Treatment Options for Urogenital Dysfunction in Parkinson’s Disease

Opinion statement Urogenital dysfunction is commonly reported in Parkinson’s disease (PD), and history taking and a bladder diary form the cornerstone of evaluation. The assessment of lower urinary tract (LUT) symptoms include urinalysis, ultrasonography, and urodynamic studies and help to evaluate concomitant urological pathologies such as benign prostate enlargement. Antimuscarinic medications are the first line treatment for overactive bladder (OAB) symptoms and solifenacin has been specifically studied in PD. Antimuscarininc drugs may exacerbate PD-related constipation and xerostomia, and caution is advised when using these medications in individuals where cognitive impairment is suspected. Desmopressin is effective for the management of nocturnal polyuria which has been reported to be common in PD. Intradetrusor injections of botulinum toxin have been shown to be effective for detrusor overactivity, however, are associated with the risk of urinary retention. Neuromodulation is a promising, minimally invasive treatment for PD-related OAB symptoms. Erectile dysfunction is commonly reported and first line treatments include phosphodiesterase-5 inhibitors. A patient-tailored approach is required for the optimal management of urogenital dysfunction in PD.


Introduction
Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by motor complaints of slowness of movements, resting tremor, and gait imbalance; however, Bnon-motor symptoms^are commonly reported and have a tremendous impact on quality of life [1,2]. Lower urinary tract (LUT) symptoms are often reported by patients, either storage symptoms (urinary urgency, frequency, nocturia, with or without incontinence) or voiding symptoms (slow and/or interrupted stream, terminal dribble, hesitancy and straining) [3]. The prevalence of LUT symptoms varies according to the study cited and ranges between 38 and 71 %, being influenced by the stage of disease and presence of LUT-related comorbidities, and parallels other manifestations of autonomic dysfunction [4][5][6][7]. The presence of LUT symptoms is associated with an increased risk for falls [8], early institutionalization and escalating health-related costs [9]. Nocturia is the most common non-motor symptom in PD but the causes for nocturia in PD are poorly understood [10,11].
Urodynamic studies may demonstrate reduced bladder capacity, poor compliance and detrusor overactivity (DO) in 43-93 % of patients of PD patients [12][13][14]. A likely mechanism for OAB symptoms in PD is disruption of the dopamine D1-GABAergic direct pathway and its GABAergic collateral to the micturition circuit [15][16][17], resulting in loss of inhibition of the micturition reflex and OAB symptoms. OAB symptoms correlate in severity with urodynamic abnormalities and dopaminergic deficit on dopamine transporter scans [3,18]. Nocturia additionally may also be due to nocturnal polyuria, characterized by increased nocturnal urine production more than 20-33 % of the entire 24-h volume [19]. Sexual dysfunction (SD) is frequently reported in PD and negatively impacts quality of life of both patients and partners. Men most commonly experience erectile dysfunction (ED) and difficulties in ejaculation, and women report reduced vaginal lubrication, painful intercourse and incontinence during sexual activity [20]. Patients may also report alterations in sexual desire such as hyposexuality or hypersexuality. Motor symptoms of PD such as tremor, muscle rigidity, dyskinesia and bradykinesia can affect sexual performance and satisfaction [20]. The management options for bladder and sexual dysfunction are discussed in this article. This article does not contain any studies with human or animal subjects performed by any of the authors.

Management of lower urinary tract dysfunction
Despite the high prevalence of LUT symptoms and impact on quality of life, treatment options are currently limited and are often poorly tolerated or ineffective in PD. Most treatment options are derived from guidance around general management of LUT symptoms in neurological patients. Comprehensive history taking is a sound starting point, as this provides insight into whether patients have storage dysfunction or voiding dysfunction, or both. Patients often have other medical comorbidities and the medications prescribed for these may contribute to LUTS, for example, diuretics used for managing hypertension increase urinary urgency and frequency. A review of concomitant medications provides an opportunity to review a patient's Banticholinergic burden^, and adding an antimuscarinic medication may increase the risk for falls, cognitive impairment and all-cause mortality [21]. Physical examination involves examining the abdomen, flank and pelvic and genital organs, and when appropriate, evaluating urogenital sensations, sacral cord-mediated reflexes (bulbocavernosus reflex, anal reflex) and anal sphincter tone and contractions. Digital rectal examination in a male patient allows evaluation of the size and consistency of the prostate gland.
The bladder diary, ideally maintained by the patient or carer for a period of time usually 3 days, provides prospective information in real-time about LUT symptoms about the fluid intake, urine output, time of voids and recorded indicators of bother and severity of symptoms. It is the only evaluation that provides information about nocturnal polyuria [22••]. Urinalysis (urine dipstick test) provides a rapid method of screening for Urinary tract infections (UTIs) which may share symptoms of OAB in the neurological population [23]. Ultrasonography is a non-invasive test that evaluates the lower and upper urinary tract for pathologies such as stones, hydronephrosis and prostate enlargement and also provides a measure of the post-void residual urine [24••, 25, 26••]. Uroflowmetry is a non-invasive urodynamic study that provides information about voiding. It can be used to diagnose bladder outflow obstruction and assess the patient's flow rate, time and pattern. Cystometry is not performed as a routine, however, may be required to evaluate the cause for LUT symptoms and exclude concomitant pathologies such as bladder outlet obstruction (

