Neo-Adjuvant chemotherapy and its affects to the axilla-Can we safely downgrade axillary surgery to mirror the approach in the breast.

The use of neo-adjuvant chemotherapy (NACT) to downgrade surgery in the breast from mastectomy to breast-conserving surgery is well-established. In certain patients, the use of adjuvant axillary radiotherapy can be safe and effective in place of axillary node clearance. What remains less clear are the alternative surgical options to the axilla following NACT. The aim of this study was to examine the effects of NACT in the axilla and whether downgrading axillary node clearance to axillary conserving surgery to mirror the approach in the breast may be a viable and safe practice. Patients undergoing neo-adjuvant chemotherapy were identified over a seven-year period between 2010 and 2017. Surgical plans were compared with pre- and post-chemotherapy. Histological information at the time of diagnosis was compared to surgical excision specimens. 349 patients were included for analysis, and 264 had axillary status documented at diagnosis. The average patient age was 51 years, and Grade 3, ER-positive, and Her2-negative cancers made the biggest histological subgroups. Complete pathological response (CPR) was seen in the breast in 27% of cases. 19% of patients requiring mastectomy had their surgery downgraded. Following NACT, axillary CPR was seen in 42% of patients and residual axillary nodal burden was limited to four nodes in 73% of patients. Axillary conserving surgery may be a safe alternative surgical approach in the downstaged axilla following neo-adjuvant chemotherapy. Advances in perioperative identification of suspicious nodes may be needed to facilitate progress.

Open-label study evaluating outpatient urethral sphincter injections of onabotulinumtoxinA to treat women with urinary retention due to a primary disorder of sphincter relaxation (Fowler's syndrome).

OBJECTIVES: To assess the efficacy (defined as improvements in maximum urinary flow rate [Qmax ] of ≥50%, post-void residual urine volume [PVR] and scores on the International Prostate Symptom Score [IPSS] questionnaire) and safety of urethral sphincter injections of onabotulinumtoxinA in women with a primary disorder of urethral sphincter relaxation, characterised by an elevated urethral pressure profile (UPP) and specific findings at urethral sphincter electromyography (EMG), i.e. Fowler's syndrome. PATIENTS AND METHODS: In this open-label pilot Institutional Review Board-approved study, 10 women with a primary disorder of urethral sphincter relaxation (elevated UPP, sphincter volume, and abnormal EMG) presenting with obstructed voiding (five) or in complete urinary retention (five) were recruited from a single tertiary referral centre. Baseline symptoms were assessed using the IPSS, and Qmax and PVR were measured. After 2% lidocaine injection, 100 U of onabotulinumtoxinA was injected into the striated urethral sphincter, divided on either side, under EMG guidance. Patients were reviewed at 1, 4 and 10 weeks after injection, and assessed using the IPSS, Qmax and PVR measurements. The UPP was repeated at week 4. RESULTS: The mean (range) patient age was 40 (25-65) years, and the mean symptom scores on the IPSS improved from 25.6 to 14.1, and the mean 'bother' score reduced from 6.1 to 3.5 at week 10. As compared with a baseline mean Qmax of 8.12 mL/s in the women who could void, the Qmax improved to 15.8 mL/s at week 10. Four of the five women in complete retention could void spontaneously, with a mean Qmax of 14.3 mL/s at week 10. The mean PVR decreased from 260 to 89 mL and the mean static UPP improved from 113 cmH2 O at baseline to 90 cmH2 O. No serious side-effects were reported. Three women with a history of recurrent urinary tract infections developed a urinary tract infection. There were no reports of stress urinary incontinence. Seven of the 10 women opted to return for repeat injections. CONCLUSIONS: This pilot study shows an improvement in patient-reported lower urinary tract symptoms, and the objective parameters of Qmax , PVR and UPP, at 10 weeks after urethral sphincter injections of onabotulinumtoxinA. No serious side-effects were reported. This treatment could represent a safe outpatient treatment for young women in retention due to a primary disorder of urethral sphincter relaxation. However, a larger study is required to confirm the findings of this pilot study.

Fowler's syndrome of urinary retention: A retrospective study of co-morbidity.

