The rationale for implantation of autologous human Schwann cells (SCs) in persons with subacute spinal cord injury (SCI) is based on evidence that transplanted SCs are neuroprotective, support local axonal plasticity, and are capable of myelinating axons. A Phase I clinical trial was conducted to evaluate the safety of autologous human SC transplantation into the injury epicenter of six subjects with subacute SCI. The trial was an open-label, unblinded, non-randomized, non-placebo controlled study with a dose escalation design and standard medical rehabilitation. Participants were paraplegics with neurologically complete, trauma-induced spinal lesions. Autologous SCs were cultured in vitro from a sural nerve harvested from each participant and injected into the epicenter of the spinal lesion. Outcome measures for safety were protocol compliance, feasibility, adverse events, stability of neurological level, absence of detectable mass lesion, and the emergence of clinically significant neuropathic pain or muscle spasticity no greater than expected for a natural course cohort. One year post-transplantation, there were no surgical, medical, or neurological complications to indicate that the timing or procedure for the cell transplantation was unsafe. There were no adverse events or serious adverse events related to the cell therapy. There was no evidence of additional spinal cord damage, mass lesion, or syrinx formation. We conclude that it is feasible to identify eligible candidates, appropriately obtain informed consent, perform a peripheral nerve harvest to obtain SCs within 5-30 days of injury, and perform an intra-spinal transplantation of highly purified autologous SCs within 4-7 weeks of injury.
Introduction: Systemic hypothermia remains a promising neuroprotective strategy. There has been recent interest in its use in patients with spinal cord injury (SCI). In this article, we describe our extended single center experience using intravascular hypothermia for the treatment of cervical SCI. Methods: Thirty-five acute cervical SCI patients received modest (33 1C) intravascular hypothermia for 48 h. Neurological outcome was assessed by the International Standards for Neurological Classification of Spinal Cord Injury scale (ISNCSCI) developed by the American Spinal Injury Association. Local and systemic complications were recorded. Results: All patients were complete ISNCSCI A on admission, but four converted to ISNCSCI B in o24 h post injury. Hypothermia was delivered in 5.76 ( ± 0.45) hours from injury if we exclude four cases with delayed admission (418 h). Fifteen of total 35 patients (43%) improved at least one ISNCSCI grade at latest follow up 10.07 ( ± 1.03) months. Even excluding those patients who converted from ISNCSCI A within 24 h, 35.5% (11 out of 31) improved at least one ISNCSCI grade. Both retrospective (n ¼ 14) and prospective (n ¼ 21) groups revealed similar number of respiratory complications. The overall risk of any thromboembolic complication was 14.2%. Conclusion:The results are promising in terms of safety and improvement in neurological outcome. To date, the study represents the largest study cohort of cervical SCI patients treated by modest hypothermia. A multi-center, randomized study is needed to determine if systemic hypothermia should be a part of SCI patients' treatment for whom few options exist. Spinal Cord (2013) 51, 395-400; doi:10.1038/sc.2012.161; published online 18 December 2012Keywords: acute cervical SCI; cooling catheter; systemic hypothermia INTRODUCTION Hypothermia continues to show promise in a variety of acute central nervous system injuries. Various factors need to be considered with systemic cooling of the spinal cord injury (SCI) patient, including methods of cooling, window from injury to initiation, duration and depth of hypothermia, and rate of re-warming. Two main methods of spinal cord cooling exist. Local cooling (epidural vs intradural) has a rich history with both experimental and clinical evidence supporting its use. 1 Systemic cooling may be applied either via a transcutaneous or intravascular route. Modern cooling blankets can be applied and have the advantage of being less invasive but also the disadvantage of being less precise with regards to temperature control. 2 While profound levels of hypothermia (T o32 1C) can be difficult to administer and are subject to increased complication rates, mild (modest) levels of hypothermia (T 32-34 1C) have been shown to provide significant protection against traumatic and ischemic neuronal cell death. 2,3 When administered after experimental acute SCI, there is a reduction in the volume of histopathological damage and a concomitant improvement in BBB walking index. 4,5 A recent study revealed beneficial effec...
