Research priorities for urological care following spinal cord injury: recommendations of an expert panel.

OBJECTIVE: A multidisciplinary panel of experts from Canada and the United States was convened by the Ontario Neurotrauma Foundation (ONF) to establish research priorities in the area of urological care following spinal cord injury (SCI). DESIGN: The panel reviewed a synthesis of published literature in five areas of urology, identified emerging opportunities in the private and public sector, and used a modified Delphi approach to reach consensus on priorities for funding. RESULTS: The panel recommendations included: clinical trials of the safety and efficacy of M3 receptor specific anti-muscarinic agents for bladder hyperactivity in SCI patients; development and testing of protocols for sacral nerve electrostimulation without sacral afferent neurectomy for management of micturition - including selective stimulation of sacral nerve fibers, high frequency blocking of the pudendal nerve to minimize the risk of urethral sphincter co-contraction and genital nerve stimulation for bladder inhibition and incontinence management; clinical trials of the efficacy and safety of intra-urethral valve catheters; trials of the efficacy of probiotics for bacterial interference i.e. to reduce colonization by uropathogens and manage the dual problems of infection and pathogen resistance to anti-microbials: innovations in the prevention or treatment of stone disease (ureteral, bladder and kidney). CONCLUSIONS: The recommendations form the strategic priorities of the ONF SCI grants program for Ontario-based investigators and their partnerships with out-of-province collaborators and organizations.

Heart failure with preserved ejection fraction: uncertainties and dilemmas.

Many uncertainties surround the syndrome of heart failure with preserved ejection fraction (HFpEF), which was the topic reviewed in an Expert Meeting at the University of Ferrara. This concluded that the absence of clear diagnostic clinical criteria was the major barrier to progress. There was general agreement that symptoms or signs of heart failure, normal LVEF despite an elevated plasma concentration of natriuretic peptides, and signs of abnormal LV relaxation, LV filling, LV hypertrophy, or left atrial enlargement, or diastolic dysfunction supported the diagnosis. However, HFpEF, like all heart failure syndromes, is heterogeneous in aetiology and pathophysiology, rather than being a single disease. HFpEF may account for about half of all patients with heart failure. The classical risk factors for developing HFpEF include age and co-morbidities, notably hypertension, atrial fibrillation, and the metabolic syndrome. When complicated by increasing congestion requiring hospital admission, the prognosis is poor; 30% or more of patients will die within 1 year (nearly two-thirds die from cardiovascular causes). Patients with chronic stable symptoms have a much better prognosis. Despite many clinical trials, there is no solid evidence that any treatment alters the natural history of HFpEF. Several treatments have shown promising early results and are now being tested in substantial randomized clinical trials. Further basic research is required to better characterize the disease and accelerate progress. Our review highlights the many difficulties encountered in performing randomized clinical trials in HFpEF, often due to difficulties in characterizing HFpEF itself.

Female urinary retention.

The urodynamic results in 68 females with urinary retention were reviewed. There were two groups: 39 patients with neurologic causes for retention, and 29 patients in whom possible causes for retention included: psychological history (15 patients), gynecologic pathology, and urinary tract infection. Nine patients in the neurogenic group and 13 patients in the non-neurogenic group had undergone urethral dilatation with no improvement. Upper urinary tract evaluation was unremarkable. Detrusor failure was the prominent bladder pattern in both groups. In the neurogenic group, low pressure detrusor activity was also present in 10 patients, 3 of whom had sphincter dyssynergia. Flow rate, surface electromyography, and bethanechol supersensitivity test could not help differentiate neurogenic from non-neurogenic detrusor failure. The notation of abnormal bladder sensation did significantly differ between the groups, but was of limited accuracy as an indicator of neurogenic retention. Self-intermittent catheterization was the most effective treatment for both groups, with some patients voiding adequately in follow-up. Although no one test can accurately differentiate neurogenic from nonneurogenic female urinary retention, careful neurourologic evaluation will help guide us to more appropriate management.

Idiopathic anejaculation treated by vibratory stimulation.

Idiopathic anejaculation is a rare cause of infertility usually treated by psychotherapy. However, electrovibration may be a simple, noninvasive adjunct to the treatment of this disorder. In our two cases, we obtained ejaculate adequate for insemination in one patient and noted some gain in orgasmic sensation in the other. The success in these two infertile patients who had already undergone lengthy psychotherapy is promising. Nevertheless, psychotherapy will continue to be the standard of therapy until we have more experience with penile electrovibration.

