Curr Urol Rep (2014) 15:435 DOI 10.1007/s11934-014-0435-0

LOWER URINARY TRACT SYMPTOMS & VOIDING DYSFUNCTION (H GOLDMAN AND G BADLANI, SECTION EDITORS)

A Review of Lower Urinary Tract Symptoms in Patients with Parkinson’s Disease Anand V. Badri & Rajveer S. Purohit & Jason Skenazy & Jeffrey P. Weiss & Jerry G. Blaivas

# Springer Science+Business Media New York 2014

Abstract To critically review recent literature on lower urinary tract symptoms (LUTS) in patients with Parkinson’s Disease.A literature search was conducted using the keywords LUTS, urinary symptoms, non-motor, and Parkinson’s disease (PD) via the PubMed/Medline search engine. In the literature, we critically examined lower urinary symptoms in Parkinson’s patients by analyzing prevalence, pathogenesis, urinary manifestations, pharmacologic trials and interventions, and prior review articles. The data collected ranged from 1986 to the present with an emphasis placed on recent publications.The literature regards LUTS in PD as a major comorbidity, especially with respect to a patient’s quality of life. Parkinson’s patients experience both storage and voiding difficulties. Storage symptoms, specifically overactive bladder, are markedly worse in patients with PD than in the general population. Surgical management of prostatic obstruction in PD can improve urinary symptoms. Multiple management options exist to alleviate storage LUTS in patients with PD, ranging from behavioral modification to surgery, and vary in efficacy.Lower urinary tract dysfunction in PD may be debilitating. Quality of life can be improved with a multi-pronged diagnosis-specific approach to treatment that takes into consideration a patient’s ability to comply with treatment. A

stepwise algorithm is presented and may be utilized by clinicians in managing LUTS in Parkinson’s patients. Keywords Parkinson’s disease . Lower urinary tract symptoms . Overactive bladder . BPH . Bladder outlet obstruction . Urinary symptoms

Introduction Parkinson’s disease (PD) is a progressive, degenerative neurological disorder classically characterized by motor symptoms, including resting tremor, bradykinesia, rigidity, and postural instability. Non-motor symptoms of PD, especially those involving the lower urinary tract, can significantly impact quality of life. The management of these non-motor LUTS in PD, from screening and prophylaxis to surgical intervention, is currently an area of research. This paper focuses on clinically relevant findings from 2012 to the present.

Pathophysiology of Parkinson’s Disease and Associated Urinary Involvement This article is part of the Topical Collection on Lower Urinary Tract Symptoms & Voiding Dysfunction A. V. Badri (*) : J. Skenazy : J. P. Weiss : J. G. Blaivas State University of New York Downstate Medical Center, Brooklyn, NY, USA e-mail: [email protected] A. V. Badri : R. S. Purohit : J. P. Weiss : J. G. Blaivas Institute for Bladder and Prostate Research, New York, NY, USA R. S. Purohit : J. G. Blaivas Weill Cornell Medical College, New York, NY, USA

The principal physiologic abnormality in PD stems from the loss of dopaminergic neurons in the substantia nigra and is histologically characterized by the presence of Lewy bodies, abnormal protein aggregates found in the neurons of Parkinson’s patients. Dopamine depletion disrupts connections between the motor cortex and thalamus, leading to parkinsonian signs such as bradykinesia and resting tremor [1]. Autonomic dysfunction has also been characterized as a common non-motor finding and plays a role in the manifestation of LUTS in PD [2•].

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Many regions of the brain have been studied in relation to the non-motor findings in PD. The frontal cortex, basal ganglia, thalamus, and anterior cingulate gyrus play a role in the development of bladder dysfunction [3]. Fowler et al. suggest that the severity of bladder dysfunction is associated with degeneration in the caudate nucleus of the basal ganglia.

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micturition reflex from voluntary control and results in uninhibited bladder contractions, the basis for OAB [7]. OAB in PD may be grouped under Neurogenic Detrusor Overactivity (NDO) because the overactivity is secondary to neural dysregulation.

Prevalence and Manifestations of LUTS in PD Defining Overactive Bladder Overactive bladder symptoms are the predominant urinary symptom in Parkinson’s patients with LUTS [2•]. The best definitions of overactive bladder (OAB) and urgency continue to be controversial. Urgency is the central, necessary symptom of OAB; for the International Continence Society (ICS), OAB is a clinical diagnosis of “urinary urgency, usually accompanied by frequency and nocturia, with or without urgency urinary incontinence, in the absence of urinary tract infection or other obvious pathology.” According to the ICS, urgency refers to the “sudden, compelling desire to pass urine which may be difficult to defer.” [4]. This definition treats urgency as a binary phenomenon (present or not) rather than a graded one. Treatment of urgency as a continuous, graded variable using the validated “Urgency Perception Score” (UPS) [5] also permits a more nuanced approach towards diagnosis and treatment of patients with OAB. The UPS correlates urgency sensed by patients with the ability to delay micturition. Inability to delay micturition substantially increases the morbidity that OAB causes patients with PD who often have difficulty quickly reaching a bathroom because of bradykinesia. Incorporating the UPS in bladder diaries can be helpful in understanding causes and direct treatment such as behavioral modification in PD patients with OAB.

