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Biomedical subjects

Clare J Fowler

Publications and source records attributed to Clare J Fowler.

At least 19 recordsLinked to original sources
PubMed2007

Update on the neurology of Parkinson's disease.

The differential diagnosis of a patient with apparent Parkinson's Disease (PD) and bladder symptoms is considered and the bladder dysfunction of Multiple System Atrophy (MSA) is reviewed. Recent insights into the progression of the neuropathology of PD have enabled thinking about the stage of the disease at which bladder dysfunction is likely to occur and the expected clinical context of the problem. Bladder symptoms of neurological origin are likely in a patient who has had treated motor symptoms for some years and in whom the ongoing neuropathology has progressed beyond involvement of the basal ganglia, so that symptoms due to cortical dysfunction as well as the adverse effects of dopaminergic medication are also confounding factors. Bladder symptoms in a man with lesser neurological disability should be investigated to exclude underlying outflow obstruction. Possible management options are considered.

Humans↗
PubMed2006

Results of double-blind placebo-controlled crossover study of sildenafil citrate (Viagra) in women suffering from obstructed voiding or retention associated with the primary disorder of sphincter relaxation (Fowler's Syndrome).

OBJECTIVES: Women with the primary disorder of sphincter relaxation find voiding difficult. Studies have identified neuronal nitric oxide synthase in the female urethral sphincter, and nitric oxide donors have been shown to decrease sphincter pressures. The aim of our study was to determine if sildenafil could improve sphincter relaxation and thereby increase flow rates and improve bladder emptying. METHODS: Twenty women with complete (5), partial retention or obstructed voiding (15) with a maximum flow rate (Qmax) of less than 15 ml/min with an elevated maximal urethral closure pressure (92--age cm H(2)O) and sphincter volume (>1.6 cm(3)) were included in the study. The study was a double-blind, randomised, placebo-control, crossover design, with patients taking sildenafil or placebo, and with measurement of flow rate and residual volume at baseline and after each treatment phase. Voiding diary, quality of life, and International Prostate Symptom Score (IPSS) data were also collected. RESULTS: No statistical significant difference was seen in any voiding parameters and diaries when sildenafil citrate was compared with placebo. There was a significant mean decrease in IPSS of 3.64 between baseline and the sildenafil phase (p=0.0083), but not when compared with placebo. In the subgroup of women with partial retention and obstructed voiding (15/20), there was a statistically significant increase in Qmax of 4.7 ml/sec (p=0.025) between sildenafil and baseline; however this difference was not seen when compared with placebo. CONCLUSIONS: This is the first study looking at sildenafil in voiding dysfunction in women. Clinical improvements with sildenafil were not significant when compared with placebo. Sildenafil was not effective as a therapeutic pharmacologic agent in this group of patients.

Adult↗
PubMed2006

Effect of intravesical Resiniferatoxin (RTX) on lower urinary tract symptoms, urodynamic parameters, and quality of life of patients with urodynamic increased bladder sensation.

OBJECTIVES: Intravesical resiniferatoxin (RTX) has been used with variable efficacy in the treatment of detrusor overactivity (DO). Patients with interstitial cystitis (IC) failed to benefit from this treatment, but a single placebo-controlled study in patients with non-IC painful bladders showed that RTX was effective in the short-term. We investigated the efficacy of intravesical RTX in patients with urgency and frequency due to increased bladder sensation. METHODS: Patients with intractable urgency and frequency, with or without urgency incontinence or bladder pain/discomfort, and with no urodynamic evidence of DO were recruited. After a single intravesical instillation of 100ml 50 nM RTX solution, patients were followed at 1, 3, and 6 mo for changes in urodynamics, bladder diary, the King's Health Questionnaire (KHQ), and degree of bladder pain. RESULTS: Fifteen patients (mean age, 52.5 yr) were treated. RTX significantly improved maximum cystometric capacity, volume at first desire to void, mean micturition volume, 24-h frequency, and daytime frequency for up to 6 mo after treatment. The overall KHQ score improved at all time points, with sustained improvements in the Symptom Severity, Incontinence Impact, and Personal Relationships domains. A >50% decrease in pain was reported by five of seven patients with painful bladders at 1 mo, but only one of seven at 6 mo. CONCLUSIONS: In our small open-label study, a single administration of intravesical RTX in patients with frequency and urgency due to increased bladder sensation significantly improved lower urinary tract symptoms, urodynamic parameters, and quality of life for up to 6 mo.

