Clinical impact of 68Ga-PSMA-11 PET on patient management and outcome, including all patients referred for an increase in PSA level during the first year after its clinical introduction.

PURPOSE: The fast-increasing use of positron emission tomography (PET) with prostate-specific membrane antigen (PSMA) ligand for the imaging of prostate cancer (PCA) biochemical recurrence has led to a rapid change in treatment concepts. Since the superiority of 68Ga-PSMA-11 PET in detecting recurrent PCA is well established, the aim of our study was to assess its effect on management and outcome in all patients imaged during the first year after its introduction into clinical routine. METHODS: Of 327 patients imaged, 223 were referred for recurrent PCA and gave written informed consent for further analysis of their data for this retrospective consecutive cohort analysis. Twenty patients were lost to further follow-up. The rate of detection of recurrence by 68Ga-PSMA-11 PET was based on the clinical reports. Management before the availability of PET diagnostic information was assessed according to guidelines (therapy option without 68Ga-PSMA-11 PET). In the 203 patients with follow-up 6 months after 68Ga-PSMA-11 PET, the therapies effectively implemented as well as follow-up PSA levels were evaluated, with a PSA value of <0.2 ng/ml representing a complete response and a decrease in PSA value of at least 50% from baseline representing a partial response. RESULTS: 68Ga-PSMA-11 PET was positive and identified recurrence in 166 of the 223 patients (74%), with a detection rate of 50% for recurrent disease at low PSA values of <0.5 ng/ml. 68Ga-PSMA-11 PET led to a change in management in 122 of the 203 patients (60%). A substantial increase in the use of metastasis-targeted treatment and a reduction in the use of systemic treatment were observed, with 59 of the 203 patients (29%) undergoing targeted radiotherapy (RTXa) only, and 20 patients (10%) undergoing RTXa with hormonal therapy as the two most frequently selected therapy options. The proportion of patients in whom systemic therapy was selected decreased from 60% (133 of 223 patients) to 34% (70 of 203 patients) on the basis of the information provided by the 68Ga-PSMA-11 PET scan. PSMA PET-directed metastasis-targeted treatment led to a complete response after 6 months in 45% of patients. CONCLUSION: The high rate of recurrence detection by PSMA PET was confirmed and PSMA PET led to a change in management in 60% of patients. Focal therapy for PSMA-positive lesions is a promising approach with complete responses in 45% of patients.

Prevalence of medication overuse headache in an interdisciplinary pain clinic.

BACKGROUND: Medication overuse headache (MOH) has been recognized as an important problem in headache patients although the pathophysiological mechanisms remain unclear. The diagnosis of MOH is based on clinical characteristics defined by the International Headache Society. The aim was the evaluation of the diagnostic criteria of MOH in a mixed population of chronic pain patients to gain information about the prevalence and possible associations with MOH. METHODS: Data of all patients referred to the interdisciplinary pain clinic at the University Hospital of Zurich between September 2005 and December 2007 were retrospectively analyzed. Demographic data (age, sex, history of migration), as well as data about duration of pain disease, category of pain disease (neurological, psychiatric, rheumatologic, other), use of medication, history of trauma, and comorbidity of depression and anxiety have been collected. RESULTS: Totally 178 of 187 consecutive chronic pain patients were included in the study. A total of 138 patients (78%) used analgesics on 15 or more days per month. Chronic headache was more prevalent among patients with analgesic overuse (39.8%) than without analgesic overuse (18%). The prevalence of MOH was 29%. The odds ratio (OR) for a patient with medication overuse to have chronic headache was 13.1 if he had a history of primary headache, compared to a patient without a primary headache syndrome. Furthermore, history of headache (OR 2.5, CI [1.13;5.44]), history of migration (OR 2.9, CI [1.31;6.32]) and comorbid depression (OR 3.5, CI [1.46;8.52]) were associated with overuse of acute medication, in general. CONCLUSIONS: Primary headaches have a high risk for chronification in patients overusing analgesics for other pain disorders. Whereas history of headache, history of migration and comorbidity of depression are independentely associated with analgesic overuse in this group of patients.

