Botulinum toxin therapy for neurologic disorders

Botulinum toxin type A, the most potent biologic neurotoxin known, enjoys a curious role as an increasingly used therapeutic agent. Its ability to produce chemical denervation in muscle makes it an intriguing option for treating focal dystonias and other neurologic disorders in which traditional therapies are of limited benefit. In this article, Drs Tim and Massey describe the therapeutic effectiveness of botulinum toxin in various disorders.     

Botulinum toxin and spinal cord injury]

OBJECTIVE: To realize a clarification about the interest of the use of botulinum toxin in spinal cord injured patients. METHOD: Interrogation of Medline database (crossing of botulinum toxin and spinal cord injury). We have also analyzed data from R. Poincaré Hospital in 2001. RESULTS: Three articles of the twenty-five selected, treated effectively of botulinum toxin effect in the limbs muscles of spinal cord injured patients. DISCUSSION: There are some indications of botulinum toxin in spinal cord injured patients ASIA C and D when spasticity induce focal functional discomfort. Indications are exceptional for ASIA A and B patients. No study showed improvement of functional abilities after botulinum toxin injection in spinal cord injured patients. Published studies only covered small number of patients.     

Utilisation de fortes doses de toxine botulique de type A chez l'enfant: intérêt et sécurité en pratique clinique

The purpose of this article is to examine the current state of administering high doses botulinum toxin type A for the treatment of chidhood spasticity, particularly Cerebral Palsy. The inter-relationship between the Cerebral Palsy neurological maturation and the early management is discussed, including identification of common gait patterns and the choice of target muscles for focal or multi focal spasticity management. High doses of botulinum toxin type A, when multilevel and integrated management approach is indicated, appear to be a safe, efficacious treatment for multi focal Cerebral Palsy spasticity. A review of literature guides the clinician about necessary adaptation of botulinum toxin doses and found no evidence that higher doses result in a increase of complications. Further studies would be interesting in order to evaluate long term safety and efficacy of this therapy in Cerebral Palsy.     

Regulation of calcitonin gene-related peptide secretion from trigeminal nerve cells by botulinum toxin type A: implications for migraine therapy

OBJECTIVES: To determine the effect of botulinum toxin type A on calcitonin gene-related peptide secretion from cultured trigeminal ganglia neurons. BACKGROUND: The ability of botulinum toxins to cause muscle paralysis by blocking acetylcholine release at the neuromuscular junction is well known. Previous studies and clinical observations have failed to demonstrate sensory changes related to botulinum toxins or the disease of botulism. Recent studies, however, have suggested that botulinum toxin type A injected into pericranial muscles may have a prophylactic benefit in migraine. This observation has renewed the debate of a mechanism of sensory inhibition mediated by botulinum toxin type A. METHODS: Primary cultures of rat trigeminal ganglia were utilized to determine whether botulinum toxin type A could directly decrease the release of calcitonin gene-related peptide, a neuropeptide involved in the underlying pathophysiology of migraine. Untreated cultures or cultures stimulated with a depolarizing stimulus (potassium chloride) or capsaicin, an agent known to activate sensory C fibers, were treated for 3, 6, or 24 hours with clinically effective doses of botulinum toxin type A or a control vehicle. The amount of calcitonin gene-related peptide secreted into the culture media following the various treatments was determined using a specific radioimmunoassay. RESULTS: A high percentage (greater than 90%) of the trigeminal ganglia neurons present in 1- to 3-day-old cultures was shown to express calcitonin gene-related peptide. Treatment with depolarizing stimuli (potassium chloride), a mixture of inflammatory agents, or capsaicin caused a marked increase (4- to 5-fold) in calcitonin gene-related peptide released from the trigeminal neurons. Interestingly, overnight treatment of trigeminal ganglia cultures with therapeutic concentrations of botulinum toxin type A (1.6 or 3.1 units) did not affect the amount of calcitonin gene-related peptide released from these neurons. The stimulated release of calcitonin gene-related peptide following chemical depolarization with potassium chloride or activation with capsaicin, however, was greatly repressed by the botulinum toxin, but not by the control vehicle. A similar inhibitory effect of overnight treatment with botulinum toxin type A was observed with 1.6 and 3.1 units. These concentrations of botulinum toxin type A are well within or below the range of tissue concentration easily achieved with a local injection. Incubation of the cultures with toxin for 24, 6, or even 3 hours was very effective at repressing stimulated calcitonin gene-related peptide secretion when compared to control values. CONCLUSIONS: These data provide the first evidence that botulinum toxin type A can directly decrease the amount of calcitonin gene-related peptide released from trigeminal neurons. The results suggest that the effectiveness of botulinum toxin type A in the treatment of migraine may be due, in part, to its ability to repress calcitonin gene-related peptide release from activated sensory neurons.     