Administration, Intravesical↗
PubMed2006

Quality of life changes in patients with neurogenic versus idiopathic detrusor overactivity after intradetrusor injections of botulinum neurotoxin type A and correlations with lower urinary tract symptoms and urodynamic changes.

OBJECTIVE: Little published data exist on the effect of intradetrusor botulinum neurotoxin type A (BoNT/A) on the quality of life (QOL) of patients with overactive bladder. We examined post-BoNT/A QOL changes of patients with neurogenic detrusor overactivity (NDO) in comparison to those with idiopathic detrusor overactivity (IDO), and their correlations with respective changes in lower urinary tract symptoms (LUTS) and urodynamic parameters. METHODS: Patients with urodynamically proven intractable DO were assessed for changes in QOL 4 and 16 wk after treatment with intradetrusor BOTOX injections (NDO 300U; IDO 200U) using the short forms of the Urinary Distress Inventory (UDI-6) and Incontinence Impact Questionnaire (IIQ-7). Percent changes in total QOL score were correlated to respective changes in clinical parameters recorded by bladder diaries and voiding cystometry. RESULTS: Forty-eight treated patients (32 NDO, 16 IDO) had QOL data in at least one follow-up. Highly significant decreases (p < 0.0001) in mean +/- standard error QOL score at 4 wk were maintained at 16 wk for both the NDO and IDO subgroups. Percent improvement in QOL score was similar for NDO versus IDO at 4 (67.6 +/- 4.5 versus 70.3 +/- 7.7, p = 0.74) and 16 wk (65.2 +/- 5.5 versus 71.9 +/- 8.8, p = 0.51). Percent changes in QOL score of the whole patient group correlated with changes in 24-h micturition frequency, number of voids associated with urgency, and number of urge incontinence episodes, but not with urodynamic parameters. CONCLUSIONS: Intradetrusor BoNT/A produces comparable, significant improvements in the QOL of patients with either NDO or IDO at least up to 16 wk after treatment. In contrast to urodynamic parameters, changes in LUTS appear to be the major determinants of improvements in the patients' QOL.

Adult↗
PubMed2006

Proposed mechanism for the efficacy of injected botulinum toxin in the treatment of human detrusor overactivity.

BACKGROUND: Treatment of human bladder overactivity with intradetrusor Botulinum-A neurotoxin (BoNT/A) injections temporarily blocks the presynaptic release of acetylcholine from the parasympathetic innervation and produces a paralysis of the detrusor smooth muscle. The efficacy of the treatment exceeds that expected from simple detrusor muscle paralysis, however, and its effect of reducing urgency is greatly welcomed by patients. OBJECTIVES: To examine whether BoNT/A has a complex effect on sensory mechanisms by inhibiting vesicular release of multiple excitatory neurotransmitters by urothelial and suburothelial nerves and reducing axonal expression of SNARE-complex dependent proteins. METHODS: A literature review. CONCLUSIONS: We propose that a primary peripheral effect of BoNT/A is the inhibition of release of acetylcholine, ATP, substance P, and reduction in the axonal expression of the capsaicin and purinergic receptors. This may be followed by central desensitization through a decrease in central uptake of substance P and neurotrophic factors. The summation of these effects is a profound and long-lasting inhibition of those afferent and efferent mechanisms that are thought to be the pathophysiological basis for DO.

