Promise of Urinary Nerve Growth Factor for Assessment of Overactive Bladder Syndrome

Overactive bladder syndrome (OAB) is highly prevalent bladder disorder in men and women. About 10–15% of the population suffers from urgency frequency with or without urgency urinary incontinence. It is estimated that 50–75% of patients with OAB may have urodynamic detrusor overactivity (DO). Urodynamic study invasive and most of the OAB patients might not accept it as a routine assessment. Therefore, a more objective and non‐invasive test for diagnosis and assessing DO from OAB patients is needed. Recently, urinary nerve growth factor (NGF) has gained great interest in detecting DO in patients with OAB. Urinary NGF level was found to increase in OAB and urodynamic DO. Urinary NGF levels correlated with severity of OAB symptoms. Patients with either idiopathic or neurogenic DO may have increased urinary NGF levels. Urinary NGF levels have been shown to decrease in patients with patients with OAB and DO who have been well treated with antimuscarinics or botulinum toxin injection, but not in those with persistent OAB after treatment. Not all patients with OAB can have an elevated urinary NGF level; it may also be increased in patients with interstitial cystitis/painful bladder syndrome and other lower urinary tract diseases, suggesting urinary NGF expression could be a product of bladder inflammation and a limited specificity of urinary NGF for diagnosing DO. The source of urinary NGF has not yet been fully explored yet. Nevertheless, urinary NGF level is likely to be a promising biomarker for diagnosis of DO from OAB patients, to monitor therapeutic outcome and predict disease progression.     

Overactive bladder with urodynamic study-induced bladder pain: An overactive bladder subtype with symptoms similar to those of interstitial cystitis/painful bladder syndrome

Overactive bladder (OAB) and interstitial cystitis/painful bladder syndrome (IC/PBS) are 2 lower urinary tract disorders with urgency and bladder pain for diagnosis and with several other shared symptoms. Because of their overlapping symptoms, precise differential diagnosis of OAB and IC/PBS remains difficult. Thus, we characterize a subgroup of OAB with bladder pain (OAB-BP) that can be differentiated from OAB alone by urodynamic study (UDS) findings. We also further examined the clinical presentations and urodynamic parameters of OAB alone, OAB-BP, and IC/PBS. Data were collected between September 2018 and April 2019. Patients were categorized into 3 groups, OAB-alone (no bladder pain during UDS, n = 39), OAB-BP (with bladder pain during UDS, n = 35), and IC/PBS (the comparator, n = 39). Chi-square tests were used to compare OAB alone, OAB-BP, and IC/PBS with respect to their clinical presentations and urodynamic parameters. Factors with P < .05 were further analyzed through post hoc comparisons with Bonferroni adjustment. An unique subgroup of OAB patients was identified (i.e., OAB-BP), bladder pain can only be induced at maximal cytometric capacity during UDS. We also identified that the case histories and UDS parameters (e.g., low first desire, normal desire, and maximum cytometric capacity) of the OAB-BP group were more similar to those of the IC/PBS group than to those of the OAB-alone group. The OAB-BP group and the IC/PBS group reported more intrusive, longer-lasting symptoms before their final diagnoses, more extensive family history of urinary tract disorder, and more associated comorbidities (e.g., irritable bowel syndrome, and myofascial pain) than the OAB-alone group. The UDS assessment induced bladder pain in the OAB-BP group to reveal their hidden symptoms. Careful attention to patient history and sophisticated UDS evaluation may help to identify this unique OAB group.     