Diet and lifestyle
Although there are no studies specifically in PD, lifestyle interventions and behaviour modifications can improve OAB symptoms in patients with neurological disorders. Caffeine and/or alcohol should be avoided where possible as these both have mild diuretic properties. Restricting fluid intake at least 4 h prior to bedtime may help with nocturia [28]. Absorption of dependent edema fluid at night may contribute to nocturia, and adequate exercise, lower limb elevation above the heart level in the afternoon and use of compression stockings may help address this. The use of diuretics in the late afternoon may help with nocturia [29]. Emptying the bladder before going to bed is also advisable. To reduce the risk for falls at night, the path to the toilet should be well-lit and the area should be made 'falls safe' to avoid falls and injuries. In patients with limited mobility but preserved continence, simple measures such as using a bedside commode or flask may obviate the need to walk to the toilet at night [ Table 2). & Antimuscarinic agents competitively antagonize muscarinic acetylcholine receptors, prevent detrusor contraction, lower intravesical storage pressures and reduce storage symptoms. The effect that these medications may have on central muscarinic receptors has attracted considerable interest in recent years [24••, 33]. The central effects of these medications may result in alterations in cognition and consciousness in susceptible individuals. Medications currently being used by the patient should be reviewed before prescribing an antimuscarinic agent, especially in older people, as the cumulative use of agents with anticholinergic properties is associated with increased risk of cognitive impairment [33]. Permeability across the blood-brain barrier differs between antimuscarinic agents based upon physicochemical properties. For example, trospium chloride is a poorly lipophilic, positively charged quaternary ammonium compound that does not readily cross the blood-brain barrier and theoretically might be associated with fewer effects on cognition, though this has not been specifically evaluated in PD [34]. & Muscarinic receptor selectivity may influence central effects. For example, darifenacin has a greater affinity for the M3 receptor subtype of relevance to bladder functions compared to the M1 receptors prevalent in the central nervous system A recent double-blind, randomized, placebo-controlled study evaluated solifenacin in 23 patients with PD and urinary symptoms. There was no significant change in the mean number of micturition per 24 h
Main drug interactions Preparations containing potassium can increase gastric intolerance, topiramate or zonisamide can increase chances of heat prostration.

Oxybutinin [36]
Standard dosage Immediate release tablet: 2.55 mg two to three times daily.
Class of evidence Level 5 for urinary dysfunction in PD [11,37] [level 1 evidence for neurogenic detrusor overactivity [39]] Contraindications Urinary retention; narrow angle glaucoma; gastric or intestinal obstruction, severe dementia or myasthenia gravis [38]. β3-Adrenoceptor agonists (Mirabegron) [44,45] & Recently, mirabegron has emerged as a potentially safe and effective treatment for OAB [44] with preliminary evidence in neurogenic OAB, though not specifically in PD [45] & However, high-level evidence supporting the use of mirabegron in the management of the neurogenic bladder is lacking.

Standard dosage 25 to 50 mg per day
Class of evidence NA [44] Contraindications Patients with severe uncontrolled hypertension (BP 9 180/110 mmHg) [46] Main drug interactions Tamoxifen levels may be reduced in patients taking this for breast cancer Desmopressin & Desmopressin, a synthetic analogue of arginine vasopressin, temporarily reduces urine production and volume-related OAB symptoms. Desmopressin works by promoting water reabsorption at the distal and collecting tubules of the kidney. It is useful for the treatment of urinary frequency or nocturia. & Desmopressin has been tried in parkinsonism including PD and multiple system atrophy; however, long-term follow-up is lacking [38, 48, 47•, ].

Class of evidence Level 5 [48]
Contraindications Kidney disease, cystic fibrosis, hyponatremia, heart failure and pedal edema. Used with caution over 65 years of age.

Main drug interactions Antidepressants-citalopram, sertraline and duloxetine can increase chances of hyponatremia with desmopressin
Main side effects Headache, hyponatremia specifically relevant in patients older than 65.
Special points Safety during pregnancy uncertain [Category C].

Botulinum toxin
Intradetrusor injection of onabotulinumtoxinA has proven to be a safe and effective treatment for neurogenic DO. In one study of 20 patients with DO moderate to marked symptom relief at 3 months and a 50 % incontinence decrease over 6 months relative to pretreatment was reported in 59 % patients (p ≤ 0.02) [49••]. Another study of eight patients reported clinical and urodynamic improvement in overactive bladder symptoms that lasted at least 6 months in patients with PD [50]. In another study, Kulacksizoglu et al. reported no increase in post-voiding residual [51]. OnabotulinumtoxinA treatment results in impaired detrusor contractility and therefore is associated with a risk for urinary retention. The potential benefits of this treatment must be weighed against the potential need to intermittently catheterize or use an indwelling catheter, and the accompanying dependence on carers or partners and possible complications including urinary tract infection, trauma, bleeding, potential for lower limb weakness and flu-like illness.