Microinjection of interleukin-1 into brain: separation of sleep and fever responses.

Interleukin-1 (IL1) and muramyl peptides are somnogenic, pyrogenic, immune response modifiers, Their central nervous system loci of action with respect to sleep and body temperature in rabbits were examined in this study using microinjection techniques. Unilateral microinjection of IL1 into various basal forebrain or brain stem sites resulted in elevated colonic temperatures (Tc), but the duration of slow-wave sleep (SWS) was unchanged compared to results obtained after control injections. Injection of IL1 into posterior hypothalamic areas failed to elicit either sleep or temperature responses. In contrast to these results, injection of either IL1 or muramyl dipeptide into the Aqueduct of Sylvius was followed by enhanced SWS and Tc. These results show that IL1-induced sleep and fever responses can be separated. Somnogenic sites of action for IL1 and muramyl peptides remain unknown.

Effects of low charge injection densities on corrosion responses of pulsed 316LVM stainless steel electrodes.

The safe charge injection density for pulsing of 316LVM electrodes has been reported to be 40 microC/cm2. However, only 20 microC/cm2 is available for nonfaradic charge transfer and double layer charge injection. Therefore, we evaluated long term pulsing at 20 microC/cm2 with capacitor coupling.

Direct bladder stimulation with suture electrodes promotes voiding in a spinal animal model: a technical report.

To determine the efficacy of a new electrode for direct bladder stimulation, five male cats were instrumented during anesthesia. Multistranded, 316LVM, stainless-steel, wire electrodes were implanted on the bladder wall serosa above the trigone area. The electrodes were made with a needle attached to the end that was cut off after suturing the electrode in place. Additional instrumentation included tubes for pressure recording and filling, and hook electrodes for leg and pelvic floor EMG recording. Bladder filling and stimulation studies were conducted in tethered animals 1 to 2 weeks following recovery. Chronic studies were conducted following recovery in tethered animals. To test these electrodes in a spinal cord injury (SCI) model, a T-1 level complete lesion was performed on the above instrumented animals. Spinal animals had successful direct bladder stimulation that induced active contractions and voiding both before and after SCI, but voiding rates were higher more than 2 weeks after SCI and at larger initial bladder volumes. Optimum stimulation parameters consisted of 40 pulses per second, 300 microseconds to 1 ms pulse duration, a stimulation period of 3 to 4 s, and 10 to 40 mA. Urethral resistance, indicated by a urethral function measure, showed that stimulation had no adverse effect on urethral function, and fluoroscopy showed an open membranous urethra during stimulation and voiding. The cat has a small penile urethra that is the flow rate controlling zone. The suture electrode did not corrode, erode into the bladder, or become dislodged, and appears suitable for chronic implantation.

Comparison of direct bladder and sacral nerve stimulation in spinal cats.

Neuroprosthetic techniques have been used to facilitate voiding via electrical stimulation for bladder management following spinal cord injury (SCI), but high urethral resistance has been a problem. This problem was investigated here in the chronic, spinal, male cat (C6-T1) using direct bladder and sacral nerve stimulation. Direct bladder stimulation was only conducted during terminal procedures with an open abdomen and with four hook electrodes inserted into the bladder wall. Sacral stimulation was conducted daily during the 10 weeks post-SCI and during terminal procedures. Stimulation was conducted with both implanted epidural electrode and surface electrodes over the sacral bone. Both of these sacral methods stimulated anterior and posterior roots. However, these sacral methods were generally ineffective for inducing voiding during the study. In three of the five animals investigated, stimulation did not empty the bladder. In the remaining two animals, the bladder was emptied with sacral stimulation, but only after return of bladder reflex activity, 2 to 4 weeks post-injury. When poor voiding occurred in spite of high bladder pressures, it indicates high urethral resistance. This was confirmed using video cystourethrography where the membranous urethra was observed to remain closed following stimulation. Direct bladder stimulation was then compared to sacral nerve stimulation during terminal procedures. Direct bladder stimulation induced voiding at a high rate both during and after stimulation, whereas sacral nerve stimulation with implanted electrodes induced voiding at a lower rate and only after stimulation. A simple urethral resistance measure, the ratio of bladder pressure to voiding rate, was lower with direct bladder stimulation than sacral nerve stimulation. Stimulation-facilitated voiding has also been associated with the development of bladder wall hypertrophy. This problem was investigated by evaluating bladder wall thickness postmortem in three groups of animals: the first group was the spinal-stimulated animals detailed above; the additional two groups were a spinal-nonstimulated but instrumented group maintained for 10 weeks following injury, and an intact group of animals. The stimulated spinal cats tended to have the thickest bladder wall followed by the nonstimulated spinal cats. The wall thickness of intact animals served as a control.