Management of overactive bladder

Many people are affected by urinary urgency, which can be highly bothersome. Urgency is the cornerstone symptom of overactive bladder (OAB), commonly occurring in conjunction with urinary frequency and nocturia. Once other medical causes of similar symptoms have been excluded, first-line OAB management comprises fluid intake advice and bladder training, supplemented by antimuscarinic drugs if necessary. Urodynamic confirmation of the diagnosis is required for OAB patients whose symptoms are refractory to first-line interventions. If patients are severely bothered by OAB despite optimization of medical treatment, they may proceed to invasive treatments, including neuromodulation, enterocystoplasty, detrusor myectomy, or urinary diversion. Our burgeoning understanding of the complex cellular, neural and integrative physiology of the bladder offers new insights into the causative mechanisms of OAB, and reasons why patients sometimes fail to respond to treatment. Study of sensory information pathways in the lower urinary tract has led to identification of the urothelium, afferent nerves and interstitial cells as key cellular elements in OAB. In-depth knowledge of the hierarchy of central nervous system control is lacking, but functional imaging is beginning to elucidate the challenges that lie ahead. New treatments under investigation include botulinum neurotoxin-A injection, oral β(3)-adrenergic agonists, and novel modalities for nerve stimulation. The subjective nature of urinary urgency, the lack of animal models and the multifactorial pathophysiology of OAB present significant challenges to effective clinical management.     

Botulinum Toxin A Injections for Non-neurogenic Overactive Bladder

Intravesical botulinum toxin A (BoNT-A) injection is effective and has been approved in the treatment of overactive bladder (OAB) syndrome in patients who are refractory or intolerable to antimuscarinic therapy. Intravesical BoNT-A injection increases bladder capacity, decreases detrusor pressure, and reduces the urgency sensation in OAB patients. Although clinical experiences have demonstrated a dose-dependent therapeutic effect of BoNT-A, the adverse events such as acute urinary retention, voiding difficulty, large post-void residual, and subsequent urinary tract infection remain problematic and increase with higher doses in frail elderly patients. Currently, 100 U of onabotulinumtoxinA has been approved by many countries for the treatment of patients with non-neurogenic OAB. The duration of therapeutic effect is around 6 to 9 months and usually remains the same after repeat treatments. The injection sites can involve the bladder wall with or without sparing the trigone. Gathered experience has also shown that BoNT-A injection is also effective in the treatment of OAB symptoms in children and in patients with stroke or Parkinson’s disease. Before BoNT-A injection, physicians should learn the injection technique and inform the potential adverse events to patients who desire this treatment.     

Current Understanding of the Interplay between Oab & Bph

Lower urinary tract symptoms (LUTS) are very common and bothersome to men. For many years all male LUTS, even the storage ones, were attributed to the prostate, which was the target of therapeutic approaches. Increasing knowledge of the contribution of bladder dysfunction to LUTS pathophysiology has brought into focus detrusor overactivity (DO) and its treatments. Available data indicate that in many cases DO and overactive bladder (OAB) symptoms are secondary to bladder outlet obstruction (BOO), due to prostatic disease. Accumulating evidence also suggests that the two pathologies may coexist because they share etiologic factors. Despite the prevalence of storage symptoms in men with benign prostatic hyperplasia (BPH), antimuscarinics, the main treatment for OAB, were infrequently used because of fear of urinary retention. Available clinical trials indicate that the addition of an antimuscarinic to prostate-targeted treatments, or treatment initiation with a combination regimen, is safe in terms of urinary retention and offers improvements in storage symptoms. Nevertheless, the improvement in overall quality of life is modest. Criteria for the selection of patients likely to benefit most from the addition of antimuscarinics to common BPH treatments are lacking.     

Inhibition of the cation channel TRPV4 improves bladder function in mice and rats with cyclophosphamide-induced cystitis

Reduced functional bladder capacity and concomitant increased micturition frequency (pollakisuria) are common lower urinary tract symptoms associated with conditions such as cystitis, prostatic hyperplasia, neurological disease, and overactive bladder syndrome. These symptoms can profoundly affect the quality of life of afflicted individuals, but available pharmacological treatments are often unsatisfactory. Recent work has demonstrated that the cation channel TRPV4 is highly expressed in urothelial cells and plays a role in sensing the normal filling state of the bladder. In this article, we show that the development of cystitis-induced bladder dysfunction is strongly impaired in Trpv4(-/-) mice. Moreover, we describe HC-067047, a previously uncharacterized, potent, and selective TRPV4 antagonist that increases functional bladder capacity and reduces micturition frequency in WT mice and rats with cystitis. HC-067047 did not affect bladder function in Trpv4(-/-) mice, demonstrating that its in vivo effects are on target. These results indicate that TRPV4 antagonists may provide a promising means of treating bladder dysfunction.     

