Optimal treatment for severe neurogenic bowel dysfunction after chronic spinal cord injury: a decision analysis.

BACKGROUND: When conservative management fails in patients with chronic spinal cord injury (SCI) and neurogenic bowel dysfunction, clinicians have to choose from a variety of treatment options which include colostomy, ileostomy, Malone anterograde continence enema (MACE) and sacral anterior root stimulator (SARS) implantation. This study employed a decision analysis to examine the optimal treatment for bowel management of young individuals with chronic refractory constipation in the setting of chronic SCI. METHODS: A decision analysis was created to compare the four surgical strategies using baseline analysis, one-way and two-way sensitivity analyses, 'worst scenario' and 'best scenario' sensitivity analyses, and probabilistic sensitivity analyses. Quality-adjusted life expectancy (QALE) was the primary outcome. RESULTS: The baseline analysis indicated that patients who underwent the MACE procedure had the highest QALE value compared with the other interventions. Sensitivity analyses showed that these results were robust. CONCLUSION: The MACE procedure may provide the best long-term outcome in terms of the probability of improving bowel function, reducing complication rates and the incidence of autonomic dysreflexia, and being congruent with patients' preferences. The analysis was sensitive to changes in assumptions about quality of life/utility, and thus the results could change if more specific estimates of utility became available.

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.

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.

Role of C-afferent fibres in the mechanism of action of sacral nerve root neuromodulation in chronic spinal cord injury.

OBJECTIVE: To determine whether sacral root neuro-modulation (a promising therapeutic modality in patients with refractory voiding and storage problems) has its effect through the blockade of C-afferent fibres that form the afferent limb of a pathological reflex arc responsible for the dysfunction of bladder storage. MATERIALS AND METHODS: The study comprised 39 female Sprague Dawley rats divided into three equal groups: normal controls (group 1); spinally transected at T10 (group 2); spinally transected and electrically stimulated bilaterally at S1 for 6 h daily (group 3). Three weeks after transection the rats were assessed using urodynamics; substance P, neurokinin A and calcitonin gene-related peptide (CGRP) were extracted from the dorsal root ganglia (DRG) of the L5 and L6 roots and quantified by radioimmunoassay. RESULTS: Spinally transected rats developed urinary bladder hyper-reflexia after 3 weeks. This was associated with a significant increase in the neuropeptide content of the DRG of L6. Electrostimulation of S1 significantly decreased the neuropeptide content of L6. In contrast, transection and S1 neurostimulation did not affect the neuropeptide content of the L5 DRG, except for CGRP, which increased after spinal transection and decreased with neurostimulation. CONCLUSIONS: In spinally transected rats, sacral root neurostimulation abolished bladder hyper-reflexia and attenuated the rise in neuropeptide content of the L6 DRG. These results suggest that the blockade of C-afferent fibre activity is one of the mechanisms of action of sacral root neuromodulation.

Assessment of a new ultrafiltration blood processing system.

PURPOSE: To report our clinical experience with a new blood processing device which uses ultrafiltration. We assessed safety and efficacy by evaluating: 1 ) the quality and the quantity of intraoperative shed blood processed and reinfused to the patient 2) homologous blood requirements 3) clinical status of the patient post-transfusion. METHODS: With Ethics Committee approval, the ultrafiltration device was used in six consenting patients undergoing major elective spinal surgery. Blood samples for haematology and biochemistry tests were collected from patients post-induction of anaesthesia (baseline), 1 hr and 24 hr post-autotransfusion. Volumes of blood collected and processed, and all autologous and homologous transfusions were recorded. Patients were assessed post-operatively for any adverse effects. RESULTS: Five patients had donated blood preoperatively. One patient required homologous blood products in addition to autologous blood. In two patients, the filtration cartridge became blocked and required changing midprocessing. No patient sustained device-related complications. One patient had postoperative haematuria which resolved spontaneously within two hours. CONCLUSION: The ultrafiltration device was safe and effective in reducing homologous blood requirements in six patients undergoing elective spinal surgery. Further evaluation of the ultrafiltration device will be necessary, especially in view of the blockage of the filtration cartridge.

Effect of a direct current field on axons after experimental spinal cord injury.

There is evidence that direct current (DC) stimulation promotes neurologic recovery in spinal cord injury. The authors conducted a morphometric analysis of axons at the site of spinal cord injury in adult rats treated with a DC field. Ten rats received a 17-g and 15 rats a 53-g clip compression injury and were treated with either a sham (control) or a functioning DC stimulator for 8 weeks. Five normal rats were also assessed. There was a significant relation (p less than 0.0001) between the severity of injury and the number of axons at the injury site. After the 17-g injury, there was no significant difference in the number of axons between control and treated rats. However, after the 53-g injury, there were significantly (p less than 0.05) more axons in treated than control rats. Both degrees of injury caused preferential destruction of large-calibre axons. Subsequent analysis showed that the axon diameter of treated rats with 17-g or 53-g injury was significantly greater (p less than 0.05) than that of control rats with 17-g or 53-g injury. These data, for the first time, show that the application of a DC field increases the number and calibre of axons at the site of a spinal cord injury and enhances the survival or regrowth of axons following spinal cord injury in the rat.

The effect of direct-current field on recovery from experimental spinal cord injury.

Recent work has indicated that direct-current (DC) fields may promote recovery after acute spinal cord injury. In the present experiments, the therapeutic value of an applied DC field was studied in 40 rats with clip compression injuries of the cord at C7-T1. The rats were randomly allocated to one of four groups including 10 rats each: two groups received a 17-gm cord injury and two groups a 53-gm injury. One group at each injury severity received implantation of a treatment (14 microA) DC stimulator and the other group a control (0 microA) stimulator. Clinical neurological function was assessed weekly by the inclined-plane technique. At 8 weeks after injury, motor and somatosensory evoked potentials (MEP's and SSEP's) were recorded, and the axonal tracer horseradish peroxidase (HRP) was introduced into the cord at T-6. The total number of HRP-labeled cells was counted in every sixth coronal section through the brain stem and motor cortex. All outcome parameters were assessed blindly. In the 17-gm group, there were no significant differences in any outcome measure between control and treated rats. In contrast, in the 53-gm group, the inclined-plane scores, the amplitude of the MEP's, and the number of labeled cells in the red nucleus, raphé nuclei, and vestibular nuclei were greater in treated than in control rats. These data strongly indicate that an applied DC field can produce functional neurological and anatomical improvement in rats with acute spinal cord injuries.