AIMS: To study the frequency of pain, psychological, or functional disorders in patients with Fowler's syndrome. METHODS: We carried out a retrospective chart review of patients with a diagnosis of Fowler's syndrome attending the Uro-Neurology centre at the National Hospital for Neurology and Neurosurgery between 2009 and 2013 looking at triggering events, physical and psychological comorbidities. RESULTS: Of 62 patients with clinical and electromyographic diagnosis of Fowler's syndrome, 31 (50%) had unexplained chronic pain syndromes, 12 (19%) of these were taking opiates. Fifteen (24%) had "functional" neurological symptoms. Abdominopelvic surgery with general anesthesia was the leading trigger (n = 21, 35%). CONCLUSIONS: We found high levels of co-morbidity with patients having some form of pain (50%), a probable functional disorder (24%), or psychological symptoms (31%). There are several potential explanations for this association including the effect of developing an apparently unexplained distressing condition, confounding effect of opiate use or referral bias. The findings suggest a need for prospective systematic study of comorbidity for this disabling condition. Neurourol. Urodynam. 35:601-603, 2016. © 2015 Wiley Periodicals, Inc.

Is overactive bladder a brain disease? The pathophysiological role of cerebral white matter in the elderly.

Small-vessel disease of the brain affecting the deep white matter characteristically manifests with neurological syndromes, such as vascular dementia and vascular parkinsonism. There is, however, compelling evidence to suggest that white matter disease can cause overactive bladder and incontinence, and in some patients these might be the initial manifestation. As white matter disease increases significantly with age, and preferentially affects the prefrontal deep white matter, white matter disease becomes an anatomical substrate in the brain etiology of overactive bladder. Treatment entails the management of small-vessel disease risk factors and anticholinergic drugs that do not easily penetrate the blood-brain barrier, to improve bladder control. In short, when caring for elderly overactive-bladder patients, we should look at both the brain and the bladder.

The neural control of micturition.

Micturition, or urination, occurs involuntarily in infants and young children until the age of 3 to 5 years, after which it is regulated voluntarily. The neural circuitry that controls this process is complex and highly distributed: it involves pathways at many levels of the brain, the spinal cord and the peripheral nervous system and is mediated by multiple neurotransmitters. Diseases or injuries of the nervous system in adults can cause the re-emergence of involuntary or reflex micturition, leading to urinary incontinence. This is a major health problem, especially in those with neurological impairment. Here we review the neural control of micturition and how disruption of this control leads to abnormal storage and release of urine.

Bladder dysfunction in a transgenic mouse model of multiple system atrophy.

Multiple system atrophy (MSA) is an adult-onset neurodegenerative disorder presenting with motor impairment and autonomic dysfunction. Urological function is altered in the majority of MSA patients, and urological symptoms often precede the motor syndrome. To date, bladder function and structure have never been investigated in MSA models. We aimed to test bladder function in a transgenic MSA mouse featuring oligodendroglial α-synucleinopathy and define its applicability as a preclinical model to study urological failure in MSA. Experiments were performed in proteolipid protein (PLP)-human α-synuclein (hαSyn) transgenic and control wild-type mice. Diuresis, urodynamics, and detrusor strip contractility were assessed to characterize the urological phenotype. Bladder morphology and neuropathology of the lumbosacral intermediolateral column and the pontine micturition center (PMC) were analyzed in young and aged mice. Urodynamic analysis revealed a less efficient and unstable bladder in MSA mice with increased voiding contraction amplitude, higher frequency of nonvoiding contractions, and increased postvoid residual volume. MSA mice bladder walls showed early detrusor hypertrophy and age-related urothelium hypertrophy. Transgenic hαSyn expression was detected in Schwann cells ensheathing the local nerve fibers in the lamina propria and muscularis of MSA bladders. Early loss of parasympathetic outflow neurons and delayed degeneration of the PMC accompanied the urological deficits in MSA mice. PLP-hαSyn mice recapitulate major urological symptoms of human MSA that may be linked to αSyn-related central and peripheral neuropathology and can be further used as a preclinical model to decipher pathomechanisms of MSA.

Nerve growth factor (NGF): a potential urinary biomarker for overactive bladder syndrome (OAB)?