Pathophysiology of refractory overactive bladder

Overactive bladder (OAB) is a common condition. The International Continence Society defines OAB as a symptom complex characterized by urgency with or without urge incontinence, usually with frequency and nocturia. The first‐line treatment for OAB includes behavioral therapy, such as caffeine reduction, fluid intake modification, weight reduction, bladder training, and pelvic floor muscle training, as well as treatment with antimuscarinic or β₃‐adrenoceptor agonist medications. However, less than half of all cases achieve satisfactory outcomes following first‐line treatment. Second‐line therapy considered if satisfactory responses are not achieved after 8 to 12 weeks treatment with first‐line therapy include intradetrusor botulinum toxin injection, neuromodulation, and surgical treatment. Patients with refractory OAB may have more severe symptoms or underlying pathophysiologies that were not resolved by the initial medication. The pathophysiologies of refractory OAB include occult neurogenic bladder, undetected bladder outlet obstruction, urethral‐related OAB, urothelial dysfunction with aging, chronic bladder ischemia, chronic bladder inflammation, central sensitization, and autonomic dysfunction. This article discusses the possible pathophysiologies of refractory OAB.     

Urinary tract infections

Urinary tract infections occur very frequently in the community and in hospitalized patients and are mainly caused by Escherichia (E.) coli. Depending on virulence determinants of uropathogenic microorganisms and host-specific defense mechanisms, urinary tract infections can manifest as cystitis, pyelonephritis (bacterial interstitial nephritis), bacteremia or urosepsis. Uncomplicated urinary tract infections in otherwise healthy women should be treated for 3-7 days depending on the antibiotic therapy chosen, even if spontaneous remission rates of up to 40% have been reported. Antibiotics of the first choice for empirical treatment of uncomplicated urinary tract infection are fluoroquinolones, pivmecillinam and fosfomycin. A huge problem is the increasing antimicrobial resistance of uropathogenic microorganisms. Complicated urinary tract infections associated with anatomical and/or functional abnormalities of the urinary tract and/or comorbidities such as diabetes or immunosuppressive therapy, need longer antibiotic treatment (e.g. 10-14 days) as well as interdisciplinary diagnostic procedures. Treatment of community acquired urosepsis includes cephalosporins of the third generation, piperacillin/tazobactam or ciprofloxacin. For nosocomial urosepsis the combination with an aminoglycoside or a carbapenem is recommended.     

透明质酸钠、肉毒素A治疗女性IC/PBS疗效观察

目的观察膀胱灌注透明质酸钠、膀胱内注射肉毒素A治疗女性间质性膀胱炎/膀胱疼痛综合征（IC/PBS）的疗效。方法 41例女性IC/PBS患者,其中行透明质酸钠膀胱灌注22例（A组）,行肉毒素A膀胱内注射19例（B组）。评估患者治疗前及治疗后1、3、6个月临床症状（每日排尿次数、最大排尿量、疼痛程度评分）及O＇Leary-Sant间质性膀胱炎问卷表评分情况,并记录不良反应发生情况。结果两组患者治疗后各时间点每日排尿次数、最大排尿量、疼痛程度评分、O＇Leary-Sant评分与治疗前相比P均〈0.05。治疗后6个月上述指标B组与A组相比P均〈0.05,而治疗前及治疗后1个月两组比较P均〉0.05。A组未出现严重不良反应。B组3例第3个月出现排尿困难,后逐渐改善,无其他不良反应。A、B组分别有2、1例在水扩张之后出现轻微肉眼血尿,后逐渐消失。A组有1例因心脏病中断治疗,其余患者均完成治疗及随访。结论膀胱内灌注透明质酸钠能有效缓解IC/PBS患者临床症状,改善其生活质量,患者耐受性及安全性较好。膀胱内注射肉毒素A短期内能缓解症状,但疗效随时间的推移进行性下降,且伴随少量不良反应的发生,不良反应随着药效的减退而逐渐改善。     