Etiology of LUTS in PD In patients with PD, the etiology of OAB is centrally mediated and modulated in complex ways that are not fully understood. OAB may be caused by lesions of the basal ganglia that interfere with the function of the Pontine Micturition Center (PMC). The PMC sends descending excitatory projections to the spinal parasympathetic preganglionic neurons innervating the bladder as well as inhibitory interneurons regulating Onuf’s nucleus, the origin of innervation for the striated muscles of the urethral sphincter. The PMC also receives afferent input from both the lumbosacral spinal cord based on bladder distention as well as the prefrontal cortex, which governs social acceptability of voiding [6]. When given the signal, the PMC may remove the inhibition of Onuf’s nucleus and initiate voiding. With PD, a reduction in nigrostriatal dopamine—specifically, decreased D1 receptor stimulation—leads to a partial or total disconnection of the

General prevalence data, as assessed by control-based validated questionnaires, suggest that lower urinary tract dysfunction is present in 27–63.9 % of patients with PD, significantly higher than in healthy controls [8–10]. Analyzing specific symptoms of the lower urinary tract, Ransmayr et al. found that urge incontinence (UI) and NDO were present in 53 % and 46 % of patients with documented PD, respectively [11]; this data corroborated the findings of Berger and Blaivas et al. who noted detrusor hyperreflexia in 90 % of their cohort of PD patients with persistent bladder symptoms [12]. Notably, Ragab et al. found nocturia to be the most prevailing symptom in patients with PD [13]. In the past year, Siegl et al. reviewed incontinence in PD. They found that although PD patients on L-Dopa therapy do not have a shortened lifespan compared with unaffected patients, they do possess many motor comorbidities that significantly decrease quality of life, including UI. The group analyzed UI in women and found it to be present in 25 % of patients with PD as compared to only 7 % of patients without PD [14••].

Diagnosis and Associated Conditions Although the diagnosis of PD is usually accomplished by neurologists and internists, patients seen in urologic clinics with lower urinary tract complaints may exhibit signs and symptoms of undiagnosed PD. Because there are no physiologic or blood tests to confirm a diagnosis of PD, and the true gold standard is neuropathologic examination, a clinical diagnosis is typically made based on patient’s history and exam findings. Bradykinesia, a slowing of movement with shuffling gait, plus one of the other cardinal manifestations—tremor or rigidity—must be present to diagnose idiopathic PD. In addition, response to dopaminergic therapy is an important criterion for diagnosis [15]. In patients with LUTS and parkinsonism, distinguishing multisystem atrophy (MSA), previously known as ShyDrager syndrome, from PD is crucial in terms of prognosis and management. MSA patients develop parkinsonian symptoms, but the disease tends to be more rapidly progressive with higher degrees of cerebellar and autonomic dysfunction and poorer response to levodopa [16, 17]. Urologic complaints in MSA tend to present prior to most motor manifestations,

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while LUTS in PD is mostly present after the onset of bradykinesia, resting tremor, and rigidity [18, 19]. Chandiramani et al. compared the onset of urinary and neurologic symptoms in patients with MSA and idiopathic PD. Of their MSA patient cohort, 60 % exhibited urinary symptoms preceding or presenting with neurological manifestations compared to 94 % of PD patients who encountered motor symptoms prior to the onset of urogenital symptoms [19]. On videourodynamics (VUD), patients with MSA will have an open bladder neck while patients with PD typically will not [20]. Parkinson’s disease is a progressive disease in all patients and progression is most commonly staged according to the modified Hoehn and Yahr system. The system is based on laterality of symptoms, postural instability and ability to ambulate; it is staged from 0–5 by increasing extent of disease and motor limitations [21].

History and Exam The clinician should elicit both storage and voiding symptoms as part of a thorough history. Specifically, urgency, incontinence, frequency, nocturia, hesitancy, straining to void, force of urinary steam, prior history of retention, and intermittency of stream, as well as duration, baseline level, and amount of bother for all symptoms should be included. Urologic symptoms prior to the development of PD should be assessed. Many older patients who develop PD will have bladder outlet obstruction and detrusor overactivity that may be related to prostatic hypertrophy and unrelated to PD. Comorbid conditions such as cerebrovascular accident, multiple sclerosis, spinal cord injury, diabetes, constipation, chronic pelvic pain, prior pelvic operations, or pelvic malignancy should be elicited. Current medications, specifically diuretics, should also be assessed. In addition to the standard urologic examination, such as assessment of prostate size in men and presence of prolapse in women as well as determination of the stage of PD, the clinician should consider assessment of sphincteric bradykinesia by asking the patient to contract their sphincter during the digital rectal exam. The inability to contract the sphincter quickly can have a substantial impact on the ability to prevent urgency incontinence. Urge Incontinence in patients with significant sphincteric bradykinesia and OAB can have substantial morbidity and negatively impact quality of life. A urinalysis should be obtained to assess for hematuria as a possible sign of malignancy as well as urinary tract infection, which should be treated if present. For those patients who cannot provide accurate intake and voiding information, a validated questionnaire is advised. Commonly used questionnaires include the International Prostate Symptom Score (IPSS) and the Lower Urinary Tract

