
==== Front
Clin Park Relat Disord
Clin Park Relat Disord
Clinical Parkinsonism & Related Disorders
2590-1125
Elsevier

S2590-1125(24)00040-9
10.1016/j.prdoa.2024.100269
100269
Original Articles
Bowel movement frequency and difficult defecation using constipation assessment scale in patients with isolated REM sleep behavior disorder
Miyamoto Tomoyuki miyatomo@dokkyomed.ac.jp
a1⁎
Nakajima Itsuo b
Arikawa Takuo b
Miyamoto Masayuki b1
a Department of Neurology, Dokkyo Medical University Saitama Medical Center, Japan
b Center of Sleep Medicine, Dokkyo Medical University, Japan
⁎ Corresponding author at: Dokkyo Medical University Saitama Medical Center, 2-1-50 Minamikoshigaya Koshigaya, Saitama 343-8555, Japan. miyatomo@dokkyomed.ac.jp
1 Contributed equally to this article.

31 8 2024
2024
31 8 2024
11 10026920 5 2024
23 7 2024
27 8 2024
© 2024 The Author(s)
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Highlights

• Constipation occurs in approximately > 60 % of IRBD patients.

• CAS-Jcan be used to assess bowel movement frequency and difficult defecation.

• CAS-J score was higher for women than for men in IRBD.

• CAS-J scores predict phenoconversion to PD or DLB.

• Treatments that relieve constipation should be considered in IRBD.

Introduction

This study evaluated constipation, including reduced bowel movement frequency and difficult defecation, in patients with isolated rapid eye movement sleep behavior disorder (IRBD), which is prodromal Parkinson’s disease (PD) or dementia with Lewy bodies (DLB) in middle-aged and older adults.

Methods

We used a validated Japanese version of the Constipation Assessment Scale (CAS-J) to evaluate bowel habits over 1 month in 117 men aged 50–86 years and 34 women aged 56–86 years with video-polysomnography-confirmed IRBD and 22 controls. Furthermore, we performed a longitudinal assessment of outcomes at follow-up visits.

Results

The CAS-J score was higher in the 22 IRBD patients than in 22 age- and gender-matched paired controls. In 151 IRBD patients, the CAS-J score was higher for women than for men. At baseline, the CAS-J score was similar between patients who developed PD and DLB, but the three IRBD patients who developed multiple system atrophy had a low CAS-J score. Those with constipation (CAS-J score ≥ 2) converted to PD or DLB in a significantly shorter time duration (i.e., time frame for phenoconversion) than those with CAS-J score < 2 (log-rank test, p < 0.001). When adjusted for age and gender, Cox hazards analysis revealed that the CAS-J score significantly predicted phenoconversion to PD or DLB (hazard ratio: 5.9, 95 % confidence interval: 1.8–19.1, p = 0.003).

Conclusions

Constipation, i.e., reduced bowel movement frequency and difficult defecation, was common in middle-aged and elderly patients with IRBD, and CAS-J score predicted phenoconversion to PD or DLB.

Keywords

Bowel habits
Bowel movement frequency
Constipation assessment scale
Isolated REM sleep behavior disorder
Parkinson’s disease
Dementia with Lewy bodies
Abbreviations

CAS-J Japanese version of the Constipation Assessment Scale

IRBD isolated REM sleep behavior disorder

PD Parkinson's disease

DLB dementia with Lewy bodies

MSA multiple system atrophy
==== Body
pmc1 Introduction

Rapid eye movement (REM) sleep behavior disorder (RBD) is a REM parasomnia characterized by dream-enacting complex behaviors and REM sleep without atonia [1]. Longitudinal studies in isolated RBD (IRBD) patients revealed an increased risk of developing synucleinopathies, including Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA) [2]. Most patients with PD describe autonomic symptoms at the time of diagnosis suggesting that these features may have potential sensitivity as clinical biomarkers of the premotor phase [3]. The recognition that damage to peripheral autonomic neurons is present in the early stages of PD has led to a search for specific abnormalities in autonomic function, such as constipation, urinary and sexual dysfunction, and reduced cardiac MIBG uptake [4], which could be predictive biomarkers or part of the parkinsonian clinical phenotype [5].

