Neurogenic Dysfunction Research Articles

MiR-155 Is Essential for Inflammation-Induced Hippocampal Neurogenic Dysfunction.

Peripheral and CNS inflammation leads to aberrations in developmental and postnatal neurogenesis, yet little is known about the mechanism linking inflammation to neurogenic abnormalities. Specific miRs regulate peripheral and CNS inflammatory responses. miR-155 is the most significantly upregulated miR in primary murine microglia stimulated with lipopolysaccharide (LPS), a proinflammatory Toll-Like Receptor 4 ligand. Here, we demonstrate that miR-155 is essential for robust IL6 gene induction in microglia under LPS stimulation in vitro. LPS-stimulated microglia enhance astrogliogenesis of cocultured neural stem cells (NSCs), whereas blockade of IL6 or genetic ablation of microglial miR-155 restores neural differentiation. miR-155 knock-out mice show reversal of LPS-induced neurogenic deficits and microglial activation in vivo. Moreover, mice with transgenic elevated expression of miR-155 in nestin-positive neural and hematopoietic stem cells, including microglia, show increased cell proliferation and ectopically localized doublecortin-positive immature neurons and radial glia-like cells in the hippocampal dentate gyrus (DG) granular cell layer. Microglia have proliferative and neurogenic effects on NSCs, which are significantly altered by microglial miR-155 overexpression. In addition, miR-155 elevation leads to increased microglial numbers and amoeboid morphology in the DG. Our study demonstrates that miR-155 is essential for inflammation-induced neurogenic deficits via microglial activation and induction of IL6 and is sufficient for disrupting normal hippocampal development.

Management of neurogenic lower urinary tract dysfunction in multiple sclerosis patients.

Multiple sclerosis (MS) can be a debilitating neurological condition that attributes significant morbidity to bladder dysfunction. Although many effective treatment options exist, symptomatic patients are often underdiagnosed and undertreated. The purpose of this article is to give an overview of the current literature including new screening tools to identify symptomatic patients and updates on treatment options including medications, botulinum toxin, and neuromodulation.

Uroneurology

The function of the pelvic organs, including the lower urinary tract (LUT), is controlled by a complex network of nerves. This leaves patients with neurologic disease vulnerable to LUT and pelvic organ dysfunction. Physicians often come across urogenital complaints in their patients with neurologic disease, the symptoms of which can result in significant distress and loss of dignity and quality of life. Due to the health and economic burden that accompanies neurogenic pelvic organ dysfunction, it is important for clinicians to understand the common forms of dysfunction, essential investigations, and modes of management. This chapter covers bladder dysfunction from a physician’s perspective. Topics include neurologic control of the LUT, large bowel, and sexual functions; male and female sexual response; neurogenic bladder dysfunction and its management; diagnostic evaluation; management of neurogenic sexual dysfunction; management of erectile dysfunction; ejaculatory dysfunction; sexual dysfunction in women; and fecal incontinence. Figures illustrate efferent innervation of the LUT, neurologic detrusor overactivity, a urethral pressure profile in a patient with Fowler syndrome, an example bladder diary, an example bladder scan, and normal and obstructed flow patterns. Tables list common causes of injury at the suprapontine, suprasacral, and infrasacral levels and storage and voiding systems. This chapter contains 6 highly rendered figures, 2 tables, 53 references, 1 teaching slide set, and 5 MCQs.