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Symptom Score (LUTSS) [22]. Both ask several questions regarding storage and voiding symptoms and allow for a subjective measurement of severity and documentation of any response to therapy. Additional potentially useful, noninvasive tests include uroflowmetry, post-void residual, and trans-abdominal ultrasonography. These can evaluate for concomitant bladder outlet obstruction (BOO), as well as anatomical abnormalities that may have led to the presenting complaints [23]. Tools critical to the evaluation of LUTS in patients with PD are a 24-hour bladder diary, and in incontinent patients, a 24-hour pad test. The 24-hour diary should include the volume and time of each void, as well as the severity of the urge that prompted urination—the urge perception score (Fig. 1) [5]. The diary is critical to understanding patients’ voiding patterns by helping assess the role of polyuria (with the total 24-hour voided volume), urgency voids (UPS), and causes of nocturia, for example. The maximum voided volume (MVV), which is the largest voided volume on the diary, is a surrogate for effective bladder capacity. Comparing pre-treatment and post-treatment MVV can provide a metric to assess the efficacy of treatment in PD patients with storage symptoms. The 24-hour pad test is typically done on the day of the diary and helps to quantify the degree of urine loss better than a standard 24-hour pad count. Patients are asked to bring in all the pads that they used in 24 hours and place them into a plastic bag (to minimize evaporative losses) and also to bring in a dry pad. The dry weight is subtracted from the weight of the wet pad to quantify the amount of urine loss. It must be noted that a pad count is a poor measure of urinary incontinence severity [24]. Invasive studies, particularly VUD and cystoscopy, are the most accurate way of delineating the underlying pathophysiology of lower urinary tract dysfunction in patients with PD. However, both of these invasive tests carry a risk of urinary tract infection (UTI) and post-procedural acute urinary retention (AUR) in men and because of this, we do not recommend these tests unless a patient is also willing to accept potentially invasive treatments, such as intermittent catheterization or trans-urethral resection of the prostate (TURP) to correct the consequence of the testing. The risk of both UTI and AUR is lower in women and the threshold for doing the VUD and cystoscopy is consequently lower. If a patient decides to proceed with VUD several variables may be gleaned from this study that can help categorize symptoms including detrusor pressure (pDet), peak flow (Qmax) and detrusor pressure at peak flow (pDet@Qmax) in both genders and in men, bladder outlet obstruction index (BOOI), and bladder contractility index (BCI), among others. As BOOI (pDet@Qmax – 2Qmax) relates to pDet and Qmax, a value>40 in men can classify a patient with obstruction (Nitti 2005). BCI

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Fig. 1 24-Hou OAB bladder diary

(pDet@Qmax+5 Qmax) and is a measure of detrusor contractility in men. A BCI>150 indicates strong contractility, a BCI between 100 and 150 is considered normal, and a BCI< 100 constitutes a weak contraction, i.e., impaired detrusor contractility [25]. VUD remains the gold standard for diagnosis of uninhibited detrusor contractions that occur during the filling phase of voiding in OAB [26]. This testing can identify PD patients with concomitant LUTS with the added benefit of accurately diagnosing the specific quality of LUTS and distinguishing complaints of urethral obstruction, OAB and neurogenic bladder, and impaired detrusor contractions. In PD patients who complain of OAB with or without urge incontinence, the VUD classification of the OAB can be

useful to guide treatment. The classification system groups OAB into four types based on the presence of involuntary detrusor contractions (IDC) and the ability of the patient to contract their voluntary sphincter to abort the contraction. Refer to Table 1 [27]. The degree of sphincteric bradykinesia in patients with PD can profoundly affect the ability of patients to delay micturition. When confronted with an IDC, many patients are unable to contract their sphincter quickly enough and suffer from urge incontinence (types 3 and type 4 OAB) and decreased quality of life [28]. In addition to affecting quality of life, the presence of sphincteric bradykinesia can also impact the efficacy of

Curr Urol Rep (2014) 15:435 Table 1 OAB sub-type classification OAB Type Findings 1 2 3 4

Urgency without IDC Urgency with IDC IDC with ability to contract sphincter to delay incontinence IDC with no ability to delay incontinence

IDC involuntary detrusor contractions

treatment, in particular, behavioral modification as will be described below.

