Neurogenic detrusor overactivity in adults: a review on efficacy, tolerability and safety of oral antimuscarinics.

OBJECTIVES: This review analyzed efficacy, tolerability and safety of oral antimuscarinic (AM) drugs in adults suffering from neurogenic detrusor overactivity (NDO). METHODS: A comprehensive search of major literature bases was conducted to identify all references. RESULTS: Thirty studies, thereof 16 randomized controlled trials (RCT), enrolling 1479 patients were identified and included in the review. Results were grouped in dose-finding, placebo- and active-controlled, flexible dose and combined high-dose AM drugs, and various studies. Key urodynamic outcome parameters, such as maximum detrusor pressure and maximum cystometric bladder capacity, demonstrated the efficacy of AM in NDO, following 2-3 weeks of treatment. Contrary to idiopathic detrusor overactivity (IDO), no placebo effects manifested. Other important parameters, such as impact on the upper urinary tract function and morphology, issues of continence, post-void residual urine, catheterisation, urinary tract infections and quality of life, were investigated to a limited extent only. Incidence rates of adverse events were comparable for NDO and IDO. Most of the studies, especially RCT, were undertaken with oxybutynin immediate release (IR), trospium chloride IR, propiverine IR and propiverine extended release. In NDO, these drugs are best investigated. CONCLUSIONS: AM drugs are effective in NDO, they normalize the intravesical pressure and increase cystometric bladder capacity. However, other important parameters are not adequately investigated so far and should be recognized in future studies.

Efficacy and tolerability of propiverine hydrochloride extended-release compared with immediate-release in patients with neurogenic detrusor overactivity.

STUDY DESIGN: Double-blind, randomised, multicentre study. OBJECTIVES: Efficacy and tolerability of propiverine extended-release (ER) compared with immediate-release (IR) were evaluated in patients with proven neurogenic detrusor overactivity (NDO). SETTING: Six Spinal Cord Injury Units located in Austria, Germany and Romania. METHODS: Propiverine ER 45 mg s.i.d. or IR 15 mg t.i.d. were administered in patients with proven NDO. Outcomes were assessed at baseline (V1), and after 21 days of treatment (V2): Reflex volume served as primary, leak point volume and maximum detrusor pressure as secondary efficacy outcomes, treatment-related adverse events as tolerability outcomes. RESULTS: Sixty-six patients with proven NDO were enrolled. Reflex volume (ml) increased significantly in the IR (V1: 100.9, V2: 202.9) and in the ER (V1: 89.8, V2: 180.3) group, no significant intergroup difference. Leak point volume increased, and maximum detrusor pressure decreased significantly in both groups, no significant intergroup differences. The percentage of patients presenting with incontinence was reduced by 14% in the IR and by 39% in the ER group, the difference is significant. Treatment-related adverse events manifested in 42 and 36% following propiverine IR and ER, respectively. CONCLUSION: The urodynamic efficacy outcomes demonstrated both galenic formulations to be equieffective. However, following propiverine ER 45 mg s.i.d. higher continence rates compared with propiverine IR 15 mg t.i.d. were achieved, possibly indicative of more balanced plasma-levels. A slight tendency for superior tolerability outcomes of propiverine ER compared with IR was demonstrated.

[Urological problems in patients with meningomyelocele. Diagnostic studies and management]. / Urologischer Erkrankungen bei Patienten mit Meningomyelozele. Diagnostik und Management.

Since the 1980s the management of children and adolescents with meningomyelocele has undergone major changes. The introduction of pharmacotherapy with antimuscarinic agents, clean intermittent catheterization (CIC) and antibacterial prophylaxis has revolutionized the management of children with neurogenic bladder. The co-operation between neonatologists, neurosurgeons, paediatric neurologists, paediatricians, paediatric urologists, paediatric nephrologists, paediatric orthopaedists and paediatric surgeons is necessary to achieve an optimized therapy in each individual patient. In this interdisciplinary consensus paper we provide definitions and classifications as well as a timetable for the appropriate investigations. The conservative and surgical options are explained in detail. A short review is given concerning orthopaedic management, incidence of latex allergy, options for bowel management, diagnosis and treatment of urinary tract infections, problems with sexuality and fertility as well as the long-term compliance of these patients and their relatives.

[Seven years of botulinum toxin type A in the treatment of neurogenic detrusor hyperactivity]. / 7 Jahre Botulinum-A-Toxin in der Behandlung der neurogenen Detrusorhyperaktivität.

