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Michael G Fehlings

Publications and source records attributed to Michael G Fehlings.

13 recordsLinked to original sources
PubMed2003

Neuroprotection by minocycline facilitates significant recovery from spinal cord injury in mice.

Acute spinal cord injury (SCI) produces tissue damage that continues to evolve days and weeks after the initial insult, with corresponding functional impairments. Reducing the extent of progressive tissue loss ('neuroprotection') following SCI should result in a better recovery from SCI, but treatment options have thus far been limited. In this study, we have tested the efficacy of minocycline in ameliorating damage following acute SCI in mice. This semi-synthetic tetracycline antibiotic has been reported to inhibit the expression and activity of several mediators of tissue injury, including inflammatory cytokines, free radicals and matrix metalloproteinases, making it a suitable candidate for study. Mice were subjected to extradural compression of the spinal cord using a modified aneurysm clip, following which they received treatment with either minocycline or vehicle beginning 1 h after injury. Behavioural testing of hindlimb function was initiated 3 days after injury using the Basso Beattie Bresnahan locomotor rating scale, and at 1 week using the inclined plane test. Functional assessments demonstrated that minocycline administration significantly improved both hindlimb function and strength from 3 to 28 days after injury compared with vehicle controls. Furthermore, gross lesion size in the spinal cord was significantly reduced by minocycline, and there was evidence of axonal sparing as determined using fluorogold labelling of the rubrospinal tract and by Bielchowsky silver stain. Finally, a comparison of minocycline against the currently approved treatment for acute SCI in humans, methylprednisolone, demonstrated superior behavioural recovery in the minocycline-treated animals.

Animals↗
PubMed2003

Medical co-morbidities, secondary complications, and mortality in elderly with acute spinal cord injury.

Despite an increasing incidence of spinal cord injury (SCI) in the elderly and evidence that age appears to influence outcome after neurotrauma, surprisingly little is known regarding clinical outcomes and secondary complications in elderly with an acute SCI. This study was undertaken to evaluate the effect of age on clinical outcomes after acute traumatic SCI managed in an acute care unit by a multidisciplinary team. A retrospective chart review of all patients with acute SCI admitted to an acute care unit at a university hospital between 1998 and 2000 was performed. Data on clinical outcomes and secondary complications in younger individuals (group 1: age < 60 years) were compared to elderly subjects (group 2: age > or = 60 years). There were 28 elderly (age 60-89 years) and 30 younger (age 17-56 years) individuals. The severity and level of SCI were similar in both groups (p = 0.11; p = 0.93). Co-morbidities were more frequent in the elderly (p < 0.01). There was a trend, which did not achieve significance, for an increased incidence of secondary complications in the elderly (57.1% versus 33.3%; p = 0.11). The most common secondary complications in both groups were infections, psychiatric disorders, pressure sores, and cardiovascular complications. Mortality rates in elderly and younger individuals with acute SCI (p = 0.41) were not significantly different. Our data suggest that rigorous attention to principles of acute SCI care can minimize previously reported higher susceptibility for secondary complications in the elderly. A multidisciplinary team approach to the management of the elderly with acute SCI is essential to minimize or prevent secondary complications.

Acute Disease↗
PubMed2003

Autonomic dysreflexia in acute spinal cord injury: an under-recognized clinical entity.

While autonomic dysreflexia (AD) is well recognized in the chronic stage of spinal cord injury (SCI) this potentially life-threatening complication has been only rarely documented in the acute phase (1 month) after SCI. Based on our clinical experience we hypothesized that AD is under-recognized in the acute phase of SCI. This study was undertaken to determine the incidence and clinical associations of early AD in our center. We reviewed the charts of patients with acute traumatic SCI admitted to the Toronto Western Hospital Spinal Program between 1998 and 2000. Among 58 patients with acute traumatic SCI (15F, 43M; ages 17-89 years, mean of 55.4), all three individuals who developed evidence of early AD had complete cervical tetraplegia (1F, 2M; ages 31-42 years, mean of 38.3). The incidence of early AD was 5.2% (3 of 58), whereas the adjusted incidence for the population at risk (SCI at T6 or above) was 5.7% (3 of 53). A significant number of patients in this series (87.9%, or 51 of 58) had a cervical SCI. While the mean resting systolic arterial blood pressure among these three individuals was 105.7+/-3 mm Hg, the mean systolic blood pressure at the time of early AD was 173.3+/-14.8 mm Hg (increase in systolic blood pressure over baseline ranged from 35.5% to 95%). The earliest episode of AD occurred on the 4(th) post-injury day. The trigger mechanisms for AD were somatic pain, fecal impaction, and abdominal distention. Although numerous reports emphasize AD as a potential complication of chronic SCI, our study demonstrates that AD occurs in 5.7% of patients with acute SCI above T6. Patients with severe cervical SCI are particularly susceptible to the early onset of AD. Clinicians need to be aware and highly vigilant of the potential development of AD in the acute phase of SCI.

