To assess which motor and non-motor symptoms are closely related to overactive bladder severity in male patients with Parkinson's disease.
To assess which motor and non-motor symptoms are closely related to overactive bladder severity in male patients with Parkinson's disease.
A total of 160 male patients (mean age 71.4 ± 8.2 years) diagnosed with Parkinson's disease were included in the present study at Osaka University and affiliated hospitals. The severity of Parkinson's disease was classified as stage 3, 4 or 5 based on the Hoehn and Yahr staging system. Disease duration was 8.9 ± 5.1 years. Age, seven items from the Unified Parkinson's Disease Rating Scale motor section part III and three non-motor symptoms were assessed by multivariate analysis for their impact on the overactive bladder symptom score, a specific questionnaire for overactive bladder.
Overactive bladder symptom score was significantly higher in the group with severe motor symptoms related to finger taps and gait than in the group with mild motor symptoms related to these two factors. Furthermore, overactive bladder symptom score of patients with erectile dysfunction and constipation was significantly higher than that in patients without these symptoms. Multivariate analysis identified only finger taps and constipation as factors independently associated with overactive bladder symptom score.
Although a study on a larger scale is required to further assess the association of Parkinson's disease symptoms with overactive bladder symptom score, information on finger taps and severity of constipation should be obtained when assessing urological patients with Parkinson's disease.
lower urinary tract symptoms
magnetic resonance imaging
overactive bladder symptom score
Unified Parkinson's Disease Rating Scale
Unified Parkinson's Disease Rating Scale motor section part III
PD is a degenerative disorder of the central nervous system characterized mainly by a loss of dopaminergic neurons in the substantia nigra and the development of Lewy bodies. It generally causes motor symptoms, such as tremor, muscle rigidity, bradykinesia and postural instability. However, non-motor symptoms, such as erectile dysfunction and urinary dysfunction as well as incontinence, have received less focus than have motor symptoms, even though these symptoms are observed relatively frequently in the clinical setting. In general, patients with PD have significantly more LUTS than do healthy controls.[1, 2] In the field of urology, it is well known that patients with PD often have LUTS[3-5] caused by neurogenic bladder. A strong correlation between LUTS and total score of the UPDRS, originally developed in the 1980s and which has become the most widely used clinical rating scale to evaluate symptoms and severity of PD, was found in several studies.[2, 7] In Japanese patients with PD, the total UPDRS score was higher in patients with urinary dysfunction than in those without it. Storage symptoms are most common among LUTS,[5, 9] and several studies with urodynamic examinations have shown that the most frequent abnormality is detrusor overactivity in patients with PD.[4, 10-12] It was also reported that frequency, urgency and urge incontinence, which are related to OAB, are present in more than 70% of urologically affected PD patients. Several studies of patients with PD using a patient self-reported questionnaire for OAB have shown that OAB symptoms are significantly more severe in PD patients than in healthy subjects. However, the relationship between symptoms of PD and symptoms of OAB has not been fully elucidated. In addition, previous studies included male and female participants together when evaluating LUTS of patients with PD. Because there is a sex-related difference in the prevalence of OAB in Japan, as shown by a large-scale epidemiological survey of LUTS, etiology, severity and quality of OAB symptoms might differ between men and women, even in PD patients. Thus, a detailed survey with restricted gender is desirable.
We have focused previously on male LUTS, including OAB, and reported several clinical findings.[16, 17] In the present study, we selected several motor and non-motor symptoms of PD, which are often seen clinically, to assess which symptoms are closely related to OAB severity in male patients with PD.
