Non-invasive electrophysiological assessment of the corticospinal tract in health and disease

PhD ThesisTo date, no candidate markers of upper motor neuron (UMN) function have performed sufficiently well to enter widespread clinical use, and the lack of such markers impedes both the diagnostic process and clinical trials in motor neuron disease (MND). We studied 15-30Hz intermuscular coherence (IMC), a novel marker of UMN function, and central motor conduction time (CMCT), an established marker of UMN function based on transcranial magnetic stimulation (TMS), in healthy volunteers and patients newly diagnosed with MND. To clarify the relative contributions of different parts of the motor system to IMC generation, we examined IMC in patients with longstanding diagnoses of hereditary spastic paraparesis (HSP), multifocal motor neuropathy (MMN) and inclusion body myositis (IBM). Previous studies reported conflicting results for the relationship between CMCT and predictors such as age and height. We only found a significant correlation between lower limb CMCT and height. IMC did not vary significantly with age, allowing data from healthy subjects across all ages to be pooled into a single normative dataset. The variability of IMC between subjects was considerable, and within a given subject variability was greater between than within recording sessions; potential contributors are discussed. Anodal transcranial direct current stimulation (tDCS) caused a significant increase in IMC, but interindividual variability was substantial, which might hinder its future use as an adjunct to IMC. To compare individual disease groups to the normal cohort, we evaluated the area under the receiver-operating characteristic curve (AUC). IMC generally matched or exceeded the performance of CMCT in discriminating patients with MND from normal, achieving AUCs of 0.83 in the upper and 0.79 in the lower limb. Previous evidence suggests that IMC abnormalities are primarily attributable to corticospinal tract (CST) dysfunction. In line with this, most patients with HSP exhibited diminished IMC. However, patients with MMN also showed decreased IMC, suggesting either that subclinical CST involvement was present or that dysfunction of lower motor neurons (LMNs) may affect IMC; clarification through computational modelling is suggested. In iii IBM, IMC was generally increased, which might reflect that the altered motor unit discharge pattern makes synchronisation more readily detectable. IMC appears to be a promising marker of CST function. It remains to be clarified how strongly it is influenced by LMN lesions, and optimisation of methods should help to minimise the variability of results. Since IMC is non-invasive and can be measured using commonly available EMG equipment, wider dissemination should prove straightforward.Wellcome Trus

Management of Degenerative Cervical Myelopathy and Spinal Cord Injury

The present Special Issue is dedicated to presenting current research topics in DCM and SCI in an attempt to bridge gaps in knowledge for both of the two main forms of SCI. The issue consists of fourteen studies, of which the majority were on DCM, the more common pathology, while three studies focused on tSCI. This issue includes two narrative reviews, three systematic reviews and nine original research papers. Areas of research covered include image studies, predictive modeling, prognostic factors, and multiple systemic or narrative reviews on various aspects of these conditions. These articles include the contributions of a diverse group of researchers with various approaches to studying SCI coming from multiple countries, including Canada, Czech Republic, Germany, Poland, Switzerland, United Kingdom, and the United States

Radiographic Assessment of Hip Disease in Children with Cerebral Palsy: Development of a Core Measurement Set and Analysis of an Artificial Intelligence System

Cerebral palsy is the most common physical disability during childhood. Cerebral palsy related hip disease is caused by an imbalance of muscle forces, resulting in progressive migration of the hip to complete dislocation. This can decrease function and quality of life. The prevention of hip dislocation is possible if detected early. Therefore, surveillance programmes have been set up to monitor children with cerebral palsy enabling clinicians to intervene early and improve outcomes. Currently, hip disease is assessed by analysing pelvic radiographs with various geometric measurements. This time-consuming task is undertaken frequently when monitoring a child with cerebral palsy. This thesis aimed to identify the key radiographic parameters used by clinicians (the core measurement set), and then build an artificial intelligence system to automate the calculation of this core measurement set. A systematic review was conducted identifying a comprehensive list of previously reported measurements from studies measuring radiographic outcomes in cerebral palsy children with hip pathologies. Fifteen measurements were identified from the systematic review, of which Reimers’ migration percentage was the most commonly reported. These measurements were used to perform a two-round Delphi study among orthopaedic surgeons and physiotherapists. Participants rated the importance of each measurement using a nine-point Likert scale (‘not important’ to critically important’). After the two rounds of the Delphi process, Reimers’ migration percentage was included in the core measurement set. Following the final consensus meeting, the femoral head-shaft angle was also included. The anteroposterior pelvic radiographs of 1650 children were then used to build an artificial intelligence system integrating the core measurement set, in collaboration with engineers from the University of Manchester. The newly developed artificial intelligence system was assessed by comparing its ability to calculate measurements and outline the pelvis and femur on a radiograph. The reliability of the dataset used to train the model was also analysed. The proposed artificial intelligence model achieved a ‘good to excellent’ inter-observer reliability across 450 radiographs when comparing its ability to calculate Reimers’ migration percentage to five clinicians. Its ability to outline the pelvis and proximal femur was ‘adequate’ with the better performance observed in the pelvis than the femur. The reliability of the training dataset used to teach the artificial intelligence model was ‘good’ to ‘very good’. Artificial intelligence systems are feasible solutions to optimise the efficiency of hip radiograph analysis in cerebral palsy. Studies are warranted to include the core measurement set as a minimum when reporting on hip disease in cerebral palsy. Future research should investigate the feasibility of implementing a risk score to predict the likelihood of hip displacement