Adolescent↗
PubMed2003

Occipitocervical reconstruction with the Ohio Medical Instruments Loop: results of a multicenter evaluation in 30 cases.

OBJECT: Stabilization of the craniocervical junction (CCJ) remains a significant challenge. In this multicenter study, the authors present the results of an evaluation of a precontoured titanium implant, the Ohio Medical Instruments (OMI) Loop, for craniocervical fixation. METHODS: In this multicenter retrospective study the authors evaluated 30 patients (16 female, 14 male; mean age 53.8 years) with rheumatoid arthritis (15 cases), traumatic occipitoatlantoaxial instability (six cases), congenital vertebral anomalies (two cases), instability due to basilar invagination in the setting of Chiari malformation (two cases), or Down syndrome (one case), tumor (one case), os odontoideum (two cases), and pseudarthrosis/other (one case), who underwent OMI Loop-assisted occipitocervical reconstruction. The mean follow-up period was 25.4 months (range 6-60 months). A solid reconstruction was achieved in 29 of 30 cases; there was only one case of hardware failure requiring reoperation. Noncritical hardware failure occurred in two patients in whom partial occipital screw backout occurred but did not necessitate reoperation. There were no perioperative neurological complications. One patient (3.3%) experienced a delayed postoperative worsening of myelopathy at 1 year that resolved with further surgery. Postoperatively, in 66.6% of patients the degree of myelopathy remained stable (as measured by American Spinal Injury Association [ASIA] scores), whereas 30% improved by one or more ASIA grade. The rate of osseous fusion was 96.6% at a mean follow-up period of 25.4 months. CONCLUSIONS: The authors found that the OMI Loop is a versatile precontoured occipitocervical fixation device that can be applied to a wide range of CCJ lesions. It provides excellent immediate rigid fixation of the CCJ, a high rate of osseous fusion, and a low rate of hardware failure.

Adolescent↗
PubMed2002

Patch-clamp recordings from white matter glia in thin longitudinal slices of adult rat spinal cord.

We developed a technique of whole cell patch-clamp recordings from white matter oligodendrocytes and astrocytes in 200-250 microm-thick horizontal slices of adult (>2 months, 240-260 g) rat thoracic spinal cord. The viability of the white matter, sectioned in Na(+)-free, low Ca(2+) media, and the function of axons were preserved for >8 h, as demonstrated by the propagation of TTX-sensitive compound action potentials (CAPs) and the sensitivity of their refractory period to K(+) channel blocker 4-aminopyridine (1 microM). Glial cells were visually identified within the slices with a 40 x water immersion objective using infra-red differential interference contrast (IR-DIC) video microscopy, and the details of their morphology were further elucidated after filling the cells with Lucifer Yellow or Alexa 350 fluorescent dyes during whole-cell recording. Using voltage steps and ramps, we revealed pronounced non-linearity of I-V relationships in both oligodendrocytes and astrocytes. Both types of cells expressed TEA-sensitive outward delayed rectifier-type currents activated at positive voltages but showed little, if any, signs of inward rectification at voltages up to -140 mV. At -70 mV holding voltage, bath-applied kainic acid (100 microM) activated inward currents in both types of cells. This novel horizontal slice preparation of adult rat thoracic cord will facilitate the examination of mature glial cell physiology, glial-axonal signaling and the pathophysiology of spinal cord trauma and ischemia.

4-Aminopyridine↗
PubMed2002

Editorial.

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Humans↗
PubMed2002

Idiopathic spinal cord herniation: report of eight cases and review of the literature.

STUDY DESIGN: A case series of eight patients with idiopathic spinal cord herniation and a review of the literature. OBJECTIVE: To report on this rare entity, provide insight on its natural history, and propose an optimal management strategy. SUMMARY OF BACKGROUND DATA: Idiopathic spinal cord herniation is a rare disease with 50 cases reported before the current study. METHODS: Eight cases (follow-up 1 month to 8 years) are reported using available information from patient charts, interviews, and assessments. All imaging studies are reviewed. The review of the literature was performed using PUBMED. RESULTS: Four patients, followed without surgical intervention, have not progressed. Of the three patients who underwent surgical repair by one of the authors, two improved and one was unchanged. A fourth patient, who was initially treated by another surgeon who failed to identify the dural defect and herniation, had a poor outcome. CONCLUSION: The pathophysiology of the dural defect is still uncertain. The typical presentation is Brown-Séquard syndrome. Microsurgical repair in cases with progression of neurologic deficits is usually successful in achieving recovery of function or arrest of progression.

