Loss of Awareness or Urinary Dysfunction? Investigating Amyloidosis and Urinary Physiology in a Transgenic Mouse

Alzheimer’s disease (AD) is a devastating disorder primarily affecting older adults and is the most common neurodegenerative disease in the US. More than one in three AD patients experience AD-associated urinary dysfunction (ADUD), which directly contributes to their institutionalization. While ADUD has been clinically regarded as a result of poor cognitive control over urinary function, the physiology underlying loss of urinary control remains unknown. We hypothesize that amyloidosis in the CNS results in pathologic changes in urinary structure and function. Tg-APP/PS1DE9 mice were used before plaque deposition (4-6 months) and after plaque accumulation (8-10 months) and compared to WT littermates. Behavioral assays (open field testing and voiding spot assays) were performed to assess cortical function. Pressure-flow cystometry was conducted under urethane anesthesia to assess autonomic control of urinary function without cortical influence. Pharmacomyography of bladder strips was used to determine tissue-level changes in the absence of CNS input. In Tg-APP/PS1DE9 mice, plaque accumulation resulted in significant cystometric changes to voiding phase parameters, but not storage phase parameters. Pharmacologic studies showed decreased sensitivity to adrenergic stimulation without change in muscarinic sensitivity. Behavioral assays demonstrated significant differences between transgenic animals and WT in locomotion and voiding spot sizes. We interpret our data to support AD-related pathology of Aβ accumulation results in a distinct urinary phenotype in our model, analogous to the ADUD observed in AD patients. Establishing and verifying models of ADUD may improve the efficacy of treating ADUD and increase quality of life for patients and their caregivers.

Chorea, Ataxia, and Disturbed Sleep

A 72-year-old man sought care for predominant choreiform movements, mild gait ataxia, urinary dysfunction, and abnormal nocturnal behaviors. Choreiform movements were nearly constant while awake, vanished during sleep, and predominantly involved his lower extremities and trunk. He also had urinary dysfunction, with urinary hesitancy and frequency. Sleep-related behaviors included sleep talking, sleep singing, sudden single-limb jerking movements, and complex hand movements. He also had daytime sleepiness. On neurologic examination, abnormal findings included postural instability at baseline with eyes open and a slightly wide-based tentative gait and inability to execute tandem walking. He had intermittent choreiform movements of the legs and the left shoulder. He also had occasional repetitive, periodic, voluntary-appearing, triple flexion–type movements of both legs. Overnight polysomnography was ordered to evaluate nocturnal movements. Polysomnography revealed rapid periodic leg movements of sleep and rapid eye movement sleep without atonia. Sleep architecture was mildly deranged, with electroencephalographic alpha intrusion throughout nonrapid eye movement sleep, as well as absent slow-wave sleep. Ferritin level was suboptimal. Evaluation of serum for autoimmune encephalitis demonstrated IgLON family member 5 antibody positivity by tissue immunofluorescence assay, confirmed by cell-based assay. The patient was diagnosed with IgLON family member 5 autoimmune encephalitis and symptomatic rapid eye movement sleep behavior disorder. The patient was instructed to maintain a safe sleep environment at home and to begin taking melatonin at bedtime. A therapeutic trial of intravenous methylprednisolone, together with mycophenolate mofetil, was followed by improvement in memory, confusion, and hallucinations, waking involuntary movements, bladder dysfunction, and sleep quality. Rapid eye movement sleep behavior disorder is a parasomnia characterized by rapid eye movement sleep without atonia, the loss or dysregulation of normal rapid eye movement sleep atonia, which is its pathophysiologic signature, and which is permissive for dream enactment behaviors during rapid eye movement sleep.

Mast cell function in prostate inflammation, fibrosis, and smooth muscle cell dysfunction

Intraurethral inoculation of mice with uropathogenic E. coli (CP1) results in prostate inflammation, fibrosis, and urinary dysfunction, recapitulating some but not all of the pathognomonic clinical features associated with benign prostatic hyperplasia (BPH) and lower urinary tract symptoms (LUTS). In both patients with LUTS and in CP1-infected mice, we observed increased numbers and activation of mast cells and elevated levels of prostate fibrosis. Therapeutic inhibition of mast cells using a combination of mast cell stabilizer (MCS), cromolyn sodium, and the histamine 1 receptor antagonist (H1RA), cetirizine di-hydrochloride, in the mouse model resulted in reduced mast cell activation in the prostate and significant alleviation of urinary dysfunction. Treated mice showed reduced prostate fibrosis, less infiltration of immune cells, and decreased inflammation. In addition, as opposed to symptomatic CP1-infected mice, treated mice showed reduced myosin light chain (MLC)-2 phosphorylation, a marker of prostate smooth muscle contraction. These results show that mast cells play a critical role in the pathophysiology of urinary dysfunction and may be an important therapeutic target for men with BPH/LUTS.

