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SPAsticity in practice (SPACE): an international, observational study of botulinum toxin type A in spasticity
S38
Abstracts / Toxicon 123 (2016) S2eS90
au.
Botulinum neurotoxin type A (BoNT/A) is a highly potent neurotoxin that elicits flaccid paralysis by enzymatic cleavage of the exocytic machinery component SNAP25 in motor nerve terminals. Emerging evidence suggests that a fraction of internalized neurotoxin is trafficked back to the central nervous system by fast retrograde axonal transport, raising some concerns regarding the ever growing array of neurological and cosmetic applications. We have found that the binding domain of BoNT/A enters rat hippocampal nerve terminals in a dynamin-dependent manner (Harper et al., 2011), in a non-recycling pool of synaptic vesicles (Harper et al., 2016). Using time-lapse confocal microscopy on hippocampal neurons cultured in microfluidic devices, we revealed that a large proportion of BoNT/A undergoing retrograde axonal transport was loaded in autophagosomes, suggesting that it follows a degradative pathway. Indeed, these retrograde carriers were found to fuse with lysosomes upon reaching the cell body in vitro and in vivo (Wang et al., 2015). We have implemented a novel technique based on the subdiffractional tracking of internalized molecules (sdTIM) to image synaptic vesicles in the crowded environment of the live hippocampal presynapse (Joensuu et al., 2016). We also adapted this method to track single molecules of BoNT/A binding domain being retrogradely transported following exposure to therapeutically relevant concentrations (Wang et al., 2015). These advances, as well as highlights of some outstanding questions in the field will be discussed. References Harper CB, Martin S, Nguyen TH, et al. Dynamin inhibition blocks botulinum type-A endocytosis in neurons and delays botulism. J Biol Chem. 2011; 286:35966-35976. Harper CB, Papadopulos A, Martin S, et al. Botulinum neurotoxin type-A enters a non-recycling pool of synaptic vesicles. Scientific Reports. 2016;6:19654. Joensuu M, Padmanabhan P, Durisic N, et al. Sub-diffractional tracking of internalized molecules reveals heterogeneous motion states of synaptic vesicles. J Cell Biol. In press. Wang T, Martin S, Papadopulos A, Harper CB, et al. Control of autophagosome axonal retrograde flux by presynaptic activity unveiled using botulinum neurotoxin type A. J. Neurosci. 2015;35(15):6179-6194. 97. SPASTICITY IN PRACTICE (SPACE): AN INTERNATIONAL, OBSERVATIONAL STUDY OF BOTULINUM TOXIN TYPE A IN SPASTICITY € rg Wissel b, Olivier Simon c, Kati Sternberg c, Nicolas Julian Harriss a,*, Jo € g. atero Roche d, Carlos Cantú-Brito e, Svetlana Khatkova f, Patrik S€ a b King’s College London, St Thomas’ Hospital, London, UK; Vivantes Hospital Spandau, Berlin, Germany; c Merz Pharmaceuticals GmbH, Frankfurt, e Hospital, AP-HP, Garches, France; e Instituto Germany; d Raymond-Poincar n, Mexico City, n Salvador Zubira Nacional de Ciencias M edicas y Nutricio Mexico; f Federal State Hospital for Treatment and Rehabilitation, Ministry €teborg, of Health, Moscow, Russia; g Sahlgrenska Universitetssjukhuset, Go Sweden * Corresponding author: St Thomas’ Hospital, Westminster Bridge Road, London, SE1 7EH, UK. E-mail address:[email protected].
