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Purpose This multicenter, randomized, double-blind, placebo-controlled phase 2 study evaluated the efficacy and safety of TAC-302, a novel drug that restores neurite outgrowth, in patients with detrusor underactivity (DU) and overactive bladder (OAB). Methods After 2–4 weeks of observation, patients were randomized 2:1 to receive oral TAC-302 200 mg or placebo twice daily for 12 weeks. The primary endpoint was detrusor contraction strength, estimated by bladder contractility index (BCI) for males and projected isovolumetric pressure 1 (PIP1) for females. Secondary endpoints included changes in bladder voiding efficiency (BVE) and safety. Results Seventy-six patients were included (TAC-302, n = 52; placebo, n = 24). The mean (standard deviation [SD]) BCI for males was 64.6 (16.6) at baseline and 75.2 (21.1) at week 12 (p n = 27), and 61.3 (16.6) and 60.5 (16.7) (p = 0.82) with placebo (n = 11). The respective mean (SD) PIP1 for females was 18.8 (6.6) and 29.4 (9.4) (p n = 15), and 20.6 (7.5) and 25.5 (9.6) (p = 0.14) with placebo (n = 7). TAC-302 significantly increased BCI in males and BVE in both sexes. TAC-302 efficacy on OAB was not clearly shown. The incidences of adverse events (AEs), serious AEs, and AEs leading to dose interruption were similar between groups; no adverse drug reactions occurred. Conclusion Considering the significant effects on BCI in males and BVE in both sexes, TAC-302 may benefit patients with DU. Registration ClinicalTrials.gov Identifier NCT03175029 registered 6/5/2017.

Parkinson’s disease (PD) and multiple system atrophy (MSA) are major neurogenerative diseases characterized pathologically by abnormal alpha-synuclein aggregation. PD and MSA are clinically characterized by motor disorder and bladder dysfunction (mainly urinary urgency and frequency, also called overactive bladder). However, few literatures are available concerning bladder dysfunction in PD or MSA. A systematic review. The bladder dysfunction in MSA is more severe than that in PD for large post-void residual or urinary retention. These bladder dysfunctions presumably reflect the different nervous system pathologies. Overactive bladder in PD reflects lesions in the brain, e.g., in the prefrontal-nigrostriatal D1 dopaminergic bladder-inhibitory pathway. Overactive bladder in MSA reflects lesions similar to PD and the cerebellum (bladder-inhibitory), and the urinary retention in MSA presumably reflects lesions in the pontine micturition center and the sacral intermediolateral nucleus of the spinal cord (bladder-facilitatory). Bladder dysfunction not only impairs an individual’s quality of life, it can also cause emergency hospitalizations due to acute retention and early institutionalization. Anticholinergics are the first-line treatment for bladder dysfunction in PD and MSA patients, but care should be taken for the management of bladder dysfunction—particularly in MSA patients due to the high prevalence of difficult emptying, which needs clean, intermittent catheterization. This review summarizes the epidemiology, pathophysiology, and management of bladder dysfunction in individuals with PD or MSA.

To explore imidafenacin's effects on bladder and cognitive function in neurologic overactive bladder (OAB) patients.Sixty-two subjects (25 men, 37 women; mean age 70 years (25-86) with OAB due to neurologic diseases) were enrolled in the study. We conducted a urinary symptom survey and cognitive tests (MMSE, FAB, ADAS-cog) in all patients. We performed urodynamics in 35 patients and measured real-time near-infrared spectroscopy (NIRS)-urodynamics in eight patients before and after the administration of imidafenacin, an anticholinergic agent, for 3 months at 0.2 mg/day.Imidafenacin significantly ameliorated urinary urgency, nighttime urinary frequency, and quality of life index (p0.05). Three cognitive measures did not change significantly. Urodynamics showed increased bladder capacity (p0.05) but detrusor overactivity did not change significantly. NIRS showed that the subtraction of oxyhemoglobin between the start of filling and the first sensation increased in the bilateral prefrontal area but without statistical significance.Imidafenacin ameliorated bladder sensation without cognitive worsening, with a trend of prefrontal activation. Regarding cognitive function, imidafenacin is safely used in OAB patients due to neurologic diseases.In order to explore imidafenacin (anticholinergic agent)'s effects on bladder and brain function, we performed urinary questionnaire, cognitive tests, urodynamics and near-infrared spectroscopy (selected cases) in 62 overactive bladder (OAB) patients due to various neurologic diseases. As a result, imidafenacin ameliorated bladder sensation without cognitive worsening, with a trend of prefrontal activation. Imidafenacin seems safe in treating OAB patients due to neurologic diseases.

