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M G Fehlings

Publications and source records attributed to M G Fehlings.

At least 19 recordsLinked to original sources
PubMed2006

Guidelines for the conduct of clinical trials for spinal cord injury as developed by the ICCP panel: spontaneous recovery after spinal cord injury and statistical power needed for therapeutic clinical trials.

The International Campaign for Cures of Spinal Cord Injury Paralysis (ICCP) supported an international panel tasked with reviewing the methodology for clinical trials in spinal cord injury (SCI), and making recommendations on the conduct of future trials. This is the first of four papers. Here, we examine the spontaneous rate of recovery after SCI and resulting consequences for achieving statistically significant results in clinical trials. We have reanalysed data from the Sygen trial to provide some of this information. Almost all people living with SCI show some recovery of motor function below the initial spinal injury level. While the spontaneous recovery of motor function in patients with motor-complete SCI is fairly limited and predictable, recovery in incomplete SCI patients (American spinal injury Association impairment scale (AIS) C and AIS D) is both more substantial and highly variable. With motor complete lesions (AIS A/AIS B) the majority of functional return is within the zone of partial preservation, and may be sufficient to reclassify the injury level to a lower spinal level. The vast majority of recovery occurs in the first 3 months, but a small amount can persist for up to 18 months or longer. Some sensory recovery occurs after SCI, on roughly the same time course as motor recovery. Based on previous data of the magnitude of spontaneous recovery after SCI, as measured by changes in ASIA motor scores, power calculations suggest that the number of subjects required to achieve a significant result from a trial declines considerably as the start of the study is delayed after SCI. Trials of treatments that are most efficacious when given soon after injury will therefore, require larger patient numbers than trials of treatments that are effective at later time points. As AIS B patients show greater spontaneous recovery than AIS A patients, the number of AIS A patients requiring to be enrolled into a trial is lower. This factor will have to be balanced against the possibility that some treatments will be more effective in incomplete patients. Trials involving motor incomplete SCI patients, or trials where an accurate assessment of AIS grade cannot be made before the start of the trial, will require large subject numbers and/or better objective assessment methods.

Clinical Trials as Topic↗
PubMed2006

Guidelines for the conduct of clinical trials for spinal cord injury (SCI) as developed by the ICCP panel: clinical trial outcome measures.

An international panel reviewed the methodology for clinical trials of spinal cord injury (SCI), and provided recommendations for the valid conduct of future trials. This is the second of four papers. It examines clinical trial end points that have been used previously, reviews alternative outcome tools and identifies unmet needs for demonstrating the efficacy of an experimental intervention after SCI. The panel focused on outcome measures that are relevant to clinical trials of experimental cell-based and pharmaceutical drug treatments. Outcome measures are of three main classes: (1) those that provide an anatomical or neurological assessment for the connectivity of the spinal cord, (2) those that categorize a subject's functional ability to engage in activities of daily living, and (3) those that measure an individual's quality of life (QoL). The American Spinal Injury Association impairment scale forms the standard basis for measuring neurologic outcomes. Various electrophysiological measures and imaging tools are in development, which may provide more precise information on functional changes following treatment and/or the therapeutic action of experimental agents. When compared to appropriate controls, an improved functional outcome, in response to an experimental treatment, is the necessary goal of a clinical trial program. Several new functional outcome tools are being developed for measuring an individual's ability to engage in activities of daily living. Such clinical end points will need to be incorporated into Phase 2 and Phase 3 trials. QoL measures often do not correlate tightly with the above outcome tools, but may need to form part of Phase 3 trial measures.

Activities of Daily Living↗
PubMed2006

Guidelines for the conduct of clinical trials for spinal cord injury as developed by the ICCP Panel: clinical trial inclusion/exclusion criteria and ethics.

The International Campaign for Cures of Spinal Cord Injury Paralysis established a panel tasked with reviewing the methodology for clinical trials for spinal cord injury (SCI), and making recommendations on the conduct of future trials. This is the third of four papers. It examines inclusion and exclusion criteria that can influence the design and analysis of clinical trials in SCI, together with confounding variables and ethical considerations. Inclusion and exclusion criteria for clinical trials should consider several factors. Among these are (1) the enrollment of subjects at appropriate stages after SCI, where there is supporting data from animal models or previous human studies; (2) the severity, level, type, or size of the cord injury, which can influence spontaneous recovery rate and likelihood that an experimental treatment will clinically benefit the subject; and (3) the confounding effects of various independent variables such as pre-existing or concomitant medical conditions, other medications, surgical interventions, and rehabilitation regimens. An issue of substantial importance in the design of clinical trials for SCI is the inclusion of blinded assessments and sham surgery controls: every effort should be made to address these major issues prospectively and carefully, if clear and objective information is to be gained from a clinical trial. The highest ethical standards must be respected in the performance of clinical trials, including the adequacy and clarity of informed consent.

