Nocturia in Patients With Parkinson's Disease

Abstract

Background

Waking up from sleep more than once to pass urine, known as nocturia, is an important nonmotor symptom in Parkinson's disease (PD). Very little is known about the cause for nocturia. The aim of this work was to evaluate lower urinary tract (LUT) symptoms in patients with PD reporting nocturia using standardized validated questionnaires and bladder diaries and to assess the impact of nocturia on quality of life and sleep.

Methods

Twenty‐three consecutive patients with PD (17 males, 6 females; mean age: 68.5 years; range, 50–85) referred to a specialist uro‐neurology clinic reporting nocturia according to the International Continence Society definition were included. Patients measured their daily fluid intake, urinary output per void, and recorded these with the timing of voids on a 3‐day bladder diary. Standardized questionnaires were used to assess LUT symptoms (Urinary Symptom Profile, International Prostate Symptom Score, and Qualiveen Short Form) and sleep quality (Parkinson's Disease Sleep Scale).

Results

Mean duration of PD was 10.1 years, and mean severity on H & Y scale was 3.0 (range, 1.0–5.0). Median duration of LUT symptoms was 6.0 years. Mean night‐time urinary frequency was 3.5 (range, 1.0–7.3), and mean nocturnal maximum voided volume was 242 mL. Mean Nocturnal Polyuria Index (NPi) was 0.4 (range, 0.13–0.75), and 13 patients (56.5%) had nocturnal polyuria (NPi > 0.33). Patients with nocturnal polyuria reported more‐severe LUT symptoms that impacted quality of life and sleep.

Conclusions

In this preliminary study, nocturnal polyuria seems to be common in patients with PD reporting nocturia and appears to affect quality of life and sleep, though this was not statistically significant. The bladder diary is an essential tool in the assessment of nocturia in patients with PD.

Parkinson's disease (PD) is the second‐most common neurodegenerative condition. Although predominantly a disorder of motor control, PD is commonly associated with nonmotor symptoms. Lower urinary tract (LUT) symptoms are common in PD, with nocturia being present in up to 60% of patients who completed the standardized, validated Non‐Motor Symptoms questionnaire.1 Nocturia is considered as one of the commonest nonmotor symptoms. Mean prevalence of nocturia in PD is 63.2%, but ranges widely (35–78%) between studies. Nocturia has an immense impact on quality‐of‐life measures, health‐related costs, and is associated with the need for early institutionalisation.2

The causes for nocturia in PD are poorly understood.3, 4, 5 Most often, nocturia may result from reduced nocturnal bladder capacity owing to an overactive bladder (OAB). Symptoms of OAB—urinary urgency, increased daytime and night‐time frequency, and incontinence—are common in PD and reported in 33% to 54% of patients.6, 7 Urodynamic investigations in PD patients reporting OAB symptoms demonstrate detrusor overactivity in most patients (43–93%),8 but nocturia may also be the result of nocturnal polyuria, which is characterized by increased nocturnal urine production, more than 20% to 33% of the entire 24‐hour volume.9 Nocturnal polyuria most often results from a systemic cause, in contrast to OAB, and has been poorly studied in PD.

The aim of this study was to evaluate a group of patients with PD reporting the symptom of nocturia using standardized questionnaires and bladder diaries and to evaluate the impact of nocturia on quality of life and sleep.

Patients and Methods

Consecutive patients with PD referred to a specialist uro‐neurology clinic from the movement disorders service of a tertiary care teaching hospital over a 6‐month period in 2011 and reporting nocturia were included in this service evaluation. Nocturia was defined according to the International Continence Society definition of waking one or more times at night to void, each void preceded and followed by sleep.10 Patients underwent a standard evaluation, including review of history and examination and bladder scan to assess postvoid residuals, and male patients underwent a digital rectal examination to assess the prostate gland. Patients measured their daily fluid intake, urinary output per void, and recorded these with the timing of voids on a 3‐day bladder diary. The timings of going to bed for sleep and awakening were recorded. From the bladder diary, severity of nocturnal polyuria was assessed by calculating the Nocturnal Polyuria Index (NPi; dividing the nocturnal urine volume by total 24‐hour urine volume; this is age dependent and values greater than 0.2 in the young and greater than 0.33 in the elderly suggest nocturnal polyuria) and an assessment of bladder capacity by calculating the Nocturnal Bladder Capacity Index (NBCi; subtracting the predicted number of nightly voids from the actual number of nightly voids; values greater than zero suggest reduced bladder capacity).11

