Fereshte Adib Saberi

Botulinum toxin: mechanisms of action

Botulinum toxin (BT) has been perceived as a lethal threat for many centuries. In the early 1980s, this perception completely changed when BTs therapeutic potential suddenly became apparent. We wish to give an overview over BTs mechanisms of action relevant for understanding its therapeutic use. BTs molecular mode of action includes extracellular binding to glycoprotein structures on cholinergic nerve terminals and intracellular blockade of the acetylcholine secretion. BT affects the spinal stretch reflex by blockade of intrafusal muscle fibres with consecutive reduction of Ia/II afferent signals and muscle tone without affecting muscle strength (reflex inhibition). This mechanism allows for antidystonic effects not only caused by target muscle paresis. BT also blocks efferent autonomic fibres to smooth muscles and to exocrine glands. Direct central nervous system effects are not observed, since BT does not cross the blood-brain barrier and since it is inactivated during its retrograde axonal transport. Indirect central nervous system effects include reflex inhibition, normalisation of reciprocal inhibition, intracortical inhibition and somatosensory evoked potentials. Reduction of formalin-induced pain suggests direct analgesic BT effects possibly mediated by blockade of substance P, glutamate and calcitonin gene-related peptide.

Botulinum Toxin: Mechanisms of Action

Botulinum toxin (BT) has been perceived as a lethal threat for many centuries. In the early 1980s, this perception completely changed when BT’s therapeutic potential suddenly became apparent. We wish to give an overview over BT’s mechanisms of action relevant for understanding its therapeutic use. BT’s molecular mode of action includes extracellular binding to glycoprotein structures on cholinergic nerve terminals and intracellular blockade of the acetylcholine secretion. BT affects the spinal stretch reflex by blockade of intrafusal muscle fibres with consecutive reduction of Ia/II afferent signals and muscle tone without affecting muscle strength (reflex inhibition). This mechanism allows for antidystonic effects not only caused by target muscle paresis. BT also blocks efferent autonomic fibres to smooth muscles and to exocrine glands. Direct central nervous system effects are not observed, since BT does not cross the blood-brain barrier and since it is inactivated during its retrograde axonal transport. Indirect central nervous system effects include reflex inhibition, normalisation of reciprocal inhibition, intracortical inhibition and somatosensory evoked potentials. Reduction of formalin-induced pain suggests direct analgesic BT effects possibly mediated by blockade of substance P, glutamate and calcitonin gene-related peptide.

Botulinum toxin type B for treatment of axillar hyperhidrosis.

Abstract. Recently, botulinum toxin type B (BT-B) became commercially available for treatment of cervical dystonia. It is the aim of this study to explore its use for treatment of bilateral axillar hyperhydrosis (HH).For this we directly compared the antihyperhydrotic effect of BT-B (NeuroBloc®/MyoBloc™) with that of botulinum toxin type A (BT-A) (Botox®). 9 patients (HD group) received BT-A 100MU unilaterally and BT-B 4000MU contralaterally. 10 patients (LD group) received BT-A 100MU and BT-B 2000MU. All patients were blinded as to which preparation was used in which side.All patients except one reported excellent HH improvement in both axillae. None of the patients had residual HH on clinical examination. The duration of HH improvement until first recurrence in the HD group was 16.0 ±4.3 weeks in the BT-A treated axillar and 16.4 ±4.5 weeks in the BT-B treated axillae (Wilcoxon rank-sum test, p = 0.336). In the LD group it was 16.4 ±5.3 weeks in the BT-B treated axillae and 17.1 ±5.7 weeks in the BT-A treated axillae (Wilcoxon rank-sum test, p = 0.059). There was also no difference in the duration of HH improvement between the axillae treated with BT-B 4000MU and BT-B 2000MU (Wilcoxon rank-sum test, p = 0.712). 5 out of 9 patients in the HD group (chi-square test, p = 0.025) and 7 out of 10 patients in the LD group (chi-square test, p = 0.008) reported more application discomfort in the BT-B treated axillae. In 6 out of 9 patients in the HD group (chi-square test, p = 0.014) and in 6 out of 10 patients in the LD group (chi-square test, p = 0.014) the onset of HH improvement appeared earlier in the BT-B treated axillae. One patient in the HD group reported dryness of the mouth and eyes and accomodation difficulties.BT-B is a safe and efficient treatment for axillar HH. Doses of BT-B 2000MU per axilla seem sufficient indicating a conversion factor between BT-A and BT-B in the order of 1:20. With a conversion factor for cervical dystonia in the order of 1:40 the autonomic nervous system seems to be relatively more sensitive to BT-B than to BT-A compared with the motor system.

Botulinum toxin therapy for treatment of spasticity in multiple sclerosis: review and recommendations of the IAB-Interdisciplinary Working Group for Movement Disorders task force.