BACKGROUND: A decompensated storage function with high pressures is the greatest risk factor regarding life expectancy and quality of life in patients with neurogenic detrusor hyperactivity. Previously, this problem could only be managed with administration of anticholinergic medications or--if this approach was either not effective enough or the patients exhibited drug intolerance--by invasive surgical interventions. The use of botulinum toxin type A to treat these patients rapidly proved to be a beneficial alternative to those two therapeutic options ever since its introduction in Germany in 1998 as a minimally invasive procedure and has become established worldwide. MATERIAL AND METHODS: The medical records of first-time users at the clinic were retrospectively analyzed for a 7-year period. The total of 492 injections in 277 patients--of which 365 injections in 216 patients were performed following a standardized protocol--represents the largest number of cases worldwide. The treatment was indicated in patients experiencing insufficient efficacy of anticholinergic agents or drug intolerance who were capable of self-catheterization. RESULTS: The standard injection contained either 300 MU Botox or 750 MU Dysport. Urodynamic parameters before and up to 8 months post-intervention showed significantly lowered detrusor pressure and improved cystometric capacity. This corresponded to the clinical assessment and subjective impression of the patients that detrusor activity had been reduced to a large extent with improved continence. Evacuation was carried out in all cases without any difficulty by aseptic intermittent catheterization. The average duration of the effect was subjectively determined to be 8.7 months. In the vast majority of cases, anticholinergic medications could be discontinued or considerably reduced. Side effects not requiring treatment developed in only four instances. Antibody formation no longer occurred with those products available on the market since 2001. Even after repeated injections (up to ten times) there was no evidence for decreased efficacy. CONCLUSION: Due to its reliable effect and low rate of side effects, botulinum toxin type A quickly became accepted worldwide for the treatment of neurogenic detrusor hyperactivity and has contributed to a substantial enrichment of the more conservative therapy options. Prospective studies focusing especially on injection site and optimizing the duration of efficacy are desirable.

[Quality of life in German-speaking patients with spinal cord injuries and bladder dysfunctions. Validation of the German version of the Qualiveen questionnaire]. / Lebensqualität bei deutschsprachigen Patienten mit Rückenmarkverletzungen und Blasenfunktionsstörungen. Validierung der deutschen Adaption des Qualiveen-Fragebogens.

BACKGROUND: Neurogenic bladder dysfunctions in patients with spinal cord lesions may cause severe limitations in the quality of life (QoL). For assessment of QoL, a validated questionnaire in French is available. The goal of the study was to validate the German version of the questionnaire. METHODS: Translation and intercultural adaptation were achieved in cooperation with an institute for health system research. The resulting German version was filled in by 439 patients in 18 centers in Germany, Austria, and Switzerland. Data were analyzed regarding clinical and sociodemographic characteristics. Quality criteria of the items and scales were tested by a detailed scale analysis. RESULTS: Of the patients 65.8% were paraplegic and 32.8% were tetraplegic. Internal consistency, reliability, and validity of the questionnaire were very good. Differential effects could be displayed in all clinical variables that were tested. CONCLUSIONS: The Qualiveen questionnaire is now available as the first instrument in the German language for the evaluation of the influence of bladder dysfunction on QoL in patients with spinal cord lesions.

[Botulinum toxin for the treatment of neurogenic detrusor hyperactivity. Consensus paper on use for neurogenic bladder dysfunction]. / Botulinumtoxin in der Therapie der neurogenen Detrusorhyperaktivität. Konsensuspapier zum Einsatz bei einer neurogenen Blasenfunktionsstörung.

Due to elevated intravesical storage pressures, neurogenic bladder dysfunction carries a high risk of renal damage. Thus, the goals of neurourologic treatment are reduction of intravesical storage pressure and intermittent bladder emptying in order to protect renal function and to achieve continence. If anticholinergic medication is either ineffective or intolerable, several open and controlled studies showed that the injection of botulinum toxin A into the detrusor muscle is a minimally invasive, safe, and effective treatment option. These studies demonstrated an effective reduction of storage pressures and a significant increase in bladder capacity. The effect has been shown to last up to a year. As this treatment is not approved by European administrations, botulinum toxin A treatment fulfills all criteria for "justified off-label use." The reduction of intravesical storage pressure leads to an improvement of life expectancy due to upper urinary tract protection. Furthermore, quality of life can be improved by low incidence of urinary tract infections, secure continence, and physiologic catheterization intervals.