All participants completed standardized validated questionnaires of LUT symptoms and quality of life. These were intended to evaluate specific domains of bladder and bowel complaints and the effects these had on quality of life. The Urinary Symptom Profile (USP) questionnaire provides a comprehensive evaluation of urinary symptoms and their severity in males and females, assessing three domains: OAB (score range: 0–21); stress urinary incontinence (score range: 0–9); and low stream (score range: 0–9). A higher score indicates greater severity.12 The International Prostate Symptom Score (IPSS) questionnaire assesses LUT symptoms and provides an indicator of its severity.13 The questionnaire was originally developed to assess voiding symptoms in men with benign prostatic hyperplasia; however, it is neither prostate nor sex specific.14, 15, 16 The Qualiveen Short Form (SF‐Qualiveen) questionnaire is a health‐related quality‐of‐life questionnaire (HRQoL) for urinary disorders. The questionnaire is composed of eight items distributed in four domains: “bother with limitations” (two items); “frequency of limitations” (two items); “fears” (two items); and “feelings” (two items). Patients are asked to recall their experience and respond to each question on a 5‐point scale (ranging from 0 indicating no impact on HRQoL to 4 indicating high impact on HRQoL). Each Qualiveen domain score is calculated as an average of the scores for the items in each domain.17 The Parkinson's Disease Sleep Scale (PDSS)18 assesses quality of sleep. This scale has 15 items related to sleep scored from 1 to 10 based on experience in the past 1 week. Item 1 scores overall sleep quality from awful to excellent and the others are scored by frequency of symptoms (always‐never). Duration of PD and severity of symptoms assessed by the H & Y scale were also recorded.

Statistical Analyses

All statistical analyses were carried out using STATA software (version 11.2; StataCorp LP, College Station, TX). Mean and standard error of the mean (SEM) were calculated for analysis. The chi‐square test was used to compare the means between the groups with or without (NPi > 0.33).

Results

Twenty‐three patients (17 males and 6 females; mean age: 68.5 years; range, 50–85) participated. Mean duration of PD was 10.1 years, and median H & Y stage was 3.0 (range, 2–5). Median duration of LUT symptoms was 6.0 years (interquartile range: 6.0). All patients were on dopaminergic treatment—levodopa (n = 22) and ropinirole (n = 1)—and 13 patients were using a combination. Eleven patients were on antimuscarinics for LUT symptoms, and 5 patients were using a morning dose of diuretics for medical indications.

Based on responses recorded on the USP questionnaire, patients experienced symptoms of an overactive bladder (OAB; n = 23), stress incontinence (n = 10), and a poor stream (n = 19). The mean postvoid residual measured by bladder scanner was 88 m (range, 0–360). Twelve men were found to have an enlarged prostate gland by digital rectal examination. None of the women had a significant gynecological history relevant to their nocturia. Medical comorbidities were diabetes mellitus (n = 1), congestive heart failure (n = 4), and obstructive sleep apnea (n = 1).

Reviewing the 3‐day bladder diaries, mean night‐time urinary frequency was 3.5 (range, 1.0–7.3). Table 1 categorizes patients according to increasing night‐time frequency. There was no association between duration and severity of PD and increasing night‐time frequency. NBCi and NPi seemed to be greater in patients with greater night‐time frequency. Mean NBCi was 2.1 (range, −1.87 to 3.75; n = 23), and therefore most patients had a reduced bladder capacity; only 2 patients had an NBCi less than zero.

Table 1.

Findings from the bladder diary in 23 patients with PD reporting nocturia reporting increasing night‐time frequency

	Increasing Night‐Time Frequency
	×1	×2	×3	×4+
No. of patients	2	4	7	9
Mean duration of PD, years	9.5	10.8	12	8.4
Mean H & Y score	3.5	3.3	2.6	3.1
Mean night‐time voided volume, mL	138	550	695	856
Mean 24‐hour volume, mL	873	1,253	1,762	2,056
Mean NPia	0.16	0.44	0.44	0.43
Mean NBCib	1.38	0.37	1.64	3.21
Mean 24‐hour fluid intake, mL	1,149	1,276	1,020	1,442

^aNPi > 0.33 suggests nocturnal polyuria.

^bNBCi > 0 suggests reduced bladder capacity.

The mean NPi was calculated to be 0.47 (range, 0.18–0.81). Eighteen patients (78.3%) were found to have nocturnal polyuria (NPi > 0.33) and 8 had NPi > 0.5. Table 2 provides a comparison between patients with and without nocturnal polyuria. There was no statistical difference in the patient characteristics or questionnaire scores in patients between the two subgroups. Patients with nocturnal polyuria were older, had a longer duration of PD, and had more advanced disease. They had more‐severe OAB symptoms, as assessed both by the USP and IPSS questionnaires, and impaired quality of life. Patients with nocturnal polyuria reported more‐severe sleep disturbances. Patients with nocturnal polyuria reported more‐severe sleep disturbances, as quantified by the overall PDSS score (see Table 2); however, no particular sleep disturbance predominated, with the exception of daytime somnolence, which was reported more often in patients with nocturnal polyuria. Fluid intake was found to be generally less in patients with nocturnal polyuria. None of the patients had global polyuria.