Intrafascial dissection significantly increases positive surgical margin and biochemical recurrence rates after robotic-assisted radical prostatectomy.

INTRODUCTION: Improved visualization and magnification in robot-assisted laparoscopic radical prostatectomy (RALRP) has tempted many urologists to dissect the neurovascular bundle closer to the prostate following the layers of the pseudo-capsule of the prostate. This might bear a higher risk of decreased tumor control. MATERIALS AND METHODS: An analysis of a consecutive series of 186 patients who underwent RALRP at our institution was performed. The outcome of patients with intrafascial nerve-sparing (INS) was compared with the outcome of patients who underwent interfascial, extrafascial or no nerve-sparing (non-INS). RESULTS: A total of 80 patients (43.0%) received INS. The overall R1 rate was 27.9%. For pT2 tumors the rate of R1 was 33.8% in INS versus 14.8% in non-INS (odds ratio 2.936, 95% confidence interval 1.338-6.443, p = 0.007). Recurrence-free survival was significantly shorter in INS (p = 0.05; hazard ratio 3.791). CONCLUSION: The intrafascial dissection technique for RALRP bears a high risk of incomplete resection in localized prostate cancer resulting in unfavorable outcome.

Long-Term Oncological Efficacy of Retroperitoneoscopic Radical Nephrectomy of Localized Renal Cell Cancer pT1-3 (≤12 cm).

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Renal tubular PD-L1 (CD274) suppresses alloreactive human T-cell responses.

Renal proximal tubular epithelial cells, a target of infiltrating T cells during renal allograft rejection, may be protected from this injury by the cell surface protein CD274 (also termed PD-L1 for programmed death ligand 1). The co-inhibitory molecules PD-L1 (CD274) and PD-L2 (CD273) are ligands of PD-1 (programmed death 1; CD279). Here we determine the functional role of PD-1/PD-L pathways in human renal allograft rejection. Treatment of human primary tubular epithelial cells with interferon-beta and -gamma caused a dose-dependent and synergistic increase of PD-L1 and PD-L2 expression. Blockade of surface PD-L1, but not PD-L2, on interferon-treated tubular epithelial cells resulted in a significant increase in CD4+ T-cell proliferation and cytokine production by CD4+ and CD8+ T cells. The expression of PD-L1, PD-L2, and PD-1 mRNA and protein was upregulated in biopsies of patients with renal allograft rejection compared to the respective levels found in the pre-transplant biopsies. Induction of PD-L1 was significantly associated with acute vascular rejection. Our study suggests that the renal epithelial PD-1/PD-L1 pathway exerts an inhibitory effect of on alloreactive T-cell responses. The upregulation of PD-L1 on proximal tubular epithelial cells in patients with acute allograft rejection may reduce T-cell-mediated injury.

Lowering the PSA threshold for prostate biopsy from 4 to 2.5 ng/ml: influence on cancer characteristics and number of men needed to biopt.

OBJECTIVE: In 1999 we lowered the prostate-specific antigen (PSA) threshold for prostate biopsy at our institution from 4 to 2.5 ng/ml. The aim of this study was to compare the differences in tumor characteristics of the detected prostate cancers (PCAs) and the detection rate for the two different PSA thresholds and to evaluate if lowering the threshold was justified by any of the detected differences. PATIENTS AND METHODS: We retrospectively analyzed the records of all patients who underwent an 8-core prostate biopsy between January 1999 and December 2004 and had a PSA between 2.5 and 10 ng/ml. Patients with a PSA between 2.5 and 4 ng/ml (group 1, n = 214, mean age 62.0 years) were compared to patients whose PSA was between 4 and 10 ng/ml (group 2, n = 292, mean age 63.2 years). Patients who were older than 75 years or had a suspicious rectal examination were excluded from this study. RESULTS: Overall, we detected 120 can-cers in 506 patients (cancer yield 23.7%). The cancer yield in group 1 was significantly lower than in group 2 (17 vs. 28%, p < 0.01). In group 1 significantly less Gleason score >or=7 (p = 0.04) and significantly more potentially insignificant cancers (p = 0.03) were identified. In 80 patients who subsequently underwent radical prostatectomy, final pathology revealed no significant differences between the two PSA groups with regard to high pT stages, Gleason score >or=7 PCA or positive surgical margins, respectively. The difference in the absolute risk of being diagnosed with high-grade PCA between a PSA threshold of 2.5 ng/ml and a PSA threshold of 4 ng/ml was 1%. CONCLUSION: Lowering the PSA threshold for prostate biopsy from 4 to 2.5 ng/ml results in a substantial increase in the number of men who undergo biopsy and may result in an increased detection of potentially insignificant cancers. If total PSA alone is used to determine the need for prostate biopsy, the disadvantages of this lower threshold probably outweigh its potential benefits.

