Sacral neuromodulation for neurogenic lower urinary tract dysfunction: systematic review and meta-analysis

Context Treatment of neurogenic lower urinary tract dysfunction (LUTD) is a challenge, because conventional therapies often fail. Sacral neuromodulation (SNM) has become a well-established therapy for refractory non-neurogenic LUTD, but its value in patients with a neurologic cause is unclear. Objective To assess the efficacy and safety of SNM for neurogenic LUTD. Evidence acquisition Studies were identified by electronic search of PubMed, EMBASE, and ScienceDirect (on 15 April 2010) and hand search of reference lists and review articles. SNM articles were included if they reported on efficacy and/or safety of tested and/or permanently implanted patients suffering from neurogenic LUTD. Two reviewers independently selected studies and extracted data. Study estimates were pooled using Bayesian random-effects meta-analysis. Evidence synthesis Of the 26 independent studies (357 patients) included, the evidence level ranged from 2b to 4 according to the Oxford Centre for Evidence-Based Medicine. Half (n = 13) of the included studies reported data on both test phase and permanent SNM; the remaining studies were confined to test phase (n = 4) or permanent SNM (n = 9). The pooled success rate was 68% for the test phase (95% credibility interval [CrI], 50–87) and 92% (95% CrI, 81–98%) for permanent SNM, with a mean follow-up of 26 mo. The pooled adverse event rate was 0% (95% CrI, 0–2%) for the test phase and 24% (95% CrI, 6–48%) for permanent SNM. Conclusions There is evidence indicating that SNM may be effective and safe for the treatment of patients with neurogenic LUTD. However, the number of investigated patients is low with high between-study heterogeneity, and there is a lack of randomised, controlled trials. Thus, well-designed, adequately powered studies are urgently needed before more widespread use of SNM for neurogenic LUTD can be recommended.

Sacral Neuromodulation for Refractory Lower Urinary Tract Dysfunction: Results of a Nationwide Registry in Switzerland

OBJECTIVE: To assess the efficacy and safety of sacral neuromodulation (SNM) in patients with refractory lower urinary tract dysfunction in Switzerland based on a nationwide registry. PATIENTS AND METHODS: A total of 209 patients (181 females, 28 males) underwent SNM testing between July 2000 and December 2005 in Switzerland. Subjective symptom improvement, bladder/pain diary variables, adverse events, and their management were prospectively registered. RESULTS: SNM testing was successful (defined as improvement of more than 50% in bladder/pain diary variables) in 102 of 209 patients (49%). An implantable pulse generator (IPG) was placed in 91 patients (89% of all successfully tested and 44% of all tested patients). Of the IPG-implanted patients, 71 had urge incontinence, 13 nonobstructive chronic urinary retention, and 7 chronic pelvic pain syndrome. After a median follow-up of 24 mo, SNM was successful in 64 of the 91 IPG-implanted patients (70%) but failed in 27 patients. SNM was continued in 15 of the 27 patients considered failures, because following troubleshooting SNM response improved subjectively and the patients were satisfied. However, improvement in bladder/pain diary variables remained less than 50%. In the other 12 patients both the leads and the IPG were explanted. During the test phase and during/following IPG implantation, 6% (12 of 209) and 11% (10 of 91) adverse event rates and 1% (3 of 209) and 7% (6 of 91) surgical revision rates were reported, respectively. CONCLUSIONS: SNM is an effective and safe treatment for refractory lower urinary tract dysfunction. Adverse events are usually transient and can be treated effectively.

Microbiological tined-lead examination: does prolonged sacral neuromodulation testing induce infection?

OBJECTIVE: To investigate whether prolonged sacral neuromodulation (SNM) testing induces a substantial risk of infection because of the percutaneous passage of the extension wire. PATIENTS AND METHODS: A consecutive series of 20 patients with negative prolonged SNM testing for >or=14 days who underwent tined-lead explantation were prospectively evaluated. The explanted tined leads were sent for microbiological examination. The tined lead, gluteal, and extension wire incision sites were investigated for clinical signs of infection according to the Centers for Disease Control and Prevention classification system. RESULTS: In all, 17 patients had bilateral and three unilateral implanted tined leads. The median (range) test period was 30 (21-62 days). Bacterial growth (Staphylococcus species) was detected in four of 20 (20%) patients on seven of 37 (19%) explanted tined leads. There were clinical signs of infection in one of 20 (5%) patients at none of 37 tined lead, one of 20 (5%) gluteal, and none of 20 extension wire incision sites. There were no clinical signs of infection in the remaining three of four patients with bacterial growth. CONCLUSIONS: After prolonged tined-lead testing, we found an infection rate comparable to that reported with the usual short test period. In addition, most patients with bacterial growth on tined leads showed no clinical signs of infection. Thus, prolonged tined-lead testing does not seem to induce clinically relevant infection, warranting randomized trials.