Table 2.

Comparison of patients with PD reporting nocturia (n = 23) with and without nocturnal polyuria, incorporating demographic features, bladder diary, and questionnaire findings

	Total	NPi
		<0.33		>0.33a
		Mean	SEM	Mean	SEM
No. of patients	23	5		18
Mean age, years	68.5	64.8	3.3	69.5	2.3
Mean duration of PD, years	9.8	6.4	1.2	10.9	1.2
Mean H & Y score	2.9	2.5	0.4	3.1	0.2
No. of patients with orthostatic hypotension	5	1		4
Bladder diary findings
Night‐time frequency, n	3.3	2.6	0.4	3.5	0.4
Daytime frequency, n	7.0	7.9	1.4	6.8	0.4
Mean night‐time voided volume, mL	242.0	181.4	53.3	289.8	32.6
Mean daytime voided volume, mL	256.7	277.1	34.2	251.1	23.7
Fluid intake, mL	1,263.8	1,445.1	195.5	1,119.1	96.7
Questionnaire scoresb
USP OAB subscore	8.9	5.6	1.3	9.8	1.0
IPSS score	16.4	11.2	1.0	17.9	2.1
SF‐Qualiveen score	2.2	1.5	0.6	2.4	0.2
PDSS score	82.3	90.5	5.9	80.0	6.5

Nocturnal polyuria defined as NPi > 0.33.

^aNPi > 0.33 suggests nocturnal polyuria.

^bSee text for normal range.

On the SF‐Qualiveen questionnaire, patients with nocturnal polyuria (NPi > 0.33) had higher total scores compared to patients with NPi < 0.33 (Table 2). Similarly, the subscore on bothers with limitation was higher in patients with nocturnal polyuria, indicative of poorer quality of life.

All patients were on l‐dopa therapy, except 1 patient with nocturnal polyuria, who was taking ropinirole and rasagaline alone. No significant differences were noted in l‐dopa dosage between patients with and without nocturnal polyuria. More patients with nocturnal polyuria were on a dopamine agonist (66%; ropinirole, n = 10; pramipexole, n = 1; apomorphine pump: n = 1), whereas only 1 patient without nocturnal polyuria was on a dopamine agonist (ropinirole). Patients belonging to both groups were on various other PD medications, including amantadine, selegiline, entacapaone, and rasagiline, though without a trend. Most patients were receiving antimuscarinic medications for the overactive bladder—those with nocturnal polyuria solifenacin (n = 2) and without nocturnal polyuria solifenacin (n = 5), fesoteridine (n = 1), tolterodine (n = 1), trospium (n = 1), oxybutinin (n = 1).

Of the 5 patients with orthostatic, 1 was taking perindopril for hypertension (Table S1).

Discussion

Nocturia is a common nonmotor symptom in PD, but has been poorly studied. In this prospective evaluation of patients with PD attending a tertiary care clinic, LUT symptoms have been evaluated using standardized questionnaires, bladder diaries, and noninvasive tests. Questionnaires provide considerable information about LUT symptoms; however, this is based on recall over a period of time. On the other hand, the bladder diary provides a prospective real‐time assessment of bladder symptoms, which is cost‐effective and relatively straightforward for patients to complete.19 It provides a more accurate assessment of night‐time frequency and voided nocturnal urine volumes.20, 21, 22

From our evaluation, it appears that nocturia results from both reduced nocturnal bladder capacity and nocturnal polyuria. When the volume of urine exceeds the bladder capacity, the patient awakens to void. As a result, patients with reduced bladder capacity report frequent small‐volume voids and symptoms of urinary urgency, as well as increased daytime frequency and incontinence in the daytime. Reduced bladder capacity in PD may be a result of impaired bladder compliance and/or detrusor overactivity, as demonstrated in urodynamic investigations.5 Other causes may contribute to reduced nocturnal bladder capacity, such as bladder outflow obstruction, most often resulting from prostate enlargement, and therefore the workup of the patient with PD reporting nocturia requires a comprehensive evaluation.

Excessive production of urine at night can result in nocturia, and patients would be expected to report large voided volumes. A balance exists between glomerular filtration and tubular reabsorption and in health; between 20% and 33% of the entire 24‐hour urine output is produced at night, depending on age. The NPi is calculated using a simple formula and is increased most often in medical conditions, such as chronic congestive heart failure, renal or hepatic failure, diabetes mellitus, obstructive sleep apnea syndrome, peripheral edema resulting from venous or lymphstasis, use of an evening diuretic, or lifestyle patterns, such as excessive night‐time drinking.23, 24 In our study, bladder diaries were useful to assess fluid intake before bedtime and during the night; it was observed that patients with nocturnal polyuria more often restricted their 24‐hour fluid intake.