Evaluation and Management of Urgency and Urge Urinary Incontinence in Men

The overactive bladder (OAB) syndrome is increasingly being recognized as a major contributor to the lower urinary tract symptoms in men previously thought to be only due to bladder outlet obstruction from benign prostatic hyperplasia. Medical and surgical treatments that have historically been used to treat women with OAB are being applied to men with great efficacy and a good safety profile. Additionally, treatments such as the β-3 agonist mirabegron, phosphodiesterase-5 inhibitors, sacral and peripheral neuromodulation, and intravesical botulinum toxin injection are promising emerging therapies for the OAB syndrome. This review discusses the evaluation of the male patient with OAB symptoms such as urgency and urge incontinence, and explores the different therapeutic options available for management of men with OAB.     

CT urography for hematuria

Hematuria can signify serious disease such as bladder cancer, upper urinary tract urothelial cell carcinoma (UUT-UCC), renal cell cancer or urinary tract stones. CT urography is a rapidly evolving technique made possible by recent advances in CT technology. CT urography is defined as CT examination of the kidneys, ureters and bladder with at least one series of images acquired during the excretory phase after intravenous contrast administration. The reasoning for using CT urography to investigate hematuria is based on its high diagnostic accuracy for urothelial cell carcinoma (UCC) and favorable comparison with other imaging techniques. The optimum diagnostic imaging strategy for patients with hematuria at high-risk for UCC involves the use of CT urography as a replacement for other imaging tests (ultrasonography, intravenous urography, or retrograde ureteropyelography) and as a triage test for cystoscopy, resulting in earlier diagnosis and improved prognosis of bladder cancer, UUT-UCC, renal cell cancer and stones. Current problems with CT urography for investigating hematuria might be solved with a formative educational program simulating clinical reporting to reduce reader error, and a new technique for image-guided biopsy of UUT-UCC detected by CT urography for histopathological confirmation of diagnosis and elimination of false-positive results. CT urography is recommended as the initial imaging test for hematuria in patients at high-risk for UCC.     

Medication and food issues for overactive bladder/lower urinary tract symptoms: When do we eat?

Overactive bladder (OAB) and lower urinary tract symptoms (LUTS) are common conditions that often require chronic medications. Treatment for OAB includes older antimuscarinic agents (oxybutynin) and newer agents (tolterodine, trospium chloride, darifenacin, and solifenacin). Treatment for LUTS includes the 5-α reductase inhibitors, (finasteride and dutasteride) and α1-adrenergic antagonists (prazosin, doxazosin, terazosin, alfuzosin, and tamsulosin). Many medications have the potential to interact with food. This article addresses the effects of food on the current treatments for OAB and LUTS and the clinical considerations for their optimal dosing with regard to food.     