This paper reviews current concepts of psychogenic urinary dysfunction (PUD) in children and adults from a uro-neurologist’s point of view. Although it is not common in urodynamic practice, PUD is an important category that all urologists have to consider. Regarding urologic aspects, PUD is basically a diagnosis of exclusion, particularly from urologic, gynecologic, and neurologic causes. In our patients, the characteristics of lower urinary tract symptoms in PUD are the situational occurrence of overactive bladder and/or difficult urination and, in some patients, extremely infrequent toileting. The characteristics of urodynamics in PUD are increased bladder sensation during bladder filling and underactive/acontractile detrusor during voiding. Regarding neuropsychiatric aspects, PUD is usually accompanied by more obvious psychologic/psychiatric features. In fact, the majority of our patients had hysterical neurosis/conversion disorder and anxiety disorders. Alteration in both emotion and micturition under such conditions most probably originates from the brain, which may reflect functional alteration in γ-aminobutyric acid (GABA)ergic, serotonergic, and corticotropin-releasing factor (CRF)ergic neuronal circuits. In addition, even in cases suggestive of PUD, a possible non-PUD pathology behind the symptoms should always be explored.

Multiple system atrophy (MSA) is a neurodegenerative disease presenting with a combination of parkinsonian, cerebellar, and autonomic (including cardiovascular, urinary, and anorectal) dysfunction. It is pathologically defined, but at present lacks a definitive clinical diagnostic test. The majority of patients with probable MSA have an abnormal sphincter EMG. Patients with idiopathic Parkinson's disease do not show marked sphincter EMG abnormalities. Therefore, these abnormalities can be used to distinguish MSA from idiopathic Parkinson's disease in the first 5 years after disease onset. In contrast, similar sphincter EMG abnormalities are found in some, though not many, patients with dementia with Lewy bodies, pure autonomic failure, progressive supranuclear palsy, and spinocerebellar ataxia type 3. Thus, the limitations of the sphincter EMG test should also be kept in mind. Sphincter EMG and relevant sacral autonomic tests are diagnostic tools for autonomic disorders, reflecting the common and significant involvement of the sacral cord in MSA.

Bladder dysfunction (urinary urgency/frequency) and bowel dysfunction (constipation) are common non-motor disorders in Parkinson's disease (PD). In contrast to motor disorder, the pelvic autonomic dysfunction is often non-responsive to levodopa treatment. Brain pathology mostly accounts for the bladder dysfunction (appearance of overactivity) via altered dopamine-basal ganglia circuit, which normally suppresses the micturition reflex. In contrast, peripheral enteric pathology mostly accounts for the bowel dysfunction (slow transit and decreased phasic contraction) via altered dopamine-enteric nervous system circuit, which normally promotes the peristaltic reflex. In addition, weak strain and paradoxical anal contraction might be the results of brain pathology. Pathophysiology of the pelvic organ dysfunction in PD differs from that in multiple system atrophy; therefore it might aid the differential diagnosis. Drugs to treat bladder dysfunction in PD include anticholinergic agents. Drugs to treat bowel dysfunction in PD include dietary fibers, peripheral dopaminergic antagonists, and selective serotonergic agonists. These treatments might be beneficial not only in maximizing patients' quality of life, but also in promoting intestinal absorption of levodopa and avoiding gastrointestinal emergency.

Both neurologists and urologists might encounter patients with acute urinary retention due to benign inflammatory nervous diseases. Based on the mechanism of urinary retention, these disorders can be divided into two subgroups: disorders of the peripheral nervous system (e.g., sacral herpes) or the central nervous system (e.g., meningitis-retention syndrome [MRS]). Laboratory abnormalities include increased herpes virus titers in sacral herpes, and increased myelin basic protein in the cerebrospinal fluid (CSF) in some cases with MRS. Urodynamic abnormality in both conditions is detrusor areflexia; the putative mechanism of it is direct involvement of the pelvic nerves in sacral herpes; and acute spinal shock in MRS. There are few cases with CSF abnormality alone. Although these cases have a benign course, management of the acute urinary retention is necessary to avoid bladder injury due to overdistension. Clinical features of sacral herpes or MRS differ markedly from those of the original “Elsberg syndrome” cases.

Analysis of answers to a new questionnaire.To examine current practice patterns of physicians in the urological surveillance and management of spinal cord injury (SCI) patients in Japan.Nationwide questionnaire survey to physicians in Japan.A Japanese version of the 14-item questionnaire survey carried out in US was mailed to 770 members of the Japanese Neurogenic Bladder Society (JNBS).We received answers to our questionnaire from 333 (43.2%) members of JNBS. The responders were all urologists. For surveillance of the upper urinary tract (UUT), 239 (71.8%) respondents preferred abdominal ultrasound. Cystometry was performed routinely by 174 (52.3%) respondents for the evaluation of vesicourethral function. Cystoscopy was carried out in cases of hematuria (88.0%) and bladder stone (55.3%). Surveillance of the urinary tract was performed every year in 154 (46.2%). For detection of bladder cancer, which 119 (37.9%) respondents have experienced, 94.9% physicians perform cystoscopy, 76.3% urinary cytology, and 60.4% ultrasound. For initial treatment of detrusor-sphincter dyssynergia (DSD), 225 (69.2%) respondents chose alpha-blocker, and 94 (28.9%) chose clean intermittent catheterization (CIC) with/without anticholinergic agent(s). For initial treatment of overactive bladder, 245 (74.7%) chose anticholinergic agent(s) only and 63 (19.2%) chose anticholinergic agent(s) with CIC. For initial treatment of areflexic bladder, 233 (73.7%) chose CIC and 63 (19.9%) chose Credé maneuver or tapping.This survey shows that there are some differences in urological surveillance and management of SCI patients between Japan and the US. Reasons for the discrepancy should be examined.