Association of cytokeratin 7 and 19 expression with genomic stability and favorable prognosis in clear cell renal cell cancer.

The purpose of our study was to demonstrate that distinct cytogenetic alterations in the most common subtype of renal cell cancer, clear cell renal cell carcinoma (ccRCC), are reflected in protein expression profiles. We performed conventional cytogenetics and immunohistochemical analysis for cytokeratins (CKs) on 126 ccRCCs. Protein expression was evaluated in situ using a semiautomated quantitative system. The results were validated using an independent cohort of 209 ccRCCs with long-term follow-up. Cytogenetic alterations were identified in 96 of 126 ccRCCs, most of them involving chromosome 3 through loss, deletion or translocation. Expression of CKs and E-cadherin in ccRCC was associated with lack of cytogenetic alterations and low nuclear grade. In the validation set, CK7 and CK19 protein expression was associated with better clinical outcome. At the multivariate level, the best model included metastatic status and CK19 expression. Expression microarray analysis on 21 primary ccRCCs and 14 ccRCC metastases identified genes significantly associated with CK7 and CK19 expressing ccRCCs. Two novel ccRCC biomarkers associated with the CK7 positive ccRCC phenotype, PMS2 and MT1-MMP (MMP14), were further validated. We conclude that the variability observed for CK expression in ccRCC can be explained by genetic heterogeneity. Distinct molecular subtypes of ccRCC with prognostic relevance were identified, and the CK7/CK19 expressing subtype is associated with better outcome.

Patients' knowledge about risk factors for erectile dysfunction is poor.

INTRODUCTION: Well informed and educated patients ideally manage to prevent or delay the onset of severe chronic diseases. With respect to erectile dysfunction (ED) this is of importance because ED is considered to herald debilitating cardiovascular diseases like coronary artery disease. AIM: This survey aimed to assess patient's knowledge about risk factors (RF) for ED and to identify their preferred source of information. MAIN OUTCOME MEASURES: Knowledge of RF for ED and sources used to gather information about ED as reported by patients with ED. METHODS: Between July 2004 and June 2006, 126 patients who presented at our outpatient clinic for an assessment of their ED were prospectively evaluated. The patients received a questionnaire about their demographic and socioeconomic circumstances, their strategies to gather information about ED, and their knowledge of specific RF for this disease. The questionnaire was completed by 81 patients (64%). RESULTS: Forty-one patients (51%) could not name one single RF for ED. Three men knew more than three RF. The two most popular sources of information were the Internet and general practitioners. Well-educated patients were significantly better informed than others. Patients using the Internet as source for health information were significantly younger and had a better knowledge about RF for ED compared to those not using the Internet. CONCLUSIONS: Patients' knowledge about RF for ED is poor. The Internet seems to be the most useful information source for patients with ED and is predominantly used by younger and better educated patients. Given that ED is considered to be a precursor of severe cardiovascular diseases, patient information and education deserves more attention.

Sympathetic sudomotor skin activity in human after complete spinal cord injury.