PD1-10 SUPRASPINAL CONTROL OF LOWER URINARY TRACT FUNCTION IN PATIENTS WITH SPINAL CORD INJURY: AN FMRI STUDY

INTRODUCTION AND OBJECTIVES: The control of the lower urinary tract (LUT) is a complex, multilevel process involving both the peripheral and central nervous system. Most patients with spinal cord injury (SCI) suffer from neurogenic LUT dysfunction and LUT symptoms severely impair the patients’ health-related quality of life. Although there are several concepts regarding neuronal control and perception in the normal and pathological LUT condition, the exact mechanisms involved remain to be elucidated. METHODS: In this functional magnetic resonance imaging (fMRI) study, we prospectively assessed 20 patients (mean age 43 years old, range 25e75) with cervical and thoracic SCI (12 with complete and 8 with incomplete lesion) suffering from neurogenic detrusor overactivity. All subjects underwent data acquisition in a 3 Tesla scanner. The scan paradigm (SP) comprised 3 different bladder stimulations: (1) repetitive bladder filling of 100mL body warm saline starting with an empty bladder, (2) repetitive infusion and withdrawal (100mL) of body warm saline starting with a pre-filled bladder and (3) repetitive bladder filling of 100mL cold saline. Date was analysed using SPM8. Second-level random effects group analysis (at a voxel-threshold of P<0.001 using false discovery rate correction at cluster level) was performed to account for between subject variability. Only subjects with significant activity (first-level analysis, P1⁄40.05 familywise error rate) were included. RESULTS: 6 subjects had to be excluded from certain analysis due to excessive head motions, autonomic dysreflexia or urinary incontinence during data acquisition. At first-level analysis, we found significant activation in 67% (12/17), 56% (9/15) and 66% (10/15) for SP (1), (2) and (3), respectively. At second-level analysis, significant activation was found in all 3 SP. (1): right inferior frontal gyrus (BA 45), left middle frontal gyrus (BA 10/46), left superior medial frontal gyrus, dorsal posterior cingulate area (BA 31) and bilateral middle temporal gyrus (BA21); (2): anterior left insula and inferior parietal lobe; (3): right precentral gyrus (BA 6) and left superior parietal lobe (BA 7). Activations were seen in both complete and incomplete SCI patients. CONCLUSIONS: In our patients with SCI, significant brain activation similar as reported for healthy subjects, non-neurological and other neurological patients with detrusor overactivity was detected. SP (1) showed activation in more brain areas than (2) and (3). Our findings suggest that extra-spinal sensory pathways might also be involved in LUT control.

1095 Neurogenic lower urinary tract dysfunction in patients with spinal cord injury: Long-term urodynamic findings

1095 Neurogenic lower urinary tract dysfunction in patients with spinal cord injury: Long-term urodynamic findings

Dysuria, Urinary Retention, and Inguinal Pain as Manifestation of Sacral Bannwarth Syndrome.

Only few cases with sacral radiculitis due to infection with Borrelia burgdorferi leading to neurogenic urinary dysfunction have been reported. A 57-year-old male developed urethral pain and urinary retention, requiring permanent catheterization. Extensive urological investigations did not reveal a specific cause, which was why neurogenic bladder dysfunction was suspected. Neurologic exam revealed only mildly reduced tendon reflexes. Cerebral and spinal MRI were noninformative. CSF investigations, however, revealed pleocytosis, elevated protein, and antibodies against Borrelia burgdorferi. Intravenous ceftriaxone for three weeks resulted in immediate improvement of bladder dysfunction, with continuous decline of residual urine volume and continuous increase of spontaneous urine volume even after removal of the catheter and initiation of self-catheterization. Sacral radiculitis due to infection with Borrelia burgdorferi is a potential cause of detrusor areflexia and urethral, perineal, inguinal, and scrotal pain and may be misinterpreted as cystitis or urethritis. Ceftriaxone may result in progressive recovery of bladder dysfunction and pain. Neuroborreliosis may manifest exclusively as neurourological problem.

A mathematical model of salt‐sensitive hypertension: the neurogenic hypothesis

AbstractSalt sensitivity of arterial pressure (salt‐sensitive hypertension) is a serious global health issue. The causes of salt‐sensitive hypertension are extremely complex and mathematical models can elucidate potential mechanisms that are experimentally inaccessible. Until recently, the only mathematical model for long‐term control of arterial pressure was the model of Guyton and Coleman; referred to as the G‐C model. The core of this model is the assumption that sodium excretion is driven by renal perfusion pressure, the so‐called ‘renal function curve’. Thus, the G‐C model dictates that all forms of hypertension are due to a primary shift of the renal function curve to a higher operating pressure. However, several recent experimental studies in a model of hypertension produced by the combination of a high salt intake and administration of angiotensin II, the AngII–salt model, are inconsistent with the G‐C model. We developed a new mathematical model that does not limit the cause of salt‐sensitive hypertension solely to primary renal dysfunction. The model is the first known mathematical counterexample to the assumption that all salt‐sensitive forms of hypertension require a primary shift of renal function: we show that in at least one salt‐sensitive form of hypertension the requirement is not necessary. We will refer to this computational model as the ‘neurogenic model’. In this Symposium Review we discuss how, despite fundamental differences between the G‐C model and the neurogenic model regarding mechanisms regulating sodium excretion and vascular resistance, they generate similar haemodynamic profiles of AngII–salt hypertension. In addition, the steady‐state relationships between arterial pressure and sodium excretion, a correlation that is often erroneously presented as the ‘renal function curve’, are also similar in both models. Our findings suggest that salt‐sensitive hypertension is not due solely to renal dysfunction, as predicted by the G‐C model, but may also result from neurogenic dysfunction.