Next generation of growth-sparing techniques: preliminary clinical results of a magnetically controlled growing rod in 14 patients

Session 3A - Early Onset Scoliosis: Paper no. 33SUMMARY: Growth-sparing techniques are commonly used for the treatment of progressive EOS. The standard growing rod (GR) technique requires multiple surgeries for lengthening. The preliminary results of MCGR has shown the comparable outcomes to standard GR without the need for repeated surgery which can be expected to reduce the overall complication rate in GR surgery. INTRODUCTION: The growing rod (GR) technique for management of progressive Early-Onset Scoliosis (EOS) is a viable alternative but with a high complication rate attributed to frequent surgical lengthenings. The safety and efficacy of a non-invasive Magnetically Controlled Growing Rod (MCGR) has been previously reported in a porcine model. We are reporting the preliminary results of this technique in EOS. METHODS: Retrospective review of prospectively collected multi-center data. Only patients who underwent MCGR surgery and at least 3 subsequent spinal distractions were included in this preliminary review. Distractions were performed in clinic without anesthesia or analgesics. T1-T12 and T1-S1 height and the distraction distance inside the actuator were analyzed in addition to conventional clinical and radiographic data. RESULTS: Patients (N=14; 7 F and 7 M) had a mean age of 8y+10m (3y+6m to 12y+7m) and underwent a total of 14 index surgeries (SR: index single rod in 5 and DR: dual rod in 9) and 91 distractions. There were 5 idiopathic, 4 neuromuscular, 2 congenital, 2 syndromic and one NF. Mean follow-up (FU) was 10 months (5.8-18.2). Mean Cobb changed from 57° pre-op to 35° post-op and correction was maintained (35°) at latest FU. T1-T12 increased by 4 mm for SR and 10 mm for DR with mean monthly gain of 0.5 and 1.39, respectively. T1-S1 gain was 4 mm for SR and 17 mm for DR with mean monthly gain of 0.5 mm for SR and 2.35 mm for DR. The mean interval between index surgery and the first distraction was 66 days and thereafter was 43 days. Complications included one superficial infection in (SR), one prominent implant (DR) and minimal loss of initial distraction in three after index MCGR (all SR). Overall, partial loss of distraction was observed following 14 of the 91 distractions (one DR and 13 SR). This loss was regained in subsequent distractions. There was no neurologic deficit or implant failure. CONCLUSION: MCGR appears to be safe and provided adequate distraction similar to the standard GR technique without the need for repeated surgeries. DR patients had better initial curve correction and greater spinal height. No major complications were observed during the short follow-up period. The FDA has not cleared the drug and/or medical device for the use described in this presentation (i.e., the drug or medical device is being discussed for an ‘off label’ use).postprin

[¹⁸F]fluorination of biorelevant arylboronic acid pinacol ester scaffolds synthesized by convergence techniques

Aim: The development of small molecules through convergent multicomponent reactions (MCR) has been boosted during the last decade due to the ability to synthesize, virtually without any side-products, numerous small drug-like molecules with several degrees of structural diversity.(1) The association of positron emission tomography (PET) labeling techniques in line with the “one-pot” development of biologically active compounds has the potential to become relevant not only for the evaluation and characterization of those MCR products through molecular imaging, but also to increase the library of radiotracers available. Therefore, since the [18F]fluorination of arylboronic acid pinacol ester derivatives tolerates electron-poor and electro-rich arenes and various functional groups,(2) the main goal of this research work was to achieve the 18F-radiolabeling of several different molecules synthesized through MCR. Materials and Methods: [18F]Fluorination of boronic acid pinacol esters was first extensively optimized using a benzaldehyde derivative in relation to the ideal amount of Cu(II) catalyst and precursor to be used, as well as the reaction solvent. Radiochemical conversion (RCC) yields were assessed by TLC-SG. The optimized radiolabeling conditions were subsequently applied to several structurally different MCR scaffolds comprising biologically relevant pharmacophores (e.g. β-lactam, morpholine, tetrazole, oxazole) that were synthesized to specifically contain a boronic acid pinacol ester group. Results: Radiolabeling with fluorine-18 was achieved with volumes (800 μl) and activities (≤ 2 GBq) compatible with most radiochemistry techniques and modules. In summary, an increase in the quantities of precursor or Cu(II) catalyst lead to higher conversion yields. An optimal amount of precursor (0.06 mmol) and Cu(OTf)2(py)4 (0.04 mmol) was defined for further reactions, with DMA being a preferential solvent over DMF. RCC yields from 15% to 76%, depending on the scaffold, were reproducibly achieved. Interestingly, it was noticed that the structure of the scaffolds, beyond the arylboronic acid, exerts some influence in the final RCC, with electron-withdrawing groups in the para position apparently enhancing the radiolabeling yield. Conclusion: The developed method with high RCC and reproducibility has the potential to be applied in line with MCR and also has a possibility to be incorporated in a later stage of this convergent “one-pot” synthesis strategy. Further studies are currently ongoing to apply this radiolabeling concept to fluorine-containing approved drugs whose boronic acid pinacol ester precursors can be synthesized through MCR (e.g. atorvastatin)