Introduction and objectives: Botulinum toxin type A (BoNT-A) injections are key for the multidisciplinary management of spasticity, but real-world routine clinical practice data on effectiveness, safety, and quality of life (QoL) are limited. Methods: The observational SPACE study included previously BoNT-A treatment-naïve adults with spasticity who were treated with any available BoNT-A formulation at their physician’s discretion. Patients were followed for 2 years. Treatment goals, injection techniques, doses used, muscles treated, QoL (EQ-5D questionnaire), and adverse drug reactions (ADRs) were documented. Results: Patients (n¼687; 61.3% male) with spasticity (mean duration 5.4 years) mainly due to stroke (64.6%) or multiple sclerosis (9.3%) participated in 9 countries. The most common spasticity patterns were flexed elbow (58.1%) and flexed wrist (50.9%) in the upper limbs and equinovarus (32.2%) and extended knee (21.0%) in the lower limbs. The most frequently treated
muscles were flexor digitorum superficialis and biceps brachialis (upper limbs), and gastrocnemius medial and soleus (lower limbs). The most frequently used guidance technique was electrostimulation (18.5%), but many injections (40.2%) were given without guidance. The most frequent treatment goals were improvements in limb function (mobility and/or dexterity) and pain relief. BoNT-A treatment improved QoL over the study duration. Sixteen (2.7%) patients (for 600 of whom ADRs were collected) had an ADR. The majority of participating physicians (101/171, 59.1%) would have injected higher BoNT-A doses if there were no labelling restrictions. Conclusions: SPACE confirmed the good tolerability of BoNT-A formulations. Many physicians would prefer to use higher BoNT-A doses to allow treatment of more spasticity patterns in complex spasticity. Further studies are required to investigate the safety and efficacy of higher doses than those generally used in current practice. Funded by Merz Pharmaceuticals. Keywords: Botulinum toxin type A; IncobotulinumtoxinA; Multiple sclerosis; Spasticity; Stroke; Real-world data 98. EFFECTIVE TREATMENT OF CAUSALGIA-DYSTONIA SYNDROME WITH HIGH DOSES OF INCOBOTULINUMTOXINA Harald Hefter*, Marek Moll. Department of Neurology, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany * Corresponding author: Department of Neurology, Heinrich-Heine-University Düsseldorf, Moorenstr. 5, 40225, Düsseldorf, Germany. E-mail address:Harald. [email protected].
Introduction and objectives: Causalgia-dystonia syndrome (CDS) can be triggered by trivial peripheral injury or occur spontaneously (Bhatia 1993). It usually manifests in young adults at the leg or arm. Patients suffer from burning pain, allodynia, and hyperpathia, along with vasomotor, sudomotor, and trophic changes. Soon after pain begins, dystonic muscle spasms develop. We report on the successful treatment of a typical CDS patient. Methods: Burning pain spontaneously occurred in the left hand of a man aged 33 years. He worked in city administration but had previously been a professional guitar player. Touch of the hand became increasingly painful, so he had to stop work. Within 2 weeks, his hand and forearm started to swell, and the skin took on a livid color; tremor and muscle jerks developed in the forearm. Four weeks later, his fingers started to flex, and his hand deviated in the ulnar direction. Two weeks later, his hand closed completely, and passive finger extension was very painful. Treatment with antiphlogistic drugs and opioids failed. In our ambulatory pain complex, regional pain syndrome was diagnosed, treatment with pregabalin was initiated, and opioid therapy was intensified. Computed tomography scan of his hand and forearm showed osteopenia, edema, severe ulnar deviation, and flexed fingers. A movement disorder specialist referred him to BoNT/A therapy. Results: The lumbricals, interossei, adductor pollicis brevis, ulnar hand flexors, and superficial and deep finger flexor muscles were injected with 500 units (U) inco-BoNT/A. Seven days later, pain and edema started to improve, ulnar deviation was reduced, and the fist could be opened. Tremor and muscle jerks disappeared. After the second injection, improvement continued. The next 2 injections were performed with 300 U, and the next 2 with 100 U. After 5 injections, the hand could be opened completely, edema was gone, individual finger movements became possible, and the patient started to work again. Now, after 6 injections, the patient is able to play the guitar. Conclusion: High doses of inco-BoNT/A are a treatment option in CDS cases. Keywords: Botulinum toxin; Complex regional pain syndrome; Dystonia Reference Bhatia KP, Bhatt MH, Marsden CD. The causalgia-dystonia syndrome. Brain. 1993;116:843-851. 99. HIGH PREVALENCE OF NEUTRALIZING ANTIBODIES IN BONT/A LONG-TERMeTREATED PATIENTS WITH FOCAL DYSTONIA AND SPASTICITY
Abstracts / Toxicon 123 (2016) S2eS90
au.