UNLABELLED: WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: The search for a biomarker in overactive bladder syndrome (OAB) is an emerging field of interest, as bladder dysfunction is a common complaint that causes significant morbidity. A biomarker may give us insight as a diagnostic tool, and also inform us about how severe the condition is, how it may progress and how it may best be treated. The protein of interest here is nerve growth factor (NGF) and it has been shown to be a dynamic molecule in the bladder of patients with OAB. Urinary levels have been seen to rise in patients with OAB and fall in those who respond to treatment. However, there have also been many studies that examine this trend in numerous other conditions, e.g. interstitial cystitis, bladder outflow obstruction, renal stone disease and patients with neurological impairment after stroke. As a result the specificity of this as a potential urinary biomarker for OAB is questioned. This is a review of published studies, which discusses the pros and cons of NGF as a potential urinary biomarker. The evidence is examined and the studies are summarised together in a Table. Questions remain about the reliability, practicality and specificity of NGF as a biomarker for OAB. These questions need to be addressed by further studies that could clarify the points raised. OBJECTIVE: To review the current literature on the use of urinary nerve growth factor (NGF) as a potential biomarker for overactive bladder syndrome (OAB). METHOD: A comprehensive electronic literature search was conducted using the PubMed database to identify publications relating to urinary NGF. RESULTS: There are a growing number of publications that have measured urinary NGF levels in different types of bladder dysfunction. These range from OAB, bladder pain syndrome, idiopathic and neurogenic detrusor overactivity, bladder oversensitivity and bladder outflow obstruction. Urinary NGF levels do appear to be raised in these pathological states when compared with healthy control samples. In patients with OAB, these raised urinary NGF levels appear to also reduce after successful treatment with antimuscarinics and botulinum toxin A, which indicates a potential use in monitoring responses to treatment. However, raised levels are not limited to OAB, which questions its specificity. Urinary NGF measurements are performed with an enzyme-linked immunosorbent assay using polyclonal antibodies to NGF. The technique requires standardisation, and the different antibodies to NGF require validating. Also a definition of what is the 'normal' range of NGF in urine is still required before it can be used as a diagnostic and prognostic tool. CONCLUSIONS: Whilst the evidence for an increased urinary NGF in OAB appears convincing, many questions about its validity remain including: specificity, sensitivity, cost- and time-effectiveness. Many criteria for what constitutes a biomarker still need to be evaluated and met before this molecule can be considered for this role.

Inhibitory control task is decreased in vascular incontinence patients.

OBJECTIVE: 'Vascular incontinence' is a part of elderly incontinence due to cerebral white matter change (WMC). We studied the relationship between performance on several cognitive tasks and urodynamic detrusor overactivity (DO) in patients with vascular incontinence. METHODS: We recruited 40 patients with lower urinary tract symptoms due to WMC [20 male, 20 female; mean age 77 years (60-89 years)]. Other neurologic, urologic, and systemic causes of LUT dysfunction were excluded. All patients underwent urodynamics tests and two sets of cognitive tasks, i.e., the Mini-Mental State Examination (MMSE) (general cognitive tasks), and the Frontal Assessment Battery (FAB) (frontal lobe tasks). RESULTS: The most common urinary symptom was urinary urgency (27 patients), followed by urinary incontinence (26) and nocturnal urinary frequency (25). The urodynamic testing revealed DO in 22 patients. The cognitive testing revealed that the patients' mean MMSE score was 25.8 (range 15-30), and their mean FAB score was 13.6 (4-18). There was no relationship between DO and the total MMSE or FAB score, but our analysis of the relationship between DO and the six subdomains of the FAB (conceptualization, mental flexibility, programming, sensitivity to interference, inhibitory control, and environmental autonomy) revealed a significant relationship between DO and the inhibitory control task (p < 0.005). CONCLUSIONS: The results of the present study showed that performance on an inhibitory control task is decreased in vascular incontinence patients with DO.

Urinary retention for the neurologist.

Urinary retention is a common problem, most often due to an anatomical lesion in the urinary tract causing obstruction, such as a urethral stricture or prostate enlargement. However, a subset of patients have no structural urological lesion, and so require neurological evaluation. We present a patient with acute urinary retention who was found to have chronic meningitis, and review the neurological causes for urinary retention.