Management Treatment of patients with PD who suffer from LUTS should focus on minimizing morbidity and maximizing quality of life by improving symptoms and the ability to cope with symptoms otherwise resistant to treatment. The combination of overall morbidity from bradykinesia and immobility and depression/cognitive impairment secondary to PD make it extremely difficult to design effective treatment, even with dedicated caregivers. The patient must be motivated otherwise treatment efficacy is limited. Given profound cognitive, psychological and motor limitations, an honest discussion with the patient regarding likely outcomes needs to be accomplished at the onset of treatment. Conservative Management Successful conservative management with behavioral modification can profoundly improve quality of life in patients with PD and LUTS. Behavioral modification includes a multipronged strategy involving patient education, bladder training, fluid and diet management, pelvic floor education, and biofeedback training. The patient’s unique living situation, mobility, and dexterity should be taken into account. Patient education, for example, may involve teaching patients who suffer from nocturnal urge incontinence to have a bedside commode or urinal in lieu of trying to ambulate to the bathroom, given motor limitations. Fluid and diet management may involve teaching avoidance of caffeine and other foods or drinks that are empirically determined to exacerbate OAB symptoms. Analysis of the voiding diary should focus on bladder capacity (through the maximum voided volume), the presence of polyuria, and the relationship of voided volume with incontinence, the correlation with grades of urgency (the urge perception score) and voided volume [5]. Patients can be taught to respond earlier to urges when they have smaller bladder volumes to allow sufficient time to get to the bathroom given their limited mobility. Teaching may also include

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fluid management strategies to decrease overall consumption and time intake, such that urine is produced at times of easy access to a restroom. Patients who do not have substantial sphincteric bradykinesia, but suffer from urge incontinence, can be taught to contract their sphincter through biofeedback to detect when they have an IDC to abort the contraction and prevent incontinence by contracting their sphincter. This type of teaching is most successful in patients who have type 2 and type 3 OAB by VUD. Medical Management Medical therapy should be started if lifestyle modifications prove ineffective. Medication choice is based on specific clinical diagnosis; patients with outlet obstruction may try alpha-blocker therapy while those with OAB and urge incontinence may try anticholinergic therapy. Anticholinergic medications use for OAB symptoms is controversial. Perez-Lloret et al. explored the management of NDO and UI by comparing muscarinic antagonists for women with PD and UI. In order of decreasing efficacy, as assessed by percent of women with restored continence, were fesoterodine > oxybutynin > trospium > solifenacin > tolterodine [29••]. In 2006, Winge et al. reviewed the management of PD and MSA patients with concomitant bladder dysfunction. They found that in PD patients with post-void residual>100 mL, the use of clean intermittent self-catheterization in addition to antimuscarinic therapy proved efficacious in relieving storage symptoms; this result was not elicited in their review of MSA patients, highlighting a difference in treatment outcomes of LUTS in patients with PD and MSA [30]. Many patients with PD also suffer from constipation, slowed speech and in late stages impaired cognition. Side effects of anticholinergics which including worsened constipation, dry mouth and confusion can exacerbate these symptoms limiting the utility of and compliance with these medications. Dopamine therapy, seen as a first-line in the treatment of PD, has been studied as a remedy to LUTS secondary to PD with mixed results. Winge et al. analyzed the effects of dopaminergic therapy on bladder capacity. The group used levo/carbi-dopa, dopamine receptor agonists, COMT-inhibitors, and selegiline in 154 patients aged 30-60 years with idiopathic PD and assessed changes in urodynamic parameters. Although dopaminergic therapy was shown to elicit a promising increase in bladder capacity in a cohort of patients with a DanPSS>10 (difference+47.1 mL, 95 % CI=0.88 – 93.25, p=0.04), more investigation is needed to assess the degree of nonmotor response to dopamine administration [31]. Minimally Invasive Management Multiple minimally invasive approaches to managing neurogenic storage symptoms comprising multifaceted therapeutic

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options ranging from self-catheterization to posterior tibial nerve stimulation have been explored. Clean intermittent catheterization (CIC) has shown favorable results in managing emptying problems in patients with NDO. Patients who performed CIC while remaining on oxybutynin achieved socially acceptable continence with improved quality of life and enhanced sexuality [32••]. Drawbacks of CIC include the need for adequate education, manual dexterity, and access to the urethra; CIC is difficult for patients with obesity, spasticity, and impaired use of upper extremities, especially those in whom the severity of parkinsonian tremor proves insurmountable. Compliance with CIC for PD patients may prove very difficult. For such patients, suprapubic access may be beneficial [32••]. First described in a urologic context by Dyktra in 1988, intravesical botulinum toxin proved to ameliorate detrusor sphincter dyssynergia and has since been used to more broadly manage detrusor overactivity, especially of neurologic origin. Of seven serotypes, botulinum toxin A has been the most extensively studied; botulinum toxin A achieves a chemical denervation of the detrusor lasting up to 9 months [2•]. Giannantoni et al., using 200 IU in women with NDO secondary to either PD or MSA, found decreased urinary frequency and subjectively improved quality of life scores. They also noted that none of the PD patient cohort reported increased postvoid residual or the need to self-catheterize postbotulinum therapy; the MSA cohort, however, reported worse outcomes on these parameters, highlighting both the efficacy of intravesical botulinum toxin in PD patients with NDO, as well as the marked difference in treatment outcomes between PD and MSA patients with LUTS [33]. Cone et al. recently corroborated previous positive findings, as intravesical botulinum toxin exhibited efficacy in NDO secondary to PD, Multiple Sclerosis (MS), and spinal cord injury by improving many overactive bladder symptoms, including urgency and frequency [32••]. Most recently, Anderson et al. described good outcomes treating 20 patients who had urge incontinence with intravesical Botox [34]. The number of patients reported overall is small and concern exists about the ability of PD patients to manage the potential risks of urinary retention and systemic side effects including lethargy and fatigue. Patients undergoing intravesical botulinum therapy must be willing to perform CIC, given the risk of post-procedural retention [32••]; the clinician must address this additional task prior to therapy, given the manual facilities needed to perform CIC, which may prove difficult for some PD patients. Posterior tibial nerve stimulation (PTNS) has also been explored for OAB and urinary retention in patients with parkinsonian syndromes. PTNS inhibits bladder activity by depolarizing somatic sacral and lumbar afferent fibers through shared nerve roots and ganglia of the bladder and the posterior tibial nerve [35•]. A literature review completed by Cone et al. noted a 92 % overall success rate in patients with NDO, as