Constipation is a common non-motor symptom in PD or DLB, negatively impacting the quality of life of patients and serving as one of the earliest markers of PD development [6]. The Honolulu Heart Program provided strong evidence supporting the presence of constipation in preclinical PD. This study followed 6,790 men over a 24-year period and found that men with < 1 bowel movement per day have a 4.5-fold higher risk of PD compared to men with 2 bowel movements per day [7].

An important barrier to developing neuroprotective therapies for neurodegenerative diseases is that the onset of the PD/DLB pathology may be up to several decades before disease diagnosis [8]. Therefore, during the development of PD, constipation may help predict the risk of developing neurodegenerative diseases in IRBD patients before dopamine synthesis is reduced in dopaminergic nerve terminals [4]. Therefore, this study investigated the defecation frequency and difficult defecation using the Constipation Assessment Scale (CAS) [9] and longitudinally assessed the relationships between baseline evaluation and outcomes of neurodegenerative diseases.

2 Materials and methods

2.1 Participants

In total, 151 IRBD patients completed the CAS at baseline between May 2008 and May 2017. IRBD was diagnosed based on a history of dream-enacting behaviors and video-PSG demonstration of increased electromyographic activity during REM sleep associated with abnormal behaviors. RBD was defined according to the International Classification of Sleep Disorders [10]. All IRBD patients were followed systematically every 1–3 months by a neurologist (MM) with expertise in both sleep disorders and neurodegenerative diseases. At each visit, the neurologist performed a comprehensive neurological examination and obtained a detailed clinical history, including for cognitive and motor problems. If follow-up assessments revealed symptoms or signs of motor or cognitive impairment, the patients were referred for more detailed assessment. A full battery of neuropsychological tests was performed if cognitive impairment was suspected. The standard diagnostic criteria for PD [11], DLB [12], and MSA [13] were used. Clinical records were reviewed between March and July 2023 (the end of the current study) to assess the presence and type of neurodegenerative diseases identified during the follow-up period by the same neurologist (MM). If a new diagnosis of PD, DLB, or MSA was made, the date of the assessment was used as the date of condition onset. (Fig. 1).Fig. 1 Study flow chart. IRBD, isolated rapid eye movement sleep behavior disorder; PSG, polysomnography; PD, Parkinson’s disease; DLB, dementia with Lewy bodies; MSA, multiple system atrophy.

We enrolled controls who had no significant medical history, such as diabetes mellitus, thyroid disease, or gastrointestinal tract diseases, at the time of complete medical checkup at the Dokkyo Medical University Saitama Medical Center Koshigaya Clinic.

The CAS [9] consists of eight constipation-related characteristics based on previous literature. Each characteristic is scored on a three-point rating scale (i.e., no problem, some problem, and severe problems), indicating scores 0, 1, and 2, respectively. The summed scores ranged from 0 for no constipation to 16 for most severe constipation. The completion time averaged about 2 min. In this study, we used the validated Japanese version of the CAS (CAS-J, Fukai et al., 1995) [14] to record the bowel movement frequency and difficult defecation. The clinician was blinded to the CAS-J score collected at a single point during baseline visits. Patients were categorized into non-constipation (CAS-J score 0 or 1) and constipation (CAS-J score ≥ 2) groups.

The study protocol was approved by our institutional ethics committee Dokkyo Medical University (approval no. R-2–22) and the Ethics Committee of Dokkyo Medical University Saitama Medical Center (approval no. 21060). Written consent was obtained from participants. However, because of the retrospective study design, some patients were unable to provide written consent and had the opportunity to opt out of the study at any time and seek further explanation.