Clinical course of neurogenic bladder dysfunction in human T-cell leukemia virus type-1-associated myelopathy/tropical spastic paraparesis: a nationwide registry study in Japan

Background Most patients with human T-cell leukemia virus type 1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) develop neurogenic bladder dysfunction. However, longitudinal changes and treatment effects remain poorly understood. This study aimed to characterize the clinical course of urinary dysfunction in this population. Methods This prospective observational study included 547 patients enrolled in HAM-net, a nationwide registry for HAM/TSP in Japan. Urinary dysfunction severity was evaluated using the HAM/TSP-bladder dysfunction symptom score (HAM-BDSS) and the HAM/TSP-bladder dysfunction severity grade (HAM-BDSG). These specific measures were recently developed for assessing urinary dysfunction in HAM/TSP. We analyzed longitudinal changes over a 6-year follow-up period, associations between urinary and gait dysfunction, and treatment efficacy of urinary catheterization and mirabegron (a β3-adrenergic agonist for overactive bladder symptoms). Results The mean (standard deviation [SD]) age and disease duration at enrollment were 61.9 (10.7) years and 16.6 (11.6) years, respectively, and 74.6% of patients were women. Only 8.0% were free from urinary symptoms (HAM-BDSG 0), 65.4% had urinary symptoms or were on medication (HAM-BDSG I), and 23.2% and 3.3% used intermittent and indwelling catheters (HAM-BDSG II and III), respectively. HAM-BDSG and BDSS were worse in patients with greater gait dysfunction (p < 0.001 for both). During the 6-year follow-up, 66.7% of patients with HAM-BDSG 0 developed new urinary symptoms. Of those with HAM-BDSG I at enrollment, 10.8% started using urinary catheters. Importantly, HAM-BDSS significantly improved after initiating catheterization (mean [SD] change, − 8.93 [10.78], p < 0.001). The number of patients receiving mirabegron increased in the fourth year. Multivariable linear regression analysis significantly associated mirabegron with improvement in HAM-BDSS (− 5.82, 95% confidence interval − 9.13 to − 2.51, p = 0.001). Conclusions Urinary dysfunction affected 92% of patients and progressed over the 6-year follow-up. Urinary symptoms were more severe in patients with poorer gait function. Urinary catheterization and mirabegron were effective in relieving symptoms. Effective utilization of real-world data is key to establishing evidence for rare diseases, such as HAM/TSP.

Relationship Between Idiopathic Normal-Pressure Hydrocephalus and Lumbar Spinal Stenosis

Object: To evaluate the relationship between idiopathic normal-pressure hydrocephalus (iNPH) and lumbar spinal stenosis (LSS).Methods: With the aging of society, the numbers of patients with iNPH and LSS are likely to increase. iNPH and LSS have similar symptoms including gait disturbance and urinary dysfunction. The prevalence of dementia is higher in older adults with LSS. However, the relationship of LSS with iNPH and the prevalence of LSS in patients with iNPH are unknown. In our department between April 2011 and March 2017, 226 patients were diagnosed with iNPH and underwent shunt operation including lumboperitoneal shunts and ventriculoperitoneal shunts. Two spine surgeons evaluated LSS on magnetic resonance imaging of the lumbar spine. Age, sex, body mass index, Timed Up and Go test, Mini Mental State Examination score, and urinary dysfunction were examined before and after surgery for iNPH. Changes in these variables were compared between patients with iNPH without LSS and with iNPH and LSS.Results: In the overall cohort, the median patient age was 78 years and there were 121 males. Among 226 patients with iNPH, 73 (32.3%) had LSS. Neurological symptoms were improved in all patients at final follow-up. The rate of symptom improvement was lower for the iNPH and LSS group compared with the iNPH without LSS group.Conclusions: Surgery to improve gait disturbance might be difficult in patients with iNPH with LSS. When examining patients with iNPH, we should consider the possibility of concomitant LSS.