Spinal cord injury (SCI) causes serious disturbances in autonomic innervation and malfunction of the sympathetic nervous system that controls the pelvic organs, blood pressure, skin temperature and sweating. We studied sympathetic sudomotor pathways in 6 healthy subjects and 14 patients with sensory and motor complete SCI on cervical, thoracic and lumbar level. Sympathetic skin responses (SSRs) were provoked by auditory bursts and electrical stimulation of median, pudendal and tibial nerve and recorded from the palmar and plantar skin. The SSRs in healthy subjects occurred generally with the same pattern and with similar latencies suggesting a common sudomotor pathway mediating the SSR. Appearance or absence of the SSRs in SCI following stimulation above the lesion depend on the spinal level of lesion and on the location of stimulation. Lesions below T3 show palmar and lesions below T12 palmar and plantar SSR. Pudendal nerve stimulation evoked plantar SSRs in patients with complete cervical and thoracic SCI. No SSRs were obtained in patients with lesions at L1 and more caudal. SSRs following pudendal nerve stimulation in complete SCI above the level L1 are mediated by sacral somatic afferents and a sympathetic pathway originating at the upper lumbar level. The underlying sacro-lumbar reflex circuit is organized on spinal level and requires intact lumbar segments. Tibial nerve stimulation was not found to elicit SSRs below a SCI lesion and we suppose that this type of electrical stimulation cannot activate the spinal sudomotor reflex circuit.

Continuous low-dose aspirin therapy in robotic-assisted laparoscopic radical prostatectomy does not increase risk of surgical hemorrhage.

BACKGROUND: Withdrawal of oral antiplatelet therapy (OAT) is a major risk factor for stent thrombosis, myocardial infarction, and cerebral strokes. In order to minimize the risk for thrombotic complications, since 2007 robotic-assisted laparoscopic radical prostatectomy (RARP) has taken place under continuous OAT with aspirin at our institution. In this retrospective study we analyzed the risk for perioperative bleeding and surgical outcome after RARP with OAT. PATIENTS AND METHODS: All patients who underwent RARP with aspirin OAT at our institution since 2007 were included in this analysis. The OAT group was compared with a group that underwent RARP without OAT, which contained twice the number of patients. Matching of the two groups was performed with regard to the tumor stage and whether a lymph node dissection or nerve-sparing was performed. RESULTS: Thirty-eight patients were assigned to the OAT group and 76 to the control group. A difference in the decrease of postoperative hemoglobin concentration was not detectable between the two groups (mean drop of 2.9±1.4 g/dL and 2.9±1.1 g/dL, respectively; P=.93). RARP was completed in all OAT patients without conversion to open surgery. Two of the 38 patients (5.3%) in the OAT group and none in the control group required blood transfusions (P=.11). Equivalent rates of positive surgical margins for pT2 tumors were detected (16% OAT versus 14% control group; P=1.0). No adverse cardiovascular events occurred in either group during the hospitalization. CONCLUSIONS: Continued perioperative OAT with aspirin in RARP is safe, feasible, and not associated with increased blood loss.

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.

Motor evoked potentials (MEP) and evoked pressure curves (EPC) from the urethral compressive musculature (UCM) by functional magnetic stimulation in healthy volunteers and patients with neurogenic incontinence.