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defined by>50 % improvement in bladder diary variables [32••]. A recent French study by Ohannessian et al. enrolled six women with PD or MSA and concomitant OAB in a prospective monocentric study to evaluate the efficacy of chronic transcutaneous tibial nerve stimulation. The group provided 20-minute daily tibial nerve stimulation for a total of 6 weeks, and subsequently measured subjective outcomes based on the Patient Global Impression of Improvement Scale (PGI-I) as well as cystometric capacity. Significantly increased cystometric capacity (211 mL±106 to 260 mL±226, p=0.6) and subjective quality of life improvement were noted. All but one patient pursued continuation of PTNS after the 6week period [36]. Surgical Management and Post-Operative ComplicationsConcern has existed about the risks of incontinence with a transurethral resection of the prostate (TURP) in PD patients with BOO, which was initially prompted by the reports of Staskin et al., who found a 28 % incidence of incontinence in these patients [37]. However, the original report had short follow-up (median 3 months) and did not exclude MSA patients with parkinsonism. A subsequent evaluation of TURP in PD patients by Roth et al. with longer follow-up and exclusion of MSA found no patients with post-op incontinence. In fact, a substantial number of patients were found to have improvement in both storage and voiding symptoms after a TURP [38]. Patients with undetermined neurological dysregulation should not undergo surgery as the diagnosis of MSA has a significant impact on outcome. Chandiramani et al. found post-TURP incontinence rates in every patient in their MSA cohort [19]. For patients with NDO, other surgical options exist. NDO may be considered an indication for augmentation cystoplasty, in addition to the other indications that include diminished bladder capacity, interstitial cystitis, and neurogenically incapacitated bladder [39]. A urinary diversion may also be employed in patients with severe refractory LUTS and PD. An incontinent urinary diversion is generally advised as continent diversions may be, or become, difficult for PD patients to manage (e.g. manual dexterity needed for self catheterization). These surgical approaches have yet to be studied specifically in PD patients, so recommendations for these procedures should be deferred and based upon the clinical judgment of a urologist experienced in managing PD.

New Findings/Discoveries Contemporary research utilizes a multi-system approach to managing neurogenic urinary dysfunction, a contrast to the

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previously narrow focus of symptomatic management and urologic intervention. Diazepam, dantrolene, and baclofen have all been investigated in PD patients for their spasmolytic effects, although the results have thus far been inconclusive [40]. Recent research has focused on Deep Brain Stimulation (DBS), which involves the implantation of small electrodes in the subthalamic nucleus to send short electrical impulses in an effort to counteract the neurogenic derangements that manifest LUTS in PD patients. The subthalamic nucleus is involved in a circuit that exhibits a net inhibitory effect on modifying motor programs; DBS reasserts this inhibitory effect and counteracts NDO. This past year, Ashkan et al. analyzed the effects of DBS and suggested that DBS has a major potential to contribute towards the holistic care of PD patients [41••]. This conclusion was based on the findings of Wolz et al., who recently reported the immediate effect of bilateral subthalamic nucleus (STN) DBS on the nonmotor symptoms of 34 PD patients; bladder urgency was among nine other nonmotor parameters assessed by the group. The study reported an overall improvement in most nonmotor symptoms (most substantially in fatigue, restlessness, and

dysphagia) and no worsening of any nonmotor symptoms, urgency included, with STN DBS [42]. The adverse effects, however, noted transient psychiatric and mood disturbance—specifically depression, hypomania, and delirium—apathy, impaired verbal fluency, and impulse control disorders. The mechanism for these adverse effects remains unclear, but may involve a lesioning effect of fronto-striatal circuits along the trajectory of the electrode, suboptimal positioning of the electrodes, current spread to adjacent structures, or non-judicial post-surgical medication adjustment [41••]. Winge et al. used the Danish Prostate Symptom Score (DanPSS) validated questionnaire data on 107 patients to analyze differences in subjective improvement between PD patients receiving various treatments (conventional, DBS, apomorphine) for lower urinary tract complaints, specifically symptoms of overactive bladder including frequency, nocturia, urgency, and UI. Defining nocturia as>two nightly voids, they found that “DBS patients reported significantly less nocturia (p=0.007) and were significantly less bothered by nocturia (p=0.01) compared to the other treatment groups, as assessed by DanPSS question #6. Fewer DBS patients (47 %) complained of