Clinical Trials as Topic↗
PubMed2006

Guidelines for the conduct of clinical trials for spinal cord injury as developed by the ICCP panel: clinical trial design.

The International Campaign for Cures of Spinal Cord Injury Paralysis established a panel tasked with reviewing the methodology for clinical trials for spinal cord injury (SCI), and making recommendations on the conduct of future trials. This is the fourth of four papers. Here, we examine the phases of a clinical trial program, the elements, types, and protocols for valid clinical trial design. The most rigorous and valid SCI clinical trial would be a prospective double-blind randomized control trial utilizing appropriate placebo control subjects. However, in specific situations, it is recognized that other trial procedures may have to be considered. We review the strengths and limitations of the various types of clinical trials with specific reference to SCI. It is imperative that the design and conduct of SCI clinical trials should meet appropriate standards of scientific inquiry to insure that meaningful conclusions about efficacy and safety can be achieved and that the interests of trial subjects are protected. We propose these clinical trials guidelines for use by the SCI clinical research community.

Clinical Trials as Topic↗
PubMed2006

Somatosensory cortical atrophy after spinal cord injury: a voxel-based morphometry study.

The authors used voxel-based morphometry to compare sensorimotor cortical gray and white matter volume on structural MR images of a group of 17 individuals with cervical spinal cord injury (SCI) and a group of 17 healthy subjects. SCI subjects had reduced gray matter volume bilaterally in primary somatosensory cortex (p < 0.001). These findings suggest that the somatosensory cortex of the human brain atrophies after SCI.

Adolescent↗
PubMed2006

Dynamic role of kallikrein 6 in traumatic spinal cord injury.

Kallikrein 6 (K6) is a member of the kallikrein gene family that comprises 15 structurally and functionally related serine proteases. In prior studies we showed that, while this trypsin-like enzyme is preferentially expressed in neurons and oligodendroglia of the adult central nervous system (CNS), it is up-regulated at sites of injury due to expression by infiltrating immune and resident CNS cells. Given this background we hypothesized that K6 is a key contributor to the pathophysiology of traumatic spinal cord injury (SCI), influencing neural repair and regeneration. Examination of K6 expression following contusion injury to the adult rat cord, and in cases of human traumatic SCI, indicated significant elevations at acute and chronic time points, not only at the injury site but also in cord segments above and below. Elevations in K6 were particularly prominent in macrophages, microglia and reactive astrocytes. To determine potential effects of elevated K6 on the regeneration environment, the ability of neurons to adhere to and extend processes on substrata which had been exposed to recombinant K6 was examined. Limited (1 h) or excess (24 h) K6-mediated proteolytic digestion of a growth-facilitatory substrate, laminin, significantly decreased neurite outgrowth. By contrast, similar hydrolysis of a growth-inhibitory substrate, aggrecan, significantly increased neurite extension and cell adherence. These data support the hypothesis that K6 enzymatic cascades mediate events secondary to spinal cord trauma, including dynamic modification of the capacity for axon outgrowth.

Adolescent↗
PubMed2005

FAS deficiency reduces apoptosis, spares axons and improves function after spinal cord injury.

After spinal cord injury (SCI), apoptosis of neurons and oligodendrocytes is associated with axonal degeneration and loss of neurological function. Recent data have suggested a potential role for FAS death receptor-mediated apoptosis in the pathophysiology of SCI. In this study, we examined the effect of FAS deficiency on SCI in vitro and in vivo. FAS(Lpr/lpr) mutant mice and wildtype background-matched mice were subjected to a T5-6 clip compression SCI, and complementary studies were done in an organotypic slice culture model of SCI. Post-traumatic apoptosis in the spinal cord, which was seen in neurons and oligodendrocytes, was decreased in the FAS-deficient mice both in vivo and in vitro particularly in oligodendrocytes. FAS deficiency was also associated with improved locomotor recovery, axonal sparing and preservation of oligodendrocytes and myelin. However, FAS deficiency did not result in a significant increase in surviving neurons in the spinal cord at 6 weeks after injury, likely reflecting the importance of other cell death mechanisms for neurons. We conclude that inhibition of the FAS pathway may be a clinically attractive neuroprotective strategy directed towards oligodendroglial and axonal preservation in the treatment of SCI and neurotrauma.

2',3'-Cyclic-Nucleotide Phosphodiesterases↗
PubMed2003

Changes in glial cell white matter AMPA receptor expression after spinal cord injury and relationship to apoptotic cell death.