Development and Validation of a Prognostic Model to Predict Overall Survival in Multiple System Atrophy.

Background: Multiple system atrophy (MSA) is a devastating disease characterized by a variable combination of motor and autonomic symptoms. Previous studies identified numerous clinical factors to be associated with shorter survival. Objective: To enable personalized patient counseling, we aimed at developing a risk model of survival based on baseline clinical symptoms. Methods: MSA patients referred to the Movement Disorders Unit in Innsbruck, Austria, between 1999 and 2016 were retrospectively analyzed. Kaplan-Meier curves and multivariate Cox regression analysis with least absolute shrinkage and selection operator penalty for variable selection were performed to identify prognostic factors. A nomogram was developed to estimate the 7 years overall survival probability. The performance of the predictive model was validated and calibrated internally using bootstrap resampling and externally using data from the prospective European MSA Study Group Natural History Study. Results: A total of 210 MSA patients were included in this analysis, of which 124 patients died. The median survival was 7 years. The following clinical variables were found to significantly affect overall survival and were included in the nomogram: age at symptom onset, falls within 3 years of onset, early autonomic failure including orthostatic hypotension and urogenital failure, and lacking levodopa response. The time-dependent area under curve for internal and external validation was >0.7 within the first 7 years of the disease course. The model was well calibrated showing good overlap between predicted and actual survival probability at 7 years. Conclusion: The nomogram is a simple tool to predict survival on an individual basis and may help to improve counseling and treatment of MSA patients.

The possible role of opiates in women with chronic urinary retention: observations from a prospective clinical study.

PURPOSE: Urinary retention in women often presents a diagnostic difficulty, and the etiology may remain unidentified even after excluding structural and neurological causes. We evaluated a group of women referred to a specialist center with unexplained urinary retention. MATERIALS AND METHODS: A total of 61 consecutive women with complete urinary retention were evaluated. Urological and neurological investigations locally had failed to identify a cause. Urethral pressure profile, sphincter volume measurement and in some cases urethral sphincter electromyography were performed to diagnose a primary disorder of sphincter relaxation (Fowler's syndrome). RESULTS: Mean patient age was 39 years (range 18 to 88). Following investigations, a probable etiology was identified in 25 (41%) women, the most common being Fowler's syndrome. Of the women 24 (39%) were being treated with opiates for various pain syndromes and in 13 no other cause of retention was identified. Opiates could be discontinued in only 2 patients, and both demonstrated improved sensations and voiding. CONCLUSIONS: The cause of urinary retention may remain unknown in spite of extensive investigations. Young women regularly using prescription opiates for various undiagnosed pain syndromes present a challenging clinical problem and this study suggests that iatrogenic causes should be considered if voiding difficulties emerge. An association between opiate use and constipation is well-known and, although urinary retention is a listed adverse event, it appears to be often overlooked in clinical practice. It is hypothesized that Fowler's syndrome is due to an up-regulation of spinal cord enkephalins and that exogenous opiates may compound any functional abnormalities predisposing young women to urinary retention.

Long-term effect on quality of life of repeat detrusor injections of botulinum neurotoxin-A for detrusor overactivity in patients with multiple sclerosis.

PURPOSE: We studied the effect of repeat detrusor botulinum neurotoxin type A injections on urinary symptoms, health and quality of life in patients with refractory neurogenic detrusor overactivity secondary to multiple sclerosis. MATERIALS AND METHODS: This was a prospective, open label, single center study in 137 patients with multiple sclerosis treated with detrusor injections of botulinum neurotoxin type A with observations made from 2002 to 2009. A minimally invasive outpatient technique was used for injection. Patients were asked to contact the department if and when they required repeat treatment. Recurrent detrusor overactivity was then identified on urodynamics. The primary outcomes measured were the change in symptoms and quality of life, as assessed by the Urogenital Distress Inventory, Incontinence Impact Questionnaire and EuroQol-5 Dimensions questionnaires (www.ion.ucl.ac.uk/departments/repair/themes/uroneurology) before and 4 weeks after botulinum treatment. Continence status, the need for clean intermittent self-catheterization before and after injections, and interinjection intervals were also analyzed. RESULTS: Mean Urogenital Distress Inventory and Incontinence Impact Questionnaire 7 scores showed considerable improvement 4 weeks after each treatment even when repeated 6 times. Almost all patients relied on clean intermittent self-catheterization after treatment. Before the first treatment 83% of patients were incontinent but 4 weeks after the first treatment 76% (104 of 137) became completely dry. This efficacy was sustained with repeat injections. The median interval between re-treatments remained constant at 12 to 13 months. CONCLUSIONS: Repeated detrusor botulinum neurotoxin type A injections for refractory neurogenic detrusor overactivity in patients with multiple sclerosis have a consistent effect on bladder control, resulting in sustained improvement in quality of life.