[Single-use intermittent catheterisation]. / Der intermittierende Einmalkatheterismus.

In patients with bladder dysfunctions, intermittent catheterisation is a bladder evacuation technique with a low complication rate. Therefore, it is regarded as the method of choice in the treatment of chronic residual urine, mostly due to a hypo- or acontractile detrusor. Regarding the incidence of urinary tract infections and urethral strictures, aseptic catheterisation seems to be superior to the clean technique. There are, however, no independent, prospective, controlled, randomised, double-blinded studies comparing the different catheter types. Thus, the question of which catheter is the ideal one cannot be answered yet. Predominantly in patients who have to perform intermittent catheterisation for good, the prevention of long-term complications, especially of the upper urinary tract, is of the utmost importance. In the long run, using an inadequate technique and catheters not optimally designed will clearly lead to a higher complication rate. Despite the lower prices of certain catheters, treatment of these complications will lead to higher instead of lower costs. The data available today clearly demonstrate that aseptic intermittent catheterisation is the technique of choice today. Important details of this treatment modality, however, have to be elucidated by prospective studies in the future.

[Neurourology. Current developments and therapeutic strategies]. / Neurourologie. Aktuelle Entwicklungen und Therapiestrategien.

There is no part of urology that has made so much progress in the last 25 years as neurourology. Seminal developments have been made in the selective effectiveness of drugs influencing neurogenic bladder dysfunction but having limited side effects. Additional advances are also likely to be made in the methods of functional electrostimulation and tissue engineering. Neurourology is predominantly influenced by our dynamic-functional understanding and the functionally oriented planning and implementation of treatment. The initial treatment options in many areas of neurourology are conservative, but, when possible, not irreversible. If these are ineffective or lead to late complications (e.g. by congenital paraplegia), there are a series of organ sparing or organ manipulating operations which can restore organ function. These make it possible to save kidney function from continuing damage, and, in many cases, to restore continence. The permanent indwelling catheter should remain excluded from the treatment of neurogenic bladder dysfunction. With adequate treatment, patients with neurogenic bladder dysfunction can be protected from severe complications and reintegrated into their normal social environment. After the acute phase of rehabilitation, urology is the most commonly required specialist area for paraplegic patients. In the past, urological problems have contributed most to the short lifespan of patients with an accident related spinal cord injury. Using modern neurourological treatment strategies, not only is lifespan increased but the quality of life of the patient is permanently improved.

Lack of ultrastructural detrusor changes following endoscopic injection of botulinum toxin type a in overactive neurogenic bladder.

INTRODUCTION: Endoscopical injections of Botulinum toxin type A into the detrusor muscle are gaining clinical acceptance in the treatment of neurogenic detrusor overactivity. Structural effects of Botulinum toxin type A are only known from studies on striated muscles, where a widespread nerve sprouting occurs temporarily. The aim of this study was to evaluate the ultrastructural effects of Botulinum toxin type A injections on the human detrusor. MATERIAL AND METHODS: 30 detrusor biopsies were obtained from 24 patients with neurogenic detrusor overactivity. Patients were divided into two groups: Group I included 13 biopsies from patients before the first Botulinum toxin type A injection. Group II included 6 biopsies from patients within 3 months after the first injection and 11 biopsies at the time of decreasing efficacy of Botulinum toxin type A. The biopsies were processed by standard procedure for detailed electron microscopic study and evaluated by 2 examiners without prior knowledge of clinical/urodynamic data. RESULTS: No statistically significant detrusor changes have been found concerning muscle cell fascicle structure (p = 0.445), width of intercellular space (p = 0.482) and number/kind of muscle cell junctions (p = 0.443). A median of 70% of intrinsic axon terminals presented with signs of degeneration in group I, a median of 66% in group II (p = 0.840). Out of 309 evaluated axon terminals in both groups, 1 sprouting axon was found in group I, 3 sprouting axons in group II (p = 0.864). Specimen from group I and group II showed only limited collagen deposits within the detrusor. No changes in the ultrastructure of the detrusor have been observed in those biopsies obtained before and after the Botulinum toxin type A injection of the same patient. CONCLUSION: This study verifies our earlier report of severe intrinsic axon degeneration in the detrusor of patients with neurogenic detrusor overactivity. It also shows nearly no structural differences of the detrusor before and after Botulinum toxin type A injections. Contrary to reports of striated muscle, axonal sprouting within the detrusor was very limited after Botulinum toxin type A injections indicating pathophysiologically different reactions to the toxin either between striated muscle and smooth muscle or between different treated diseases.

