Special Issue "Clinical Use of Botulinum Toxins"
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A special issue of Toxins (ISSN 2072-6651).
Deadline for manuscript submissions: closed (31 August 2012)
Special Issue Editor
Guest Editor
Prof. Dr. Bahman Jabbari
Department of Neurology, Yale University School of Medicine, New Haven, CT 06519, USA
E-Mail: bahman.jabbari@yale.edu
Special Issue Information
Dear Colleagues,
Introduction of Botulinum toxins(BoNTs) as therapeutic agents in clinical medicine have significantly improved management of involuntary movement disorders, debilitating spasticity and pain associated with a number of medical ailments. Animal data have shown that BoNTs do not only block the release of acetylcholine from presynaptic vesicles but also inhibit the release of a number of neurotransmitters and peptides most notable among them pain modulators (glutamate, substance P, calcitonin gene related peptide). The goal of this issue is to provide latest information about clinical utility of the BoNTs in clinical medicine. Those clinical conditions in which blinded and placebo controlled studies indicate efficacy is covered in details. The efficacy will be defined according to the guidelines of the American Academy of Neurology. The areas with potential efficacy based on smaller blinded studies or multiple prospective open observations will be mentioned briefly at the end of this issue.
The topics of this issue include: The molecular structure and mechanisms of action of botulinum toxins, blepharospasm, hemifacial spasm and facial dystonias, cervical dystonia and focal limb dystonia, headache and other pain disorders, conditions of increased muscle tone (spasicity and rigidity), genitourinary and gastrointestinal indications, orthopaedic indications , authonomic disorders (sialorhea and hyperhidrosis), tremors and tics, cosmetic indications, potential indications for future use.
Prof. Dr. Bahman Jabbari
Guest Editor
Submission
Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. Papers will be published continuously (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.
Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are refereed through a peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Toxins is an international peer-reviewed Open Access monthly journal published by MDPI.
Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 800 CHF (Swiss Francs).
Keywords
- botulinum toxin
- pain
- headaches
- spasticiy
- dysonia
- sialorrhea
- hyperhidrosis
- blepharospasm
- hemifacial spasm
- tremor
Published Papers (13 papers)
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Received: 27 June 2012; in revised form: 9 August 2012 / Accepted: 10 August 2012 / Published: 13 August 2012
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Abstract: Botulinum Neurotoxin A (BoNT-A) injections have been used for the treatment of muscle contractures and spasticity. This study assessed the influence of (BoNT-A) injections on passive biomechanical properties of the muscle-tendon unit. Mouse gastrocnemius muscle (GC) was injected with BoNT-A (n = 18) or normal saline (n = 18) and passive, non-destructive, in vivo load relaxation experimentation was performed to examine how the muscle-tendon unit behaves after chemical denervation with BoNT-A. Injection of BoNT-A impaired passive muscle recovery (15% vs. 35% recovery to pre-stretching baseline, p < 0.05) and decreased GC stiffness (0.531 ± 0.061 N/mm vs. 0.780 ± 0.037 N/mm, p < 0.05) compared to saline controls. The successful use of BoNT-A injections as an adjunct to physical therapy may be in part attributed to the disruption of the stretch reflex; thereby modulating in vivo passive muscle properties. However, it is also possible that BoNT-A injection may alter the structure of skeletal muscle; thus modulating the in vivo passive biomechanical properties of the muscle-tendon unit.