AIMS: The aim of this study is to assess neurogenic lesions of the somatomotor efferent nervous pathway to the urethral compressive musculature (UCM) by means of motor evoked potentials (MEP) and simultaneously recorded evoked pressure curves (EPC). METHODS: Nine healthy subjects and 33 patients (15 spinal cord injury, 14 cauda equina lesion, and 4 multiple sclerosis (MS)) with neurogenic urinary incontinence were prospectively examined by means of urodynamics and electrophysiology. MEP responses from the UCM were evoked after transcranial (tc) and lumbosacral (ls) single pulse magnetic stimulation. A ratio out of tx/ls latencies was calculated to distinguish between central (i.e., spinal) and peripheral lesions. The mechanical UCM pressure responses (=EPC) were recorded simultaneously with electromyographic (EMG) recordings using a microtip pressure transducer catheter with integrated bipolar surface electrodes. RESULTS: In nine healthy subjects the central latency was 19.0 msec, the peripheral latency was 4.25 msec, and the ratio was 4.4. In patients with incomplete spinal cord lesion the central latency was significantly delayed (22.7 msec), whereas the peripheral responses were normal. The ratio (5.5) was increased. Thirteen of these 15 patients suffered from neurogenic incontinence. Patients with a complete spinal lesion showed no UCM reaction after tc stimulation, whereas peripheral responses were normal. Patients with MS showed significantly prolonged central latencies (25.5 msec). The increased ratio of 6.0 indicated a spinal lesion. Ten patients with incomplete cauda equina lesions and urinary incontinence had normal central latencies but prolonged peripheral latencies of 6.7 msec. The ratio of 3.4 indicated a lesion of the sacral caudal roots. In patients with complete cauda injury neither central nor peripheral responses could be evoked. Tc evoked mechanical pressure responses (i.e., contractions) from the UCM could only be recorded in intact or incompletely injured spinal and peripheral motor nervous pathways, whereas they could be evoked after ls stimulation only in cases with partially preserved sacral caudal roots independent of a spinal lesion. CONCLUSIONS: MEP and EPC from the UCM proved to be a well tolerated disgnostic tool in patients with neurogenic incontinence that distinguished central and peripheral lesions of the motor efferent pathways to the UCM.

Can neurologic examination predict type of detrusor sphincter-dyssynergia in patients with spinal cord injury?

OBJECTIVES: To assess the correlations in males with spinal cord injury (SCI) between the neurologic status and type of detrusor-sphincter dyssynergia (DSD) observed during urodynamic examinations and to evaluate the change in the DSD pattern over time. METHODS: A total of 105 male patients with chronic SCI were neurologically examined according to the American Spinal Cord Injury Association protocol and underwent video-urodynamic examinations. DSD observed during urodynamic studies was classified according to the Blaivas classification. To assess the stability of the DSD over time, patients who had been recently injured were clinically and urodynamically controlled after 1 year and thereafter. RESULTS: A statistically significant positive correlation was found between the DSD type and completeness or incompleteness of the SCI lesion. Patients with an incomplete sensory and motor SCI lesion presented with DSD type 1 compared with patients with complete sensory and motor SCI lesion, who had DSD type 2 to type 3. A correlation was also found between the American Spinal Cord Injury Association scores and the DSD type. No correlation was found between the DSD type and lesion level. At medium to long-term follow-up, a significant change was found in the DSD type. CONCLUSIONS: The neurologic status and DSD type after SCI showed significant correlations. Therefore, neurologic examination and determination of the DSD type might be helpful to complete the neurourologic diagnosis and to assist in confirming completeness of the lesion after acute injury. Because DSD seems to become aggravated with time, regular urodynamic follow-up examinations are mandatory in patients with DSD to adjust their treatment, if necessary.

Sacral magnetic stimulation in non-inflammatory chronic pelvic pain syndrome.

OBJECTIVES: To prospectively evaluate sacral magnetic high-frequency stimulation as a treatment option for patients with non-inflammatory chronic pelvic pain syndrome (CPPS, category IIIB). PATIENTS AND METHODS: Fourteen men with CPPS IIIB were treated with high-frequency sacral magnetic stimulation, with 10 treatment sessions once a week for 30 min at a frequency of 50 Hz. The National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI) and quality-of-life index were determined before and after treatment. RESULTS: All patients tolerated the stimulation well and 12 of 14 reported agreeable sensations during stimulation. There were no complications; only one patient did not complete the treatment course. The mean (range) total NIH-CPSI score did not change with treatment, at 27 (18-38) before and 27 (4-40) after treatment. Moreover, there was no sustained effect on the mean scores for pain, micturition complaints or quality of life. CONCLUSIONS: High-frequency sacral magnetic stimulation in patients with CPPS IIIB only reduces pain during stimulation, with no sustained relief of symptoms. Therefore, intermittent sacral magnetic stimulation cannot be recommended as a treatment option for CPPS IIIB.

Value of sensory examination in predicting bladder function in patients with T12-L1 fractures and spinal cord injury.

