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.

[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.

[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.

[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.

[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.

[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.

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.

Blood flow, metabolism, cellular microenvironment, and growth rate of human tumor xenografts.

Better understanding of the micromilieu of human tumors in situ is mandatory for further improvement of diagnostic and therapeutic interventions. Since investigations of untreated tumors of a wide size range are precluded in humans for ethical reasons, size-dependent changes in the pathophysiology of primary and metastatic human tumors were studied using "tissue-isolated" xenografts in nude rats. Tumor types included lung and breast cancers, ovarian and thyroid carcinomas, uterus tumors, and melanomas. A 10-fold variation in weight-adjusted tumor perfusion indicated large variations in angiogenesis which were unrelated to tumor type. Flow values obtained were consistent with data from clinical observations and were comparable to that in isografted rodent tumors. Using actual consumption and supply rates, maximum oxygen and glucose uptake rates were calculated for each tumor type. The capacity to consume oxygen and glucose varied 9-fold and 4-fold, respectively. However, considering actual consumption rates, blood flow was the principal modulator of substrate supply and tumor metabolism in these human tumor xenografts. Consequently, therapeutically relevant parameters of the metabolic micromilieu largely depended on the efficacy of the tumor circulation. Hereby, high metabolic rates concomitant with high flow values coincided with rapid tumor growth. Thus, in order to design the best individualized therapy, flow-related data should supplement histological classification and clinical staging and grading. Further development of relatively noninvasive technologies (magnetic resonance imaging, magnetic resonance spectroscopy, or positron emission tomography) might permit such monitoring.

Acute changes of systemic parameters in tumour-bearing rats, and of tumour glucose, lactate, and ATP levels upon local hyperthermia and/or hyperglycaemia.

Arterial blood pressure and relevant parameters of the arterial blood (O2 and CO2 tensions, pH, haematocrit, serum electrolytes and osmolality) were determined in tumour-bearing rats upon local hyperthermia (HT) and/or hyperglycaemia (HG). Tumour heating was performed in a saline bath (44 degrees C) for 120 min; hyperglycaemia was induced by i.v. infusion of 40% glucose solution for 150 min [blood glucose levels: 35-40 mM during heating; total amount of glucose: 1.19 g/100 g body wt.; infusion rates: 0.31 ml (100 g body wt.)-1 min-1 for 2 min, 0.02 ml (100 g body wt.)-1 min-1 for 88 min, and 0.01 ml (100 g body wt.)-1 min-1 for 60 min]. Immediately after treatment, glucose, lactate and ATP levels were determined in tumour and muscle specimens and compared to these values under normothermic (NT) and/or normoglycaemic (NG) conditions. In all groups (NT/NG, NT/HG, HT/NG, HT/HG) there were only minor but characteristic changes in blood parameters, which were mainly due to the volume and type of the infused fluids (glucose solution, saline). During hyperglycaemia, tumour glucose levels rose 13- to 17-fold, whereas muscle glucose concentrations exhibited only a 3- to 5-fold increase; lactate levels were 1.9-2.5 times higher in tumours than in muscle, indicating an increase in the metabolic differences between normal and malignant tissues. Despite an increased glucose availability, tumours did not show an improved energy status and, thus, would not be expected to develop a decrease in thermal sensitivity or stimulation in growth rate. The good systemic tolerability of the combined treatment (HT/HG) and the differential changes in malignant and normal tissue occurring under these conditions, support further attempts to manipulate tumour metabolic environment by glucose in order to achieve better therapeutic results.

Laser Doppler flux and tissue oxygenation of experimental tumours upon local hyperthermia and/or hyperglycaemia.

