces a rapid and pronounced increase in twitch tensions highlighting the role of the K+ channels in transmitter release and BoNT/A mechanism of action.In the present stu
The basis of botulinum toxin use as a neuromedicine started over 40 years ago when the first serotype was chosen for key initial studies in monkeys by Alan Scott and colleagues in the USA. From that point on, the protein has been used extensively and worldwide for treatment of many clinical conditions. But much remains to be documented about the earliest times, the very beginning years when critical choices and decisions were made. This first article in a series looks at the choice of the first botulinum toxin serotype used and why that choice was made.
Botulinum neurotoxin (BoNT) causes the disease known as botulism, which can be lethal. Rapid determination of exposure to BoNT is an important public health goal. Our laboratory has developed Endopep-MS, a mass spectrometry-based endopeptidase method for detecting and differentiating BoNT. Here, we demonstrate that this method is very sensitive, detecting as little as 0.5 mouse LD 50 of BoNT/A and as little as 0.05 mouse LD 50 of BoNT/B, /E, and /F spiked into human serum samples. Additionally, the ability to further differentiate BoNT as the subtype of BoNT/A spiked into milk using toxin proteomics and mass spectrometry has been demonstrated. This method does not require DNA and can be performed on the same sample as that used for Endopep-MS analysis. The combination of these techniques, all performed on the same sample, provides a sensitive and selective analysis of BoNT isolated from a food or clinical sample and measures the toxin’s activity.
Botulinum neurotoxin (BoNT) is produced by Clostridium botulinum as a dichain protein of ~ 150 kDa that blocks acetylcholine release resulting in muscular paralysis. Diagnosis of BoNT often relies on the mouse bioassay that has a detection limit of 10–20 pg/mL and can take up to four days to complete. Rapid in vitro methods for toxin detection are needed and to date, most rely on either immunoassay or endopeptidase activity. In the latter, many also use specific antibodies to concentrate the toxin. We have developed panels of monoclonal antibodies (mAbs) to purified toxin, serotypes A, B and E, as well as mAbs to the non-toxic associated proteins. Application of these mAbs in sandwich ELISAs and assay performance in milk and other foods is discussed. The assays described here are able to detect toxin in a few hours, at levels lower than the mouse bioassay.
Clostridium botulinum produces seven antigenically distinct serotypes of botulinum neurotoxin (BoNTs, A-G) the most potent toxins to humans.They cause paralysis at less than picomolar concentration by blocking neurotransmitter release.BoNT consists of a heavy chain and a light chain.The C-terminal half of the heavy chain allows the toxin to bind to the presynaptic membrane while the N-terminal half helps in forming a channel in the endosomal membrane to allow the light chain to escape into the cytosol.While the binding and catalytic mechanisms are well understood now, the details of translocation still remain a mystery.A full length BoNT/A heavy chain (BAHC) has been cloned, over expressed and purified from inclusion bodies by solubilising with a detergent.Preliminary crystallographic results show that BAHC forms a tetramer in the crystal lending experimental support for tetrameric pore formation for the light chain to pass through the endosomal membrane.
Rapid increases in the number of available Clostridium botulinum genome sequences have permitted the development of new molecular subtyping methods for this organism.Our laboratory has developed various DNA microarrays in an effort to differentiate strains based on differences in gene content.This review will focus on both high density comparative genomic hybridisation (CGH) microarrays and various focused (low density) oligonucleotide spotted microarrays.Comparison of gene content using DNA microarrays provides investigators with the ability to simultaneously differentiate unrelated strains and to identify strain variable genes.Such genes may play important roles in the pathogenesis, growth, and survival of this organism.Moreover, probes may be optimised as new genome sequences become available leading to improvements in the ability to characterise novel or unusual strains.
Near infrared imaging (NIR), using dyes that emit between 700 and 900 nm, overcome many of the absorption and light scatter problems that have been associated with whole body and tissue imaging. This review summarises current areas in which NIR provides an excellent non-invasive technology for tracking and investigating molecular movement in vivo.
Single molecule arrays (SiMoA) make it possible to detect subfemtomolar concentrations of proteins in complex samples.We describe the basis of SiMoA and its potential application in the detection of proteins, such as botulinum neurotoxin (BoNT), from pathogenic bacteria.We also provide a concept for an integrated handheld SiMoA device for the detection of very low concentrations of BoNT in the field.
Investigators adopted the mouse LD50 unit for quantifying botulinum neurotoxin (BoNT) in the early 1900s, and through a combination of necessity and tradition, public health agencies, laboratory researchers, clinicians and manufacturers of BoNT have continued to use the mouse LD50 unit as the gold standard for expressing toxin quantity and potency.A recent article by Pickett (2011) questions whether there is still a need in the botulinum community to continue to use this bioassay and raises issues regarding a lack of standardisation in the reporting of toxin preparations.
Rapid, specific, and sensitive detection of airborne bacteria, viruses, and toxins is critical for biodefense, yet the diverse nature of the threats poses a challenge for integrated surveillance, as each class of pathogens typically requires different detection strategies. Here, we present a laboratory-on-a-chip microfluidic device (LOC-DLA) that integrates two unique assays for the detection of airborne pathogens: direct linear analysis (DLA) with unsurpassed specificity for bacterial threats and Digital DNA for toxins and viruses. The LOC-DLA device also prepares samples for analysis, incorporating upstream functions for concentrating and fractionating DNA. Both DLA and Digital DNA assays are single molecule detection technologies, therefore the assay sensitivities depend on the throughput of individual molecules. The microfluidic device and its accompanying operation protocols have been heavily optimized to maximize throughput and minimize the loss of analyzable DNA. We present here the design and operation of the LOC-DLA device, demonstrate multiplex detection of rare bacterial targets in the presence of 100-fold excess complex bacterial mixture, and demonstrate detection of picogram quantities of botulinum toxoid.
The botulinum neurotoxins (BoNTs) are among the most lethal substances known to humankind.The work described herein examined the oral toxicity of the BoNTs and compared oral toxicity to in vitro stability in simulated gastrointestinal tract conditions.Our results demonstrate that a majority of the BoNTs tested were less stable in simulated intestinal fluid (SIF) as compared to simulated gastric fluid (SGF), and that oral toxicity correlated with the molecular weight of the BoNT complex.These results suggest that stability in the intestinal tract plays a critical role in the oral toxicity of the BoNTs.
Botulinum neurotoxins are the most potent neurotoxins known and are ranked by the CDC as category A bioterrorist agents.There is an urgent need to discover and develop small molecule inhibitors as countermeasures for botulinum neurotoxin intoxication.In this report, we summarise our molecular modelling results which contribute to the SAR development and binding site identification of small molecule inhibitors of BoNT/A metalloprotease.