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Received: 13 August 2012; in revised form: 9 October 2012 / Accepted: 12 October 2012 / Published: 19 October 2012
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Abstract: Botulinum neurotoxins (BoNTs) cause flaccid paralysis by interfering with vesicle fusion and neurotransmitter release in the neuronal cells. BoNTs are the most widely used therapeutic proteins. BoNT/A was approved by the U.S. FDA to treat strabismus, blepharospam, and hemificial spasm as early as 1989 and then for treatment of cervical dystonia, glabellar facial lines, axillary hyperhidrosis, chronic migraine and for cosmetic use. Due to its high efficacy, longevity of action and satisfactory safety profile, it has been used empirically in a variety of ophthalmological, gastrointestinal, urological, orthopedic, dermatological, secretory, and painful disorders. Currently available BoNT therapies are limited to neuronal indications with the requirement of periodic injections resulting in immune-resistance for some indications. Recent understanding of the structure-function relationship of BoNTs prompted the engineering of novel BoNTs to extend therapeutic interventions in non-neuronal systems and to overcome the immune-resistance issue. Much research still needs to be done to improve and extend the medical uses of BoNTs.
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Received: 31 August 2012; in revised form: 25 September 2012 / Accepted: 18 October 2012 / Published: 24 October 2012
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Abstract: In patients suffering from oral cavity cancer surgical treatment is complex because it is necessary to remove carcinoma and lymph node metastasis (through a radical unilateral or bilateral neck dissection) and to reconstruct the affected area by means of free flaps. The saliva stagnation in the post-operative period is a risk factor with regard to local complications. Minor complications related to saliva stagnation (such as tissue maceration and wound dehiscence) could become major complications compromising the surgery or the reconstructive outcome. In fact the formation of oro-cutaneous fistula may cause infection, failure of the free flap, or the patient’s death with carotid blow-out syndrome. Botulinum injections in the major salivary glands, four days before surgery, temporarily reduces salivation during the healing stage and thus could reduce the incidence of saliva-related complications. Forty three patients with oral cancer were treated with botulinum toxin A. The saliva quantitative measurement and the sialoscintigraphy were performed before and after infiltrations of botulinum toxin in the major salivary glands. In all cases there was a considerable, but temporary, reduction of salivary secretion. A lower rate of local complications was observed in the post-operative period. The salivary production returned to normal within two months, with minimal side effects and discomfort for the patients. The temporary inhibition of salivary secretion in the post-operative period could enable a reduction in saliva-related local complications, in the incidence of oro-cutaneous fistulas, and improve the outcome of the surgery as well as the quality of residual life in these patients.
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Received: 6 July 2012; in revised form: 2 October 2012 / Accepted: 29 October 2012 / Published: 7 November 2012
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Abstract: Background: Two decades ago, botulinum neurotoxin (BoNT) type A was introduced to the commercial market. Subsequently, the toxin was approved by the FDA to address several neurological syndromes, involving muscle, nerve, and gland hyperactivity. These syndromes have typically been associated with abnormalities in cholinergic transmission. Despite the multiplicity of botulinal serotypes (designated as types A through G), therapeutic preparations are currently only available for BoNT types A and B. However, other BoNT serotypes are under study for possible clinical use and new clinical indications; Objective: To review the current research on botulinum neurotoxin serotypes A-G, and to analyze potential applications within basic science and clinical settings; Conclusions: The increasing understanding of botulinal neurotoxin pathophysiology, including the neurotoxin’s effects on specific neuronal populations, will help us in tailoring treatments for specific diagnoses, symptoms and patients. Scientists and clinicians should be aware of the full range of available data involving neurotoxin subtypes A-G.
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Received: 3 September 2012; in revised form: 25 October 2012 / Accepted: 31 October 2012 / Published: 7 November 2012
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Abstract: The objective of this paper is to discuss the classification, diagnosis, pathophysiology and management of Thoracic outlet syndrome (TOS). Thoracic outlet syndrome (TOS) is a complex entity that is characterized by different neurovascular signs and symptoms involving the upper limb. TOS is defined as upper extremity symptoms due to compression of the neurovascular bundle in the area of the neck just above the first rib. Compression is thought to occur at one or more of the three anatomical compartments: the interscalene triangle, the costoclavicular space and the retropectoralis minor spaces. The clinical presentation can include both neurogenic and vascular symptoms. TOS can be difficult to diagnose because there is no standardized objective test that can be used and the clinician must rely on history and several positive findings on physical exam. The medial antebrachial cutaneous nerve conduction may be a sensitive way to detect pathology in the lower trunks of the brachial plexus which is promising for future research. Treatment options continue to be conservative and surgical. However, for those who have failed physical therapy there is research to suggest that botulinum toxin may help with symptom relief. However, given that there has been conflicting evidence, further research is required using randomized controlled trials.