Laser Doppler fluxmetry and oxygen partial pressure (pO2) histography have been applied to investigate the acute effects of hyperthermia (HT) and/or hyperglycaemia (HG) on microcirculatory function and tissue oxygenation of subcutaneous rat tumours growing on the dorsum of the hind foot. The experiments were performed to test whether, and to what extent, the two adjunct treatment modalities applied alone or in combination can modify these therapeutically relevant parameters. Local HT was performed in a saline bath (44 degrees C) for 2 h; HG was induced by i.v. infusion of 40% glucose solution for 2.5 h (blood glucose levels: 35-40 mM during heating). Laser Doppler flux (LDF) in superficial tumour tissue regions was recorded over the entire treatment period; tumour pO2 distribution was evaluated immediately after termination of the treatment. HG alone reduced the average LDF signal to 18% of the baseline reading before treatment, but did not influence the tumour oxygenation status and the proportion of pO2 readings occurring in the radiobiologically hypoxic class (pO2 = O-2.5 mm Hg). This phenomenon is most probably due to the occurrence of the Crabtree effect (reduction of the O2 consumption rate when excess glucose is available within a malignant tumour). Hyperthermia alone reduced LDF to approximately the same extent, and led to a rise in the number of pO2 readings in the hypoxic range with only minor changes in the average pO2. The combined treatment (HT/HG) neither increased the fraction of "hypoxic" pO2 readings nor intensified the flow drop already present at the end of the tumour heating. It is thus concluded that under hyperglycaemia the oxygenation status of normothermic and heated tumours is maintained. It may therefore be hypothesized that hyperthermia in conjunction with hyperglycaemia might be a better "radiosensitizer" than hyperthermia alone.

A computer model of human thermoregulation for a wide range of environmental conditions: the passive system.

A dynamic model predicting human thermal responses in cold, cool, neutral, warm, and hot environments is presented in a two-part study. This, the first paper, is concerned with aspects of the passive system: 1) modeling the human body, 2) modeling heat-transport mechanisms within the body and at its periphery, and 3) the numerical procedure. A paper in preparation will describe the active system and compare the model predictions with experimental data and the predictions by other models. Here, emphasis is given to a detailed modeling of the heat exchange with the environment: local variations of surface convection, directional radiation exchange, evaporation and moisture collection at the skin, and the nonuniformity of clothing ensembles. Other thermal effects are also modeled: the impact of activity level on work efficacy and the change of the effective radiant body area with posture. A stable and accurate hybrid numerical scheme was used to solve the set of differential equations. Predictions of the passive system model are compared with available analytic solutions for cylinders and spheres and show good agreement and stable numerical behavior even for large time steps.

Management of neurogenic fecal incontinence in myelodysplastic children by a modified continent appendiceal stoma and antegrade colonic enema.

OBJECTIVES: Antegrade colonic enemas for neurogenic fecal incontinence via reverse reimplanted appendices (Mitrofanoff principle) have been primarily reported by Malone and coworkers in 1990. We used a modification of the described surgical technique and treated the first 10 patients with neurogenic fecal incontinence due to spina bifida. The surgical procedure and the results are reported. METHODS: Since November 1991, we have used a surgical procedure similar to the appendiceal continence mechanism in urinary diversion to establish a continent colonic cutaneous stoma for antegrade enemas in 10 myelodysplastic patients (4 females, 6 males; median age 13.2 years [range 6 to 26]) with severe neurogenic fecal incontinence. The average follow-up is now 26.4 months (range 12.5 to 50). All patients had neurogenic bladder dysfunction successfully managed by clean intermittent catheterization, anticholinergic drugs, or artificial sphincter implantation. The surgical technique for fecal incontinence included the partial orthotopic submucosal imbedding of the appendix into a cecal tenia and the fixation of the ileocecal region at the inner side of the abdominal wall after creation of an appendicocutaneous catheterizable stoma. RESULTS: All patients reached fecal continence for at least 38 hours (median 45.3) by using antegrade colonic enemas with 1.5% saline solution (n = 9) or GoLYTELY solution (n = 1), 0.5 to 1.5 L every 2 to 3 days. All other therapies (diet, oral medication, rectal purgative, or enema) to reach fecal continence had previously failed. There were only two complications seen at the follow-up. One boy with an artificial urinary sphincter presented with infection of the sphincter system, which led to explantation. Another boy presented 15 months after creation of the colonic appendiceal stoma with saline intoxication possibly due to a homemade saline solution. CONCLUSIONS: We conclude that the antegrade colonic enema via an orthotopic continent appendiceal stoma is a safe and highly effective treatment modality for fecal incontinence in patients with neurogenic bowel dysfunction if nonsurgical management has failed.

Protective effect of vitamin E in a rat model of focal cerebral ischemia.