Fig. 2 Management of LUTS in PD. Key- Urinary Tract Infection, UTI; Urinalysis, UA; Urine Culture, UCx; Neurogenic Detrusor Overactivity, NDO; Urge Incontinence, UI; Stress Incontinence, SI; Clean Intermittent

Catheterization, CIC; Posterior Tibial Nerve Stimulation, PTNS; Deep Brain Stimulation, DBS; Trans-Urethral Resection of the Prostate, TURP

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nocturia compared to conventionally treated (88 %, p= 0.01) and to apomorphine pump-treated (66 %, p=0.9) patients” [43••].

Conclusion The topic of lower urinary tract dysfunction in patients with Parkinson’s disease is one of great importance in its impact on quality of life and potentially debilitating sequelae. An important issue for future research is distinguishing centrally mediated LUTS secondary to PD from LUTS that is merely coincidental. Figure 2 demonstrates a stepwise algorithm that clinicians may employ to aid in the management of LUTS in a patient with PD. An emphasis must be placed on the merits of behavioral modification in alleviating LUTS in PD patients and should be encouraged. Clinicians should engage in a discussion with patients regarding the interplay of bradykinetic motor limitations and voiding complaints, especially considering the difficulty in arising from a chair and reaching a restroom to void. Videourodynamics may help in determining OAB, BOO, or both co-occurring in PD patients. This can be invaluable as it guides management, provided that patients are willing to accept treatment for complications that arise from testing. OAB symptoms in patients with PD are difficult to cure, but can often be effectively managed with behavioral modification. The most effective treatment in a patient with BOO is TURP, which carries a low risk of incontinence provided that MSA is excluded. Compliance with Ethics Guidelines Conflict of Interest Dr. Anand V. Badri, Dr. Rajveer S. Purohit, and Dr. Jason Skenazy each declare no potential conflicts of interest. Dr. Jeffrey P. Weiss reports personal fees from Ferring, personal fees from Pfizer, personal fees from Astellas, personal fees from Allergan, and personal fees from Vantia. Dr. Jerry G. Blaivas reports other from Symptelligence Medical Informatics, LLC, personal fees from Astellas Pharma US, and personal fees from Mesh Lawsuits. 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.

References Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance 1.

Hornykiewicz O. The discovery of dopamine deficiency in the parkinsonian brain. J Neural Transm Suppl 2006; 9.

Curr Urol Rep (2014) 15:435 2.• Kapoor S, Bourdoumis A, Mambu L, Barua J. Effective management of lower urinary tract dysfunction in idiopathic Parkinson’s Disease. Int J Urol. 2013;20(1):79–84. This article represents an effective and useful literature review of the urologic sequelae of PD. Taking data from 2012 and earlier, the group presents a cohesive, systematic approach to managing LUTS in PD. 3. Fowler CJ, Dalton C, Panicker JN. Review of neurologic diseases for the urologist. Urol Clin N Am. 2010;37:517–26. 4. Haylen BT, de Ridder D, Freeman RM, et al. An International Urogynecological Association (IUGA)/International Continence Society (ICS) joint report on the terminology for female pelvic floor dysfunction. Neurourol Urodyn. 2010;29:4. 5. Blaivas JG, Panagopolous G, Weiss JP, Somaroo C, Chaikin DC. The Urgency Perception Score: Validation and Test-Retest. J Urol. 2007;177:199–202. 6. Fowler CJ, Griffiths D, de Groat WC. The neural control of micturition. Nat Rev Neurosci. 2008;6:453–66. 7. Blackett H, Walker R, Wood B. Urinary dysfunction in Parkinson’s disease: A review. Parkinsonism Relat disord. 2009;15(2):81–7. 8. Araki I, Kuno S. Assessment of voiding dysfunction in Parkinson’s disease by the international prostate symptom score. J Neurol Neurosurg Psychiatry. 2000;68:429–33. 9. Lemack GE, Dewey RB, Roehrborn CG, et al. Questionnaire-based assessment of bladder dysfunction in patients with mild to moderate Parkinson’s disease. Urology. 2000;56:250–4. 10. Sakakibara R, Uchiyama T, Yamanishi T, et al. Bladder and bowel dysfunction in Parkinson’s Disease. J Neural Transm. 2008;115: 443–60. 11. Ransmayr GN, Holliger S, Schletterer K, et al. Lower urinary tract symptoms in dementia with Lewy bodies, Parkinson disease, and Alzheimer disease. Neurology. 2008;70:299–303. 12. Berger Y, Blaivas JG, DeLaRocha ER, Salinas EM. Urodynamic findings in Parkinson’s Disease. J Urol. 1987;138(4):836–8. 13. Ragab MM, Mohammed ES. Idiopathic Parkinson’s disease patients at the Urologic Clinic. Neurourol Urodyn. 2011;20:1258–61. 14.•• Siegl E, Lassen B, Saxer S. “Incontinence—a common issue for people with Parkinson’s disease. A systematic literature review”. [Article in German]. Pflege Z. 2013;66(9):540–4. -This review sought to look into the literature to determine the incidence of urinary and fecal incontinence as well as different measures for treatment or improvement. -Consisted of a review of three studies with a total sample size of n = 1077. Comparing urge incontinence between women with and without PD, they found an incidence of 25 % and 7 %, respectively. Similarly, they found an incidence of 28 % and 6 % in men with and without PD, respectively. -Suggest that pelvic floor muscle exercises as well as botulinum toxin A injections can reduce urinary incontinence, but the review doesn’t offer recommendations. 15. Hughes AJ, Daniel SE, Kilford L, Lees AJ. Accuracy of clinical diagnosis of idiopathic Parkinson’s disease: a clinicopathologic study of 100 cases. J Neurol Neurosurg Psychiatry. 1992;55:181. 16. Wenning GK, Colosimo C, Geser F, Poewe W. Multiple system atrophy. Lancet Neurol. 2004;3:93. 17. Ozawa T, Paviour D, Quinn NP, et al. The spectrum of pathological involvement of the striatonigral and olivopontocerebellar systems in multiple system atrophy: clinicopathological correlations. Brain. 2004;127:2657. 18. Kircchof K, Apostolidis AN, Mathias CJ, Fowler CJ. Erectile and urinary dysfunction may be the presenting features in patients with multiple system atrophy: a retrospective study. Int J Impot Res. 2003;15:293–8. 19. Chandiramani VA, Palace J, Fowler CJ. How to recognize patients with parkinsonism who should not have urological surgery. Br J Urol. 1997;80:100–4.