Clinical study of ammonium acid urate urolithiasis

Ammonium acid urate (AAU) urolithiasis is a rare condition; however, it is endemic in some countries, with an especially high incidence in Asia. This study was conducted to investigate the special presentation of patients with AAU urolithiasis in Taiwan. Reports of 3457 stones were retrospectively reviewed from January 2005 to January 2010 and 25 patients with urinary stones (0.7%) containing AAU crystals were identified. The clinical and biochemical presentation of all stones were compared to evaluate the specific comorbidities of AAU stones. AAU stones were observed in 11 males (44%) and 14 females (56%) with a mean age of 60.60 ± 16.81 years and mean body mass index of 25.55 ± 3.73 kg/m(2). AAU stones were frequently observed in the bladder (44%) and they were significantly larger (mean size 1.90 cm) than the non-AAU stones (mean size 1.22 cm). Other significant comorbidities of AAU stones included chronic kidney disease (CKD) (60%), urinary tract infections (UTIs) (52%), irritable bowel syndrome (IBS) (36%), and gout (28%). In addition, there were also three patients with coexisting urothelial carcinoma (12%) in the AAU-stone group. Patients with AAU urolithiasis were predominantly female, older in age, had increased bladder presentation, larger stones and a high percentage of coexisting CKD, UTIs, IBS, gout, and even urothelial carcinoma. Therefore, it is important for clinicians to evaluate and protect renal function in patients with AAU urolithiasis.     

Evaluation and Management of Urinary Retention Following Colorectal and Gynecologic Oncologic Surgery

Urinary retention after radical pelvic surgery is a relatively common, well-recognized complication. The primary problem is neural disruption to or from the bladder during curative surgery. Resulting symptoms may include urinary retention presenting post operatively early or late. Other symptoms include overflow incontinence, to controlled stress incontinence, or urinary tract infections. Management is predicated on the clinical history, examination, physical findings and urodynamic evaluations. The principles of neurogenic bladder management are based on management of urinary incontinence or retention, prevention of urinary tract infections, prevention of stone disease and preservation of renal function. While not all patients who undergo radical pelvic surgery for oncological disease, develop neurogenic bladder, it must be considered in patient??s with urinary retention. In men, retention after pelvic surgery may not be caused by BPH, but neurogenic bladder, thus a transurethral resection of prostate may not be the appropriate management. Management of urological complications of pelvic surgery depends on a full neurourological assessment of the patient, and a treatment plan based on objective findings of the complete examination.     

Complications of Chronic Prostatitis

Chronic prostatitis (CP) is a pelvic condition in men that needs to be distinguished from other forms of prostatitis, such as acute and chronic bacterial prostatitis. CP is characterized by pelvic or perineal pain lasting longer than 3 months without evidence of urinary tract infection. Symptoms may wax and wane and pain may radiate to the back and perineum, causing discomfort while sitting. Dysuria, frequency, urgency, arthralgia, myalgia, unexplained fatigue, abdominal pain, and burning sensation in the penis may be present. Post-ejaculatory pain, mediated by nerves and muscles, is a hallmark of the condition and serves to distinguish CP/chronic pelvic pain syndrome (CPPS) patients from men with benign prostatic hyperplasia and healthy men. Some patients report low libido, sexual dysfunction, and erectile difficulties. The symptoms of CP/CPPS appear to result from interplay between psychological factors and dysfunction in the immune, neurological, and endocrine systems. Some researchers have suggested that CPPS is a form of painful bladder syndrome/interstitial cystitis (PBS/IC). Therapies shown to be effective in treating IC/PBS (eg, quercetin) have shown some efficacy in CP/CPPS. Recent research has focused on genomic and proteomic aspects of the related conditions. There are no definitive diagnostic tests for CP/CPPS. This is a poorly understood disorder, even though it accounts for 90% to 95% of prostatitis diagnoses. Its peak incidence is in men 35 to 45 years old. In 2007, the National Institute of Diabetes and Digestive and Kidney Diseases began using the umbrella term urologic chronic pelvic pain syndromes to refer to pain syndromes associated with the bladder (eg, IC/PBS) and prostate gland (eg, CP/CPPS). The prognosis for CP/CPPS has improved greatly with the advent of multimodal treatment, including phytotherapy, pelvic nerve myofascial trigger point release, anxiety control, and chronic pain therapy.     