2.2 Statistical analyses

Descriptive, demographic, and CAS-J data are presented as means with standard deviation or numbers with percentages, as appropriate. Comparisons between groups were performed using the χ2 test or Mann-Whitney U Test, as appropriate. Neurological disease-free survival rates were estimated using Kaplan–Meier analysis and Cox-proportional hazards analysis. Disease-free survival rates were assessed from the date of CAS-J to the date of PD, DLB, or MSA diagnosis or to the last follow-up for censored observations.

All statistical analyses were performed using Prism software (version 10.3.0.0 for Mac; GraphPad Software, Inc., San Diego, CA, USA) and SPSS (version 29.0; IBM Corp., Armonk, NY, USA). Statistical significance was set at p < 0.05.

3 Results

Among the 22 age- and gender-matched paired patients with IRBD (disease duration: 8.7 ± 11.8 years), awareness of constipation (p = 0.0019) and frequency of laxative use (p = 0.0093) were significantly higher than those in healthy controls. With regard to the defecation frequency, IRBD patients were significantly less likely to defecate every day or more than twice a day (p = 0.0452) and more likely to defecate 3–6 times a week (p = 0.1324). The total CAS-J score was significantly higher in IRBD (median 4.0, interquartile range [IQR] = 2–6) compared to healthy controls (median 1.5, [IQR] = 1–2) (p = 0.0001). With regard to the individual items of CAS-J, compared to healthy individuals, 12 (54.5 %) IRBD patients had less frequent bowel movements (p = 0.0006), 13 (59.1 %) had rectal fullness or pressure (p = 0.0040), and 19 (86.4 %) had low stool volume (p = 0.0005) (Table 1). The receiver operating characteristic curve analysis showed that the optimal CAS-J cutoff scores of 1.5 and 2.5 discriminated between IRBD patients and controls with sensitivity rates of 86.4 % and 50.0 % and specificity rates of 68.2 and 86.4 %, respectively. Compared to the control group, the IRBD group had a higher number of individuals in the constipation group (CAS-J score of 2 or more; 86.4 %) than in the non-constipation group (CAS-J score of 0 or 1; 13.6 %).Table 1 Defecation symptoms and CAS-J for age- and sex-mached healthy controls and IRBD patients.

	IRBD	Controls	P value	
Number of cases	22	22	N/A	
Sex, M:F	18:4	18:4	N/A	
Age, y	63.4 ± 6.7	63.4 ± 6.6	0.3145*	
Awareness of constipation, n (%)	15 (68.2)	4 (18.2)	0.0019	
Laxative use (more than 1–2 times a month), n (%)	9 (40.9)	1 (4.5)	0.0093	
Bowel movement frequency				
Every day or more than one time each day, n (%)	12 (54.5)	19 (86.4)	0.0452	
Three to six times each week, n (%)	7 (31.8)	2 (9.1)	0.1324	
Two or less than two times each week, n (%)	3 (13.6)	1 (4.5)	0.6069	
CAS-J				
Total score, mean ± standard deviation	4.3 ± 2.9	1.6 ± 1.1	0.0001*	
Total score, median [interquartile range]	4.0 [2–6]	1.5 [1–2]		
CAS 0–1, n (%)	3 (13.6)	11 (50.0)	0.0217	
CAS 2 or more, n (%)	19 (86.4)	11 (50.0)		
CAS item				
1. Abnormal distension or bloating, n (%)	13 (59.1)	6 (27.3)	0.0666	
2. Change in amount of gas passed rectally, n (%)	4 (18.2)	3 (13.6)	> 0.9999	
3. Less frequent bowel movements, n (%)	12 (54.5)	1 (4.5)	0.0006	
4. Oozing liquid stool, n (%)	14 (63.6)	8 (36.4)	0.1308	
5. Rectal fullness or pressure, n (%)	13 (59.1)	3 (13.4)	0.0040	
6. Rectal pain with bowel movement, n (%)	6 (27.3)	1 (4.5)	0.0946	
7. Small volume of stool, n (%)	19 (86.4)	7 (31.8)	0.0005	
8. Unable to pass stool, n (%)	4 (18.2)	7 (31.8)	0.4876	
CAS-J, Japanese version of the Constipation Assessment Scale; IRBD, isolated REM sleep behavior disorder. p-value, Fisher’s exact test p-value for the difference between the percentages of controls and IRBD patients. *, p-value, Mann-Whitney U Test. Bold values were statistically significant.	