Curr Urol Rep (2014) 15:435 20.

Salinas JM, Berger Y, De La Rocha RE, Blaivas JG. Urological evaluation in the Shy Drager Syndrome. J Urol. 1986;135(4):741–3. 21. Gancher ST. Modified Hoehn And Yahr Staging. In: Factor SA, Weiner WJ, editors. Parkinson’s Disease: Diagnosis and Clinical Management. New York: Demos Medical Publishing; 2002. 22. Weiss JP, Blaivas JG, Tash Anger JA, Di Blasio CJ, Panagopoulos G, Gerboc J. Development and validation of a new treatment outcome score for men with LUTS. Neurourol Urodyn. 2004;23(2):88–93. 23. AUA Practice Guidelines Committee. AUA guideline on management of benign prostatic hyperplasia (2003), Chapter 1: Diagnosis and treatment recommendations. J Urol. 2003;170:530. 24. Tsui JF, Shah MB, Weinberger JM, Ghanaat M, Weiss JP, Purohit RS, et al. Pad count is a poor measure of the severity of urinary incontinence. J Urol. 2013;190(5):1787–90. 25. Nitti VW. Pressure Flow Urodynamic Studies: The Gold Standard for Diagnosing Bladder Outlet Obstruction. Rev Urol. 2005;7 Suppl 6:S14–21. 26. Dmochowski RR. Bladder outlet obstruction: etiology and evaluation. Rev Urol. 2005;7 Suppl 6:S3. 27. Flisser AJ, Walmsley K, Blaivas JG. Urodynamic classification of patients with symptoms of overactive bladder. J Urol. 2003;169(2): 529–33. discussion 533-4. 28. Santos-Garcia D, de la Fuente-Fernandez R. Impact of non-motor symptoms on health-related and perceived quality of life in Parkinson’s disease. J Neurol Sci. 2013;332(1–2):136–40. 29.•• Perez-Lloret S, Rey MV, Pavy-Le Traon A, Rascol O. Emerging drugs for autonomic dysfunction in Parkinson’s disease. Expert Opin Emerg Drugs. 2013;18(1):39–53. -Pharmacotherapeutical article assessing multiple drugs for PD-associated autonomic dysfunction. -Specifically for this review, compared muscarinic antagonists for women with urge incontinence. In order of decreasing efficacy (#women with restored continence/1000): fesoterodine → oxybutynin (Only one that’s FDA approved although less efficacious) → trospium → solifenacin → tolterodine. -Botulinum Toxin A – positive effect for incontinence, detrusor overactivity, painful bladder syndrome, BPH. -Suggests need for further study based on IPSS and DanPSS for subjectivity and weighing protective pads for incontinence testing pre/post treatment for objectivity. 30. Winge K, Fowler CJ. Bladder dysfunction in Parkinsonism: Mechanisms, Prevalence, Symptoms and Management. Mov Dis. 2006;21:737–45. 31. Winge K, Werdelin L, Nielsen K, Stimpel H. Effects of dopaminergic treatment on bladder function in Parkinson’s disease. Neurourol Urodyn. 2004;23:689–96. 32.•• Cone EB, Ellsworth P. Neurogenic detrusor overactivity: an update on management options. R I Med J. 2013;96(4):38–40. -Paper good for informing clinicians about mechanisms of treatments and the treatments available in a stepwise form from least to most invasive. -Goals should be 1) prevent upper tract damage and 2) improve symptoms/quality of life/independent living. 33. Giannantoni A, Conte A, Proietti S, et al. Botulinum toxin type A in patients with Parkinson’s disease and refractory overactive bladder. J Urol. 2011;186:960–4. 34. Anderson RU, Orenberg EK, Glowe P. Onabotulinumtoxin A office treatment for neurogenic bladder incontinence in Parkinson’s disease. Urology. 2014;83(1):22–7. 35.• Phé V, Caremel R, Bart S, Castel-Lacanal E, de Sèze M, Duchêne F, et al. le Comité de neuro-urologie de l’Association française d’urologie. “Lower urinary tract dysfunctions in parkinsonian syndromes: a review by the Neuro-Urology Comittee of the French