Adult↗
PubMed2002

Upregulation of Kv 1.4 protein and gene expression after chronic spinal cord injury.

After spinal cord injury (SCI), white matter tracts are characterized by demyelination and increased sensitivity to the K(+) channel blocker 4-aminopyridine (4-AP). These effects appear to contribute to neurological impairment after SCI, although the molecular changes in K(+) channel subunit expression remain poorly understood. We examined changes in gene expression of the 4-AP-sensitive voltage-gated K(+) channel Kv 1.4 after chronic SCI in the rat. Quantitative immunoblotting showed that Kv 1.4 protein was significantly increased at 6 weeks, but not at 1 week, after SCI in spinal cord white matter. Kv 1.4 was localized to astrocytes, oligodendrocytes, and oligodendrocyte progenitor cells but not to axons in both the normal and the injured spinal cord white matter. Because glial cells proliferate after SCI, we used immunogold electron microscopy to quantify Kv 1.4 protein in individual glial cells and found a sixfold increase of Kv 1.4 in cells of the oligodendrocyte lineage after chronic injury. Finally, quantitative in situ hybridization showed that Kv 1.4 mRNA was significantly upregulated in spinal cord white matter, but not gray matter, after SCI. In summary, we show that Kv 1.4 is expressed in glial cells and not in axons in the rat spinal cord white matter and that its expression is markedly increased in cells of the oligodendrocyte lineage after chronic SCI. Given that K(+) channels play a role in glial cell proliferation, cells exhibiting changes in Kv 1.4 expression may represent proliferating oligodendroglia in the chronically injured spinal cord.

Animals↗
PubMed2002

Secondary injury mechanisms of spinal cord trauma: a novel therapeutic approach for the management of secondary pathophysiology with the sodium channel blocker riluzole.

Traumatic spinal cord injury is a consequence of a primary mechanical insult and a sequence of progressive secondary pathophysiological events that confound efforts to mitigate neurological deficits. Pharmacotherapy aimed at reducing the secondary injury is limited by a narrow therapeutic window. Thus, novel drug strategies must target early pathological mechanisms in order to realize the promise of efficacy for this form of neurotrauma. Research has shown that an accumulation of intracellular sodium as a result of trauma-induced perturbation of voltage-sensitive sodium channel activity is a key early mechanism in the secondary injury cascade. As such, voltage-sensitive sodium channels are an important therapeutic target for the treatment of spinal cord trauma. This review describes the evolution of acute spinal cord injury and provides a rationale for the clinical utility of sodium channel blockers, particularly riluzole, in the management of spinal cord trauma.

Animals↗
PubMed2002

An in vitro model of neurotrauma in organotypic spinal cord cultures from adult mice.

Cellular degeneration after spinal cord injury (SCI) involves numerous pathways. It is essential to use appropriate experimental models in order to understand the complex processes, which evolve after the initial trauma. The purpose of this study was to develop and assess an in vitro model of neurotrauma using organotypic slice culture of adult mice spinal cord. This model will facilitate the investigation of primary and secondary mechanisms of cell death that occurs after SCI. We modified previously described methods for generating organotypic cultures of murine spinal cord. The viability of organotypic cultures was assessed by observing the outgrowth of neurites and by using a mitochondria dependent dye for live cells (tetrazolium dye; MTT). The morphological integrity of cultures was examined histologically by hematoxylin and eosin (H&E) staining for general morphology and with luxol fast blue (LFB) for myelin. Neuronal and glial (GFAP; CNPase) markers were used to identify neurons, astrocytes and oligodendroglia, respectively. Primary injury was achieved by using a weight drop (0.2 g) model of injury. Cell death after primary injury was attenuated by pre-treatment with two known neuroprotective agents: the AMPA/KA blocker CNQX and methylprednisolone. The nuclear markers Propidium iodide and Sytox-green, as well as the TUNEL (in situ terminal deoxytransferase-mediated dUTP nick end labeling) technique, were used as a quantitative indicators of cell death at 24, 48 and 72 h post-injury using a confocal microscope and image analysis software. This novel in vitro model of SCI is easy to reproduce, will facilitate the examination of post-trauma cell death mechanisms and the neuroprotective effects of pharmacological agents and aid in the study of transgenic murine models.