Effect of exercise on the mobilization of retinol and retinyl esters in plasma of sled dogs.

Fasting dogs do transport vitamin A (VA) in plasma not only as retinol but predominantly as retinyl esters. Contrary to retinol, nothing is known concerning the effects of athletic performance on plasma retinyl ester concentrations. The aim of this study was therefore to examine whether physical stress because of exercise and modification of the oxidative stress by supplementation of alpha-tocopherol influences the concentrations of retinol and retinyl esters in plasma of sled dogs. The study was carried out on 41 trained adult sled dogs, which were randomly assigned into two groups. One group (19 dogs) was daily substituted with 50 mg dl-alpha-tocopheryl acetate per kilogram body weight and the control group (22 dogs) was maintained on a basal diet during 3 months prior to exercise. The plasma concentrations of retinol, retinyl esters, alpha-tocopherol and triglycerides were measured immediately before, directly after and 24 h after exercise. The supplementation of alpha-tocopheryl acetate had no effect on plasma retinol and retinyl ester concentrations at any measurement time point. However, retinyl ester levels doubled in the non-supplemented group immediately after the race (p < 0.001), whereas in the supplemented group similar high levels were observed not until 24 h post-racing (p < 0.001). The high levels of retinyl esters were paralleled to some extent by an increase in plasma triglyceride concentrations, which were significantly higher 24 h post-racing than immediately before (p < 0.001) and after exercise (p < 0.001) in both groups. The increase in retinyl ester concentrations might be indicative of their mobilization from liver and adipose tissue. Whether plasma retinyl esters can be used as an indicator for the extent of nutrient mobilization during and post-exercise in sled dogs remains to be elucidated.

Intraoperative urodynamics in spinal cord surgery: a study of feasibility.

Intraoperative monitoring (IOM) of bladder function in spinal cord surgery is a challenging task due to vegetative influences, multilevel innervation and numerous supraspinal modulating factors. Despite routine use of urodynamics in neurosurgery for implantation of bladder stimulators or denervation of nerve fibres in spastic reflex bladders, application of IOM in patients with spinal cord tumours or tethered-cord syndrome is not widespread. Combining urodynamics with sphincter electromyography (EMG) in IOM enables identification of bladder efferents responsible for contraction and continence. We monitored four patients with ependymoma of the Cauda equina, one patient with tethered-cord syndrome and two patients with cervical intramedullary tumours. In all patients undergoing operations of the Cauda equina, identification of bladder efferents responsible for detrusor contraction was possible. There was good correlation between preoperative bladder dysfunction, preoperative urodynamics and intraoperative pressure increase by bladder contraction or latency between stimulation and contraction. This method proved unsuitable for intramedullary tumours where no contraction of the bladder could be observed while stimulating the spinal cord. Intraoperative monitoring of urodynamics is an effective tool for identifying bladder efferents in the Cauda equina. Intraoperative conclusions on bladder dysfunction through registration of pressure increase and latency are possible.

Computer prediction of human thermoregulatory and temperature responses to a wide range of environmental conditions.

A mathematical model for predicting human thermal and regulatory responses in cold, cool, neutral, warm, and hot environments has been developed and validated. The multi-segmental passive system, which models the dynamic heat transport within the body and the heat exchange between body parts and the environment, is discussed elsewhere. This paper is concerned with the development of the active system, which simulates the regulatory responses of shivering, sweating, and peripheral vasomotion of unacclimatised subjects. Following a comprehensive literature review, 26 independent experiments were selected that were designed to provoke each of these responses in different circumstances. Regression analysis revealed that skin and head core temperature affect regulatory responses in a nonlinear fashion. A further signal, i.e. the rate of change of the mean skin temperature weighted by the skin temperature error signal, was identified as governing the dynamics of thermoregulatory processes in the cold. Verification and validation work was carried out using experimental data obtained from 90 exposures covering a range of steady and transient ambient temperatures between 5 degrees C and 50 degrees C and exercise intensities between 46 W/m2 and 600 W/m2. Good general agreement with measured data was obtained for regulatory responses, internal temperatures, and the mean and local skin temperatures of unacclimatised humans for the whole spectrum of climatic conditions and for different activity levels.