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Received: 3 September 2012; in revised form: 24 October 2012 / Accepted: 9 November 2012 / Published: 20 November 2012
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Abstract: The safety and efficacy of botulinum toxin for the treatment of focal hand and cranial dystonias are well-established. Studies of these adult-onset focal dystonias reveal both shared features, such as the dystonic phenotype of muscle hyperactivity and overflow muscle contraction and divergent features, such as task specificity in focal hand dystonia which is not a common feature of cranial dystonia. The physiologic effects of botulinum toxin in these 2 disorders also show both similarities and differences. This paper compares and contrasts the physiology of focal hand and cranial dystonias and of botulinum toxin in the management of these disorders.
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Received: 30 August 2012; in revised form: 12 November 2012 / Accepted: 21 November 2012 / Published: 27 November 2012
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Abstract: Stroke imposes significant burdens on health services and society, and as such there is a growing need to assess the cost-effectiveness of stroke treatment to ensure maximum benefit is derived from limited resources. This study compared the cost-effectiveness of treating post-stroke upper limb spasticity with botulinum toxin type A plus an upper limb therapy programme against the therapy programme alone. Data on resource use and health outcomes were prospectively collected for 333 patients with post-stroke upper limb spasticity taking part in a randomized trial and combined to estimate the incremental cost per quality adjusted life year (QALY) gained of botulinum toxin type A plus therapy relative to therapy alone. The base case incremental cost-effectiveness ratio (ICER) of botulinum toxin type A plus therapy was £93,500 per QALY gained. The probability of botulinum toxin type A plus therapy being cost-effective at the England and Wales cost-effectiveness threshold value of £20,000 per QALY was 0.36. The point estimates of the ICER remained above £20,000 per QALY for a range of sensitivity analyses, and the probability of botulinum toxin type A plus therapy being cost-effective at the threshold value did not exceed 0.39, regardless of the assumptions made.
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Received: 19 November 2012; in revised form: 19 December 2012 / Accepted: 21 December 2012 / Published: 28 December 2012
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Abstract: This retrospective study was performed to verify the efficacy and safety of Onabotulinumtoxin A (BTX-A) in treating children with neurogenic bladder (NB) secondary to myelomeningocele (MMC) with detrusor overactivity/low compliance. From January 2002 to June 2011, 47 patients out of 68 with neuropathic bladder were selected (22 females, 25 males, age range 5–17 years; mean age 10.7 years at first injection). They presented overactive/poor compliant neurogenic bladders on clean intermittent catheterization, and were resistant or non compliant to pharmacological therapy. Ten patients presented second to fourth grade concomitant monolateral/bilateral vesicoureteral reflux (VUR). All patients were incontinent despite catheterization. In the majority of patients Botulinum-A toxin was administered under general/local anesthesia by the injection of 200 IU of toxin, without exceeding the dosage of 12IU/kg body weight, diluted in 20 cc of saline solution in 20 sites, except in the periureteral areas. Follow-up included clinical and ultrasound examination, urodynamics performed at 6, 12 and 24 weeks, and annually thereafter. Seven patients remained stable, 21 patients required a second injection after 6–9 months and 19 a third injection. VUR was corrected, when necessary, in the same session after the BT-A injection, by 1–3 cc of subureteral Deflux®. Urodynamic parameters considered were leak point pressure (LPP), leak point volume (LPV) and specific volume at 20 cm H2O pressure. The results were analyzed using the Wilcoxon test. All patients experienced a significant 66.45% average increase of LPV (Wilcoxon paired rank test = 7169 × 10 −10) and a significant 118.57% average increase of SC 20 (Wilcoxon paired rank test = 2.466 × 10 −12). The difference between preoperative and postoperative LPP resulted not significant (Wilcoxon paired rank test = 0.8858) No patient presented severe systemic complications; 38/47 patients presented slight hematuria for 2–3 days. Two patients had postoperative urinary tract infection. All patients were hospitalized for 24 h with catheterization. Thirty-eight out of 47 patients achieved dryness between CIC; nine patients improved their incontinence but still need pads. Ten patients have resumed anticholinergic agents. Our results suggest that the use of BTX-A is safe and effective in patients with MMC with a positive effect on their dryness and quality of life.
