br Funding Association Fran aise contre les Myopathies AFM

Funding Association Française contre les Myopathies (AFM-Téléthon), French National Health Institute (INSERM), French National Research Agency (ANR), Bettencourt-Schueller Foundation, Cognacq Jay Foundation, Fondamental Foundation, Servier Laboratories.
Role of the Funding Sources
Aknowledgements The authors are thankful to I-Stem\'s HTS platform staff for constant technical support. We thank the cell bank of Pitié-Salpétrière hospital and the Clinical Investigation Center of Robert Debré hospital for assistance with patient recruitment, information, sampling and fibroblast preparation. H.D. received a PhD grant from Servier\'s Laboratories. I-Stem is part of the Biotherapies Institute for Rare Diseases (BIRD) supported by the Association Française contre les Myopathies (AFM-Téléthon). This study has been in part funded by grants from “Investissements d\'Avenir” – (ANR-11-INBS-0009 - INGESTEM – and ANR-11-INBS-0011 - NeurATRIS), the French National Research Agency ANR (ANR-13-SAMA-0006; SynDivAutism), the Laboratory of Excellence GENMAD (ANR-10-LABX-0013), the Bettencourt-Schueller Foundation, the Cognacq Jay Foundation, and the Fondamental Foundation. This study used samples from the NINDS Human Genetics Resource Center DNA and Cell Line Repository, as well as clinical data. NINDS Repository sample numbers corresponding to the samples used are GM 1869.
Introduction Spasticity is a common movement disorder after neurologic injury of cerebral and spinal origin such as stroke, traumatic dacomitinib injury, brain tumor, cerebral palsy, spinal cord injury, and multiple sclerosis. Upper limb spasticity is associated with reduced functional independence and a four-fold increase in direct care costs during the first year post-stroke alone (Lundstrom et al., 2010). The prevalence of spasticity increases over time, contributing to further disability long after the neurologic injury (Lundstrom et al., 2008). Spasticity is challenging to treat because the underlying neural and non-neural mechanisms and their interactions are not fully understood. The neural mechanism underlying spasticity is hyper-excitability of the stretch reflex due to disinhibition of cortical influences on spinal cord circuitry, which results in velocity-dependent increase in tonic stretch reflexes (Lance, 1980). However, many patients with spasticity do not show any signs of hyperreflexia (Sinkjaer and Magnussen, 1994). Instead, muscle stiffness, defined here as increased resistance to passive movement, is the most common presenting sign in individuals with spasticity (Sheean and McGuire, 2009). Muscle stiffness adds further insult to the underlying weakness. It both prevents full passive movement (leading to abnormal posturing that can become fixed over time) and makes active movement more difficult in patients who are already weak from the neurologic injury. Non-neural peripheral mechanisms are thought to cause muscle stiffness (Burke et al., 2013; Stecco et al., 2014), although this has not been shown conclusively. Current treatment options for spasticity include oral medications such as benzodiazepines, baclofen, and tizanidine that are central nervous system depressants used to suppress spinal hyper-excitability, and local injections of botulinum toxin used to suppress muscle over-activity. Whereas the oral medications can produce cognitive deficits, fatigue, and muscle weakness, botulinum toxin injections produce focal muscle weakness (Phadke et al., 2015). It is thus necessary to carefully balance the risks and benefits of treatment, which often remains inadequate. Furthermore, these treatments do not directly address muscle stiffness.
Methods
Results All patients (n=20) were assessed pre-injection (T0) and within 2weeks post-injection (T1). The mean time for post-injection assessments was 7 (SD 4) days. All patients tolerated the injections without immediate adverse effects. None of the patients demonstrated a hypersensitivity reaction to the skin test. The most common adverse reaction was soreness at the injection sites with onset within 24h of the injection, lasting 24–48h. The mean time for first post-injection follow up (T2) was 43 (SD 15) days, and it was 96 (SD 39) days for the second post-injection follow up (T3). Three patients (#13, 17, and 19) did not present for follow up within the T2 and T3 time frame. Patients #13 and 17 did not experience any adverse effects. Patient #19 experienced a delayed hypersensitivity reaction characterized by a pruritic rash over the injected areas on post-injection day two, which subsided on treatment with oral diphenhydramine and topical 1% hydrocortisone over 7days. Four patients (#1, 2, 4, and 7) did not present for follow-up within the T3 time frame. Patient #1 developed an unrelated wound on his back from a burn, patient #2 did not experience any adverse effects, patient #4 had an unrelated fall with a humeral fracture, and patient #7 had an unrelated fall from a treadmill. The patients subsequently healed and were followed in the clinic. Of note, 15 of the 20 patients (Table 1) voluntarily received subsequent treatment with hyaluronidase after the period of follow-up specified in this report.