Botulinum-A toxin for treating detrusor hyperreflexia in spinal cord injured patients: a new alternative to anticholinergic drugs? Preliminary results.

PURPOSE: We evaluated the efficacy of botulinum-A toxin injections into the detrusor muscle in patients with spinal cord injury, detrusor hyperreflexia and urge incontinence resistant to anticholinergic drugs. The purpose of treatment was to suppress incontinence episodes and increase functional bladder capacity. MATERIALS AND METHODS: Included in our prospective nonrandomized study done at 2 clinics were 31 patients with traumatic spinal cord injury who emptied the bladder by intermittent self-catheterization. These patients had severe detrusor hyperreflexia and incontinence despite a high dose of anticholinergic medication. Pretreatment evaluation included a clinical examination and complete urodynamic investigation. Under cystoscopic control a total of 200 to 300 units of botulinum-A toxin were injected into the detrusor muscle at 20 to 30 sites (10 units per ml. per site), sparing the trigone. Clinical and urodynamic followup was planned for 6, 16 and 36 weeks after treatment. Patients were asked to decrease their intake of anticholinergic drugs during week 1 after treatment. RESULTS: Of the 21 patients 19 underwent a complete examination 6 weeks after the botulinum-A toxin injections, and 11 at 16 and 36 weeks. At the 6-week followup complete continence was restored in 17 of 19 cases in which anticholinergic medication was markedly decreased or withdrawn. Less satisfactory results in 2 cases were associated with an insufficient dose of 200 units botulinum-A toxin. After the injections overall mean reflex volume and mean maximum cystometric bladder capacity plus or minus standard deviation significantly increased from 215.8 +/- 90.4 ml. to 415.7 +/- 211.1 (p <0.016) and 296.3 +/- 145.2 to 480.5 +/- 134.1 (p <0.016), respectively. There was also a significant decrease after treatment in mean maximum detrusor voiding pressure from 65.6 +/- 29.2 cm. water to 35 +/- 32. 1 (p <0.016). Mean post-void residual urine volume catheterized at the end of the urodynamic examination increased significantly from a mean of 261.8 +/- 241.3 ml. to 490.5 +/- 204.8 (p <0.016). Moreover, autonomic dysreflexia associated with bladder emptying that manifested as a hypertensive crisis during voiding disappeared after treatment in the 3 patients with tetraplegia. Satisfaction was high in all successfully treated patients and no side effects were observed. Ongoing improvement in urodynamic parameters and incontinence was already present in all patients reevaluated at 16 and 36 weeks. CONCLUSIONS: Botulinum-A toxin injections into the detrusor seem to be a safe and valuable therapeutic option in spinal cord injured patients with incontinence resistant to anticholinergic medication who perform clean intermittent self-catheterization. Successfully treated patients become continent again and may withdraw from or markedly decrease anticholinergic drug intake. A dose of 300 units botulinum-A toxin seems to be needed to counteract an overactive detrusor. The duration of bladder paresis induced by the toxin is at least 9 months, when repeat injections are required.

Oncotic pressure in solid tumors is elevated.

Oncotic and hydrostatic pressure differences control the movement of fluid and large molecules across the microvascular wall of normal and tumor tissues. Recent studies have shown that the interstitial fluid pressure in tumors is elevated and is approximately equal to the microvascular pressure. Whereas oncotic pressure in blood plasma of various species is known, no data are available on the oncotic pressure in the interstitial space of tumors. We hypothesize that because of the leaky nature of tumor vessels, oncotic pressure in tumor interstitium should be close to that in plasma. To this end, we first developed a chronic wick method for the direct measurement of oncotic pressures in the interstitial fluid of tumors grown in mice. We found interstitial oncotic pressures in four human tumor xenografts to be higher than in s.c. tissue and comparable to that in plasma [rhabdomyosarcoma (RD), 24.2+/-4.7; squamous cell carcinoma (FaDu), 19.9+/-1.9; small cell lung carcinoma (54A), 21.1+/-2.8; colon adenocarcinoma (LIS174T), 16.7+/-3.0 mm Hg; s.c. tissue, 8.2+/-2.3; plasma, 20.0+/-1.6 mm Hg]. These results support our hypothesis that the oncotic pressure difference across the tumor microvascular wall is low. The high oncotic pressure in tumors is consistent with the elevated interstitial fluid pressure, and it contributes to the suboptimal delivery of large therapeutic agents to neoplastic cells.