Do direct current electric fields enhance micturition in the spinal cat?

Changes in micturition behavior and motoneuron ultrastructure were studied in spinal cats to determine the effects of direct current (DC) electric field treatment. Adult cats received a complete injury at T8. A treatment group with an implanted 15 microA DC source and electrodes positioned near the lesion site was compared with non-treatment groups that were either operated or unoperated. Both bladder emptying with Crede and the withdrawal reflex were improved in the treatment group compared with the non-treatment group. Urodynamic procedures showed that high urethral resistance and pelvic floor activity following spinal injury was partially reduced in the stimulated cat, indicating inhibition of the urethral sphincter. The ultrastructural analysis of Onuf's nucleus suggested a similar synaptic input in all three groups. In conclusion, possible activation of inhibitory processes and/or neural plasticity best explain the early improvement of bladder function seen following electrical stimulation.

Evaluation of a thin-film peripheral nerve cuff electrode.

This is a study of the reaction of large nerves to implantation using a flexible, thin-film cuff electrode. Cuff electrodes were implanted on the sciatic nerve of three cats. An implantation period of six weeks allowed sufficient time for any injury responses in the nerve and connective tissue sheath around the cuff to develop. The electrode came off the nerve in one of the cats. In the remaining two cats, gross observation following explantation of the electrodes revealed encapsulation of the cuffs without swelling of nerve tissue. Histological evaluation did not demonstrate nerve injury. The nerve cuff electrodes, which are comprised of titanium and iridium coatings on a fluorocarbon polymer substrate, appeared unaffected by the implantation, and connective tissue encapsulation did not adhere to either the polymer substrate or metallization. Evaluation of the electrodes using activated iridium oxide charge injection sites in more extended studies is now being undertaken.

Botulinum toxin injections for voiding dysfunction following SCI.

Botulinum toxin (BT) injections have been used successfully to treat spastic muscle conditions, including detrusor-sphincter dyssynergia (DSD) seen in spinal cord injury (SCI) patients. In our urology clinic, we used BT to treat three SCI patients who had voiding dysfunction, using a transperineal needle with electromyographic (EMG) monitoring. Two of the patients reported excellent results following the treatment. One patient, with whom the staff had difficulty doing intermittent catheterization (IC), improved significantly. The other patient had improved voiding with an external catheter and minimal urinary residual. The third patient had no improvement of leg spasms with his voiding dysfunction and required a sphincterotomy. Although patients may need repeat injections, BT is minimally invasive and easy to administer with no side effects. Overall, BT injection is an excellent method of managing voiding in SCI patients, especially those on continuous external catheters and with IC management who refuse or are not good candidates for surgery.

Direct bladder stimulation with percutaneous electrodes and impedance monitoring of volume in an SCI animal model.

Bladder responses to percutaneous electrodes were investigated with stimulation in three male spinal cats. The animals had been spinalized (T1 level lesion) 10 weeks prior to these studies and had been instrumented with chronic bladder had been spinalized (T1 level lesion) 10 weeks prior to these studies and had been instrumented with chronic bladder wall electrodes and suprapubic bladder catheters for filling and pressure recording. percutaneous stimulation in tethered animals was conducted wit hook electrodes inserted with a needle in the abdomen bilaterally adjacent to the bladder trigone. Stimulation was conducted with 40 Hz pulse trains of 10 to 30 mA for three seconds. Stimulation with both percutaneous and chronic electrodes induced high bladder pressures and voiding. In addition, with chronically implanted electrodes, impedance monitoring of bladder volume was found to be an effective recording technique.

Multielectrode nerve cuff stimulation of the median nerve produces selective movements in a raccoon animal model.