Evaluation of urinary dysfunction by urodynamic tests, electromyography and quality of life questionnaire before and after surgery for deep infiltrating endometriosis

ObjectiveTo evaluate urinary dysfunction and quality of life before and after surgery for deep infiltrating endometriosis (DIE). MethodsThis prospective study included 50 patients with DIE who required surgery. Urinary dysfunction was evaluated before and after surgery by both urodynamic tests and electromyography, and the Bristol Female Lower Urinary Tract Symptoms (BFLUTS) quality-of-life questionnaire. ResultsPreoperative electromyography showed that 14 patients (28%) had neurogenic alteration involving sacral reflex and pelvic floor muscles correlated with the presence of colorectal endometriosis (p=0.003). Postoperative quality of life and BFLUTS total scores were improved compared to preoperative scores (p=0.001 and p=0.005, respectively). After an initial improvement in BFLUTS, an alteration is observed at long-term (median follow-up of 66 months). In the 34 patients with pre- and postoperative urodynamic measurements, no difference was found before and after surgery. De novo peripheral neuropathy was only observed in patients who underwent DIE resection with colorectal resection (p=0.02). ConclusionsOur results support that patients with DIE have a high incidence of preoperative urinary symptoms and neurogenic dysfunction. Colorectal resection appears to be a determinant factor of de novo peripheral neuropathy.

Management of benign prostatic hyperplasia: role of phosphodiesterase-5 inhibitors.

Several studies have highlighted a strong association between benign prostatic hyperplasia/lower urinary tract symptoms (BPH/LUTS) and erectile dysfunction (ED), particularly in elderly men. Many epidemiological trials, such as in vitro and in vivo studies, have reported the emerging role of metabolic syndrome, including abdominal obesity, impaired glucose metabolism, hypertriglyceridemia, low high-density lipoprotein cholesterol, and hypertension, in the development and progression of urinary and sexual symptoms. Moreover, many authors have focused their studies on the identification of all the shared pathogenetic mechanisms of LUTS/BPH and ED, including alteration of cyclic guanosine monophosphate and RhoA-ROCK pathways or vascular and neurogenic dysfunction. All these are potential targets for proposed phosphodiesterase type 5 inhibitors (PDE5-Is). Therefore, several trials have recently been designed to evaluate the role of PDE5-Is alone or in combination with conventional treatment for BPH, such as α-adrenergic blockers, in men affected by LUTS/BPH, with or without ED. Different PDE5-Is are in clinical use worldwide and currently six of them are licensed for the oral treatment of ED. All these compounds differ in pharmacokinetic factors, with influence on drug action, and subsequently in the overall safety and efficacy profile.

