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.

Symptomatic Breast Cancers and Why Breast Pain May not Always Need Clinical Review.

OBJECTIVE: Breast pain contributes a heavy burden to the symptomatic breast clinic, accounting for a large number of referrals due to patient/clinician subjective anxiety and unclear aetiology. We assess the link between breast pain and cancer with a view to easing the demand on breast services. MATERIALS AND METHODS: All new breast cancer diagnoses were identified from the multidisciplinary team outcomes for the 12 months between October 2017 and October 2018. Presenting symptoms were identified from the General Practice referrals and consultant letters. Examination findings were checked with details on imaging requests. RESULTS: 436 new symptomatic cancer diagnoses were made in patients with a median age of 68 (range 25-97). 334 patients were referred by General Practice as two-week waits who formed the cohort selected for analysis (77%). New lumps accounted for 294 ipsilateral cancer diagnoses (88%), nipple symptoms for 28 (8%) and pain with normal examination for 12 (4%, all screening aged patients). All 12 cancers in the patients presenting with pain were correctly identified on mammography, including 4 cancers in the symptomatic breast and 8 Incidental cancers in the contralateral, non-symptomatic breast. CONCLUSION: Pain does not appear to be frequent symptom of breast cancer presentation. It was more common for patients to have incidental, contralateral asymptomatic cancer than it was for patients with pain alone to have underlying ipsilateral cancer. In such cases, new cancers were identified accurately on mammography. Patients presenting with pain as an isolated symptom, having been carefully assessed in Primary Care, may yield little benefit in repeat clinical examination by a Breast Specialist. Direct to test with mammography could be safe, effective and efficient alternative practice.

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.

Misconceptions surrounding pregnancy-associated breast cancer.

This case report describes a 31-year-old woman who presented with a right painless breast lump. A mammogram and ultrasound scan showed the lump was suspicious of cancer. Core biopsy and immunohistochemistry of the lump confirmed a triple negative, poorly differentiated, invasive ductal carcinoma of the right breast. One week following her diagnosis, the patient found out she was pregnant. The patient was worried about what the implications this diagnosis would have on both her baby and her own cancer treatment.

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.

Lower urinary tract dysfunction in the neurological patient: clinical assessment and management.

Lower urinary tract (LUT) dysfunction is a common sequela of neurological disease, resulting in symptoms that have a pronounced effect on quality of life. The site and nature of the neurological lesion affect the pattern of dysfunction. The risk of developing upper urinary tract damage and renal failure is much lower in patients with slowly progressive non-traumatic neurological disorders than in those with spinal cord injury or spina bifida; this difference in morbidity is taken into account in the development of appropriate management algorithms. Clinical assessment might include tests such as uroflowmetry, post-void residual volume measurement, renal ultrasound, (video-)urodynamics, neurophysiology, and urethrocystoscopy, depending on the indication. Incomplete bladder emptying is most often managed by intermittent catheterisation, and storage dysfunction by antimuscarinic drugs. Intradetrusor injections of onabotulinumtoxinA have transformed the management of neurogenic detrusor overactivity. Neuromodulation offers promise for managing both storage and voiding dysfunction. An individualised, patient-tailored approach is required for the management of LUT dysfunction associated with neurological disorders.

Lower urinary tract dysfunction in patients with multiple sclerosis.

Lower urinary tract (LUT) dysfunction is common in multiple sclerosis (MS), and has a considerable impact on quality of life. It most often results from involvement of the spinal cord, which results in detrusor overactivity and detrusor sphincter dyssynergia. LUT symptoms may change with time, paralleling the dynamic course of MS, and therefore the need for regular follow-up assessments is essential. A formal evaluation includes history taking, measurement of the postvoid residual volume (PVR), testing for urinary tract infections and urodynamic studies in select cases. If the PVR is elevated, incomplete bladder emptying is best managed by intermittent self-catheterization. Several options exist for managing the overactive bladder, including antimuscarinics, desmopressin, tibial nerve stimulation, and botulinum toxin A. A stepwise approach is adopted for managing LUT dysfunction in MS.

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 neurological organization of micturition.

The role of the lower urinary tract (LUT) is to act as a reservoir for urine at low pressures and to empty at appropriate times. In health the bladder becomes gradually filled during the storage phase, and afferent pathways convey signals of bladder fullness. When deemed to be a socially appropriate time and place, there is a switch from the storage phase to the voiding phase. Voiding, which involves co-ordinated activity between detrusor contraction and urethral sphincter relaxation occurs until the bladder is empty. The level of co-ordinated activity is complex, requiring both voluntary and autonomic control. In health, the control of LUT activity is achieved at several levels involving the peripheral nerves, spinal cord and cerebral cortex. The pathway becomes damaged following neurological disease resulting in LUT dysfunction. This chapter outlines the neural organization and control of micturition and the consequences of neurological disease.