In this study, an electrode system consisting of twelve small platinum dot electrodes imbedded in a spiral silicone rubber insulating cuff was used to investigate the feasibility of selective (regional) stimulation of the median nerves of the raccoon. Acute experiments in four raccoons consisted of functional responses observations, isometric force recordings from tendon attachments and postmortem fascicular mapping. Functional responses (elbow, wrist and/or digit flexion, pronation and/or thumb abduction) to selective stimulation were noted as dependent upon cuff electrode configuration (longitudinal tripole with and without field steering, as well as a transverse bipolar arrangement) and current level (threshold, 1/2 maximal, maximal). Muscle force recruitment curves (force as a function of stimulus amplitude) were plotted for flexor digitorum superficialis, flexor digitorum profundus, flexor carpi radialis, palmaris longus and pronator teres of three raccoons. Fascicular maps at the level of the nerve cuff were created indicating the approximate position of innervation to each of the aforementioned muscles, as well as other innervation such as paw fascicles, sensory fascicles, and elbow innervation (such as coracobrachialis). The greatest selectivity was observed at or near threshold current levels. In all four raccoons studied, a threshold electrode choice and stimulation strategy could be identified enabling selective production of either digit flexion, wrist flexion and/or digit and wrist flexion. It was possible to elicit a selective pronation response at threshold in three of the four animals. Selective elbow flexion at threshold could be produced in all four experiments. With stronger currents, additional movements were usually induced. The raccoon therefore appears to be a suitable, if challenging, animal model for further development of not only nerve cuff electrode approaches but perhaps other stimulation electrode technologies prior to human neuroprosthetic studies.

Characteristics of persons with spinal cord injury as documented by use of an interactive data system.

RATIONALE: Physicians need information about their rehabilitation practices that shows the types of patients being seen and the outcomes for their rehabilitation programs. In order to obtain more information on secondary medical complications and prevention programs, and to provide the information to the spinal cord injury (SCI) rehabilitation team, an interactive data management system was developed. RESULTS: Initial findings for the first 99 patients with SCI were presented for staff review. Demographic information indicated that patients typically lived in private residences, had at least a high school education, and had annual incomes < $20,000. There were nearly equal numbers of paraplegic and tetraplegic patients; 63% of patients were more than 50 years of age and 69% were more than 10 years post-injury. Over 80% of the patients reported satisfactory health, were physically active, and had adequate transportation. Paraplegic and tetraplegic patients had similar profiles for secondary complications. CONCLUSIONS: The SCI staff was surprised that greater than 35% of patients with SCI reported current problems with spasticity, pain, and pressure ulcers. The staff was interested in obtaining additional patient-perception information including the severity of each problem, how the problem interfered with daily activity, and the desire for additional care. The staff felt that patients were reporting problems more often to the interviewer than to their physician. There was unanimous support for the ongoing collection of patient-perception information.

Home monitoring of bladder pressure and volume in individuals with spinal cord injury and multiple sclerosis.

Individuals with spinal cord injury and multiple sclerosis are at high risk for developing kidney dysfunction due to high bladder pressures. We have developed a device for frequent monitoring of bladder pressures at home in those patients who use intermittent catheterization to empty their bladders. Of eight subjects enrolled in the study, only five conducted home recording of pressure. Vesical and abdominal pressures measured at home were significantly lower than clinical cystometric pressures. However, subtracted detrusor pressures obtained from home records and cystometric records were not significantly different. The home detrusor pressures were consistent over a large time and volume range. Therefore, the home monitoring method could be used to establish a normal range of bladder pressures at home and to rapidly identify high bladder pressures in advance of upper urinary tract deterioration.

Indications for a home standing program for individuals with spinal cord injury.

Additional analyses were conducted on a recently published survey of persons with spinal cord injury (SCI) who used standing mobility devices. Frequency and duration of standing were examined in relation to outcomes using chi square analyses. Respondents (n = 99) who stood 30 minutes or more per day had significantly improved quality of life, fewer bed sores, fewer bladder infections, improved bowel regularity, and improved ability to straighten their legs compared with those who stood less time. Compliance with regular home standing (at least once per week) was high (74%). The data also suggest that individuals with SCI could benefit from standing even if they were to begin several years after injury. The observation of patient benefits and high compliance rates suggest that mobile standing devices should be more strongly considered as a major intervention for relief from secondary medical complications and improvement in overall quality of life of individuals with SCI.

The raccoon as an animal model for upper limb neural prosthetics.