Safety of prolonged sacral neuromodulation tined lead testing

OBJECTIVE: Prolonged sacral neuromodulation (SNM) testing is more reliable for accurate patient selection than the usual test period of 4-7 days. However, prolonged testing was suspected to result in a higher complication rate due to infection via the percutaneous passage of the extension wire. Therefore, we prospectively assessed the complications associated with prolonged tined lead testing. PATIENTS AND METHODS: A consecutive series of 44 patients who underwent prolonged tined lead testing for at least 14 days between May 2002 and April 2007 were evaluated. Complications during prolonged tined lead testing, during and after tined lead explantation and during follow-up after implantation of the implantable pulse generator (IPG) were registered prospectively. RESULTS: Four patients suffered from urgency-frequency syndrome, 13 from urge incontinence, 18 from non-obstructive chronic urinary retention and nine from chronic pelvic pain syndrome. The median test phase was 30 days (interquartile range [IQR] 21-36). Thirty-two of the 44 patients (73%) had successful prolonged tined lead testing and 31 of these (97%) underwent the implantation of the IPG. The median follow-up of the IPG implanted patients was 31 months (IQR 20-41). The complication rate was 5% (2/44) during prolonged tined lead testing and 16% (5/31) during follow-up of the IPG implanted patients, respectively. None of the complications could be attributed to prolonged testing. No infections were observed during the study period. CONCLUSIONS: This prospective, observational non-randomised study suggests prolonged SNM tined lead testing is a safe procedure. Based on the low complication rate and the increased reliability for accurate patient selection, this method is proposed as a possible standard test procedure, subject to confirmation by further randomised, controlled clinical studies.

Protocol for a randomized, placebo-controlled, double-blind clinical trial investigating sacral neuromodulation for neurogenic lower urinary tract dysfunction

BACKGROUND Sacral neuromodulation has become a well-established and widely accepted treatment for refractory non-neurogenic lower urinary tract dysfunction, but its value in patients with a neurological cause is unclear. Although there is evidence indicating that sacral neuromodulation may be effective and safe for treating neurogenic lower urinary tract dysfunction, the number of investigated patients is low and there is a lack of randomized controlled trials. METHODS AND DESIGN This study is a prospective, randomized, placebo-controlled, double-blind multicenter trial including 4 sacral neuromodulation referral centers in Switzerland. Patients with refractory neurogenic lower urinary tract dysfunction are enrolled. After minimally invasive bilateral tined lead placement into the sacral foramina S3 and/or S4, patients undergo prolonged sacral neuromodulation testing for 3-6 weeks. In case of successful (defined as improvement of at least 50% in key bladder diary variables (i.e. number of voids and/or number of leakages, post void residual) compared to baseline values) prolonged sacral neuromodulation testing, the neuromodulator is implanted in the upper buttock. After a 2 months post-implantation phase when the neuromodulator is turned ON to optimize the effectiveness of neuromodulation using sub-sensory threshold stimulation, the patients are randomized in a 1:1 allocation in sacral neuromodulation ON or OFF. At the end of the 2 months double-blind sacral neuromodulation phase, the patients have a neuro-urological re-evaluation, unblinding takes place, and the neuromodulator is turned ON in all patients. The primary outcome measure is success of sacral neuromodulation, secondary outcome measures are adverse events, urodynamic parameters, questionnaires, and costs of sacral neuromodulation. DISCUSSION It is of utmost importance to know whether the minimally invasive and completely reversible sacral neuromodulation would be a valuable treatment option for patients with refractory neurogenic lower urinary tract dysfunction. If this type of treatment is effective in the neurological population, it would revolutionize the management of neurogenic lower urinary tract dysfunction. TRIAL REGISTRATION TRIAL REGISTRATION NUMBER http://www.clinicaltrials.gov; Identifier: NCT02165774.

Dysfunction of Cortical Dendritic Integration in Neuropathic Pain Reversed by Serotoninergic Neuromodulation

Neuropathic pain is caused by long-term modifications of neuronal function in the peripheral nervous system, the spinal cord, and supraspinal areas. Although functional changes in the forebrain are thought to contribute to the development of persistent pain, their significance and precise subcellular nature remain unexplored. Using somatic and dendritic whole-cell patch-clamp recordings from neurons in the anterior cingulate cortex, we discovered that sciatic nerve injury caused an activity-dependent dysfunction of hyperpolarization-activated cyclic nucleotide-regulated (HCN) channels in the dendrites of layer 5 pyramidal neurons resulting in enhanced integration of excitatory postsynaptic inputs and increased neuronal firing. Specific activation of the serotonin receptor type 7 (5-HT7R) alleviated the lesion-induced pathology by increasing HCN channel function, restoring normal dendritic integration, and reducing mechanical pain hypersensitivity in nerve-injured animals in vivo. Thus, serotoninergic neuromodulation at the forebrain level can reverse the dendritic dysfunction induced by neuropathic pain and may represent a potential therapeutical target.