Botulinum neurotoxin type A (BoNT/A) is a highly potent neurotoxin that elicits flaccid paralysis by enzymatic cleavage of the exocytic machinery component SNAP25 in motor nerve terminals. Emerging evidence suggests that a fraction of internalized neurotoxin is trafficked back to the central nervous system by fast retrograde axonal transport, raising some concerns regarding the ever growing array of neurological and cosmetic applications. We have found that the binding domain of BoNT/A enters rat hippocampal nerve terminals in a dynamin-dependent manner (Harper et al., 2011), in a non-recycling pool of synaptic vesicles (Harper et al., 2016). Using time-lapse confocal microscopy on hippocampal neurons cultured in microfluidic devices, we revealed that a large proportion of BoNT/A undergoing retrograde axonal transport was loaded in autophagosomes, suggesting that it follows a degradative pathway. Indeed, these retrograde carriers were found to fuse with lysosomes upon reaching the cell body in vitro and in vivo (Wang et al., 2015). We have implemented a novel technique based on the subdiffractional tracking of internalized molecules (sdTIM) to image synaptic vesicles in the crowded environment of the live hippocampal presynapse (Joensuu et al., 2016). We also adapted this method to track single molecules of BoNT/A binding domain being retrogradely transported following exposure to therapeutically relevant concentrations (Wang et al., 2015). These advances, as well as highlights of some outstanding questions in the field will be discussed. References Harper CB, Martin S, Nguyen TH, et al. Dynamin inhibition blocks botulinum type-A endocytosis in neurons and delays botulism. J Biol Chem. 2011; 286:35966-35976. Harper CB, Papadopulos A, Martin S, et al. Botulinum neurotoxin type-A enters a non-recycling pool of synaptic vesicles. Scientific Reports. 2016;6:19654. Joensuu M, Padmanabhan P, Durisic N, et al. Sub-diffractional tracking of internalized molecules reveals heterogeneous motion states of synaptic vesicles. J Cell Biol. In press. Wang T, Martin S, Papadopulos A, Harper CB, et al. Control of autophagosome axonal retrograde flux by presynaptic activity unveiled using botulinum neurotoxin type A. J. Neurosci. 2015;35(15):6179-6194. 97. SPASTICITY IN PRACTICE (SPACE): AN INTERNATIONAL, OBSERVATIONAL STUDY OF BOTULINUM TOXIN TYPE A IN SPASTICITY € rg Wissel b, Olivier Simon c, Kati Sternberg c, Nicolas Julian Harriss a,*, Jo € g. atero Roche d, Carlos Cantú-Brito e, Svetlana Khatkova f, Patrik S€ a b King’s College London, St Thomas’ Hospital, London, UK; Vivantes Hospital Spandau, Berlin, Germany; c Merz Pharmaceuticals GmbH, Frankfurt, e Hospital, AP-HP, Garches, France; e Instituto Germany; d Raymond-Poincar n, Mexico City, n Salvador Zubira Nacional de Ciencias M edicas y Nutricio Mexico; f Federal State Hospital for Treatment and Rehabilitation, Ministry €teborg, of Health, Moscow, Russia; g Sahlgrenska Universitetssjukhuset, Go Sweden * Corresponding author: St Thomas’ Hospital, Westminster Bridge Road, London, SE1 7EH, UK. E-mail address:[email protected].
