The role of excitotoxicity in secondary mechanisms of spinal cord injury: a review with an emphasis on the implications for white matter degeneration

Following an initial impact after spinal cord injury (SCI), there is a cascade of downstream events termed 'secondary injury', which culminate in progressive degenerative events in the spinal cord. These secondary injury mechanisms include, but are not limited to, ischemia, inflammation, free radical-induced cell death, glutamate excitotoxicity, cytoskeletal degradation and induction of extrinsic and intrinsic apoptotic pathways. There is emerging evidence that glutamate excitotoxicity plays a key role not only in neuronal cell death but also in delayed posttraumatic spinal cord white matter degeneration. Importantly however, the differences in cellular composition and expression of specific types of glutamate receptors in grey versus white matter require a compartmentalized approach to understand the mechanisms of secondary injury after SCI. This review examines mechanisms of secondary white matter injury with particular emphasis on glutamate excitotoxicity and the potential link of this mechanism to apoptosis. Recent studies have provided new insights into the mechanisms of glutamate release and its potential targets, as well as the downstream pathways associated with glutamate receptor activation in specific types of cells. Evidence from molecular and functional expression of glutamatergic AMPA receptors in white matter glia (and possibly axons), the protective effects of AMPA/kainate antagonists in posttraumatic white matter axonal function, and the vulnerability of oligodendrocytes to excitotoxic cell death suggest that glutamate excitotoxicity is associated with oligodendrocyte apoptosis. The latter mechanism appears key to glutamatergic white matter degeneration after SCI and may represent an attractive therapeutic target.     

Evidence-based review of patient-reported outcomes with botulinum toxin type A

This review systematically examines the effects of botulinum toxin type A (BTX-A) on patient-reported outcomes across disorders using evidence-based criteria. The evidence provided by these studies ranged from randomized, controlled trials to case series. The effects of BTX-A on quality of life or global treatment outcomes were assessed in 48 studies across 16 different conditions. All but 7 of these reported benefits of BTX-A over baseline or the comparator condition (placebo or other treatment). The effects of BTX-A on impairment, activities, or participation were assessed in 46 studies across 17 different conditions. All but 4 reported benefits of BTX-A over baseline or the comparison group. The effects of BTX-A on satisfaction or preference were assessed in 14 studies across 11 different conditions, all of which reported high rates of satisfaction with BTX-A or preference over the comparator. These studies provide evidence that BTX-A exerts meaningful benefits on the quality of life of patients treated with this biologic agent.     

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.     

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.     

Depletion and sizes of motor units in spinal muscular atrophy

Motor unit number estimation (MUNE) was applied to the biceps brachii muscles of 13 young patients (age 5--24 years) with spinal muscular atrophy (SMA) and the results compared with those of healthy control subjects matched for age and gender. In the SMA patients, all motor unit (MU) estimates fell below the control range, and there was good correspondence between the values for the two arms in the same subject. No correlation could be found between the MUNEs and the severity of the weakness. This unexpected result was attributed to the presence of small and normal-sized MUs in the muscles of patients, in addition to MUs that appeared to be considerably enlarged. The threefold mean increase in MU potential size was insufficient to compensate for the MU loss. In addition, the study confirmed that there are, on average, approximately 130 MUs in the healthy biceps brachii muscle.     

Behavioural Effects of the Methanolic Root Bark Extract of Securinega Virosa in Rodents

Securinega virosa is used traditionally as sedative in children and in mental illnesses. In this study, the behavioral effects of methanolic root bark extract of S. virosa were investigated in mice. The results revealed that the extract significantly (P<0.05) and dose-dependently reduced the onset and prolonged the duration of sleep. The extract significantly (P<0.05) decreased exploratory activity and reduced the rate of apomorphine-induced stereotyped climbing at the doses tested (6.25–25mg/kg). It also produced a significant and dose-dependent motor coordination deficit in mice at the doses tested (P<0.01). The intraperitoneal median lethal dose in mice was 774.6mg/kg while the preliminary phytochemical screening revealed the presence of alkaloids, tannins, saponins and flavonoids. These results suggest that methanolic root bark extract of S. virosa contains biologically active principles that are sedative in nature and lend pharmacological credence to the ethnomedical use of the plant.     

Pulmonary lymphangitic spread of carcinoma: appearance on CT scans

Chest computed tomography (CT), including high-resolution CT with thin (1.5-mm) sections was used to evaluate proved (pathologically or clinically) lymphangitic spread (LS) of tumor in 12 patients. These appearances were compared with thin-section scans obtained in 11 healthy subjects. Thin-section CT demonstrated findings consistent with thickening of the normal lung interstitium. In all patients, thin sections showed an increase in the number of peripheral lines (1-2 cm in length) that were diffuse in generalized disease and localized in focal disease. Normal peripheral arcades were not increased in number, but the limbs forming the arcades were thickened in all patients. A diffuse increase in linear and curvilinear structures (reticular pattern) was seen toward the center of the lung. Polygonal structures 1-2 cm in diameter were seen in seven patients with LS but not in healthy subjects. Fissures were thickened in nine patients. Selected 1.5-mm-thick CT sections are recommended through abnormal areas (seen at CT or on chest radiographs) or if these are normal at three levels (midapex, hilus, and 3 cm above the diaphragm) when scanning patients with tumors known to cause LS.     

Obstetric and nonmalignant gynecologic bleeding: treatment with angiographic embolization

Eight patients (seven post partum, one post abortion) with massive pelvic hemorrhage related to pregnancy and one patient with uncontrollable bleeding following a cervical biopsy underwent angiography to facilitate the identification and treatment of bleeding sites. In all nine patients pelvic hemorrhage was successfully controlled with embolization under angiographic guidance. Angiographic embolization allowed preservation of the uterus in six patients referred prior to hysterectomy, and one patient subsequently became pregnant. When conservative measures and minor surgical repairs have failed, embolization should be the next step in the treatment of postpartum hemorrhage to avoid major surgery in an unstable patient and to maintain reproductive function.