Comparison of the impact on health-related quality of life of repeated detrusor injections of botulinum toxin in patients with idiopathic or neurogenic detrusor overactivity.

STUDY TYPE: Therapy (case series). LEVEL OF EVIDENCE: 4. What's known on the subject? and What does the study add? We know that repeated injections of botulinum toxin A are effective in treating refractory detrusor overactivity particularly in NDO. This study shows that in both NDO and IDO repeated injections of the toxin improve quality of life as assessed by three validated questionnaires. The effect is most marked after the first injection in NDO patients but thereafter similar in both groups. OBJECTIVE: To compare the effect of repeated detrusor injections of botulinum toxin (BoNT-A) on health-related quality of life (HRQL) in patients with idiopathic (IDO) or neurogenic detrusor overactivity (NDO). PATIENTS AND METHODS: Between 2003 and 2009, 151 patients (109 with NDO and 42 with IDO) were treated by BoNT-A (Botox®, Allergan Inc., Irvine, CA, USA). Changes in HRQL were assessed using the validated short forms of Urogenital Distress Inventory (UDI-6), the Incontinence Impact Questionnaire (IIQ-7) and EuroQOL-5D (EQ-5D) before and 4 weeks after BoNT-A. RESULTS: The maximum number of repeated injections was five (mean±sd, 2.8±1.05). Mean±sd follow-up was 27.49±17.01 months. The UDI-6 and IIQ-7 questionnaires showed a consistent improvement after repeated injections in both groups with detrusor overactivity. The EQ-5D was not statistically different before and after each injection in either the NDO or IDO population. After repeated injections, no statistical differences in the change on the UDI-6 and IIQ-7 scores were found between NDO and IDO, except after the first treatment, when the decrease in UDI-6 was higher in NDO than in IDO. The EQ-5D anxiety and depression subscore improved in both groups after each injection and with the number of injections. In IDO, after the second injection, no patient reported extreme anxiety or depression and, after the fourth injection, none had anxiety or depression. The inter-injection interval was shorter after the first injection in those with NDO than in IDO but was similar thereafter. CONCLUSIONS: Intradetrusor injections of BoNT-A improved the HRQL of both NDO and IDO patients. Although improvement in HRQL was greater and the duration of efficacy shorter in NDO patients after the first injection, there was no significant difference after subsequent injections. Mean inter-injection interval in IDO and in NDO patients was similar from the second injection onwards and improvements in HRQL score were the same.

Bowel biofeedback treatment in patients with multiple sclerosis and bowel symptoms.