Addition of an anesthetic agent to enhance the predictability of the effects of botulinum toxin type A injections: a randomized controlled study

OBJECTIVE: To determine whether the paralyzing effect of botulinum toxin type A reconstituted in a solution of lidocaine with epinephrine is as effective as that of the same toxin reconstituted in saline and to determine whether the addition of lidocaine with epinephrine enhances the predictability of outcomes of botulinum toxin injections. SUBJECTS AND METHODS: This double-blind, within-subject, randomized controlled study was conducted in 10 volunteer subjects. Lidocaine was added to botulinum toxin type A to achieve an immediate paralyzing effect on the injected muscle, and epinephrine was added to minimize diffusion of the injected toxin to adjacent muscles. This combination of agents was injected to temporarily paralyze the frontalis, corrugator supercilii, and procerus muscles on 1 side of the forehead of the 10 volunteers. The contralateral side was injected with the same dosage of the toxin, reconstituted in an equal volume of saline, to serve as control. Photographic and video documentation of the drugs' effects was obtained before injection and at 5 to 10 minutes, 1 week, and 3 months after the injections. RESULTS: Immediate paralysis ensued on the experimental side (botulinum toxin type A + lidocaine + epinephrine) in all 10 volunteers. As assessed by 3 blinded evaluators, the extent of immediate paralysis resulting from the anesthetic agent was predictive of the extent of delayed paralysis resulting from the botulinum toxin. The botulinum toxin-induced paralysis wore off symmetrically in all subjects. CONCLUSION: The injection of botulinum toxin reconstituted in lidocaine with epinephrine provided the physician immediate feedback on the extent of paralysis to be expected from the chemodenervating action of the botulinum toxin. This may enhance the safety and predictability of botulinum toxin injections in many applications.     

Treatment of focal upper limb spasticity with botulinum toxin after stroke. Interest of an individual approach.]

INTRODUCTION: It is now demonstrated that botulinum toxin can improve upper limb spasticity after stroke. OBJECTIVES: This study was designed to assess the efficacy of botulinum toxin on upper limb spasticity with an individual approach. METHODS: Prospective study on 18 patients who had disabling spasticity of upper limb after stroke. For each patient, the treatment's target was fixed preliminary to botulinum toxin injection. Evaluation of efficacy (Ashworth scale and predefined targets) was performed at 1 month and treatment continuation was decided individually. RESULTS: A beneficial effect was reported by most patients when the treatment was aimed at improving comfort or quality of life. In one case, the treatment was designed to improve grasping. In that case, no effect was reported. For three patients, a neurotomy was performed in order to obtain a long lasting effect. For nine patients, repeated injections were decided. For the six other patients, no long-standing treatment was performed. DISCUSSION: This study confirms that botulinum toxin can improve comfort of patients with upper limb spasticity. On the base of our experience, we discussed contribution of botulinum toxin to enhance and optimise strategies for the treatment of focal upper limb spasticity with emphasis on the comparison with selective neurotomy.     

