Repair of brachial Plexus avulsion: clinical outcome, strategies for cellular repair and MR imaging protocols

This thesis comprises of three studies investigating the repair of brachial plexus avulsion injury from three different perspectives. The first aim of this thesis was to investigate the long-term effects of reimplantation surgery in patients with complete brachial plexus avulsion injury using standardized assessments. Patients are assessed with clinical examination, neurophysiological studies and patient-reported outcome questionnaires. It is shown that patients who have undergone brachial plexus re-implantation surgery demonstrate small, yet significant, improved function in motor and sensory recovery compared with patients who have not had this surgical intervention. These results are encouraging, but functional improvements are limited. One strategy aimed at further improving the effects of re-implantationis the transplantation of OECs during the surgical repair. The second study presented in this thesis comprises of a prospective observational study of human biopsies of nasal mucosa by endonasal dissection of the mucosa of the nasal septum during the approach for routine sinus surgery. Samples are cultured in the laboratory, and the yield of olfactory ensheathing cells is compared as to the location, size, and weight of the biopsies and patient characteristics including age, smoking, nasal disease severity. OEC yield is associated with mucosal disease and patients age. The third aim of this thesis is to develop novel MRI techniques that can be used in human trials of cell mediated repair of the brachial plexus to assess patients’ spinal cord regeneration after OEC transplantation and provide a more robust outcome measure for comparing different strategies of brachial plexus repair. We focus on magnetic resonance spectroscopy and demonstrate that this technique is sensitive to pathological changes that occur in the spinal cord above the injury. Myo-Inositol to creatine ratio is correlated with disability and is negatively correlated to time from injury. The implications of the above findings are discussed

Long-term outcome of brachial plexus re-implantation after complete brachial plexus avulsion injury.

BACKGROUND: Complete brachial plexus avulsion injury is a severe disabling injury due to traction to the brachial plexus. Brachial plexus re-implantation is an emerging surgical technique for the management of complete brachial plexus avulsion injury. OBJECTIVE: We assessed the functional recovery in 15 patients who have undergone brachial plexus re-implantation surgery after complete brachial plexus avulsion injury with clinical examination and electrophysiological testing METHODS: We included all patients that underwent brachial plexus re-implantation in our institution between 1997 and 2010. Patients were assessed with detailed motor and sensory clinical examination and motor and sensory electrophysiological tests. RESULTS: We found that patients who had re-implantation surgery demonstrated an improvement in MRC power in the deltoid, pectoralis and infraspinatous muscles and "global MRC score". Eight patients achieved at least grade 3 MRC power in at least one muscle group of the arm. Improved re-innervation by EMG criteria was found in infraspinatous, biceps and triceps muscles. There was evidence of ongoing innervation in three patients. Sensory testing in affected dermatomes also showed better recovery at C5, C6 and T1 dermatomes. The best recovery was seen in the C5 dermatome. CONCLUSION: Our results demonstrate a definite but limited improvement in motor and sensory recovery following re-implantation surgery in patients with complete brachial plexus injury. We hypothesize that further improvement may be achieved by using regenerative cell technologies at the time of repair

Low Myo‐inositol indicating astrocytic damage in a case series of neuromyelitis optica

Astrocytic necrosis is a prominent pathological feature of neuromyelitis optica (NMO) lesions and is clinically relevant. We report 5 NMO‐related cases, all with longitudinally extensive lesions in the upper cervical cord, who underwent cervical cord 1H‐magnetic resonance spectroscopy. Lower myo‐inositol/creatine values, suggesting astrocytic damage, were consistently found within the NMO lesions when compared with healthy controls and patients with multiple sclerosis (MS), who showed at least 1 demyelinating lesion at the same cord level. Therefore, the in vivo quantification of myo‐inositol may distinguish NMO from MS. This is an important step toward developing imaging markers for clinical trials in NMO

Transplantation of canine olfactory ensheathing cells producing chondroitinase ABC promotes chondroitin sulphate proteoglycan digestion and axonal sprouting following spinal cord injury