OBJECTIVE: To determine whether early sensory examination, voluntary anal sphincter contraction, or bulbocavernosus reflex (BCR) might predict bladder function in patients with a spinal fracture at the thoracolumbar level. DESIGN: Longitudinal study of consecutive patients admitted to a spinal cord injury (SCI) rehabilitation center. SETTING: Primary care center, university facility in Switzerland. PARTICIPANTS: Fifty-five patients with thoracolumbar fractures. INTERVENTIONS: Neurologic (American Spinal Injury Association [ASIA] protocol) and urodynamic examination during the first hospitalization and at follow-up. MAIN OUTCOME MEASURES: Neurologic sensory scores and type of neurogenic bladder. RESULTS: At first examination, there was no correlation between the sensory examination, voluntary anal sphincter contraction, BCR, and neurogenic bladder type. At follow-up (time since first examination: mean, 698+/-47.2d; median, 481d), the sensory examination remained of no value in distinguishing the neurogenic bladder type. However, voluntary anal sphincter contraction distinguished between complete and incomplete neurogenic bladders and BCR differentiated between complete bladder dysfunction of the lower motoneuron and upper motoneuron type. At follow-up, the bladder function (51 patients) remained unchanged in 44 cases and normalized in only 7 cases. Patients who improved their bladder function tended to have higher initial sensory ASIA scores (P<.05, Kruskal-Wallis test). Of the 7 patients who improved their bladder function, all but 1 (85%) had initial perineal pinprick sensation. Nevertheless, preservation of perineal pinprick sensation was of no positive predictive value, because 21 patients (48%) who initially had perineal pinprick sensation did not improve their voiding function, a finding similar to that of the 23 (52%) without initial perineal pinprick sensation whose bladder function also did not improve. CONCLUSIONS: In SCI patients with thoracolumbar fractures, neurogenic voiding dysfunction cannot be predicted by the sensory evaluation. In patients with an SCI at the thoracolumbar level, pinprick sensation in the perineal area is of negative predictive value: absence of pinprick sensation predicts poor bladder recovery. Most patients with a spinal fracture at T12-L1 did not improve in voiding function.

Afferent fibers of the pudendal nerve modulate sympathetic neurons controlling the bladder neck.

AIMS: Pudendal nerve stimulation is known to have a potential modulative effect on bladder function. However, even if its efficiency has been established for various neurogenic and non-neurogenic bladder dysfunctions, the underlying neuronal mechanism, and the involved pathways in humans remain unknown. In this prospective study we focused on the effects of pudendal nerve stimulation in complete spinal cord injured patients to identify neuromodulative processes that occur on spinal level. METHODS: Twenty complete spinal male presenting with upper motor neuron lesion and neurogenic incontinence underwent pudendal nerve stimulation. Bladder, bladder neck (BN), and external urethral sphincter (EUS) pressures were continuously recorded with a three channel microtip pressure transducer catheter. Fifty six pudendal stimulations using biphasic rectangular impulses (0.2 ms, 10 Hz) with intensities up to 100 mA were applied to the dorsal penile nerve. In six patients, 18 stimulations were repeated after intravenous (i.v.) administration of 7 mg phentolamine. RESULTS: Mean BN and EUS pressure increased during stimulation significantly (P < 0.001). The latencies to the EUS responses range between 27 and 41 ms and those to the BN responses between 188 and 412 ms. Phentolamine decreased initial BN pressure and reduced the pressure rise during stimulation significantly (P < 0.05). CONCLUSIONS: Pudendal nerve stimulation evoked somatic responses in the EUS and autonomic responses in the smooth muscle sphincter controlling the BN. Longer latencies of the BN responses and the sensitivity to the alpha-blocking agent phentolamine suggest that sympathetic alpha-adrenergic fibers are involved. Somatic afferent fibers of the pudendal nerve are supposed to project on sympathetic thoracolumbar neurons to the BN and modulate their function. This neuromodulative effect works exclusively at the spinal level and appears to be at least partly responsible for BN competence and at least continence.