Included in the present study were 161 male patients (mean age 71.4 ± 8.2 years) diagnosed with PD by clinical examination, brain CT or MRI, pharmacological response (a good response to anti-parkinsonian medication) and the previously reported criteria in Osaka University and affiliated hospitals, who have been registered in our clinical database since 2005. On the database registration form, brain CT or MRI findings and clinical neurological findings are described so that other neurological diseases, such as spinal disease, can be ruled out. Patients with BPH, which can induce urinary retention, were not included in the present study. The OABSS questionnaire, which was recently developed to assess and diagnose OAB, was handed personally to each patient by a physician or was mailed to the patient's residence. Patient characteristics are shown in Table 1. The Hoehn and Yahr staging system is used clinically to assess the progress of PD. It includes stages 1 through 5 defined as follows: stage 1, unilateral involvement only usually with minimal or no functional disability; stage 2, bilateral or midline involvement without impairment of balance; stage 3, bilateral disease: mild to moderate disability with impaired postural reflexes, physically independent; stage 4, severely disabling disease, still able to walk or stand unassisted; and stage 5, confinement to bed or wheelchair unless aided. Severity of PD in all study patients was classified as stage 3, 4 or 5 by the Hoehn and Yahr staging system. The OABSS was 5.6 ± 3.4, and disease duration was 8.9 ± 5.1 years.
|Age (years)||71.4 ± 8.2|
|OABSS||5.6 ± 3.4|
|UPDRS III score|
|Hoehn and Yahr staging, n (%)||III (96, 59.6%)||12.6 ± 2.7|
|IV (51, 31.7%)||16.1 ± 2.5|
|V (14, 8.7%)||19.7 ± 2.6|
|Disease duration (years)||8.9 ± 5.1|
All patients were informed of the nature of the study, and informed consent was obtained from each participant. The study protocol was approved by the Institutional Review Board for Clinical Research at Osaka University Hospital and local ethics committees. The data, which did not contain personally identifiable information, was collected at Osaka University and subjected to statistical analysis.
Seven items from the UPDRS-III considered to be representative motor symptoms (tremor at rest, finger taps, rigidity, arising from chair, gait, posture and postural stability), and three items considered to be representative non-motor symptoms observed frequently in the clinical setting (erectile dysfunction, constipation and syncope/blackout) were assessed for their impact on OAB symptoms. Each question of the UPDRS-III is anchored with five responses that are linked to commonly accepted clinical terms: 0 = normal, 1 = slight, 2 = mild, 3 = moderate and 4 = severe.[6, 20] According to the scoring of each motor symptom, patients were divided into the mild group, with a UPDRS score of 1 or 2, indicating mild symptom severity, and the severe group, with a UPDRS score >2, indicating greater symptom severity, for each item. The OABSS was compared between the two groups by Wilcoxon rank sum test. The patients were also divided into a negative or positive group on the basis of the absence (blank) or presence, respectively, of the non-motor symptoms of erectile dysfunction, constipation and syncope/blackout, and the OABSS was also compared between these two groups by Wilcoxon rank sum test. Finally, to identify factors with an independent effect on the OABSS, the 10 factors from the UPDRS-III (the seven motor symptoms and three non-motor symptoms) were evaluated again by multivariate analysis. A P-value of <0.05 was considered statistically significant. All statistical analyses were carried out with a validated software package (sas version 9.1.3; SAS Institute Japan, Tokyo, Japan).
In the present study, 77 of the 161 men (47.8%) were diagnosed as having OAB by the OABSS criteria. When comparing motor symptoms between the mild and severe groups, a significant difference was found in the severity of the motor symptoms of finger taps (P < 0.01; Fig. 1b) and gait (P < 0.05; Fig. 1e) in relation to OABSS. For both symptoms, OABSS of the severe group was significantly higher than that of the mild group. For the other five motor symptoms (resting tremor, rigidity, arising from chair, posture and postural stability), the OABSS did not differ significantly between the two groups (Fig. 1a,c,d,f,g). In regard to the three non-motor symptoms, the OABSS of patients with erectile dysfunction (P < 0.05; Fig. 1h) and constipation (P < 0.01; Fig. 1i) was significantly higher than that of patients without these symptoms. Multivariate analysis with all 10 factors identified just two factors, finger taps and constipation, as factors that independently affect OABSS (Table 2).