Cleavage of SNAP-25 by botulinum toxin type A requires receptor-mediated endocytosis, pH-dependent translocation, and zinc

Previously we reported that SNAP-25, synaptobrevin II, and syntaxin I, the intracellular substrates of botulinum toxin originally identified in nontarget tissues, were present in a recognized mammalian target tissue, the mouse hemidiaphragm. Furthermore, we reported that SNAP-25, syntaxin I, and synaptobrevin II were cleaved by incubation of the intact hemidiaphragm in botulinum serotypes A, C, and D, respectively. The objective of the current study was to use the mouse phrenic nerve-hemidiaphragm preparation and botulinum serotype A to investigate 1) the relationship of substrate cleavage to toxin-induced paralysis, and 2) the relevance of substrate cleavage to the mechanism of toxin action. Immunoblot examination of tissues paralyzed by botulinum toxin type A (10(-8) M) revealed < or =10% loss of SNAP-25 immunoreactivity at 1 h postparalysis, and > or =75% loss at 5 h postparalysis. Triticum vulgaris lectin, an agent that competitively antagonizes toxin binding, antagonized toxin-induced paralysis as well as SNAP-25 cleavage. Methylamine hydrochloride, an agent that prevents pH-dependent translocation, also antagonized toxin-induced paralysis and SNAP-25 cleavage. Furthermore, zinc chelation antagonized toxin-induced paralysis and SNAP-25 cleavage. These results demonstrate that cleavage of SNAP-25 by botulinum serotype A fulfills the requirements of the multistep model of botulinum toxin action that includes receptor-mediated endocytosis, pH-dependent translocation, and zinc-dependent proteolysis. Furthermore, the minimal amount of SNAP-25 cleavage at 1 h postparalysis suggests that inactivation of only a small but functionally important pool of SNAP-25 is necessary for paralysis.     

Single-site botulinum toxin type a injection for elimination of migraine trigger points

BACKGROUND: Botulinum toxin may be effective in suppressing migraine. Most injection regimens utilized have involved multiple sites. PURPOSE: To evaluate prospectively the effect of botulinum toxin type A injections into the corrugator supercilii muscles alone on the frequency and severity of migraine. METHODS: Twenty-nine patients (24 women, 5 men) with migraine were enrolled in the study. Average age was 45 years (range, 24 to 63). The frequency (number of migraines per month) and intensity (recorded on an analog scale of 1 to 10, 10 being most severe) of headache were recorded before and after treatment. Twenty-five units of botulinum toxin type A was injected into each corrugator supercilii muscle, for a total of 50 units. RESULTS: At 2 months, 24 (83%) of 29 patients reported a positive response to the injection of botulinum toxin type A (P <.001). Sixteen patients (55%) reported complete elimination of headache (P <.001), 8 (28%) experienced significant improvement (at least 50% reduction in frequency or intensity) (P <.04), and 5 (17%) did not notice a change in headache. The duration of efficacy of the botulinum toxin type A injections ranged from 6 to 12 weeks, with an average of 8 weeks. In patients who had improvement in migraine but not complete elimination, the headache frequency decreased from 6.4 to 2.1 per month on average (P <.04), and the intensity decreased from 8.6 to 6.1 (P <.04). CONCLUSION: These results support the hypothesis that focal injection of botulinum toxin type A may be an effective therapy for migraine.     

Botulinum C2 toxin ADP-ribosylates actin and enhances O2- production and secretion but inhibits migration of activated human neutrophils.

The binary botulinum C2 toxin ADP-ribosylated the actin of human neutrophils. Treatment of human neutrophils with botulinum C2 toxin for 45 min increased FMLP-stimulated superoxide anion (O2-) production 1.5-5-fold, whereas only a minor fraction of the cellular actin pool (approximately 20%) was ADP-ribosylated. Effects of botulinum C2 toxin depended on toxin concentrations, presence of both components of the toxin, and incubation time. Cytochalasin B similarly enhanced O2- production. The effects of botulinum C2 toxin and cytochalasin B were additive at submaximally, but not maximally effective concentrations and incubation time of either toxin. Botulinum C2 toxin also enhanced stimulation of O2- production by Con A and platelet-activating factor, but not by phorbol 12-myristate 13-acetate (PMA). Botulinum C2 toxin increased FMLP-induced release of N-acetyl-glucosaminidase by 100-250%; release of vitamin B12-binding protein induced by FMLP and PMA was enhanced by approximately 150 and 50%, respectively. Botulinum C2 toxin blocked both random migration of neutrophils and migration induced by FMLP, complement C5a, leukotriene B4, and a novel monocyte-derived chemotactic agent. The data suggest that botulinum C2 toxin-catalyzed ADP-ribosylation of a minor actin pool has a pronounced effect on the activation of human neutrophils by various stimulants.     