Assistive procedures
Clean intermittent self catheterization The finding of a high post-void residue (PVR) is unusual in patients with PD. If the PVR volume is consistently more than 100 mL, clean intermittent catheterization has been advocated. Specific issues related to dexterity in PD may make this challenging. Experienced health-care professionals, such as a continence adviser, should be involved in teaching the technique and exploring possible barriers to successful catheterization. Neuromodulation & Percutaneous tibial nerve stimulation (PTNS) is an emerging treatment option that may help patients who have contraindications or are refractory to medical treatment. Following acute PTNS, the functional bladder capacity has been shown to be increased [53]. Chronic stimulation has been reported to decrease frequency, urinary and urge urinary incontinence in neurogenic bladder, but long term outcomes in PD are lacking [53] & Transcutaneous tibial nerve stimulation (TTNS) was found effective in the treatment of LUT symptoms in 13 patients with PD, reducing urgency and nocturia [54] & Sacral neuromodulation (SNM) may be effective and safe for the treatment of patients with neurogenic lower urinary tract dysfunction (LUTD). However, studies specifically in PD are lacking. A systematic review and meta-analysis included only four patients with PD and this group was not separately analysed. [55].
Specific therapies for Parkinson's disease in management of urological dysfunction

Dopaminergic treatment
The effects of levodopa on LUT symptoms are variable [3,56,57]. There may be a period of initial worsening after starting levodopa but this may improve later [3]. One study showed that treatment with levodopa for 3 months in PD patients was associated with slightly improved storage urodynamic parameters [3]. In another study, DO was shown to worsen with levodopa in some patients and lessened in others. The effect on micturition of treatment with dopaminergic drugs in PD was unpredictable in another study [56]. Dopaminergic drugs like bromocriptine can lead to decreased storage parameters and pergolide improved nocturia in a small study [57].
In an open label study including three patients 12 weeks of treatment with pergolide improved LUT symptoms and nocturia frequency in all three patients and an improvement of sleep QOL in two [57].

Deep brain stimulation
DBS (DBS) is a well-accepted treatment option in advanced PD. Deep brain stimulation can have variable effects on LUT symptoms with worsening reported in some and improvement in other studies [58, 60, 59••, ]. Although the studies have not specifically focused on nocturia, there is evidence that subthalamic nucleus DBS-treated patients exhibit significantly less nocturia. In a study comparing DBS (GPi) and other forms of treatment in 107 patients with PD, the overall amount of urinary symptoms were similar but fewer DBS patients (47 %) complained of nocturia compared to conventionally treated (88 %) and to apomorphine pumptreated (66 %) patients [61]. Not only did the patients who had DBS reported less nocturia (P = 0.007) but also they were also less bothered by nocturia (P = 0.01) compared to the other treatment groups, as assessed by the Danish Prostate Symptom Score (DanPSS) [61]. More studies may be needed to establish definite correlation and to understand the pathophysiology of this association.

Surgical therapies for bladder outflow obstruction
Benign prostate enlargement is a common cause for bladder outflow obstruction in middle age and elderly men and is often a contributory factor for LUT dysfunction in PD. It was widely believed for several years that men with PD should not undergo prostate surgery because of the high risk of incontinence [62]. There is some evidence to support transurethral prostate resection for bladder outflow obstruction in patients with PD. In a study on 23 patients with PD, TURP was successful in up to 70 %. The risk of de novo urinary incontinence after surgery was reported as minimal [63••]. The management of hypersexuality as part of an impulse control disorder includes reduction/stopping of dopamine receptor agonist and practical therapeutic strategies including psychological therapies but not limited to counselling, psychotherapy, sex, couple and behavioural therapies [65••]. Hormonal treatment specifically testosterone has been tried in PD [67].

Sildanefil
Standard dosage 25-100 mg taken 1 h before sexual activity Class of evidence Level 5 Contraindications Hypotension (blood pressure below 90/50 mmHg) Main drug interactions Organic nitrates in any form, alpha-blockers and antihypertensives may cause hypotension.
Main side effects Headache, flushing and dyspepsia. Temporary visual symptoms (mainly colour-vision disturbances) may occur with higher doses 100 mg Special points Used once or twice per week.

Tadalafil
Standard dosage 10 mg orally once a day, as needed, prior to sexual activity

Class of evidence Level 5
Contraindications Hypotension (blood pressure below 90/50 mmHg) Main drug interactions Organic nitrates in any form, alpha-blockers and antihypertensives may cause hypotension.
Main side effects Headache, flushing and dyspepsia. Temporary visual symptoms (mainly colour-vision disturbances) may occur with higher doses 100 mg Special points Used once or twice per week.

Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

References and Recommended Reading
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