764 Ice water test in patients with neurogenic lower urinary tract dysfunction: Before or after urodynamics?

764 Ice water test in patients with neurogenic lower urinary tract dysfunction: Before or after urodynamics?

769 Sacral neuromodulation in patients with neurogenic lower urinary tract dysfunction

769 Sacral neuromodulation in patients with neurogenic lower urinary tract dysfunction

MP80-14 BOTULINUM TOXIN A: THE SHIFT TO A MINIMALLY INVASIVE MANAGEMENT OF NEUROGENIC BLADDER

INTRODUCTION AND OBJECTIVES: The key in management of neurogenic dysfunction of the lower urinary tract is the maintenance of low storage pressures. First line treatment is anticholinergic therapy with intermittent catheterization. Once patients are refractory to anticholinergic therapy, augmentation cystoplasty (AC) has traditionally been used to create a high capacity, low-pressure reservoir. Yet, this procedure is associated with a high complication rate. The FDA approved Botulinum toxin A (BTX-A) in August of 2011 for the treatment of neurogenic detrusor over activity (NDO). Multiple studies have shown its effectiveness in neurogenic bladders with associated improvements in incontinence episodes and urodynamic parameters. Our study reviews how the advent of BTX-A has changed modern treatment of NDO. METHODS: We performed a retrospective chart review from 2003-2013 of patients seen in our Urology practice with anticholinergic refractory NDO that underwent AC or cystectomy with urinary diversion. We analyzed their charts and testing data to see how many patients would have met the indication for BTX-A. Furthermore, we compared our practice since the incorporation of BTX-A to see how our treatment of NDO has changed. RESULTS: 59 patients met inclusion criteria for our study. 34 patients underwent reconstructive surgery for NDO. The remaining 25 patients have been managed with BTX-A detrusor injections (available since August 2011). Review of the 34 patients that underwent open surgery revealed 21 (62%) would have met indication for BTX-A injections. Additionally, 30 of the 34 patients that underwent reconstructive surgery had surgery in the first 8 years of the study resulting in nearly 4 open surgeries for NDO per year. After BTX-A was introduced in 2011 the number of open reconstructive surgeries at our institution was reduced to less than 2 per year. During that same time period an average of 12 patients per year were managed with BTX-A. Of the 34 reconstructive patients, 14 (41%) had a complication with 10 (29%) requiring a repeat procedure. Conversely, only one BTX-A patient (4%) had a complication for which further intervention was not required. CONCLUSIONS: Anticholinergic refractory NDO is a complex disorder that impairs quality of life and often threatens the upper urinary tracts. Although it is not the answer for every patient, BTX-A has become an effective minimally invasive alternative to urinary reconstruction. This study demonstrates how the addition of BTX-A is evolving the care of NDO patients.

Neuroanatomy, Neurophysiology, and Dysfunction of the Female Lower Urinary Tract

The 2 major functions of the lower urinary tract are the storage and emptying of urine. These processes are controlled by complex neurophysiologic mechanisms and are subject to injury and disease. When there is disruption of the neurologic control centers, dysfunction of the lower urinary tract may occur. This is sometimes referred to as the "neurogenic bladder." The manifestation of dysfunction depends on the level of injury and severity of disruption. Patients with lesions above the spinal cord often have detrusor overactivity with no disruption in detrusor-sphincter coordination. Patients with well-defined suprasacral spinal cord injuries usually present with intact reflex detrusor activity but have detrusor sphincter dyssynergia, whereas injuries to or below the sacral spinal cord usually lead to persistent detrusor areflexia. A complete gynecologic, urologic, and neurologic examination should be performed when evaluating patients with neurologic lower urinary tract dysfunction. In addition, urodynamic studies and neurophysiologic testing can be used in certain circumstances to help establish diagnosis or to achieve better understanding of a patient's vesicourethral functioning. In the management of neurogenic lower urinary tract dysfunction, the primary goal is improvement of a patient's quality of life. Second to this is the prevention of chronic damage to the bladder and kidneys, which can lead to worsening impairment and symptoms. Treatment is often multifactorial, including behavioral modifications, bladder training programs, and pharmacotherapy. Surgical procedures are often a last resort option for management. An understanding of the basic neurophysiologic mechanisms of the lower urinary tract can guide providers in their evaluation and treatment of patients who present with lower urinary tract disorders. As neurologic diseases progress, voiding function often changes or worsens, necessitating a good understanding of the underlying physiology in question.

Urodynamics for Spinal Cord Injury – How, When, Why

Patients with spinal cord injury (SCI) often have lower urinary tract dysfunction. Their urological dysfunction should be managed as part of their overall holistic care in a specialist SCI unit. Whilst level of disease can cause broad categories of urological problems, lower urinary tract symptoms may be complex and difficult. Urodynamic studies investigate the urinary tract by measurement of flow and pressure. Urodynamic studies perform an important role in the urological management of patients with SCI. Invasive video urodynamic studies are the gold standard urodynamics of choice in these patients due to the extra information that can be gleaned from fluoroscopy. The major complication of neurogenic lower urinary tract dysfunction is of a risk to the upper tracts. Baseline urodynamic studies are performed in patients with SCI to assess symptoms and risk to the upper tracts, so that management can be planned accordingly. The optimum follow-up schedule for urodynamics remains controversial.