The raccoon was evaluated as an animal model for upper limb neural prosthetics. This animal was selected primarily because the functional use of its forelimb mimics in many ways the usage in humans and because of its optimal size and commercial availability. Eight cadaver and fresh specimen forearms were dissected. Important characteristics of the raccoon forearm were: 1) large muscles in the volar forearm, 2) large digits in the paw that appear more similar to humans than to other species such as cat or dog, 3) persistence of two median nerve cords into the forearm, 4) no separation of individual tendons of flexor digitorum superficialis and flexor digitorum profundus in the carpal tunnel, 5) a small thumb digit with little function and 6) a primary origin of flexor policis longus on the proximal ulna with a secondary origin on the radius. Four animals were anesthetized and responses of the forearm and paw to stimulation of the volar forearm muscles with percutaneous electrodes were evaluated. A pair of stimulating electrodes was placed in each of four muscles or muscle groups. Recording electrodes were placed in two muscles which showed the greatest separation of muscle movements to stimulation. Stimulation currents just above threshold produced discrete motion as well as recordable EMG M-waves. Incremental increases in stimulation current produced an increase in M-wave amplitude up to a maximal stimulating current. Torque recordings for pronation, wrist flexion and finger flexion showed graded and selective responses. These results including anatomical descriptions indicate both the limitations of this animal model and its potential use in the development of upper limb neural prosthetics. We conclude that the raccoon model may be superior to other nonprimate animal models such as the cat because of its extensive forearm and paw movements.

Optimization of sacral ventral root stimulation following SCI: two case reports with six-month follow-up.

Sacral ventral root stimulation in conjunction with sacral dorsal rhizotomy has been effective in promoting voiding in individuals with upper-motor-neuron spinal cord injury. We report on two patients who had variable voiding responses to stimulation during the first six months after electrode implantation. We used videourodynamic records and daily voiding records to characterize their voiding difficulties. Different methods were used to improve voiding, including seating adjustments and changes in stimulation parameters. The first patient was unable to empty his bladder on a regular basis with stimulation using 24 pulses per sec stimulating frequency for the first two months after implantation. Voiding was substantially improved by using 35 pulses per sec. At the end of six months, he is regularly emptying his bladder with stimulation and is on an every-second-day bowel program. However, his bowel program has been irregular. The second patient had very good voiding when stimulation was applied in bed, but he had poor voiding with high residual volumes when sitting in his wheelchair. Voiding was improved when he used a wheelchair cushion that was cut out in the back or lifted his buttocks off the chair. These procedures appeared to reduce perineal pressures. This patient has bowel care on alternate days and his bowel care time has been reduced following implantation of the device. Neither of the patients experienced an erection with the device. Both patients feel positive about their implant experience.

Short-term bladder-wall response to implantation of microstimulators.

This study examined the histological response of the bladder wall serosa to the implantation of wireless microstimulators secured with a single polypropylene suture. Two to three microstimulators were implanted in each of three casts for an eight week implantation period to allow sufficient time for a bladder-wall injury-response to develop. Gross observation revealed encapsulation of the microstimulators with no perforation to the bladder lumen or migration from the bladder wall. Histological evaluation confirmed that all the microstimutators were encapsulated with a thin connective tissue sheath and a thickened subserosal layer. There was no remarkable difference in tissue morphology compared with normal bladder wall sections for five of seven stimulators. Two microstimulators in one cat revealed a moderate to severe inflammatory response confined to a small area around the stimulator. In a second cat, a suture extended through the bladder wall. The microstimulators were observed with a scanning electron microscope after explantation. The electrode surfaces, bonding interface between silicon and glass and insulating films that were exposed to biological fluids were carefully inspected. All these observations indicate that the glass capsule reliably protected the sealed cavity of the microstimulators from moisture. These results indicate the microstimulator should be considered for further studies such as effects of stimulation and long-term implantation.

Follow-up assessment of standing mobility device users.

The use of standing devices by spinal cord-injured subjects was investigated through a national survey of a sample of individuals who returned their manufacturer's warranty card to two companies. We obtained a 32% response rate (99/310). The majority of respondents were male (87%) with a median age between 41 and 50 years. Seventy-seven percent were paraplegic and 21% were quadriplegic. Forty percent had between 1 and 5 years experience with their device, and 84% of those responding were currently using their standing device. Forty-one percent used their standing device one to six times a week; two-thirds stood between 30 minutes and 1 hour for each use. Less than 10% of subjects experienced any side effects, such as nausea or headaches, from standing. Twenty-one percent of subjects reported being able to empty their bladder more completely. There was also a favorable response by some individuals on the effects of the standing devices on bowel regularity, reduction of urinary tract infections, leg spasticity, and number of bed sores. Finally, 79% of subjects highly recommended use of standing devices to other people with spinal cord injury. The positive responses of individuals using standing devices is a strong recommendation for the assistive technology community to make these devices more available to individuals with spinal cord injury.