Acetylcholine↗
PubMed2006

Bladder dysfunction in Parkinsonism: mechanisms, prevalence, symptoms, and management.

The advent of functional imaging methods has increased our understanding of the neural control of the bladder. This review examines current concepts of the role of brain function in urinary control with particular emphasis on the putative role of dopamine receptors. Dopaminergic mechanisms play a profound role in normal bladder control and the dysfunction of these may result in symptoms of overactive bladder in Parkinsonism. The importance of this nonmotor disorder has been overlooked. We address the problem of bladder dysfunction as it presents to patients and their neurologist. The prevalence of bladder symptoms in Parkinson's disease is high; the most common complaint is nocturia followed by frequency and urgency. In multiple-system atrophy, the combination of urge and urge incontinence and poor emptying may result in a complex combination of complaints. The management of bladder dysfunction in Parkinsonism addresses treatment of overactive detrusor as well as incontinence.

Brain↗
PubMed2006

Integrated control of lower urinary tract--clinical perspective.

The neural mechanisms that determine social bladder control are reviewed, with a particular emphasis on the role played by sensation in the process. Much has been learnt about the neural control of the bladder from studying patients with neurological disease and those disorders that are known to disrupt bladder storage are described. Possible approaches to treatment of the resulting incontinence are reviewed and it is acknowledged that in the future, the optimal treatment for incontinence may be determined by its precise underlying pathophysiology in each instance, for example, suprapontine causes requiring different medication to spinal causes. Although the main emphasis of urological research and development so far has been the treatment of incontinence, effective therapy for other bladder disorders such an impaired emptying or bladder pain could have an important impact on the bladder symptoms of many patients.

Animals↗
PubMed2006

Urinary retention in women: its causes and management.

OBJECTIVE: To report the experience of the last 4 years from a centre to which women with voiding difficulties and urinary retention were referred nationally, describing what investigations were helpful in making a diagnosis and the management strategies used. PATIENTS AND METHODS: Women with voiding difficulties and urinary retention remain a diagnostic and management challenge, and those with no anatomical or neurological basis for their symptoms may be dismissed, assuming that their retention has a psychogenic basis. The finding of an electromyographic (EMG) abnormality of the striated urethral sphincter explaining their disorder (Fowler's syndrome) has led to the referral of women for consideration of that diagnosis. Thus we audited the referrals to the centre over a 4-year period of such women. RESULTS: In all, 247 women (mean age 35 years) with complete (42%) or partial retention (58%) were referred; 175 (71%) had urethral pressure profilometry, 141 (57%) had a transvaginal ultrasonographic measurement of the sphincter volume, and 95 (39%) had sphincter EMG. The mean maximum urethral closure pressure difference between patients with an EMG abnormality (101.5 cmH(2)O) and the patients with known other causes of voiding dysfunction (66.2 cmH(2)O) was 35.3 cmH(2)O (P < 0.05). In patients with complete retention there was a significant difference in sphincter volume between those who were EMG-positive (2.14 mL) or EMG-negative (1.64 mL) (P < 0.05). CONCLUSION: These investigations helped to classify the cause of retention in two-thirds of cases. The commonest diagnosis was Fowler's syndrome, in which sacral nerve stimulation is the only intervention that restores voiding.

Adolescent↗
PubMed2006

Management of lower urinary tract symptoms in men with progressive neurological disease.