Animals↗
PubMed2002

Development and characterization of a novel, graded model of clip compressive spinal cord injury in the mouse: Part 1. Clip design, behavioral outcomes, and histopathology.

In order to take advantage of various genetically manipulated mice available to study the pathophysiology of spinal cord injury (SCI), we adapted an extradural clip compression injury model to the mouse (FEJOTA mouse clip). The dimensions of the modified aneurysm clip blades were customized for application to the mouse spinal cord. Three clips with different springs were made to produce differing magnitudes of closing force (3, 8, and 24 g). The clips were calibrated regularly to ensure that the closing force remained constant. The surgical procedure involved a laminectomy at T3 and T4, followed by extradural application of the clip at this level for 1 min to produce SCI. Three injury severities (3, 8, and 24 g), sham (passage of dissector extradurally at T3-4), and transection control groups were examined (n = 12/group). Quantitative behavioural assessments using the Basso, Beattie, and Bresnahan (BBB; H > 46; df = 4; p < 0.001; Kruskal-Wallis one-way ANOVA) and inclined plane (IP; F = 123; df = 4; p < 0.0001; two-way repeated measures ANOVA) tests showed a significant graded increase in neurological deficits with increasing severity of injury. By day 14, the motor recovery of the mice plateaued. Qualitative examination of the injury site morphology indicated that microcystic cavitation, degenerating axons, and robust astrogliosis were characteristic of the murine response to clip compressive SCI. Morphometric analyses of H&E/Luxol Fast Blue stained sections at every 50 microm from the injury epicenter indicated that with greater injury severity there was a progressive decrease in residual tissue (F = 220, df = 3; p < 0.0001; two-way ANOVA). In addition, statistically significant differences were found in the amount of residual tissue at the injury epicenter between all of the injury severities (p < 0.05, SNK test). This novel, graded compressive model of SCI will facilitate future studies of the pathological mechanisms of SCI using transgenic and knockout murine systems.

Animals↗
PubMed2002

Development and characterization of a novel, graded model of clip compressive spinal cord injury in the mouse: Part 2. Quantitative neuroanatomical assessment and analysis of the relationships between axonal tracts, residual tissue, and locomotor recovery.

A detailed examination of the histopathological features of the clip compression injury in mice was performed to understand the relationships between neurological function and existing pathology of the spinal cord. Adult, female CD1 mice underwent three grades of extradural clip compression injury (3-g, 8-g, and 24-g FEJOTA mouse clips), transection, and sham injury at T3-4. Quantitative behavioural assessments were performed for 4 weeks following SCI. After 4 weeks, Fluoro-Gold was introduced caudal to the SCI site, at T9, and was retrogradely transported for 5 days to the origin of spared axons through the injury site. Counts of retrogradely labeled neurons in the brain-stem, midbrain, and sensory-motor cortex indicated that the number of intact descending axons that traversed the lesion decreased with increasing injury severity (F > 28; df = 4; p < 0.0001; one-way ANOVA). Independent linear correlation analyses were performed between indices of neurological recovery (BBB and IP test), counts of retrogradely labeled neurons and morphometric assessments of normal residual tissue at the injury epicenter. The BBB test correlated strongly with the amount of residual tissue at the injury epicenter (R = 0.945, df = 28, p < 0.0001). Counts of neurons retrogradely labeled with Fluoro-Gold were also strongly correlated with the BBB scores. The extrapyramidal (raphespinal, reticulospinal, vestibulospinal, and rubrospinal) tracts had Pearson correlation coefficients (R) of 0.814, 0.812, 0.813, and 0.747, respectively (df = 28, p < 0.0001). The pyramidal (corticospinal) tract had a correlation of R = 0.747, df = 28, p < 0.0001 with the BBB scores. The IP scores also correlated strongly with the persistence of extrapyramidal (raphespinal, reticulospinal, vestibulospinal and rubrospinal) tracts with correlation coefficients of 0.801, 0.782, 0.790, and 0.836, respectively (df = 28, p < 0.0001). These data indicate that the counts of retrogradely labeled neurons at the origin of distinct descending motor pathways are predictors of the variance of the functional recovery measured by the BBB and IP tests following spinal cord injury. In addition, we provide a detailed neuroanatomical study of clip compression injury in mice that can be used to study the molecular mechanisms of SCI in knockout and transgenic mice.

Animals↗