Increasing evidence suggests that AMPA receptors (AMPARs) play a key role in mediating excitotoxic cell damage after acute spinal cord injury (SCI). However, the role of glial AMPARs in posttraumatic white matter injury requires further clarification. In the present study we examined the changes in AMPAR expression after SCI, the cellular distribution of these changes, and their association with apoptosis. Western blots revealed expression of GluR1, 3, and 4, but not GluR2, in spinal cord white matter. Immunohistochemistry was used to examine the distribution of AMPARs in spinal cord white matter. Quantification of AMPAR-expressing cells in spinal cord white matter indicated predominantly GluR3 expression in oligodendrocytes and predominantly GluR4 expression in astrocytes. A clip compression model of SCI was used to examine the changes in AMPAR expression in dorsal column white matter after injury. Quantitative analysis of GluR3 levels of expression indicated a significant decrease at 3 days postinjury compared to uninjured animals, followed by a recovery of expression by 2 weeks. GluR4 subunits followed a similar expression pattern. Gene message expression of GluR3 and GluR4 flip/flop mRNA splice variants exhibited a pattern of expression that correlated with protein expression. GluR3-expressing glia appeared to be more susceptible to apoptosis than GluR4-expressing cells. A large decline in GluR3-expressing oligodendrocytes suggests that this subunit may be associated with the induction of apoptosis in white matter glia, thus contributing to secondary injury mechanisms.

Alternative Splicing↗
PubMed2003

Autonomic dysreflexia after spinal cord transection or compression in 129Sv, C57BL, and Wallerian degeneration slow mutant mice.

To study plasticity of central autonomic circuits that develops after spinal cord injury (SCI), we have characterized a mouse model of autonomic dysreflexia. Autonomic dysreflexia is a condition in which episodic hypertension occurs after injuries above the midthoracic segments of the spinal cord. As synaptic plasticity may be triggered by axonal degeneration, we investigated whether autonomic dysreflexia is reduced in mice when axonal degeneration is delayed after SCI. We subjected three strains of mice, Wld(S), C57BL, and 129Sv, to either spinal cord transection (SCT) or severe clip-compression injury (CCI). The Wld(S) mouse is a well-characterized mutant that exhibits delayed Wallerian degeneration. The CCI model is an injury paradigm in which significant the axonal degeneration is due to secondary events and therefore delayed relative to the time of the initial injury. We herein demonstrate that the incidence of autonomic dysreflexia is reduced in Wld(S) mice after SCT and in all mice after CCI. To determine if differences in afferent arbor sprouting could explain our observations, we assessed changes in the afferent arbor in each mouse strain after both SCT and CCI. We show that independent of the type of injury, 129Sv mice but not C57BL or Wld(S) mice demonstrated an increased small-diameter CGRP-immunoreactive afferent arbor after SCI. Our work thus suggests a role for Wallerian degeneration in the development of autonomic dysreflexia and demonstrates that the choice of mouse strain and injury model has important consequences to the generalizations that may be drawn from studies of SCI in mice.

Afferent Pathways↗
PubMed2002

Adaptation in the motor cortex following cervical spinal cord injury.

BACKGROUND: The nature of the adaptive changes that occur in the cerebral cortex following injury to the cervical spinal cord are largely unknown. OBJECTIVE: To investigate these adaptive changes by examining the relationship between the motor cortical representation of the paretic right upper extremity compared with that of the tongue. The tongue was selected because the spinal cord injury (SCI) does not affect its movement and the cortical representation of the tongue is adjacent to that of the paretic upper extremity. METHODS: FMRI was used to map cortical representations associated with simple motor tasks of the right upper extremity and tongue in 14 control subjects and 9 patients with remote (>5.5 months) cervical SCI. RESULTS: The mean value for the site of maximum cortical activation during upper limb movement was identical between the two groups. The site of maximum left hemispheric cortical activation during tongue movement was 12.8 mm (p < 0.01) medial and superior to that of control subjects, indicating the presence of a shift in cortical activation. CONCLUSION: The findings indicate that the adult motor cortex does indeed adapt following cervical SCI. The nature of the adaptation and the underlying biological mechanisms responsible for this change require further investigation.

Adaptation, Physiological↗
PubMed2002

Importance of access to research information among individuals with spinal cord injury: results of an evidenced-based questionnaire.

OBJECTIVE: To assess the interests and accessibility of patients with a spinal cord injury (SCI) to information in different areas of SCI. SETTING: Spinal Program, Toronto Western Hospital, University Health Network. METHODS: An interest assessment survey and the SF-36 (short form-36) questionnaire were mailed to SCI patients living in the community. The interest assessment examined patients' interest in information in many areas related to SCI, their current knowledge in these areas and the accessibility of different information formats. RESULTS: Fourteen patients (45%) completed the questionnaires. Regardless of physical or mental health status, all patients expressed a high level of interest in SCI research and clinical trials. An Internet website proved to be the most preferred, accessible and comfortable information format for these patients. Patients expressed a lower interest in support groups and organizations. Results from the SF-36 showed poor social functioning was related to interest in support groups, and poor general health perception was related to interest in occupational and physical therapy. CONCLUSION: The majority of SCI patients have a high interest in accessing SCI research information. The Internet is a favorable, comfortable and accessible tool for providing this information and will benefit all SCI patients. These results suggest that a significant number of patients with SCI would benefit from an accessible Internet-based information database that is relevant to the SCI patients population.