Urinary dysfunction in women following total mesorectal excision versus partial mesorectal excision for treatment of rectal cancer

Background Colorectal cancer is a condition which is associated with substantial morbidity and mortality. The aim of this study was to assess urinary dysfunction and its effect on quality of life in women who underwent total mesorectal excision compared to women treated by partial mesorectal excision for treatment of rectal cancer. Methods We performed a retrospective cohort study at a tertiary university hospital between January 2014 and December 2019. A comparison was performed between women who underwent total mesorectal excision as opposed to partial mesorectal excision for treatment of rectal cancer. Pre-operative, intra-operative and post-operative data were compared between groups. Data regarding radiation therapy was recorded and compared as well. Urinary dysfunction and its impact on quality of life were assessed using UDI-6 and USIQ questionnaires. Further univariate and multivariate analyses were performed in the attempt of assessing risk factors for urinary dysfunction. Results A total of 107 women were included in the study, 73 women underwent partial mesorectal excision as opposed to 34 women who were treated by total mesorectal excision. Twenty-five women in the TME group underwent radiation therapy prior to surgery as opposed to none in the PME group (p < 0.001). Urinary dysfunction following surgery as assessed using the UDI-6 questionnaire did not differ between groups. Similar findings were recorded with regard to the impact of urinary dysfunction on quality of life as assessed using the USIQ questionnaire. Following multivariate analysis longer hospital stay was associated with increased risk of some degree of urinary dysfunction. Conclusions Women undergoing total mesorectal excision have comparable results to partial mesorectal excision with regard to urinary dysfunction.

Bladder Hyperactivity Induced by Oxidative Stress and Bladder Ischemia: A Review of Treatment Strategies with Antioxidants

Overactive bladder (OAB) syndrome, including frequency, urgency, nocturia and urgency incontinence, has a significantly negative impact on the quality-of-life scale (QoL) and can cause sufferer withdrawal from social activities. The occurrence of OAB can result from an imbalance between the production of pro-oxidants, such as free radicals and reactive species, and their elimination through protective mechanisms of antioxidant-induced oxidative stress. Several animal models, such as bladder ischemia/reperfusion (I/R), partial bladder outlet obstruction (PBOO) and ovarian hormone deficiency (OHD), have suggested that cyclic I/R during the micturition cycle induces oxidative stress, leading to bladder denervation, bladder afferent pathway sensitization and overexpression of bladder-damaging molecules, and finally resulting in bladder hyperactivity. Based on the results of previous animal experiments, the present review specifically focuses on four issues: (1) oxidative stress and antioxidant defense system; (2) oxidative stress in OAB and biomarkers of OAB; (3) OAB animal model; (4) potential nature/plant antioxidant treatment strategies for urinary dysfunction with OAB. Moreover, we organized the relationships between urinary dysfunction and oxidative stress biomarkers in urine, blood and bladder tissue. Reviewed information also revealed the summary of research findings for the effects of various antioxidants for treatment strategies for OAB.

Is There a Place for Spinal Cord Stimulation in the Management of Patients with Multiple Sclerosis? A Systematic Review of the Literature

Objective. Spinal cord stimulation (SCS) is a minimally invasive technique mainly used to treat neuropathic pain associated with failed back surgery syndrome. However, this therapy has been utilized to treat other chronic painful conditions, such as pain associated with multiple sclerosis (MS). Nonetheless, the efficacy of SCS in MS patients has not been fully established. In fact, in most of SCS series, MS patients represent only a subset of a bigger cohort which comprises different causes of pain, motor disorder, and other functional limitations. The aim of our study was to systematically review the literature to evaluate the effectiveness of SCS in MS patients. Methods. A literature search was performed through different databases (PubMed, Scopus, and Embase) using the following terms: “multiple sclerosis,” “spinal cord stimulation,” and “dorsal column stimulation,” according to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) guidelines. Results. A total of 452 articles were reviewed, and 7 studies were included in the present analysis. 373 MS patients were submitted to a stimulation trial, and 82 MS patients underwent a de novo implantation. 285/373 (76.4%) of cases submitted to the SCS trial were enrolled for permanent stimulation. We found a long-lasting improvement in 193/346 (55.8%) MS patients with motor disorders, in 90/134 (67.13%) MS patients with urinary dysfunction, and in 28/34 (82.35%) MS patients with neuropathic pain. The efficacy of SCS was higher for urinary dysfunction ( p = 0.0144) and neuropathic pain ( p = 0.0030) compared with motor disorders. Conclusions. Our systematic review evidences that SCS is effective in MS patients. Urinary dysfunction and pain symptoms seem to be most responsive to SCS. Further studies are needed to improve the patient selection and clarify the best timing to perform SCS in these patients.