Expression of adenosine A2a receptor gene in rat dorsal root and autonomic ganglia

The adenosine A2a receptors (A2aR) play an important role in the purinergic mediated neuromodulation. The presence of A2aR in the brain is well established. In contrast, little is known about their expression in the periphery. The purpose of this study was to investigate the expression of A2aR gene in the autonomic (otic, sphenopalatine, ciliary, cervical superior ganglia and carotid body) and in the dorsal root ganglia of normal rat. Hybridization histochemistry with S35-labelled radioactive oligonucleotide probes was used. An expression of A2aR gene was found in the large neuronal cells of the rat dorsal root ganglia. The satellite cells showed no expression of A2aR gene. In the superior cervical ganglion, isolated ganglion cells expressed A2aR. In the carotid body clusters of cells with a strong A2aR gene expression were found. In contrast, the ciliary and otic ganglia did not expressed A2aR gene, and only few small sized A2aR expressing cells were demonstrated in the sphenopalatine ganglion. The discrete distribution of A2aR gene expression in the peripheral nervous system speaks for a role of this receptor in the purinergic modulation of sensory information as well as in the sympathetic nervous system.

Electrode location and clinical outcome in hippocampal electrical stimulation for mesial temporal lobe epilepsy

PURPOSE To study the clinical outcome in hippocampal deep brain stimulation (DBS) for the treatment of patients with refractory mesial temporal lobe epilepsy (MTLE) according to the electrode location. METHODS Eight MTLE patients implanted in the hippocampus and stimulated with high-frequency DBS were included in this study. Five underwent invasive recordings with depth electrodes to localize ictal onset zone prior to chronic DBS. Position of the active contacts of the electrode was calculated on postoperative imaging. The distances to the ictal onset zone were measured as well as atlas-based hippocampus structures impacted by stimulation were identified. Both were correlated with seizure frequency reduction. RESULTS The distances between active electrode location and estimated ictal onset zone were 11±4.3 or 9.1±2.3mm for patients with a >50% or <50% reduction in seizure frequency. In patients (N=6) showing a >50% seizure frequency reduction, 100% had the active contacts located <3mm from the subiculum (p<0.05). The 2 non-responders patients were stimulated on contacts located >3mm to the subiculum. CONCLUSION Decrease of epileptogenic activity induced by hippocampal DBS in refractory MTLE: (1) seems not directly associated with the vicinity of active electrode to the ictal focus determined by invasive recordings; (2) might be obtained through the neuromodulation of the subiculum.

Self-control in social decision making: A neurobiological perspective

Self-control is defined as the process in which thoughts, emotions, or prepotent responses are inhibited to efficiently enact a more focal goal. Self-control not only allows for more adaptive individual decision making but also promotes adaptive social decision making. In this chapter, we examine a burgeoning area of interdisciplinary research: the neuroscience of self-control in social decision making. We examine research on self-control in complex social contexts examined from a social neuroscience perspective. We review correlational evidence from neuroimaging studies and causal evidence from neuromodulation studies (i.e., brain stimulation). We specifically highlight research that shows that self-control involves the lateral prefrontal cortex (PFC) across a number of social domains and behaviors. Research has also begun to directly integrate nonsocial with social forms of self-control, showing that the basic neurobiological processes involved in stopping a motor response appear to be involved in social contexts that require self-control. Further, neural traits, such as baseline activation in the lateral PFC, can explain sources of individual differences in self-control capacity. We explore whether techniques that change brain functioning could target neural mechanisms related to self-control capacity to potentially enhance self-control in social behavior. Finally, we discuss several research questions ripe for examination. We broadly suggest that future research can now turn to exploring how neural traits and situational affordances interact to impact self-control in social decision making in order to continue to elucidate the processes that allow people to maintain and realize stable goals in a dynamic and often uncertain social environment.

Diminishing risk-taking behavior by modulating activity in the prefrontal cortex: a direct current stimulation study.

Studies have shown increased risk taking in healthy individuals after low-frequency repetitive transcranial magnetic stimulation, known to transiently suppress cortical excitability, over the right dorsolateral prefrontal cortex (DLPFC). It appears, therefore, plausible that differential modulation of DLPFC activity, increasing the right while decreasing the left, might lead to decreased risk taking, which could hold clinical relevance as excessively risky decision making is observed in clinical populations leading to deleterious consequences. The goal of the present study was to investigate whether risk-taking behaviors could be decreased using concurrent anodal transcranial direct current stimulation (tDCS) of the right DLPFC, which allows upregulation of brain activity, with cathodal tDCS of the left DLPCF, which downregulates activity. Thirty-six healthy volunteers performed the risk task while they received either anodal over the right with cathodal over the left DLPFC, anodal over the left with cathodal over the right DLPFC, or sham stimulation. We hypothesized that right anodal/left cathodal would decrease risk-taking behavior compared with left anodal/right cathodal or sham stimulation. As predicted, during right anodal/left cathodal stimulation over the DLPFC, participants chose more often the safe prospect compared with the other groups. Moreover, these participants appeared to be insensitive to the reward associated with the prospects. These findings support the notion that the interhemispheric balance of activity across the DLPFCs is critical in decision-making behaviors. Most importantly, the observed suppression of risky behaviors suggests that populations with boundless risk-taking behaviors leading to negative real-life consequences, such as individuals with addiction, might benefit from such neuromodulation-based approaches.