Use of homeopathy for prophylaxis of urinary tract infections in patients with neurogenic bladder dysfunction

Background: Patients with neurogenic bladder dysfunction are prone to various urologic disorders which sometimes cannot be appropriately treated. Especially recurrent urinary tract infections (UTI) in patients with spinal cord injury are a frequent clinical problem. Often, conventional preventive measures are not successful. We present our initial results of collaboration between homeopaths and urologists in these patients. Materials and Methods: after exclusion of morphologic abnormalities and initiation of a standard regime for prophylaxis, all patients with a neurogenic lower urinary tract dysfunction (NLUTD) due to spinal cord injury (SCI) with more than 3 symptomatic UTI/year were offered additional homeopathic care (classical homeopathy with an individualized approach). UTI symptoms were fever, incontinence, increased spasticity, decreased bladder capacity or pain/decreased general health combined with significant bacteriuria. Results: Five of seven patients opted for homeopathic treatment. The bacterial strains detected in urinalysis were E. coli, proteus mirabilis and Klebsiella pneumonia, respectively. Morphologic and functional reasons for recurrent UTI were excluded by sonography, cystoscopy and urodynamics. After treatment, with a median follow-up of 15 months, 3 of these patients remained free of UTI, whereas UTI frequency was reduced in the other 2 patients. In three patients, standard prophylactic treatment could be reduced. No side effects were encountered. Conclusion: Our initial experience with homeopathic prevention of UTI is encouraging. Keys for a fruitful cooperation are well-qualified partners, mutual respect and the motivation to cooperate closely. For an evidence-based evaluation of this concept, prospective studies are required.

Usefulness of classical homoeopathy for the prevention of urinary tract infections in patients with neurogenic bladder dysfunction: A case series

Context: In patients with neurogenic lower urinary tract dysfunction due to Spinal Cord Injury (SCI), recurrent Urinary Tract Infections (UTI), is a frequently encountered clinical problem. Often, conventional preventive measures are not successful. Aims: To treat the patients of SCI suffering from recurrent UTI with classical homoeopathy as add-on to standard urologic care. Materials and Methods: After exclusion of morphological abnormalities and initiation of a standard regime for prophylaxis, all patients with a neurogenic lower urinary tract dysfunction due to SCI, with more than three symptomatic UTI/year, were offered additional homoeopathic care. Symptoms were fever, incontinence, increased spasticity, decreased bladder capacity or pain/decreased general health combined with significant bacteriuria. Descriptive statistics was used for analysis. Results: Eight patients were followed up for a median period of 15 months. Five patients remained free of UTI, whereas UTI frequency was reduced in three patients. Conclusion: Our initial experience with homoeopathic prevention of UTI as add on to standard urologic prophylactic measures is encouraging. For an evidence-based evaluation of this concept, prospective studies are required. Keys for the positive outcome of this case series are co-operation of well-qualified partners, mutual respect and the motivation to co-operate closely.

Dysautonomia and its underlying mechanisms in the hypermobility type of Ehlers–Danlos syndrome