The study was not designed to evaluate the cause for nocturnal polyuria. It was noted, however, that patients with increasing age and greater duration and severity of PD were more likely to have nocturnal polyuria. Four of the five patients with orthostatic hypotension had nocturnal polyuria; patients with orthostatic hypotension have fluctuating blood pressure levels and often have supine hypertension. Renal perfusion improves at night when adopting the supine position, resulting in improved glomerular filtration and urine output.25 Nocturnal polyuria has been reported in other neurological disorders associated with cardiovascular dysautonomia, such as familial dysautonomia,26 where biopsies in individuals with renal impairment demonstrate ischemic‐type glomerulosclerosis and deficient vascular innervation.27 Studies in healthy elderly men with nocturnal polyuria have demonstrated alterations in the circadian pattern of blood pressure variations, increased daytime mean arterial blood pressure, nocturnal natriuresis, and reduced angiotensin II and arginine vasopressin levels, compared to controls.20 Hypothalamic involvement resulting in impaired regulation of renal salt and water clearance is speculative; however, loss of hypocretin and melanin‐concentrating hormone neurones in the hypothalamus have been demonstrated to occur as part of PD‐related degenerative changes and may contribute to nocturnal polyuria.28

Nocturia has a considerable impact on quality of life,6, 29 both for patients and their carers,30, 31 and is associated with falls,32 hip fractures, and even increased mortality.33, 34, 35 Patients are particularly vulnerable owing to the need at night to visit the toilet during the period their neurological symptoms are often least controlled. It was observed that patients with nocturia had poor quality of life and sleep, more so in patients with nocturnal polyuria. The small sample size, however, precluded any statistical tests to assess significance of this observation. Understanding the cause for nocturia helps to optimize management; problems of reduced bladder capacity owing to poor compliance or detrusor overactivity are best addressed by antimuscarinic medications, neuromodulation, or botulinum toxin,19, 36 whereas options for managing nocturnal polyuria are more limited and include minimizing fluid intake before sleep, leg elevation, and the use of desmopressin37, 38 or an early afternoon diuretic.39, 40

The study included only a limited group of patients reporting nocturia at a specialist tertiary center, and therefore the overall prevalence of nocturia or nocturnal polyuria in PD could not be assessed given that more severely affected patients might have been referred. Moreover, the design of the study precluded any assessment of the cause for reduced bladder capacity or nocturnal polyuria. Some of the patients had medical conditions that could contribute to nocturia, for example: congestive heart failure; diabetes mellitus; and obstructive sleep apnea. We did not find any clear difference in the results of patients with or without these conditions; however, an impact of these conditions on the results could not be excluded. There may be a contribution to nocturia by other causes of night‐time awakening, such as difficulty in turning over or rapid eye movement sleep behavior disorder. However, this should not affect the night‐time voided volume. A larger study with a control group would be required to assess the impact of dopaminergic medications on voiding patterns, as well as the effects of drugs with anticholinergic properties and of diuretics, which are commonly used in this population. It is notable, however, that those patients on antimuscarinic agents for the bladder continued to report significant nocturia. Our study highlights the importance of using bladder diaries using quantification of urine volume in the assessment of patients with PD reporting nocturia. A significant proportion of patients with PD reporting nocturia have nocturnal polyuria, and further studies are needed to enhance the understanding of nocturnal polyuria in PD.

Author Roles

(1) Research Project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript: A. Writing of the First Draft, B. Review and Critique.

M.S.: 1C, 2A, 2B, 3A

J.S.: 1B, 2C, 3B

A.B.: 1A, 1B, 2C, 3B

J.H.: 1B, 2C, 3B

K.P.B.: 1A, 2C, 3B

J.N.P.: 1A, 1B, 1C, 2A, 2C, 3A, 3B

Disclosures

Funding Sources and Conflicts of Interest: The work was undertaken at UCLH/UCL Institute of Neurology and is supported, in part, by funding from the United Kingdom's Department of Health NIHR Biomedical Research Centers funding scheme. M.S. received an elective research bursary from the Wellcome Trust. J.S. was awarded funding from The Urology Foundation and InComb project. The authors report no conflicts of interest.

Financial Disclosures for previous 12 months: K.P.B. receives royalties from Oxford University Press. He received funding for travel from GlaxoSmithKline (GSK), Orion Corporation, Ipsen, and Merz Pharmaceuticals. J.N.P. receives royalties from Cambridge University Press; has been involved in trials supported by Wellspect, FirstKind Ltd, and Allergan; and has received speaker honoraria from Wellspect, Astellas, and Allergan.

Supporting information

Table S1. Table of clinical details of the included patients with details of the drugs and doses that the patients were taking.