PURPOSE OF REVIEW: Progressive neurological disease can cause lower urinary tract symptoms similar to those seen in bladder outflow obstruction. Increasingly common with age, these two groups of conditions often coexist. The complex pathophysiology of men with this combination of problems is often poorly understood and suboptimally managed, mostly with long-term indwelling catheters. This review looks at recent diagnostic advances and emerging therapeutic alternatives. RECENT FINDINGS: For various neurogenic bladder disorders, urodynamic studies may demonstrate typical constellations of abnormalities, but no pathognomonic features. Other modalities such as sphincter electromyography and central nervous system imaging have been proposed to aid diagnosis. Functional brain imaging has helped to understand the complex nature of bladder storage and micturition control. A new generation of bladder-selective antimuscarinics has graduated through phase-III randomized controlled trials and these are now available for routine use. These agents are as efficacious as oxybutynin but have better side-effect profiles. Modern minimally invasive techniques such as desensitizing bladder instillations or injections of botulinum toxin have safely been used and are achieving excellent results. SUMMARY: Urodynamic studies are important and increasingly regarded as mandatory in all men considered for outflow surgery. Neurogenic bladder and sphincter dysfunction can be managed conservatively or with new minimally invasive techniques. Surgery should be reserved for severely symptomatic treatment failures. A working knowledge of common neurological disease associated with lower urinary tract dysfunction is important for urologists to diagnose these conditions or initiate an appropriate referral. This article gives an overview of recent work that has implications for the diagnosis and management of neurological disorders of micturition.

Administration, Intravesical↗
PubMed2005

Cost-consequence analysis evaluating the use of botulinum neurotoxin-A in patients with detrusor overactivity based on clinical outcomes observed at a single UK centre.

OBJECTIVE(S): This study aimed to assess the resource utilisation, health benefits and cost-effectiveness of intra-detrusor injections of botulinum neurotoxin-A (BoNT/A) in patients with overactive bladder (OAB). METHODS: 101 patients with urodynamically-proven detrusor overactivity of either neurogenic (NDO; n = 63) or idiopathic (IDO; n = 38) origin received intra-detrusor injections of 200-300 units of BoNT/A in 20-30 ml saline as part of a research protocol. Twenty-nine patients received repeat injections after 7-26 months. Symptom severity and urodynamic parameters were assessed at 0, 4 and 16 weeks. The cost of therapy was quantified based on the NHS resources used by typical patients and was used to calculate the cost-effectiveness of BoNT/A compared with standard care from the perspective of the UK NHS. RESULTS: In an intent-to-treat analysis, 82% of patients showed a 25% or greater improvement in at least two out of five parameters (urinary frequency, urgency, urgency incontinence episodes, maximum cystometric capacity and maximum detrusor pressure) four weeks after treatment, reducing to 65% after 16 weeks. A 50% or greater improvement in the frequency of micturition, urgency or urgency incontinence was seen in 73% of patients at four weeks and 54% at 16 weeks. There were no significant differences between IDO and NDO patients in the proportion meeting these endpoints. Therapy cost pounds 826 per patient, with a cost-effectiveness ratio of pounds 617 per patient-year with > or = 25% clinical improvement. CONCLUSION(S): This study demonstrates that intra-detrusor BoNT/A is an effective treatment for OAB that is highly likely to be cost-effective in both idiopathic and neurogenic disease.

Adult↗
PubMed2005

Is sphincter electromyography a helpful investigation in the diagnosis of multiple system atrophy? A retrospective study with pathological diagnosis.

Sphincter electromyography (spEMG) is often used as an ancillary test when multiple system atrophy (MSA) is suspected. Our aim was to determine the clinical features associated with spEMG being performed, the influence of the result on the final clinical diagnosis, and its utility as a clinical investigation. A retrospective audit of all cases in the Queen Square Brain Bank between 1989 and 2002 was performed. The clinical features and diagnostic accuracy were compared between patients in whom spEMG was performed and those in whom it was not. From 845 sets of complete clinical records, we identified 37 (4.4%) cases that had been investigated with spEMG. Thirty of these cases had a pathological diagnosis of MSA. Of these 30, 24 had abnormal spEMGs, 5 had a borderline result, and only 1 had a normal spEMG. Sixty-six cases had pathologically proven MSA but no spEMG. Those investigated with spEMG were younger at disease onset (P < 0.001), more frequently male (P = 0.03), and more likely to have had other investigations performed. They had a greater incidence of pyramidal tract signs at final clinical diagnosis, and the final clinical diagnostic accuracy was higher (P = 0.04). Due to the retrospective nature of the study, balanced populations for calculation of sensitivity and specificity were not available. In this selected series of pathologically confirmed cases, investigation with spEMG was one of several factors associated with improved clinical diagnostic accuracy. A normal spEMG is unlikely in pathologically proven MSA, at least in cases with a mean symptom duration of more than 5 years when the test is performed.