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Received: 30 September 2012; in revised form: 14 December 2012 / Accepted: 24 December 2012 / Published: 7 January 2013
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Abstract: The treatment of children with cerebral palsy with Botulinum Toxin is considered safe and effective, but is only approved for children older than two years of age. The effect of BoNT-A injection on juvenile skeletal muscle especially on neuromuscular junction density, distribution and morphology is poorly delineated and concerns of irreversible damage to the motor endplates especially in young children exist. In contrast, earlier treatment could be appropriate to improve the attainment of motor milestones and general motor development. This review systematically analyzes the evidence regarding this hypothesis. A database search, including PubMed and Medline databases, was performed and all randomized controlled trials (RCTs) comparing the efficacy of Botulinum Toxin in children younger than two years were identified. Two authors independently extracted the data and the methods of all identified trials were assessed. Three RCTs met the inclusion criteria. The results of the analysis revealed an improvement in spasticity of the upper and lower extremities as well as in the range of motion in the joints of the lower limbs. However, evidence of an improvement of general motor development could not be found, as the assessment of this area was not completely specified for this patient group. Based on available evidence it can not be concluded that Botulinum Toxin treatment in children younger than two years improves the achievement of motor milestones. However, there is evidence for the reduction of spasticity, avoiding contractures and delaying surgery. Due to some limitations, the results of this review should be cautiously interpreted. More studies, long-term follow up independent high-quality RCTs with effectiveness analyses are needed.
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Received: 26 September 2012; in revised form: 25 December 2012 / Accepted: 27 December 2012 / Published: 8 January 2013
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Abstract: Tetanus toxin, the product of Clostridium tetani, is the cause of tetanus symptoms. Tetanus toxin is taken up into terminals of lower motor neurons and transported axonally to the spinal cord and/or brainstem. Here the toxin moves trans-synaptically into inhibitory nerve terminals, where vesicular release of inhibitory neurotransmitters becomes blocked, leading to disinhibition of lower motor neurons. Muscle rigidity and spasms ensue, often manifesting as trismus/lockjaw, dysphagia, opistotonus, or rigidity and spasms of respiratory, laryngeal, and abdominal muscles, which may cause respiratory failure. Botulinum toxin, in contrast, largely remains in lower motor neuron terminals, inhibiting acetylcholine release and muscle activity. Therefore, botulinum toxin may reduce tetanus symptoms. Trismus may be treated with botulinum toxin injections into the masseter and temporalis muscles. This should probably be done early in the course of tetanus to reduce the risk of pulmonary aspiration, involuntary tongue biting, anorexia and dental caries. Other muscle groups are also amenable to botulinum toxin treatment. Six tetanus patients have been successfully treated with botulinum toxin A. This review discusses the use of botulinum toxin for tetanus in the context of the pathophysiology, symptomatology, and medical treatment of Clostridium tetani infection.