Antimuscarinic agents are the most widely used therapy for urge incontinence, but have side effects such as constipation, tachycardia and dry mouth, resulting from a lack of selectivity for the bladder. M2 receptors are the predominant cholinoceptors present in urinary bladder, but mainly the minor population of M3 receptors mediate its contraction. M2 receptors modulate detrusor contraction by several mechanisms, and may contribute more to contraction of the bladder in pathological states such as bladder denervation or spinal cord injury. Prejunctional inhibitory M2 or M4 receptors and prejunctional facilitatory muscarinic Ml receptors in the bladder have all been reported. In clinical studies, tolterodine, a non-selective muscarinic antagonist, has been reported to be as effective as oxybutynin but inducing less dry mouth. Thus, although it is not certain which antimuscarinic drugs have the better efficacy and tolerability, the non-selective antimuscarinic drugs seem to be better than M3-selective antagonists in their clinical efficacies. However, controlled release, or intravesical, intravaginal, or rectal administrations of oxybutynin have been reported to cause fewer side effects. Darifenacin, a new M3 selective antagonist, has been reported to have selectivity for the bladder over the salivary gland in vivo. To verify which antimuscarinic drugs selective for the muscarinic subtypes have the best efficacy and tolerability, comparative clinical trials between M3 selective antagonists and non-selective compounds, such as olterodine, are required in the future.

Electrical stimulation has been reported to be effective for stress incontinence, cure and improvement rates being reported to range from 30% to 50%, and from 6% to 90%, respectively. However, clinical application of this treatment is not common because there is little physiological and technical information. Electrodes for electrical stimulation are divided into two types: external (non-implantable) and internal (implantable), and there are two methods of stimulation: chronic (long-term, continuous) and short-term. Frequencies of 20–50 Hz, with a pulse duration of 1–5 ms, have been reported to be effective for urethral closure. The effectiveness of the treatment should be verified with placebo-controlled double-blinded trials, and four such studies using an active and a sham device have been reported. Two of these verified the superiority of the active device over the sham device, but the others did not demonstrate any significant difference between the two with regard to efficacy. Electrical stimulation has been reported to result in a long-term continuation of therapeutic effect. The effect has been explained as a re-education or a reactivation of lost functions of the pelvic floor muscles. As to adverse effects, there may be some complications in relation to anesthesia or surgical procedures, such as infection, pain and bleeding with implantable electrodes. The incidence of adverse effects in short-term electrical stimulation is less than 14%. In conclusion, short-term electrical stimulation using non-implantable anal or vaginal electrodes is the most recommendable because of safety and ease of use.

In ten patients with acute transverse myelitis (ATM), seven patients had urinary retention, and the other three patients had difficulty in voiding within 1 month from the onset of the disease. Five of the patients with retention became able to urinate. After the mean follow-up period of 40 months, nine still had urinary symptoms including difficulty in voiding in five and urinary frequency, urgency and incontinence in four patients. Four patients had urinary disturbance as the sole sequel of ATM. Urodynamic studies performed on nine patients revealed that all of the three patients with the urgent incontinence had detrusor hyperreflexia, all of the four patients with retention had an areflexic cystometrogram as well as sphincter hyperreflexia, and three of five patients with voiding difficulty had detrusor-sphincter dyssynergia. An areflexic cystometrogram tended to change to a low compliance bladder, followed by detrusor hyperreflexia or a normal cystometrogram. Analysis of the motor unit potentials of the external sphincter revealed that two of the three patients had high amplitude or polyphasic neurogenic changes. Supranuclear as well as nuclear types of parasympathetic and somatic nerve dysfunctions seemed to be responsible for micturition disturbance in our patients with ATM.

In 5 patients with multiple system atrophy, administration of 15 mg/day of amezinium metilsulfate, an adrenergic agent, during 6 months for the treatment of postural hypotension exacerbated post-micturition residuals as compared to that before treatment (178 ml versus 113 ml for a change of 37 %, p0.05). Amezinium metilsulfate most probably stimulates both alpha1B-receptors in the vascular wall and alpha1A/D-receptors in the proximal urethra.