The use of botulinum toxin in pediatric disorders

Botulinum toxins have an exciting and important role in treating the child with hypertonia. The guidelines presented in this article are those that have been published representing the safe use of botulinum toxins in children. Experience and a decade of research have provided the framework for using botulinum toxins in decreasing deformity and promoting function. In children, a window of opportunity exists with botulinum toxin that allows improved motor control and elongation of shortened muscles. Although 3 to 4 months in an adult life is short, for a child it is a relatively greater proportion of their life experience and may be long enough for skill development. The improvement noted in function after botulinum toxin use is facilitated by comprehensive rehabilitation. The pediatric physiatrist has a unique role in the management of children with cerebral palsy and other conditions with hypertonia. Their knowledge and training reflect an understanding of anatomy and development that allows accurate evaluation of specific functional problems in children related to hypertonia. The pediatric physiatrist has experience in localization of muscles by EMG, nerve stimulation, and surface anatomy. Although many other physicians inject botulinum toxins, goal-directed management is the cornerstone to the physiatrist's thinking and treatment plan. Orthopedic surgery ultimately may be the intervention of choice if persistent contracture or progression of contractures occurs. Working in collaboration with an orthopedist identifies the timing of optimal surgical intervention for alignment. For persistent and severe hypertonia, the treatment team includes a neurosurgeon. All options for spasticity, such as selective posterior rhizotomy and intrathecal baclofen, should be considered. Re-evaluation of the child after selective dorsal rhizotomy or intrathecal baclofen is appropriate and should be discussed with therapists for focal intervention. Communication between members of the team and the family is desirable and frequently is one of the major contributions of the pediatric physiatrist. For children with focal hypertonia, botulinum toxins offer a dramatic but temporary repeatable change that affects rehabilitation. Research rapidly has captured the positive effect of the toxins on impairment and functional limitations. Not to be overlooked are outcomes related to quality of life. The long-term use of botulinum toxins and the role the toxins play throughout the life span of the person with a childhood hypertonic disorder are yet to be determined.     

Focal spasticity therapy with botulinum toxin: effects on function, activities of daily living and pain in 100 adult patients.

OBJECTIVE: Analysis of the effects of a comprehensive focal spasticity program in adult patients. DESIGN: Retrospective study of an out-patient cohort. PATIENTS: One hundred patients were enrolled in the study (54 men and 46 women, mean age 41 years (SD 14). Cerebral palsy and stroke were equally common (80% in total). The remaining patients had miscellaneous diagnoses, including traumatic brain injury. METHODS: On average 230 units (SD 101) of botulinum toxin A Botox was given for 227 principal therapy targets chosen by the patient or the caregiver. One patient could have several targets for therapy. Administration of botulinum toxin was combined with 260 additional therapeutic interventions, most of which were forms of physical therapy. The effects were assessed after 6 weeks and compared with baseline functional abilities 1-2 weeks prior to therapy. RESULTS: Improvement was observed for 211 (93%) therapy targets, no change in 15 (7%), and impairment in 1, corresponding to an overall improvement in 90 patients (90%), 9 unchanged (9%) and worsening in 1. Spasticity assessment (Ashworth scale 0-4; 30 patients) showed a statistically significant improvement (median at baseline was 3 vs 2 after therapy, mean difference 1.2, p<0.001). CONCLUSION: Improvement was observed in >or=90% of patients and in their principal therapeutic targets in a cohort receiving their first focal spasticity treatment with botulinum toxin A and additional therapy. A strict strategy for patient selection and comprehensive management was followed.     

Prise en charge de la spasticité dans la sclérose en plaques

Spasticity is a frequent symptom in cases of multiple sclerosis. The treatment depends on whether the spasticity is focal or diffuse. The recent recommendations issued by AFSSAPS give details concerning first-line therapy: botulinum toxin A for cases of focal spasticity and intrathecal baclofen for diffuse spasticity. A prior evaluation can be made with the help of reversible tests to set out the functional objectives of the therapy.     