Adult↗
PubMed2005

Capsaicin receptor TRPV1 in urothelium of neurogenic human bladders and effect of intravesical resiniferatoxin.

OBJECTIVES: To study TRPV1 immunoreactivity in the urothelium of patients with neurogenic detrusor overactivity (NDO) before and after treatment with resiniferatoxin (RTX) and controls. Functional capsaicin TRPV1 receptors have been demonstrated in urothelial cells of rodent urinary bladder, and TRPV1-knockout mice exhibit diminished nitric oxide and stretch-evoked adenosine triphosphate release from urothelial cells. In patients with NDO, TRPV1 suburothelial nerve density is increased, which is reversed by successful treatment with intravesical RTX. However, the role of urothelial TRPV1 in human bladder disorders is unknown. METHODS: Flexible cystoscopic bladder biopsies were obtained from 14 patients with NDO before and after treatment with RTX and from 8 control patients. Using a specific antibody for immunostaining, TRPV1 immunoreactivity in the urothelium was quantified by image analysis. RESULTS: TRPV1 immunoreactivity was observed in basal and apical urothelial cells. Basal cell layer TRPV1 immunoreactivity was significantly increased in NDO compared with control bladders (P = 0.003). In 5 patients who responded clinically to RTX, basal cell layer and total urothelial TRPV1 immunoreactivity decreased significantly after treatment (P = 0.032 and P = 0.016, respectively). The decreases in the basal cell layer TRPV1 immunoreactivity after RTX were comparable to the decreases in suburothelial TRPV1 nerve fibers in the biopsies previously studied from the same patients. CONCLUSIONS: Increased urothelial TRPV1 in patients with NDO may play a role in the pathophysiology, in concert with increased TRPV1 nerve fibers. Although it is not known whether similar pathogenic mechanisms are involved in the increase of urothelial and neuronal TRPV1, both may be targeted by successful RTX therapy.

Administration, Intravesical↗
PubMed2005

Therapy Insight: bladder dysfunction associated with multiple sclerosis.

Bladder dysfunction is a common problem for patients with multiple sclerosis. The severity of symptoms often correlate with the degree of spinal cord involvement and, hence, the patient's general level of disability. The emphasis of management is now mainly medical and is increasingly offered by nonurologists. Treatments can be highly effective, relieving patients of what are otherwise very troublesome symptoms that would compound their neurological disability. This article gives an overview of the neural control of the bladder, followed by an explanation of the pathophysiology of detrusor overactivity secondary to neurological disease. A review of methods available for treating bladder dysfunction in multiple sclerosis then follows. The treatment options for this disorder are largely medical and include established first-line measures such as anticholinergics, clean intermittent self-catheterization and the use of desmopressin, as well as potential second-line agents, such as cannabinoids, intravesical vanilloids and intradetrusor botulinum neurotoxin type A. The diminishing role of surgical intervention is also discussed.

Algorithms↗
PubMed2005

A comparison between the response of patients with idiopathic detrusor overactivity and neurogenic detrusor overactivity to the first intradetrusor injection of botulinum-A toxin.