BACKGROUND: Bowel symptoms are common in patients with multiple sclerosis, but current treatment is empirical. OBJECTIVE: This study aimed to identify effect of biofeedback on bowel symptoms, mood, and anorectal physiology in patients with multiple sclerosis. DESIGN: This was a prospective observational study: the amount of change between pre- and posttreatment values of outcome measures was compared and analyzed. Responders were considered to be patients who demonstrated an improvement greater than or equal to the 25th percentile of the change in bowel score. Comparison between responders and nonresponders was performed. SETTINGS: This investigation was conducted at a neurogastroenterology clinic, tertiary referrals center. PATIENTS: Thirty-nine patients with multiple sclerosis and constipation and/or fecal incontinence were included in the study. INTERVENTION: Patients were given bowel biofeedback therapy. MAIN OUTCOME MEASURES: The primary outcome measures were the Wexner Constipation and Wexner Incontinence scores. The secondary outcome measures were hospital anxiety and depression scores and anorectal physiology parameters. RESULTS: Data are reported as median and interquartile ranges. After biofeedback there was significant improvement in Wexner Constipation (12 (5-19) pretreatment vs 8 (4-14) posttreatment, P = .001), Wexner Incontinence (12 (3-15) pretreatment vs 4 (2-10) posttreatment, P < .001) and hospital depression scores (7 (3-11) pretreatment vs 5 (3-10) posttreatment, P = .015). The 5-second endurance squeeze pressure was also improved (21 (11-54) mmHg pretreatment vs 43 (26-59) mmHg posttreatment, P = .001). Posttreatment change of Wexner Constipation was -2(-5/0), and of Wexner Incontinence was -3(-9/0) ("-" indicates improvement). Therefore, those patients who had a reduction of at least 5 points in the Wexner Constipation score and/or of at least 9 points in the Wexner Incontinence score were considered responders (18 patients, 46%). They showed a greater improvement of only 5-second endurance squeeze pressure (23.5 (7.5/32.75) mmHg responders vs 4 (-6/20) mmHg nonresponders, P = .008); no difference was observed in the comparison of baseline variables with nonresponders. Significant negative relationship existed between the change in the Wexner Constipation score (-2 (-5/0)) and the pretreatment Wexner Constipation score (12 (5/19), ß = -0.463, P < .001), and the change in the Wexner Incontinence score (-3 (-9/0)) with the pretreatment Wexner Incontinence score (12 (3/15), ß = -0.590, P < .001). So, the higher the initial bowel symptom score, the greater the improvement. LIMITATIONS: This study was limited by the lack of a control group. CONCLUSIONS: Biofeedback improves bowel symptoms, depression, and 5-second endurance squeeze pressure in patients with multiple sclerosis.

Neurogenic detrusor overactivity in patients with spinal cord injury: evaluation and management.

Lower urinary tract dysfunction can have a significant impact on patients with spinal cord injury. Over the years, many treatment options have become available. This article reviews the assessment and management of neurogenic detrusor overactivity, with a particular focus on articles from the recent literature. Recent guidelines on the subject will be discussed. Management options include antimuscarinics and bladder emptying measures, botulinum toxin A, and neuromodulation in refractory cases and surgery for intractable cases. Recent and relevant publications in these areas will be summarized and discussed.

Urinary incontinence following deep brain stimulation of the pedunculopontine nucleus.

Low-frequency deep brain stimulation (DBS) of the pedunculopontine nucleus (PPN) has been reported to improve akinesia and gait difficulties in patients with Parkinson's disease (PD). We report on a patient with PD and L: -dopa refractory gait symptoms who developed detrusor over-activity immediately after right PPN DBS. Proximity between caudal PPN and brainstem structures implicated in control of micturition is a possible explanation.

Immunohistochemical expression of muscarinic receptors in the urothelium and suburothelium of neurogenic and idiopathic overactive human bladders, and changes with botulinum neurotoxin administration.

PURPOSE: To investigate the possible associations of urothelial and suburothelial muscarinic receptors with human bladder pathophysiology we examined the immunohistochemical expression of muscarinic receptors types 1, 2 and 3 in the bladder urothelium and suburothelium of patients with neurogenic or idiopathic detrusor overactivity compared with that in controls. We also examined associations with patient quantified symptoms and the effect of intradetrusor botulinum neurotoxin type A treatment. MATERIALS AND METHODS: We obtained bladder biopsies from 36 patients with detrusor overactivity before, and 4 and 16 weeks after treatment with intradetrusor botulinum neurotoxin type A via flexible cystoscopy. Patients with neurogenic detrusor overactivity were injected with 300 U botulinum neurotoxin type A and those with idiopathic detrusor overactivity received 200 U. Control biopsies were taken from 7 patients during investigation for asymptomatic microscopic hematuria. We studied muscarinic receptor immunohistochemical expression using commercial antibodies to muscarinic receptors 1, 2 and 3 with results quantified by image analysis. RESULTS: We noted decreased suburothelial muscarinic receptor immunoreactivity in detrusor overactivity biopsies vs controls, which were significant for muscarinic receptors 1 and 3. After successful botulinum neurotoxin treatment we noted only increased muscarinic receptor 1 and 2 immunoreactivity. Urothelial muscarinic receptor 1 and 3 immunoreactivity was increased after treatment. We identified no substantial urothelial muscarinic receptor 2 immunoreactivity. Receptor levels showed inverse correlations with patient urgency and frequency. CONCLUSIONS: Decreased muscarinic receptor levels in the urothelium and suburothelium of patients with detrusor overactivity were largely restored to control levels after successful treatment with botulinum neurotoxin type A. Correlations of receptor levels with patient symptoms further support a role for urothelial and suburothelial muscarinic receptors in detrusor overactivity in humans.