Olfactory ensheathing cell (OEC) transplantation is a promising strategy for treating spinal cord injury (SCI), as has been demonstrated in experimental SCI models and naturally occurring SCI in dogs. However, the presence of chondroitin sulphate proteoglycans within the extracellular matrix of the glial scar can inhibit efficient axonal repair and limit the therapeutic potential of OECs. Here we have used lentiviral vectors to genetically modify canine OECs to continuously deliver mammalian chondroitinase ABC at the lesion site in order to degrade the inhibitory chondroitin sulphate proteoglycans in a rodent model of spinal cord injury. We demonstrate that these chondroitinase producing canine OECs survived at 4 weeks following transplantation into the spinal cord lesion and effectively digested chondroitin sulphate proteoglycans at the site of injury. There was evidence of sprouting within the corticospinal tract rostral to the lesion and an increase in the number of corticospinal axons caudal to the lesion, suggestive of axonal regeneration. Our results indicate that delivery of the chondroitinase enzyme can be achieved with the genetically modified OECs to increase axon growth following SCI. The combination of these two promising approaches is a potential strategy for promoting neural regeneration following SCI in veterinary practice and human patients

The current state-of-the-art of spinal cord imaging: methods.

A first-ever spinal cord imaging meeting was sponsored by the International Spinal Research Trust and the Wings for Life Foundation with the aim of identifying the current state-of-the-art of spinal cord imaging, the current greatest challenges, and greatest needs for future development. This meeting was attended by a small group of invited experts spanning all aspects of spinal cord imaging from basic research to clinical practice. The greatest current challenges for spinal cord imaging were identified as arising from the imaging environment itself; difficult imaging environment created by the bone surrounding the spinal canal, physiological motion of the cord and adjacent tissues, and small cross-sectional dimensions of the spinal cord, exacerbated by metallic implants often present in injured patients. Challenges were also identified as a result of a lack of "critical mass" of researchers taking on the development of spinal cord imaging, affecting both the rate of progress in the field, and the demand for equipment and software to manufacturers to produce the necessary tools. Here we define the current state-of-the-art of spinal cord imaging, discuss the underlying theory and challenges, and present the evidence for the current and potential power of these methods. In two review papers (part I and part II), we propose that the challenges can be overcome with advances in methods, improving availability and effectiveness of methods, and linking existing researchers to create the necessary scientific and clinical network to advance the rate of progress and impact of the research

Magnetic resonance imaging for detecting root avulsions in traumatic adult brachial plexus injuries: protocol for a systematic review of diagnostic accuracy

Background Adult brachial plexus injuries (BPI) are becoming more common. The reconstruction and prognosis of pre-ganglionic injuries (root avulsions) are different to other types of BPI injury. Preoperative magnetic resonance imaging (MRI) is being used to identify root avulsions, but the evidence from studies of its diagnostic accuracy are conflicting. Therefore, a systematic review is needed to address uncertainty about the accuracy of MRI and to guide future research. Methods We will conduct a systematic search of electronic databases alongside reference tracking. We will include studies of adults with traumatic BPI which report the accuracy of preoperative MRI (index test) against surgical exploration of the roots of the brachial plexus (reference standard) for detecting either of the two target conditions (any root avulsion or any pseudomeningocoele as a surrogate marker of root avulsion). We will exclude case reports, articles considering bilateral injuries and studies where the number of true positives, false positives, false negatives and true negatives cannot be derived. The methodological quality of the included studies will be assessed using a tailored version of the QUADAS-2 tool. Where possible, a bivariate model will be used for meta-analysis to obtain summary sensitivities and specificities for both target conditions. We will investigate heterogeneity in the performance of MRI according to field strength and the risk of bias if data permits. Discussion This review will summarise the current diagnostic accuracy of MRI for adult BPI, identify shortcomings and gaps in the literature and so help to guide future research