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.

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.

The natural history of multiple system atrophy: a prospective European cohort study.

BACKGROUND: Multiple system atrophy (MSA) is a fatal and still poorly understood degenerative movement disorder that is characterised by autonomic failure, cerebellar ataxia, and parkinsonism in various combinations. Here we present the final analysis of a prospective multicentre study by the European MSA Study Group to investigate the natural history of MSA. METHODS: Patients with a clinical diagnosis of MSA were recruited and followed up clinically for 2 years. Vital status was ascertained 2 years after study completion. Disease progression was assessed using the unified MSA rating scale (UMSARS), a disease-specific questionnaire that enables the semiquantitative rating of autonomic and motor impairment in patients with MSA. Additional rating methods were applied to grade global disease severity, autonomic symptoms, and quality of life. Survival was calculated using a Kaplan-Meier analysis and predictors were identified in a Cox regression model. Group differences were analysed by parametric tests and non-parametric tests as appropriate. Sample size estimates were calculated using a paired two-group t test. FINDINGS: 141 patients with moderately severe disease fulfilled the consensus criteria for MSA. Mean age at symptom onset was 56·2 (SD 8·4) years. Median survival from symptom onset as determined by Kaplan-Meier analysis was 9·8 years (95% CI 8·1-11·4). The parkinsonian variant of MSA (hazard ratio [HR] 2·08, 95% CI 1·09-3·97; p=0·026) and incomplete bladder emptying (HR 2·10, 1·02-4·30; p=0·044) predicted shorter survival. 24-month progression rates of UMSARS activities of daily living, motor examination, and total scores were 49% (9·4 [SD 5·9]), 74% (12·9 [8·5]), and 57% (21·9 [11·9]), respectively, relative to baseline scores. Autonomic symptom scores progressed throughout the follow-up. Shorter symptom duration at baseline (OR 0·68, 0·5-0·9; p=0·006) and absent levodopa response (OR 3·4, 1·1-10·2; p=0·03) predicted rapid UMSARS progression. Sample size estimation showed that an interventional trial with 258 patients (129 per group) would be able to detect a 30% effect size in 1-year UMSARS motor examination decline rates at 80% power. INTERPRETATION: Our prospective dataset provides new insights into the evolution of MSA based on a follow-up period that exceeds that of previous studies. It also represents a useful resource for patient counselling and planning of multicentre trials.

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.

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.

Neurogenic lower urinary tract dysfunction.

The two roles of the lower urinary tract are storage of urine and emptying at appropriate times. Optimal and coordinated activity of the bladder and urethra is subject to complex neural control which involves all levels of the nervous system, from cortex to peripheral nerve. This explains the high prevalence of urinary disturbances in neurological disease. Information obtained from history taking and supplemented by use of a bladder diary forms the cornerstone of evaluation. Ultrasonography is used to assess the degree of incomplete bladder emptying, and for assessing the upper tracts. Urodynamic tests, with or without simultaneous fluoroscopic monitoring, assess detrusor and bladder outlet function and give fundamental information about detrusor pressure and thus the risk of upper tract damage. Impaired emptying is most often managed by clean-intermittent self-catheterization, which should be initiated if the postvoid residual urine exceeds one-third of bladder capacity or is greater than 100mL, or rarely if spontaneous voiding is dangerous due to high detrusor pressure. Storage symptoms are most often managed using antimuscarinic medications. Intradetrusor injection of botulinum toxin type A is emerging as an effective treatment for managing detrusor overactivity. Understanding of the underlying mechanism of lower urinary tract dysfunction is crucial for effective management.

Vascular incontinence: incontinence in the elderly due to ischemic white matter changes.

This review article introduces the new concept of vascular incontinence, a disorder of bladder control resulting from cerebral white matter disease (WMD). The concept is based on the original observation in 1999 of a correlation between the severity of leukoareosis or WMD, urinary symptoms, gait disorder and cognitive impairment. Over the last 20 years, the realization that WMD is not a benign incidental finding in the elderly has become generally accepted and several studies have pointed to an association between geriatric syndromes and this type of pathology. The main brunt of WMD is in the frontal regions, a region recognized to be crucial for bladder control. Other disorders should be excluded, both neurological and urological, such as normal-pressure hydrocephalus, progressive supranuclear palsy, etc., and prostatic hyperplasia, physical stress incontinence, nocturnal polyuria, etc. Treatment involves management of small vessel disease risk factors and anticholinergic drugs that do not easily penetrate the blood brain barrier to improve bladder control.