|Clinical finding||Category||OABSS||Age-adjusted model|
|Mean ± SD||Regression coefficient||P-value||Regression coefficient||P-value|
|Resting tremor||Mild||5.7 ± 3.6||Reference||–||Reference||–|
|Severe||5.1 ± 2.8||−1.022||NS||−0.896||NS|
|Finger taps||Mild||5.2 ± 3.3||Reference||–||Reference||–|
|Severe||7.6 ± 3.6||1.961||0.020||1.830||0.027|
|Rigidity||Mild||5.5 ± 3.4||Reference||–||Reference||–|
|Severe||5.9 ± 3.4||−0.614||NS||−0.524||NS|
|Arising from chair||Mild||5.3 ± 3.4||Reference||–||Reference||–|
|Severe||6.3 ± 3.6||−0.615||NS||−0.795||NS|
|Gait||Mild||5.3 ± 3.4||Reference||–||Reference||–|
|Severe||6.7 ± 3.3||1.229||NS||1.192||NS|
|Posture||Mild||5.4 ± 3.4||Reference||–||Reference||–|
|Severe||6.5 ± 3.7||0.184||NS||0.208||NS|
|Postural stability||Mild||5.4 ± 3.4||Reference||–||Reference||–|
|Severe||6.7 ± 3.5||−0.425||NS||−0.638||NS|
|Erectile dysfunction||Negative||5.1 ± 3.3||Reference||–||Reference||–|
|Positive||6.7 ± 3.6||1.029||NS||0.833||NS|
|Constipation||Negative||4.6 ± 2.9||Reference||–||Reference||–|
|Positive||6.3 ± 3.6||1.283||0.028||1.255||0.030|
|Syncope/blackout||Negative||5.3 ± 3.2||Reference||–||Reference||–|
|Positive||6.8 ± 4.1||0.472||NS||0.555||NS|
In the present study, we found that 77 of the 161 men (47.8%) were diagnosed as OAB, although this prevalence is relatively higher than that of recent studies, probably due to the high age of our participants and various factors such as clinical characteristics and study design.[21, 22] In general, the prevalence of urinary dysfunction was 55–80% in PD patients with non-motor symptoms. The majority of patients with PD with non-motor symptoms experience pelvic organ dysfunction including bowel, sexual and bladder dysfunction. In a previous study using questionnaire-based assessment of pelvic organ dysfunction, the prevalence of bladder and bowel dysfunction increased with the severity of PD, although no significant relationship between sexual dysfunction and bladder dysfunction was found. Furthermore, the most striking features of bowel dysfunction were constipation and difficulty in expulsion. The close relationship between constipation and OAB symptoms found in the present study might be a result of the severity of the symptoms in our participants, because it was recently reported by a systematic review that constipation could contribute to the development of LUTS, including OAB.
The relationship between motor symptoms and LUTS has been investigated in previous questionnaire-based studies. Regarding individual motor symptoms from the UPDRS-III, a study reported that urinary dysfunction was associated with rigidity, but not with tremor. When focusing on OAB in urinary dysfunction, however, a significant correlation between the severity of OAB symptoms and motor symptoms of the UPDRS-III was found not only with rigidity, but also with tremor and bradykinesia by Pearson's correlation coefficient. In the present study, we also found that OABSS in the severe group was significantly higher than that in the mild group in terms of finger taps and gait. Interestingly, finger taps was the only factor that independently affected OABSS by multivariate analysis in the present study. This discrepancy in the influence of motor symptoms on OAB between a previous study showing rigidity, tremor and bradykinesia, and the present study showing finger taps might be related to the following differences in study design: the clinical characteristics in the study participants such as age, sex, severity, disease duration, medication, type of PD and complication, and the OAB symptom questionnaire. The OAB questionnaire was used for the evaluation of OAB in the previous study, which assessed the impact of OAB symptoms on health-related quality of life. We used the OABSS, for which we have reported several findings in male OAB patients with BPH and sleep apnea syndrome. The OABSS does not attach a high value to health-related quality of life, unlike the OAB questionnaire.