Activities of Daily Living↗
PubMed2002

Attenuation of the electrophysiological function of the corpus callosum after fluid percussion injury in the rat.

This study describes a new method used to evaluate axonal physiological dysfunction following fluid percussion induced traumatic brain injury (TBI) that may facilitate the study of the mechanisms and novel therapeutic strategies of posttraumatic diffuse axonal injury (DAI). Stimulated compound action potentials (CAP) were recorded extracellularly in the corpus callosum of superfused brain slices at 3 h, and 1, 3, and 7 days following central fluid percussion injury and demonstrated a temporal pattern of functional deterioration. The maximal CAP amplitude (CAPA) covaried with the intensity of impact 1 day following sham, mild (1.0-1.2 atm), and moderate (1.8-2.0 atm) injury (p < 0.05; 1.11 +/- 0.10, 0.82 +/- 0.11, and 0.49 +/- 0.08 mV, respectively). The CAPA in sham animals were approximately 1.1 mV and did not vary with survival interval (3 h, and 1, 3, and 7 days); however, they were significantly decreased at each time point following moderate injury (p < 0.05; 0.51 +/- 0.11, 0.49 +/- 0.08, 0.46 +/- 0.10, and 0.75 +/- 0.13 mV, respectively). The CAPA at 7 days in the injured group were higher than at 3 h, and 1 and 3 days. H&E and amyloid precursor protein (APP) light microscopic analysis confirmed previously reported trauma-induced axonal injury in the corpus callosum seen after fluid percussion injury. Increased APP expression was confirmed using Western blotting showing significant accumulation at 1 day (IOD 913.0 +/- 252.7; n = 3; p = 0.05), 3 days (IOD 753.1 +/- 159.1; n = 3; p = 0.03), and at 7 days (IOD 1093.8 = 105.0; n = 3; p = 0.001) compared to shams (IOD 217.6 +/- 20.4; n = 3). Thus, we report the characterization of white matter axonal dysfunction in the corpus callosum following TBI. This novel method was easily applied, and the results were consistent and reproducible. The electrophysiological changes were sensitive to the early effects of impact intensity, as well as to delayed changes occurring several days following injury. They also indicated a greater degree of attenuation than predicted by APP expression changes alone.

Action Potentials↗
PubMed2001

Epidemiology, demographics, and pathophysiology of acute spinal cord injury.

Spinal cord injury occurs through various countries throughout the world with an annual incidence of 15 to 40 cases per million, with the causes of these injuries ranging from motor vehicle accidents and community violence to recreational activities and workplace-related injuries. Survival has improved along with a greater appreciation of patterns of presentation, survival, and complications. Despite much work having been done, the only treatment to date known to ameliorate neurologic dysfunction that occurs at or below the level of neurologic injury has been intravenous methylprednisolone therapy. Much research over the past 30 to 40 years has focused on elucidating the mechanisms of spinal cord injury, with the complex pathophysiologic processes slowly being unraveled. With a greater understanding of both primary and secondary mechanisms of injury, the roles of calcium, free radicals, sodium, excitatory amino acids, vascular mediators, and apoptosis have been elucidated. This review examines the epidemiology, demographics, and pathophysiology of acute spinal cord injury.

Age Factors↗
PubMed2001

The role and timing of decompression in acute spinal cord injury: what do we know? What should we do?

The management of acute spinal cord injury has traditionally concentrated on preventative measures as well as, for the better part of the previous century, conservative care. Pharmacologic interventions, in particular intravenous methylprednisolone therapy, have shown modest improvements in clinical trials and are still undergoing evaluation. More recent interest has focused on the role of surgical reduction and decompression, particularly "early" surgery. A review of the current evidence available in the literature suggests that there is no standard of care regarding the role and timing of surgical decompression. There are insufficient data to support overall treatment standards or guidelines for this topic. There are, however, Class II data indicating that early surgery (<24 hours) may be done safely after acute SCI. Furthermore, there are Class III data to suggest a role for urgent decompression in the setting of 1) bilateral facet dislocation and 2) incomplete spinal cord injury with a neurologically deteriorating patient. Whereas there is biologic evidence from experimental studies in animals that early decompression may improve neurologic recovery after SCI, the relevant time frame in humans remains unclear. To date, the role of decompression in patients with SCI is only supported by Class III and limited Class II evidence and accordingly can be considered only a practice option. Accordingly, there is a strong rationale to undertake prospective, controlled trials to evaluate the role and timing of decompression in acute SCI.

Acute Disease↗