PURPOSE: Several studies have shown that intradetrusor injections of botulinum neurotoxin type A (BoNT/A) may effectively treat intractable spinal neurogenic detrusor overactivity (NDO), but fewer reports exist on the use of BoNT/A in patients with idiopathic detrusor overactivity (IDO). The purpose of this study was to investigate whether comparable efficacy could be displayed in the response of patients with IDO to those with NDO. MATERIALS AND METHODS: In a prospective, open label study, patients with urgency, and/or urgency incontinence due to urodynamically proven intractable detrusor overactivity received 300 units (NDO) or 200 units (IDO) of Botox injected into the bladder with a minimally invasive outpatient technique. Urodynamic maximum cystometric capacity and maximum detrusor pressure during filling, frequency of voids (frequency), number of incontinence episodes (leak) and number of voids associated with urgency per 24 hours (urgency) from 4-day voiding diaries were compared between the 2 groups at baseline and for changes at 4 and 16 weeks after treatment. RESULTS: A total of 44 patients with spinal NDO and 31 with IDO were treated. At 16 weeks, mean +/- standard error maximum cystometric capacity increased from 229.1 +/- 24.8 to 427.0 +/- 26.9 ml, p <0.0001 in NDO and from 193.6 +/- 24.0 to 327.1 +/- 36.1 ml, p=0.0008 in IDO. Maximum detrusor pressure during filling decreased from 60.7 +/- 6.8 to 26.1 +/- 3.7 cm H2O, p <0.0001 in NDO and from 62.1 +/- 10.8 to 45.1 +/- 8.1 cm H2O, p=0.027 in IDO. Frequency decreased from 12.3 +/- 0.7 to 6.6 +/- 0.6 voids per 24 hours, p <0.0001 in NDO and from 13.6 +/- 1.1 to 8.3 +/- 0.7, p=0.0002 in IDO. Leak decreased from 3.9 +/- 0.5 to 0.7 +/- 0.2 incontinence episodes per 24 hours, p <0.0001 in NDO and from 3.2 +/- 0.8 to 0.6 +/- 0.3, p=0.0017 in IDO, and urgency decreased from 7.5 +/- 0.6 to 1.44 +/- 0.3 episodes per 24 hours, p <0.0001 in NDO and from 10.9 +/- 1.7 to 4.9 +/- 1.1, p <0.0001 in IDO. The 2 groups were comparable for baseline data, but percent improvement in urgency was greater in patients with NDO at 4 weeks (78.2% vs 56.3%, p=0.019) and 16 weeks (78.3% vs 50.7%, p=0.013). Of patients with NDO 69% required self-catheterization de novo posttreatment compared with 19.3% of those with IDO. CONCLUSIONS: Patients with intractable IDO respond to intradetrusor BoNT/A with equally significant improvements in urodynamic and lower urinary tract symptom parameters as those with spinal NDO, despite the lower dose of toxin used.

Adult↗
PubMed2005

Changes in brain activity following sacral neuromodulation for urinary retention.

PURPOSE: Sacral nerve stimulation (neuromodulation) can restore bladder sensation and the ability to void in women with urinary retention due to sphincter overactivity (Fowler's syndrome). Modulation of central afferent activity is considered critical to this therapeutic effect but the neural mechanisms are poorly understood. Therefore, we undertook a functional brain imaging study to determine how neuromodulation acts on brain centers involved in the representation and control of bladder function. MATERIALS AND METHODS: Eight patients with Fowler's syndrome and 8 healthy controls underwent brain imaging with positron emission tomography to identify regions of brain activity relating to the perception of bladder fullness and their modulation by sacral nerve stimulation. RESULTS: In healthy controls bladder fullness enhanced activity in brainstem (midbrain) and limbic cortical regions. Women with urinary retention showed no significant brainstem activity but did show enhanced limbic cortical activity when the bladder was full in the absence of neuromodulation. Neuromodulation restored a normal pattern of midbrain activity and decreased cortical activity in this group. CONCLUSIONS: Our study provides novel neuroimaging evidence for the existence of abnormal interaction between brainstem and cortical centers in women with urinary retention. Furthermore, we have been able to show evidence that the therapeutic effect of sacral neuromodulation is achieved through restoration of activity associated with brainstem autoregulation and attenuation of cingulate activity.

Adult↗