Under certain pathological conditions such as cerebral ischemia and reperfusion the occurrence of free radicals is remarkably increased. However, only very little information is available on their quantitative relevance for the pathophysiology and final outcome of diseases. The aim of the present study was to evaluate the contribution of oxygen radicals in the pathogenesis of a stroke. For this purpose a rat model for stroke was used. Two of three vitamin E deficient groups were repleted with different dosages of DL-alpha-tocopherylacetate. No signs of vitamin E deficiency could be observed. However, the weight gain during repletion was increased in the vitamin E repleted groups. Brain infarction was created by occlusion of the right middle cerebral artery (MCAO) for two hours. After 24 hours the measurements of infarct volumes were taken. The infarct volume of the group with the highest repletion dosage was significantly reduced by 81%. This was also expressed in a higher rate of gait disturbances after MCAO of the deficient animals. The control of vitamin E status exhibited a similar repletion-dependent level in plasma and brain. These results strongly support the hypothesis that the generation of oxygen radicals occurring during reperfusion is an important aspect of the pathophysiological mechanism in brain infarction.

[Surgical therapy of voiding disorders in patients suffering from spinal cord injury (author's transl)]. / Die operative Behandlung der Blasenentleerungsstörung beim Querschnittgelähmten.

The development of modern urodynamic examinations permits improved differentiation of bladder voiding disturbances in paraplegic patients. This allows surgical approaches to be more specific and individually oriented. Transurethral intervention at the closure mechanism of the urethra is indicated prior to the appearance of secondary alterations of the urinary tract. Surgical intervention should bring about bladder emptying in which the pressure-flow relationship approaches nearly physiologic values. Even when advanced secondary alterations are present, effective improvement is possible under avoidance of major surgery. It is preferable to bring these patients together in specialized departments. Regular, annual urodynamic follow-up investigations are important since they appear to improve the prognosis of the paraplegic patient.

[Urinary tract infection in the paraplegic patient (author's transl)]. / Die Infektion der Harnwege beim Querschnittgelähmten.

Incomplete bladder emptying due to infravesical outflow obstruction appears as the main cause of urinary tract infection in patients suffering from spinal cord injury. Antibiotic therapy is only considered helpful when appropriate diagnosis or surgical therapy demonstrate a balanced micturition. The particular situation of the paraplegic patient is demonstrated with respect to causative factors, therapy, and prophylaxis of infection and follow-up treatment.

[High-dose trospium chloride in therapy of detrusor hyperreflexia]. / Hochdosierte Applikation von Trospiumchlorid zur Therapie der Detrusorhyperreflexie.

The efficacy and tolerance of a high-dose treatment with trospium chloride (20 mg twice daily) were investigated in pilot studies carried out in three trial centres and involving a total of 29 patients suffering from reflex bladder due to transverse lesions of the spinal cord with paraplegia. In all three centres the trial procedure was the same. Urodynamic measurements (maximum bladder capacity, bladder compliance, maximum detrusor pressure during micturition, urinary flow and residual urine) were taken both before and after treatment with trospium chloride for a period of at least 2 weeks. In almost all patients there was a clear rise in maximum bladder capacity, a marked decrease in maximum detrusor pressure and an increase in bladder compliance. As a result the frequency of micturitions was lowered. In the majority of patients, urinary incontinence caused by detrusor hyperreflexia was brought under control through depression of detrusor activity, and urinary continence was achieved. If necessary, intermittent catheterization was continued to empty the bladder. Tolerance of the test preparation was good, and side-effects were rare and mild.

[Detrusor myectomy (autoaugmentation) in the treatment of hyper-reflexive low compliance bladder]. / Die Detrusormyektomie (Autoaugmentation) in der Behandlung der hyperreflexiven Low-compliance-Blase.

After unsuccessful medical treatment of a neurogenic hyperreflexive bladder dysfunction further treatment options are the ileal bladder augmentation, the detrusor-myectomy (bladder auto-augmentation) and the sacral root deafferentation. All techniques lead to a low-pressure bladder with enlarged storage volume. The authors here report about their personal experience with the detrusor myectomy in 62 patients with hyperreflexive neurogenic bladder dysfunction from 1989 until 1998. Indication, surgical technique, and long-time results are presented.