Metabolic Changes in the Spinal Cord After Brachial Plexus Root Re-implantation

To investigate metabolic changes within the spinal cord using proton magnetic resonance spectroscopy ((1)H-MRS) and determine their relationship with clinical function in patients with complete brachial plexus avulsion who underwent reimplantation of the ventral roots

Four-part proximal humeral fractures: diagnosis with the ‘sunset’ sign on anteroposterior radiograph

INTRODUCTION Four-part proximal humeral fractures require surgical intervention. However, they can be difficult to diagnose in radiological images. We aim to define a new, easily recognisable, radiological sign as a predictor of four-part fracture of the proximal humerus in a plain anteroposterior radiograph of the shoulder.PATIENTS AND METHODS We describe our 'sunset' sign as 'articular surface of humeral head pointing away from the glenoid and tilted upwards, in the presence of a displaced greater tuberosity fracture'. We postulate that a patient with proximal humerus fracture showing this sign has four-part fracture until proven otherwise. Between 2002 and 2006, 80 consecutive patients had surgical treatment of their proximal humeral fractures in our unit. Pre-operative radiographs and operative notes of 79 patients were evaluated independently by three blinded observers. The presence of 'sunset' sign was recorded. Findings were then correlated with the operative diagnoses to confirm whether they were four-part fractures or not. With 95% confidence interval, we calculated the sensitivity, specificity, positive and negative predictive values for our diagnostic sign.RESULTS Of 79 patients, 30 displayed 'sunset' sign in their pre-operative radiograph. Of these, 28 had confirmed four-part fractures operatively. The positive predictive value of 'sunset' sign was 93%. The specificity and sensitivity were 95% and 78%, respectively. The sensitivity was affected by eight patients with four-part fractures with displaced articular head fragment which had dropped either medially or posteriorly.CONCLUSIONS These results suggest that, in patients with proximal humeral fractures, the presence of 'sunset' sign in the anteroposterior radiograph is a reliable indicator of four-part fracture

Enhanced Anti-lymphoma Activity of CAR19-iNKT Cells Underpinned by Dual CD19 and CD1d Targeting

Chimeric antigen receptor anti-CD19 (CAR19)-T cell immunotherapy-induced clinical remissions in CD19+ B cell lymphomas are often short lived. We tested whether CAR19-engineering of the CD1d-restricted invariant natural killer T (iNKT) cells would result in enhanced anti-lymphoma activity. CAR19-iNKT cells co-operatively activated by CD1d- and CAR19-CD19-dependent interactions are more effective than CAR19-T cells against CD1d-expressing lymphomas in vitro and in vivo. The swifter in vivo anti-lymphoma activity of CAR19-iNKT cells and their enhanced ability to eradicate brain lymphomas underpinned an improved tumor-free and overall survival. CD1D transcriptional de-repression by all-trans retinoic acid results in further enhanced cytotoxicity of CAR19-iNKT cells against CD19+ chronic lymphocytic leukemia cells. Thus, iNKT cells are a highly efficient platform for CAR-based immunotherapy of lymphomas and possibly other CD1d-expressing cancers

Degenerative Disc Disease Mimicking Spondylodiscitis with Bilateral Psoas Abscesses.

Sequestered disc fragments may present as a lesion with peripheral enhancement on magnetic resonance imaging. When located in the psoas muscle compartment, this finding could mimic an abscess. We describe a case of a 52-year-old man who returned from Togo after 2 years of living in precarious conditions. He was afebrile and complaining of lumbar back pain. The magnetic resonance imaging showed L3 and L4 vertebral body enhancement with bilateral psoas lesions in continuity with the disc space, suggesting spondylodiscitis with a differential diagnosis of inflammatory herniated disc. A computed tomography-guided biopsy of the right psoas lesion was performed to rule out spondylodiscitis. Histology was compatible with extruded disc material. Herniated disc fragments should be considered as a differential diagnosis of psoas abscesses. Coronal plane images may show the continuity of bilateral herniated disc fragments, mimicking psoas abscesses