ObjectivesMany non-musculoskeletal complaints in EDS-HT may be related to dysautonomia. This study therefore aims to investigate whether dysautonomia is present and to explore the underlying mechanisms. MethodsA total of 39 females with EDS-HT and 35 age-matched controls underwent autonomic function testing. Resting autonomic tone was assessed using heart rate variability (frequency domain) and baroreflex sensitivity analysis (cross correlation). Autonomic reactivity was assessed using the Autonomic Reflex Screen test battery. Factors suspected to contribute to dysautonomia, e.g., neuropathy, medication use, decreased physical activity, depression, pain-induced sympathetic arousal, and connective tissue laxity, were quantified using validated questionnaires, the Beighton score, and measurement of skin extensibility. ResultsThe EDS-HT group showed autonomic deregulation with increased sympathetic activity at rest and reduced sympathetic reactivity to stimuli. Increased resting activity was indicated by a higher LF/HF ratio compared to controls (1.7 ± 1.23 vs 0.9 ± 0.75, p = 0.002); decreased reactivity by a greater BP fall during valsalva (−19 ± 12 vs −8 ± 10, p < 0.001), and a smaller initial diastolic BP increase during tilt (7% vs 14%, p = 0.032). Orthostatic intolerance was significantly more prevalent in EDS-HT than controls (74% vs 34%) and was most frequently expressed as postural orthostatic tachycardia. Lowered QSART responses suggest that sympathetic neurogenic dysfunction is common in patients (p < 0.013), which may explain the dysautonomia in EDS-HT. Further, connective tissue laxity and vasoactive medication use were identified as important factors in aggravating dysautonomia (p < 0.035). ConclusionDysautonomia consisting of cardiovascular and sudomotor dysfunction is present in EDS-HT. Neuropathy, connective tissue laxity, and vasoactive medication probably play a role in its development.

Update on Female Neurogenic Lower Urinary Tract Dysfunction

There are various etiologies to neurogenic lower urinary tract dysfunction (NLUTD). Anticholinergic therapy and intermittent catheterization have been the mainstay in management of these patients. Newer modalities including neuromodulation (not US Food and Drug Administration approved for this Indication) and intravesical botulinum toxin injection continues to advance the care of these patients resulting in improved quality of life. Female patients with NLUTD offer specific challenges in management that the provider must consider to provide the highest quality of care. This article reviews the various options available today as well as several potential therapies that may be available in the future.

Uroneurology

The function of the pelvic organs, including the lower urinary tract (LUT), is controlled by a complex network of nerves. This leaves patients with neurologic disease vulnerable to LUT and pelvic organ dysfunction. Physicians often come across urogenital complaints in their patients with neurologic disease, the symptoms of which can result in significant distress and loss of dignity and quality of life. Due to the health and economic burden that accompanies neurogenic pelvic organ dysfunction, it is important for clinicians to understand the common forms of dysfunction, essential investigations, and modes of management. This chapter covers bladder dysfunction from a physician’s perspective. Topics include neurologic control of the LUT, large bowel, and sexual functions; male and female sexual response; neurogenic bladder dysfunction and its management; diagnostic evaluation; management of neurogenic sexual dysfunction; management of erectile dysfunction; ejaculatory dysfunction; sexual dysfunction in women; and fecal incontinence. Figures illustrate efferent innervation of the LUT, neurologic detrusor overactivity, a urethral pressure profile in a patient with Fowler syndrome, an example bladder diary, an example bladder scan, and normal and obstructed flow patterns. Tables list common causes of injury at the suprapontine, suprasacral, and infrasacral levels and storage and voiding systems. This review contains 6 highly rendered figures, 2 tables, and 53 references.

Electrophysiological study of the bulbocavernosus reflex: normative data.

In the clinical setting the bulbocavernosus reflex (BCR) is elicited by squeezing the glans penis and digitally palpating the contraction of the bulbocavernosus (BC) muscle. In neurophysiology the BCR is obtained by stimulating the dorsal nerve of the penis or clitoris and by recording the response from BC muscle and it should be performed in selected patients with suspected urinary, bowel, or sexual neurogenic dysfunction. The BCR is considered one of the sacral neurophysiological tests of the greatest clinical utility. Previous normative data were obtained on small samples. The aim of this study was to determine normative values for the BCR in a large sample of men. We studied a large population (105 men; mean age 53 years, range 19-73 years) without central or peripheral neurological diseases. In each subject the sacral reflex was elicited by electrical stimulation of the base of the dorsum penis and recorded using a surface electrode from the BC muscle. We recorded the latency, calculated at onset, and the maximal amplitude of response, calculated peak to peak. We were able to detect the BCR in all the men. No correlation between BCR latency and age was found (r=0.136; p=0.160). The mean onset latency value was 33.0±4.85 ms (mean±2SD, range 26.8-39.4). The mean amplitude value was 16.53±12.21 μV (mean±2SD, range 4.2-43.6). Our normative data on the BCR were similar to previously published data.