Botulinum toxin (BT) therapy is an established treatment of spasticity due to stroke. For multiple sclerosis (MS) spasticity this is not the case. IAB-Interdisciplinary Working Group for Movement Disorders formed a task force to explore the use of BT therapy for treatment of MS spasticity. A formalised PubMed literature search produced 55 publications (3 randomised controlled trials, 3 interventional studies, 11 observational studies, 2 case studies, 35 reviews, 1 guideline) all unanimously favouring the use of BT therapy for MS spasticity. There is no reason to believe that BT should be less effective and safe in MS spasticity than it is in stroke spasticity. Recommendations include an update of the current prevalence of MS spasticity and its clinical features according to classifications used in movement disorders. Immunological data on MS patients already treated should be analysed with respect to frequencies of MS relapses and BT antibody formation. Registration authorities should expand registration of BT therapy for spasticity regardless of its aetiology. MS specialists should consider BT therapy for symptomatic treatment of spasticity.

Strategies for treatment of dystonia

Treatment of dystonias is generally symptomatic. To produce sufficient therapy effects, therefore, frequently a multimodal and interdisciplinary therapeutic approach becomes necessary, combining botulinum toxin therapy, deep brain stimulation, oral antidystonic drugs, adjuvant drugs and rehabilitation therapy including physiotherapy, occupational therapy, re-training, speech therapy, psychotherapy and sociotherapy. This review presents the recommendations of the IAB—Interdisciplinary Working Group for Movement Disorders Special Task Force on Interdisciplinary Treatment of Dystonia. It reviews the different therapeutic modalities and outlines a strategy to adapt them to the dystonia localisation and severity of the individual patient. Hints to emerging and future therapies will be given.

Defining spasticity: a new approach considering current movement disorders terminology and botulinum toxin therapy

Spasticity is a symptom occurring in many neurological conditions including stroke, multiple sclerosis, hypoxic brain damage, traumatic brain injury, tumours and heredodegenerative diseases. It affects large numbers of patients and may cause major disability. So far, spasticity has merely been described as part of the upper motor neurone syndrome or defined in a narrowed neurophysiological sense. This consensus organised by IAB—Interdisciplinary Working Group Movement Disorders wants to provide a brief and practical new definition of spasticity—for the first time—based on its various forms of muscle hyperactivity as described in the current movement disorders terminology. We propose the following new definition system: Spasticity describes involuntary muscle hyperactivity in the presence of central paresis. The involuntary muscle hyperactivity can consist of various forms of muscle hyperactivity: spasticity sensu strictu describes involuntary muscle hyperactivity triggered by rapid passive joint movements, rigidity involuntary muscle hyperactivity triggered by slow passive joint movements, dystonia spontaneous involuntary muscle hyperactivity and spasms complex involuntary movements usually triggered by sensory or acoustic stimuli. Spasticity can be described by a documentation system grouped along clinical picture (axis 1), aetiology (axis 2), localisation (axis 3) and additional central nervous system deficits (axis 4). Our new definition allows distinction of spasticity components accessible to BT therapy and those inaccessible. The documentation sheet presented provides essential information for planning of BT therapy.

Rehabilitation of Dystonia

Dystonia is a syndrome characterized by “sustained or intermittent muscle contractions causing abnormal, often repetitive movements, postures, or both. Dystonic movements are typically patterned, twisting, and may be tremulous. It is usually classified according to its location within the body. Other classifications are based on the age at manifestation, the continuity of occurrence (continuous, intermittent, paroxysmal) and the conditions of occurrence (task-specific, action-induced, spontaneous). Causal factors may also be considered for classification: idiopathic, symptomatic owing to structural lesions, pharmacological interactions, metabolic disorders and psychogenic reactions. Dystonia may occur as an isolated symptom or in the context of other symptoms or conditions arising from basal ganglia dysfunction.

Botulinum toxin in myotonia congenita: it does not help against rigidity and pain

Botulinum toxin (BT) is a potent local muscle relaxant with analgetic properties. Myotonia congenita (MC) is a genetic disorder producing muscle rigidity and pain. BT injected into the trapezius produced mild paresis, but no effect on rigidity and pain. There were no signs of systemic effects. Lack of BT efficacy on MC rigidity confirms its origin from muscle membrane dysfunction rather than from inappropriate neuromuscular activation. Lack of BT efficacy on pain could be caused by lack of anti-rigidity effect. It could also be due to separate non-muscular pain mechanisms unresponsive to BT.

Poster 274 Botulinum Toxin Therapy of Cervical Dystonia (CD): Duration of Therapeutic Effects

destroys motor neurons. Mutations in the senataxin gene causes ALS4. This case report describes the use of ITB to treat the spasticity in a person with ALS4. Oral agents may be ineffective or poorly tolerated. ITB can provide excellent control of spasticity with less side effects than oral agents. Conclusions: ITB to treat spasiticty in ALS4, or Juvenile Onset ALS, has not been reported in the literature. ALS4 is a life-long disease and is slowly progressive (unlike classical ALS) and can be associated with signficant spasticity. People with ALS4 and spasticity should have ITB as an option; a test doses of ITB, or a trial , will determine if it will be effective. After implantation, careful titration based on effect may improve function and quality of life.