Introduction and objectives: Botulinum toxin type A (BoNT-A) injections are key for the multidisciplinary management of spasticity, but real-world routine clinical practice data on effectiveness, safety, and quality of life (QoL) are limited. Methods: The observational SPACE study included previously BoNT-A treatment-naïve adults with spasticity who were treated with any available BoNT-A formulation at their physician’s discretion. Patients were followed for 2 years. Treatment goals, injection techniques, doses used, muscles treated, QoL (EQ-5D questionnaire), and adverse drug reactions (ADRs) were documented. Results: Patients (n¼687; 61.3% male) with spasticity (mean duration 5.4 years) mainly due to stroke (64.6%) or multiple sclerosis (9.3%) participated in 9 countries. The most common spasticity patterns were flexed elbow (58.1%) and flexed wrist (50.9%) in the upper limbs and equinovarus (32.2%) and extended knee (21.0%) in the lower limbs. The most frequently treated
muscles were flexor digitorum superficialis and biceps brachialis (upper limbs), and gastrocnemius medial and soleus (lower limbs). The most frequently used guidance technique was electrostimulation (18.5%), but many injections (40.2%) were given without guidance. The most frequent treatment goals were improvements in limb function (mobility and/or dexterity) and pain relief. BoNT-A treatment improved QoL over the study duration. Sixteen (2.7%) patients (for 600 of whom ADRs were collected) had an ADR. The majority of participating physicians (101/171, 59.1%) would have injected higher BoNT-A doses if there were no labelling restrictions. Conclusions: SPACE confirmed the good tolerability of BoNT-A formulations. Many physicians would prefer to use higher BoNT-A doses to allow treatment of more spasticity patterns in complex spasticity. Further studies are required to investigate the safety and efficacy of higher doses than those generally used in current practice. Funded by Merz Pharmaceuticals. Keywords: Botulinum toxin type A; IncobotulinumtoxinA; Multiple sclerosis; Spasticity; Stroke; Real-world data 98. EFFECTIVE TREATMENT OF CAUSALGIA-DYSTONIA SYNDROME WITH HIGH DOSES OF INCOBOTULINUMTOXINA Harald Hefter*, Marek Moll. Department of Neurology, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany * Corresponding author: Department of Neurology, Heinrich-Heine-University Düsseldorf, Moorenstr. 5, 40225, Düsseldorf, Germany. E-mail address:Harald. [email protected].
Introduction and objectives: Causalgia-dystonia syndrome (CDS) can be triggered by trivial peripheral injury or occur spontaneously (Bhatia 1993). It usually manifests in young adults at the leg or arm. Patients suffer from burning pain, allodynia, and hyperpathia, along with vasomotor, sudomotor, and trophic changes. Soon after pain begins, dystonic muscle spasms develop. We report on the successful treatment of a typical CDS patient. Methods: Burning pain spontaneously occurred in the left hand of a man aged 33 years. He worked in city administration but had previously been a professional guitar player. Touch of the hand became increasingly painful, so he had to stop work. Within 2 weeks, his hand and forearm started to swell, and the skin took on a livid color; tremor and muscle jerks developed in the forearm. Four weeks later, his fingers started to flex, and his hand deviated in the ulnar direction. Two weeks later, his hand closed completely, and passive finger extension was very painful. Treatment with antiphlogistic drugs and opioids failed. In our ambulatory pain complex, regional pain syndrome was diagnosed, treatment with pregabalin was initiated, and opioid therapy was intensified. Computed tomography scan of his hand and forearm showed osteopenia, edema, severe ulnar deviation, and flexed fingers. A movement disorder specialist referred him to BoNT/A therapy. Results: The lumbricals, interossei, adductor pollicis brevis, ulnar hand flexors, and superficial and deep finger flexor muscles were injected with 500 units (U) inco-BoNT/A. Seven days later, pain and edema started to improve, ulnar deviation was reduced, and the fist could be opened. Tremor and muscle jerks disappeared. After the second injection, improvement continued. The next 2 injections were performed with 300 U, and the next 2 with 100 U. After 5 injections, the hand could be opened completely, edema was gone, individual finger movements became possible, and the patient started to work again. Now, after 6 injections, the patient is able to play the guitar. Conclusion: High doses of inco-BoNT/A are a treatment option in CDS cases. Keywords: Botulinum toxin; Complex regional pain syndrome; Dystonia Reference Bhatia KP, Bhatt MH, Marsden CD. The causalgia-dystonia syndrome. Brain. 1993;116:843-851. 99. HIGH PREVALENCE OF NEUTRALIZING ANTIBODIES IN BONT/A LONG-TERMeTREATED PATIENTS WITH FOCAL DYSTONIA AND SPASTICITY