The mechanism behind the close relationship between finger taps and OAB symptoms is not obvious. In general, the basal ganglia that include the striatum are thought to be related to inhibition of micturition. However, the response is quite different in patients with PD: the bladder becomes hyperactive when the basal ganglia are activated. Recent neuroimaging studies carried out during bladder filling have shown different findings between normal volunteers and patients with PD, such that the globus pallidus is activated in normal volunteers and the putamen is activated in patients with PD. It was also reported in patients with PD that dopamine transporter imaging is decreased in patients with urinary dysfunction, but not in those without it.[8, 29] Electrical stimulation of the substantia nigra pars compacta inhibits the micturition reflex. A recent study with adult male cats also showed that striatal dopamine levels increase significantly during the bladder relaxation phase, and that electrical stimulation applied to the striatum educes inhibition of spontaneous bladder contraction. Detrusor hyperreflexia can be caused in experimental models of parkinsonism with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine or 6-OH-dopamine. Presently, it is believed that the micturition reflex is under the influence of dopamine, although the relationship between the basal ganglia circuit and the micturition circuit has not been fully elucidated. In patients with PD, it is also speculated that the degeneration of dopaminergic neurons in the substantia nigra leads to the detrusor hyperreflexia, probably because of a failure of activation of dopamine D1 receptors. However, it was reported that bimanual forefinger–thumb tap is significantly slower in patients with PD than in age-matched controls, and clinical tests of upper limb motor function, such as finger taps, have high positive predictive value for PD. Furthermore, it was recently reported from a study with functional MRI that the amplitude of the cerebral responses increases in the striatum, particularly the right caudate nucleus, during training for a finger tapping task. Thus, the degeneration of striatum might worsen the symptom of finger taps and cause detrusor hyperreflexia. This hypothesis might explain our finding of the close relationship between finger taps and OAB symptoms. Furthermore, there is a possibility that systematic neural disorder causing gradual movement in finger taps might affect the development of functional lower urinary tract disease including OAB.
The present study includes several limitations for the analyses. First is the possibility of an effect of prostate enlargement on OAB symptoms in our participants, because the mean age of our male participants was 71.4 years. Although BPH is one of the key factors for onset of OAB, prostate volume was not evaluated for all participants in this questionnaire-based study. Second, drug therapy for PD affects OAB symptoms. Several studies have shown that the use of anti-parkinsonian drugs, such as apomorphine, levodopa, pergolide and bromocriptine, affects detrusor contraction.[11, 37, 38] Finally, we did not assess information on the treatment history of LUTS in our participants. However, we believe that our findings are still valuable and informative for urologists to assess the severity of OAB symptoms on the basis of symptoms of PD in the clinical setting.
In conclusion, we found by multivariate analysis that finger taps and constipation were the factors that were independently associated with OAB symptoms of 161 male patients with PD. Particularly interesting is the novel finding that finger taps are closely related to symptoms of OAB. A larger-scale study will be necessary to assess symptoms of PD associated with OAB symptoms because of the variability in the degree of symptoms of PD. However, information on finger taps, as well as severity of constipation, should be obtained when patients with PD visit the urological clinic.
We thank Fuminobu Sugai and Yoshiro Nishikawa at Otemae Hospital; Tomoyuki Uemichi at Kinki Central Hospital; Chikao Tatsumi at Toyonaka Municipal Hospital; Kei Fukada, Jinichi Sawada and Takanori Hazama at Osaka General Medical Center; Harutoshi Fujimura at Toneyama National Hospital; Masaru Yokoe and Ryoko Yasui at the Department of Neurology, Osaka University, Graduate School of Medicine; and Koji Kozaki at The Institute of Scientific and Industrial Research, Osaka University, for the data collection and useful discussion.