Insufficient donor nerve graft material in peripheral nerve surgery remains an obstacle for successful long-distance regeneration. Schwann cells (SCs) can be isolated from adult mammalian peripheral nerve biopsies and can be grown in culture and retain their capacity to enhance peripheral nerve regeneration within tubular repair strategies in multiple animal models. Human Schwann cells (hSCs) can be isolated, expanded in number, and retain their ability to promote regeneration and myelinate axons, but have never been tested in a clinical case of peripheral nerve injury. A sural nerve biopsy and peripheral nerve tissue from the traumatized sciatic nerve stumps was obtained after Food and Drug Administration (FDA) and Institutional Review Board (IRB) approval as well as patient consent. The SCs were isolated after enzymatic digestion of the nerve and expanded with the use of heregulin β1 (0.1 µg/ml) and forskolin (15 mM). After two passages the Schwann cell isolates were combined with sural nerve grafts to repair a large sciatic nerve defect (7.5 cm) after a traumatic nerve injury. The sural nerve and the traumatized sciatic nerve ends both served as an excellent source of purified (90% and 97%, respectively) hSCs. Using ultrasound and magnetic resonance imaging (MRI) we were able to determine continuity of the nerve graft repair and the absence of tumor formation. The patient had evidence of proximal sensory recovery and definitive motor recovery distal to the repair in the distribution of the tibial and common peroneal nerve. The patient did experience an improvement in her pain scores over time. The goals of this approach were to determine the safety and clinical feasibility of implementing a new cellular repair strategy. In summary, this approach represents a novel strategy in the treatment of peripheral nerve injury and represents the first reported use of autologous cultured SCs after human peripheral nerve injury.
Involuntary electromyographic (EMG) activity has only been analyzed in the paralyzed thenar muscles of spinal cord injured (SCI) subjects for several minutes. It is unknown if this motor unit activity is ongoing. Longer duration EMG recordings can investigate the biological significance of this activity. Since no software is currently capable of classifying 24 hours of EMG data at a single motor unit level, the goal of this research was to devise an algorithm that would automatically classify motor unit potentials by tracking the firing behavior of motor units over 24-hours. Two-channels of thenar muscle surface EMG were recorded over 24-hours from 7 SCI subjects with a chronic cervical level injury using a custom data logging device with custom software. The automatic motor unit classification algorithm developed here employed multiple passes through these 24-hour EMG recordings to segment, cluster, form global templates and classify motor unit potentials, including superimposed potentials. The classification algorithm was able to track an average of 19 global classes in 7 24-hour recordings with a mean (± SE) accuracy of 89.9 % (± 0.98%) and classify potentials from these individual motor units with a mean accuracy of 90.3% (± 0.97%). The algorithm could analyze 24 hours of data in 2-3 weeks with minimal input from a person, while a human operator was estimated to take more than 2 years. This automatic method could be applied clinically to investigate the fasciculation potentials often found in motoneuron disorders such as amyotrophic lateral sclerosis. Correspondence to Jeffrey Winslow, jwinslow@cableone.net. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript IntroductionSpinal cord injured (SCI) individuals often have no voluntary control over skeletal muscles that are innervated from spinal segments below the lesion. However, these paralyzed muscles can contract involuntarily (spasm) in response to various stimuli such as vibration, cutaneous inputs, and changes in temperature and body position (Kawamura et al., 1989;Little et al., 1989;Thomas and Ross, 1997). In other situations, weak involuntary contractions have been recorded for up to 30 minutes, particularly in hand muscles Zijdewind and Thomas 2001; Zijdewind et al. 2004). Whether this spontaneous motor unit activity takes place over extended time periods is unknown. This activity appears to be spontaneous in that no obvious stimulus generates the motor unit activity. These different types of muscle activity can be...
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