Use of botulinum toxin type A in neuro-ORL]

Dystonia is the result of abnormal contractions of muscles, which may disturb activities between agonist and antagonist muscles. Since synchronization of laryngeal and masticatory muscles is highly necessary to allow opening and closure of the larynx or the mouth, expression of dystonia is especially exhibited. Focal laryngeal dystonia may disturb phonation, but also breathing or swallowing, which may be difficult to identify. In ORL, the botulinum toxin is used to treat focal dystonias, especially laryngeal (spamodic dysphonia being predominant) and oromandibular dystonias. Beside these indications, intracutaneous injections of botulinum toxin may be helpful in Frey's syndrome in patients with gustatory sweating; injections in the upper esophageal sphincter are also performed in cricopharyngeal dysphagia although this indication is mainly controversial.     

A型肉毒素在皮肤科疾病治疗中的进展

A型肉毒素是肉毒梭状芽孢杆菌在繁殖过程中分泌的A型毒性蛋白质,具有很强的神经毒性。其在皮肤美容方面的疗效显著而被熟知。除皮肤美容外,临床实践和前期研究均证实A型肉毒素在治疗皮肤病方面亦有明显疗效,且部分疾病经治疗预后明显优于传统治疗,如瘢痕与多汗症等。     

The effect of botulinum toxin type-A injection on spasticity, range of motion and gait patterns in children with spastic diplegic cerebral palsy: an Egyptian study

Spasticity is defined as increased resistance to passive movement, secondary to hyperreflexia after an upper motor neuron lesion. In children with cerebral palsy (CP), it can interfere with mobility and self-care and can contribute to development of fixed myostatic contractures. This study investigated the efficacy of botulinum toxin type-A, a neuromuscular blocking agent that reduces muscle tone, in a variety of neuromuscular disorders, injections in a prospective, 3-month, controlled study involving 40 children with spastic diplegic CP. The patients were divided into two groups: Group 1 (20 patients) entered a botulinum toxin type-A injection+physiotherapy rehabilitation program; Group 2 (20 patients) were given the physiotherapy rehabilitation program only. Patients were assessed at 4, 8 and 12 weeks post-treatment using the Modified Ashworth Scale (MAS), dynamic gait pattern, ankle range-of-motion measurements and quantification of muscle denervation by nerve conduction techniques. The botulinum toxin type-A group demonstrated statistically significantly decreased spasticity, improved gait function and improved range of motion with evidence of partial denervation of the injected muscle compared to the control group. In conclusion, botulinum toxin type-A injections are a well-tolerated, non-surgical technique that can improve overall response to physiotherapy.     

Identification of the factors that govern the ability of therapeutic antibodies to provide postchallenge protection against botulinum toxin: a model for assessing postchallenge efficacy of medical countermeasures against agents of bioterrorism and biological warfare

Therapeutic antibodies are one of the major classes of medical countermeasures that can provide protection against potential bioweapons such as botulinum toxin. Although a broad array of antibodies are being evaluated for their ability to neutralize the toxin, there is little information that defines the circumstances under which these antibodies can be used. In the present study, an effort was made to quantify the temporal factors that govern therapeutic antibody use in a postchallenge scenario. Experiments were done involving inhalation administration of toxin to mice, intravenous administration to mice, and direct application to murine phrenic nerve-hemidiaphragm preparations. As part of this study, several pharmacokinetic characteristics of botulinum toxin and neutralizing antibodies were measured. The core observation that emerged from the work was that the window of opportunity within which postchallenge administration of antibodies exerted a beneficial effect increased as the challenge dose of toxin decreased. The critical factor in establishing the window of opportunity was the amount of time needed for fractional redistribution of a neuroparalytic quantum of toxin from the extraneuronal space to the intraneuronal space. This redistribution event was a dose-dependent phenomenon. It is likely that the approach used to identify the factors that govern postchallenge efficacy of antibodies against botulinum toxin can be used to assess the factors that govern postchallenge efficacy of medical countermeasures against any agent of bioterrorism or biological warfare.     

Botulinum toxin type A or selective neurotomy for treating focal spastic muscle overactivity?