Presentation, diagnosis, and management of multiple system atrophy in Europe: final analysis of the European multiple system atrophy registry.

Multiple system atrophy (MSA) is a Parkinson's Disease (PD)-like α-synucleinopathy clinically characterized by dysautonomia, parkinsonism, cerebellar ataxia, and pyramidal signs in any combination. We aimed to determine whether the clinical presentation of MSA as well as diagnostic and therapeutic strategies differ across Europe and Israel. In 19 European MSA Study Group centres all consecutive patients with a clinical diagnosis of MSA were recruited from 2001 to 2005. A standardized minimal data set was obtained from all patients. Four-hundred thirty-seven MSA patients from 19 centres in 10 countries were included. Mean age at onset was 57.8 years; mean disease duration at inclusion was 5.8 years. According to the consensus criteria 68% were classified as parkinsonian type (MSA-P) and 32% as cerebellar type (MSA-C) (probable MSA: 72%, possible MSA: 28%). Symptomatic dysautonomia was present in almost all patients, and urinary dysfunction (83%) more common than symptomatic orthostatic hypotension (75%). Cerebellar ataxia was present in 64%, and parkinsonism in 87%, of all cases. No significant differences in the clinical presentation were observed between the participating countries. In contrast, diagnostic work up and therapeutic strategies were heterogeneous. Less than a third of patients with documented orthostatic hypotension or neurogenic bladder disturbance were receiving treatment. This largest clinical series of MSA patients reported so far shows that the disease presents uniformly across Europe. The observed differences in diagnostic and therapeutic management including lack of therapy for dysautonomia emphasize the need for future guidelines in these areas.

A functional magnetic resonance imaging study of the effect of sacral neuromodulation on brain responses in women with Fowler's syndrome.

STUDY TYPE: Aetiology (case series). LEVEL OF EVIDENCE: 4. OBJECTIVE: To examine brain responses to bladder filling in young women with Fowler's syndrome (FS, a sphincter abnormality manifested by impaired voiding and bladder sensation), treated with sacral neuromodulation (SNM). PATIENTS AND METHODS: Six women, aged 18-39 years with FS underwent functional brain magnetic resonance imaging (fMRI) immediately after SNM and when untreated (baseline). Data were collected at four sessions: after SNM with an empty and a full bladder, and at baseline with an empty and a full bladder. In each session, 280 whole-brain scans were acquired while repeatedly infusing and withdrawing 50 mL of saline, using push-buttons to report changing desire to void. Data were analysed using Statistical Parametric Mapping. RESULTS: At baseline with an empty bladder, extensive responses (contrast = infusion-withdrawal) were almost exclusively negative ('deactivations'), e.g. in the right insula, seat of visceral sensation. Increased bladder volume and/or SNM treatment reduced deactivations and strengthened normal (positive) responses, e.g. in the periaqueductal grey (PAG) terminus of ascending spinal afferents. At baseline, there was significant correlation of brain responses with maximum urethral closure pressure. CONCLUSION: These data show that brain responses to bladder filling are abnormal in FS. The explanation for this that best explains the evidence is that the primary abnormality is an overactive urethra that generates abnormally strong inhibitory afferent signals, so effectively blocking bladder afferent activity at the sacral level and deactivating the PAG and higher centres, with consequent loss of bladder sensation and ability to void. Apparently, a normal mechanism for suppression of incontinence involving the striated urethral sphincter becomes exaggerated in FS and prevents voiding. SNM seems to act at the sacral level, by blocking inhibition by urethral afferents.