Pharmacologic management of overactive bladder

Overactive bladder (OAB) is a prevalent and costly condition that can affect any age group. Typical symptoms include urinary urgency, frequency, incontinence and nocturia. OAB occurs as a result of abnormal contractions of the bladder detrusor muscle caused by the stimulation of certain muscarinic receptors. Therefore, antimuscarinic agents have long been considered the mainstay of pharmacologic treatment for OAB. Currently, there are five such agents approved for the management of OAB in the United States: oxybutynin, tolterodine, trospium, solifenacin and darifenacin. This article summarizes the efficacy, contraindications, precautions, dosing and common side effects of these agents. All available clinical trials on trospium, solifenacin and darifenacin were reviewed to determine its place in therapy.     

Management of Bladder Diverticula in the Pediatric Population

Bladder diverticula represent protrusion of the urothelial mucosa through the bladder muscular layers and may be either congenital or acquired. Congenital bladder diverticula are usually located adjacent to the ureteral orifices and often are associated with vesicoureteral reflux. Acquired bladder diverticula are usually multiple in nature and are secondary to bladder outlet obstruction or neurogenic bladder. When bladder diverticula are small and do not cause symptoms, non-surgical observation is an acceptable management strategy. The absolute need for surgical intervention of bladder diverticula remains a controversial topic, where current surgical indications for bladder diverticula include diverticula larger than 3 cm, recurrent urinary tract infections, associated severe vesicoureteral reflux, voiding dysfunction, urinary retention, bladder stones, and lower urinary tract symptoms that are persistent after conservative treatment. Open surgical repair has traditionally been the primary treatment choice for bladder diverticula. However, recent advancements in laparoscopic and robotic technology have led to minimally invasive surgical treatment options as alternatives to open surgery with similar success rates, but with reduced morbidity, decreased hospital stay lengths, reduced pain medication requirements, and improved cosmesis.     

Lower Urinary Tract Symptoms: Defining Syndromes in Urology

Lower urinary tract symptoms (LUTS) comprise a complex network of interrelated symptoms affecting different stages of the micturition cycle. With the prevalence of LUTS steadily increasing, there is great emphasis on the need for appropriate diagnosis and treatment. The current classification of LUTS into various urologic syndromes is controversial and poses a diagnostic and treatment dilemma. In this review, we present a comprehensive overview of four frequently encountered syndromes associated with LUTS—overactive bladder, interstitial cystitis/painful bladder syndrome, benign prostatic obstruction, and chronic prostatitis/chronic pelvic pain syndrome—and also discuss the current trend in the management of these symptoms and syndromes.     

Intravesical capsaicin for the treatment of interstitial cystitis: a pilot study

OBJECTIVES: To study the safety and efficacy of intravesically administered capsaicin, a C-fiber afferent neurotoxin, in patients with interstitial cystitis (IC). METHODS: A pilot study of intravesical capsaicin therapy was performed on 5 female patients diagnosed with IC using NIDDK criteria. Patients were evaluated with cystoscopy and CMG on initial presentation. Bladder capacity, urinary histamine, PGE2 and substance P were measured before and after treatment. A symptom score, visual analogue pain score and frequency/nocturia charts were completed before treatment and weekly thereafter by each patient. Topical anesthesia (30 mls of 0.5% bupivacaine) was instilled intravesically for 30 minutes prior to each treatment with capsaicin. The initial instillation consisted of vehicle (1% ethanol in normal saline) and subsequent weekly instillations of capsaicin in increasing concentrations (10, 50, 100, and 250 uM solutions in 1% ethanol) were given as tolerated by the patient. RESULTS: Four out of 5 of the patients experienced subjective improvement in both symptom and pain score. Bladder capacity improved in 1 patient and symptoms of frequency and nocturia improved in 2 patients. Urinary histamine and PGE2 revealed no trend between before and after treatment; however, 3 out of 5 of the patients did have a trend to decreased substance P. No complications were noted during the course of this study. CONCLUSIONS: Intravesical capsaicin is a safe and promising treatment for interstitial cystitis. A potential mechanism of action is desensitization of bladder C-fiber afferents which presumably initiate painful sensations in IC patients. Low dose intravesical capsaicin therapy represents a potential treatment option for interstitial cystitis.