ObjectiveTo discuss the effectiveness, indications, limitations and side effects of botulinum toxin type A and selective neurotomy for treating focal spastic muscle overactivity to help clinicians choose the most appropriate treatment.MethodsExpert opinion based on scientific evidence and personal experience.ResultsBotulinum toxin type A can decrease muscle tone in different types of spastic muscle overactivity, which allows for treating a large variety of spastic patterns with several etiologies. The toxin effect is sometimes insufficient to improve functional outcome and is transient, thereby requiring repeated injections. Selective neurotomy is a permanent surgical treatment of the reflex component of the spastic muscle overactivity (spasticity) that is effective for spastic equinovarus foot. The neurotomy provides a greater and more constant reduction in spasticity. However, the long-lasting effect on the non-reflex muscle overactivity, especially dystonia, is doubted. The effectiveness, clinical indications, advantages, side effects and limitations of both techniques are discussed.ConclusionBotulinum toxin type A has the highest level of evidence and the largest range of indications. However, the botulinum toxin effect is reversible and seems less effective, which supports a permanent surgical treatment such as selective neurotomy, especially for the spastic foot. Further research is needed to compare the effect of botulinum toxin type A and selective neurotomy for the different types of spastic muscle overactivity and clinical patterns.     

Early physiotherapy after injection of botulinum toxin increases the beneficial effects on spasticity in patients with multiple sclerosis

OBJECTIVE: To determine whether additional physiotherapy increases botulinum toxin type A effects in reducing spasticity in patients with multiple sclerosis. DESIGN: A single-blind, randomized, controlled pilot trial with a 12-week study period. SUBJECTS: Thirty-eight patients with progressive multiple sclerosis affected by focal spasticity and who were observed at the Multiple Sclerosis Centre operating in the S. Andrea Hospital in Rome. INTERVENTIONS: For intervention all patients received botulinum toxin type A; the treatment group also received additional physiotherapy to optimize management through passive or active exercise and stretching regimens. MAIN MEASURES: To measure objective and subjective level of spasticity, patients were assessed at baseline, 2, 4 and 12 weeks post treatment by Modified Ashworth Scale and visual analogue scale. RESULTS: When compared with the control group, we found a significant decrease of spasticity by Modified Ashworth Scale (P < 0.01 by t-test) in the treatment group at week 2 (2.73 versus 3.22), week 4 (2.64 versus 3.33) and week 12 (2.68 versus 3.33). The mean (%) difference in Modified Ashworth Scale score between baseline and the end of follow-up was -0.95 (26.1) in the treatment group and -0.28 (7.7) in the control group (P < 0.01). The combined treatment proved also to be more effective by visual analogue scale (P < 0.01) at week 4 (6.95 versus 5.50) and at week 12 (7.86 versus 6.56) but not at week 2 (5.18 versus 5.50; P = 0.41). CONCLUSIONS: Our data suggest that physiotherapy in combination with botulinum toxin type A injection can improve overall response to botulinum toxin.     

Botulinum toxin type B: an overview of its biochemistry and preclinical pharmacology

Produced by Clostridium botulinum, botulinum toxins are high molecular weight protein complexes consisting of the neurotoxin and additional nontoxic proteins that function to protect the toxin molecule. The neurotoxin acts to inhibit the release of acetylcholine at the neuromuscular junction, causing muscle paralysis. Purified toxin complexes have found a niche in the treatment of clinical disorders involving muscle hyperactivity. The different serotypes are structurally and functionally similar; however, specific differences in neuronal acceptor binding sites, intracellular enzymatic sites, and species sensitivities suggest that each serotype is its own unique pharmacologic entity. Recently, botulinum toxin type B has been developed as a liquid formulation to avoid the lyophilization (vacuum-drying) and reconstitution processes associated with decreasing the potency and stability of current type A toxin preparations. Biochemical tests were conducted to evaluate the quality of toxin in this formulation. In 3 consecutive manufacturing lots, the botulinum toxin type B complex was found to be highly purified, intact, uniform, and consistent from lot to lot. Also, it showed long-term stability at refrigerator and room temperatures (2 to 25 degrees C). Electrophysiologic studies in cynomolgus monkeys showed that botulinum toxin type B is effective in paralyzing injected muscle groups, with minimal spread to relatively distant noninjected muscles.