Page 9 of 9, 435 Association of Urology.” [Article in French]. Prog Urol. 2013;23(5):296–308. -A review of LUTS in parkinsonian syndromes completed by the French Association of Urology. -The review discussed the efficacy of Posterior Tibial Nerve Stimulation very well. 36. Ohannessian A, Kaboré FA, Agostini A, Lenne Aurier K, Witjas T, Azulay JP, et al. Transcutaneous tibial nerve stimulation in the overactive bladder syndrome in patients with Parkinson’s syndromes. Prog Urol. 2013;23(11):936–9. 37. Staskin DS, Vardi Y, Siroky MB. Post-prostatectomy continence in the parkinsonian patient: the significance of poor voluntary sphincter control. J Urol. 1988;140(1):117–8. 38. Roth B, Studer UE, Fowler CJ, Kesslet TM. Benign prostatic obstruction and parkinson’s disease – should transurethral resection of the prostate be avoided? J Urol. 2009;181(5):2209–13. 39. Reyblat P, Ginsberg DA. Augmentation Cystoplasty: what are the indications? Curr Urol Rep. 2008;9(6):452–8. 40. Pannek J, Stohrer M, Blok B et al. Guidelines on neurogenic lower urinary tract dysfunction. EAU Guidelines. 2012;pp. 8–36. 41.•• Ashkan K, Samuel M, Reddy P, Ray CK. The impact of deep brain stimulation on the nonmotor symptoms of Parkinson’s disease. J Neural Transm. 2013;120(4):639–42. -This paper suggests that “DBS has a major potential to contribute towards the holistic care of PD patients.” This is in light of an increase in the ability to more objectively assess the effect of DBS on the nonmotor burden in PD pts. -Nonmotor Symptoms Screening Questionnaire (NMSQuest) is a 30-item validated questionnaire to assess nonmotor burden in 545 pts with PD pre/post DBS. -Suggest that DBS shows no worsening of symptomatology. -Adverse effects include: transient psychiatric and mood disturbance (depression, hypomania, delirium), apathy, impaired verbal fluency, and impulse control disorders. Mechanism unclear, but may involve lesioning effect of frontostriatal circuits along the trajectory of the electrode, suboptimal positioning of the electrodes, current spread to adjacent structures, or non-judicial post-surgical medication adjustment. 42. Wolz M, Hauschild J, Fauser M, et al. Immediate effects of deep brain stimulation of the subthalamic nucleus on nonmotor symptoms in Parkinson’s disease. Parkinsonism Relat Disord. 2012;18: 994–7. 43.•• Winge K, Nielsen KK. Bladder dysfunction in advanced Parkinson’s disease. Neurourol Urodyn. 2012;31(8):1279–83. – Aim: To assess severity of bladder dysfunction in PD as stratified by symptomatic treatment, specifically DBS and Apomorphine vs medical treatment. – Used two validated questionnaires: DanPSS and IPSS. Used these to assess symptomatology and impact on quality of life. – The analysis found that in the conventional group, the severity of bladder dysfunction (DanPSS ≥ 10) correlated with a greater PD stage (based on the modified Hoehn and Yahr PD staging from 0 to 5). This did not hold for the nonconventional group, however, which included those treated with DBS or apomorphine and also did not hold when given the IPSS validated questionnaire. – They completed a further analysis based on specific symptoms and found that DBS patients had significantly less nocturia (as defined by > 2 episodes of voiding per night) and were less bothered by it. – Drawbacks: ○ Definition of nocturia in the DanPSS isn’t rigorous as the established ICS definition of nocturia (minimum one episode of waking to void that is preceded and followed by sleep) ○ Low N in general (N=107), but specifically in Apomorphine group (n=9). Unable to draw substantial conclusions from such a low sample size. ○ Only looked into questionnaire-based evaluation. Lacks the objectivity of other studies, as it doesn’t include urodynamic testing, etc.