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Received: 17 September 2012; in revised form: 12 December 2012 / Accepted: 5 January 2013 / Published: 11 January 2013
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Abstract: Botulinum toxin injections may significantly improve lower limb kinematics in gait of children with spastic forms of cerebral palsy. Here we aimed to analyze the effect of lower limb botulinum toxin injections on trunk postural control and lower limb intralimb (intersegmental) coordination in children with spastic diplegia or spastic hemiplegia (GMFCS I or II). We recorded tridimensional trunk kinematics and thigh, shank and foot elevation angles in fourteen 3–12 year-old children with spastic diplegia and 14 with spastic hemiplegia while walking either barefoot or with ankle-foot orthoses (AFO) before and after botulinum toxin infiltration according to a management protocol. We found significantly greater trunk excursions in the transverse plane (barefoot condition) and in the frontal plane (AFO condition). Intralimb coordination showed significant differences only in the barefoot condition, suggesting that reducing the degrees of freedom may limit the emergence of selective coordination. Minimal relative phase analysis showed differences between the groups (diplegia and hemiplegia) but there were no significant alterations unless the children wore AFO. We conclude that botulinum toxin injection in lower limb spastic muscles leads to changes in motor planning, including through interference with trunk stability, but a combination of therapies (orthoses and physical therapy) is needed in order to learn new motor strategies.
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Received: 10 December 2012; in revised form: 17 January 2013 / Accepted: 23 January 2013 / Published: 4 February 2013
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Abstract: Local chemodenervation with botulinum toxin (BoNT) injections to relax abnormally contracting muscles has been shown to be an effective and well-tolerated treatment in a variety of movement disorders and other neurological and non-neurological disorders. Despite almost 30 years of therapeutic use, there are only few studies of patients treated with BoNT injections over long period of time. These published data clearly support the conclusion that BoNT not only provides safe and effective symptomatic relief of dystonia but also long-term benefit and possibly even favorably modifying the natural history of this disease. The adverse events associated with chronic, periodic exposure to BoNT injections are generally minor and self-limiting. With the chronic use of BoNT and an expanding list of therapeutic indications, there is a need to carefully examine the existing data on the long-term efficacy and safety of BoNT. In this review we will highlight some of the aspects of long-term effects of BoNT, including efficacy, safety, and immunogenicity.
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Received: 19 March 2013; in revised form: 12 April 2013 / Accepted: 15 April 2013 / Published: 23 April 2013
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Abstract: Patients with cervical dystonia (CD) receive much of their care at university based hospital outpatient clinics. This study aimed to describe the clinical characteristics and treatment experiences of patients who continued care at our university based movement disorders clinic, and to document the reasons for which a subset discontinued care. Seventy patients (77% female) were recruited from all patients at the clinic (n = 323). Most (93%) were treated with botulinum neurotoxin (BoNT) injection, and onabotulinumtoxinA was initially used in 97%. The average dose of onabotulinumtoxinA was 270.4 U (range 50–500) and the median number of injections was 14 (range: 1–39). Twenty one patients later received at least one cycle of rimabotulinumtoxinB (33%); of those, 10 switched back to onabotulinumtoxinA (48%). The initial rimabotulinumtoxinB dose averaged 11,996 units (range: 3000–25,000 over 1–18 injections). Twenty one patients (30%) discontinued care. Reasons cited included suboptimal response to BoNT therapy (62%), excessive cost (24%), excessive travel burden (10%), and side effects of BoNT therapy (10%). Most patients (76%) did not seek further care after leaving the clinic. Patients who terminated care received fewer treatment cycles (5.5 vs. 13.0, p = 0.020). There were no other identifiable differences between groups in gender, age, disease characteristics, toxin dose, or toxin formulation. These results indicate that a significant number of CD patients discontinue care due to addressable barriers to access, including cost and travel burden, and that when leaving specialty care, patients often discontinue treatment altogether. These data highlight the need for new initiatives to reduce out-of-pocket costs, as well as training for community physicians on neurotoxin injection in order to lessen the travel burden patients must accept in order to receive standard-of-care treatments.
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Last update: 18 May 2012