Among the 151 IRBD patients, constipation was perceived by 62.4 % of men and 76.5 % of women, whereas 52.9 % of women used laxatives compared to 32.5 % of men (p = 0.0428). The CAS-J score for IRBD was higher for women than for men (p = 0.0063). With regard to the individual items of CAS-J, women had significantly higher rates of feeling bloated or bloating (p = 0.0017) and diarrhea-like or watery stools (p = 0.00191) compared to men (Table 2). In the IRBD group, compared to men, women were more commonly included in the constipation group (CAS-J score of 2 or more; 91.2 %) than in the non-constipation group (CAS-J score of 0 or 1; 8.8 %).Table 2 Gender differences in defecation symptoms and CAS-J in IRBD patients.

	Total	Men	Women	P value	
Number of cases	151	117 (77.5)	34 (22.5)	< 0.0001	
Age, y	67.7 ± 6.3	67.5 ± 6.3	68.6 ± 6.5	0.6769*	
Awareness of constipation, n (%)	99 (65.6)	73 (62.4)	26 (76.5)	0.1538	
Laxative use (more than 1–2 times a month), n (%)	56 (37.1)	38 (32.5)	18 (52.9)	0.0428	
Bowel movement frequency					
Every day or more than one time each day, n (%)	77 (51.0)	59 (50.4)	8 (23.5)	0.0060	
Three to six times each week, n (%)	54 (35.8)	46 (39.3)	18 (52.9)	0.1721	
Two or less than two times each week, n (%)	20 (13.2)	12 (10.3)	8 (23.5)	0.0797	
CAS-J					
Total score, mean ± standard deviation	3.9 ± 2.8	3.6 ± 2.7	5.1 ± 2.9	0.0063*	
Total score, median [interquartile range]	4.0 [2–6]	3.0 [1–5]	5.0 [2–7.25]		
CAS 0–1, n (%)	34 (22.5)	31 (26.5)	3 (8.8)	0.0352	
CAS 2 or more, n (%)	117 (77.5)	86 (73.5)	31 (91.2)		
CAS item					
1. Abnormal distension or bloating, n (%)	70 (46.4)	46 (39.3)	24 (70.6)	0.0017	
2. Change in amount of gas passed rectally, n (%)	35 (23.2)	24 (20.5)	11 (32.4)	0.1690	
3. Less frequent bowel movements, n (%)	74 (49.3)	53 (45.3)	21 (61.8)	0.1190	
4. Oozing liquid stool, n (%)	79 (52.3)	55 (47.0)	24 (70.6)	0.0019	
5. Rectal fullness or pressure, n (%)	47 (31.1)	36 (30.8)	11 (32.4)	0.8268	
6. Rectal pain with bowel movement, n (%)	48 (32.0)	34 (29.1)	14 (41.2)	0.2113	
7. Small volume of stool, n (%)	116 (76.8)	88 (75.2)	28 (82.4)	0.4913	
8. Unable to pass stool, n (%)	31 (20.7)	23 (19.7)	8 (23.5)	0.6338	
CAS-J, Japanease version of the Constipation Assessment Scale; IRBD, isolated REM sleep behavior disorder. p-value, Fisher's exact test p-value for the difference between the men and women in IRBD patients. *, p-value, Mann-Whitney U Test for men vs. women. Bold values indicate significant difference.	

Furthermore, 50 (33.1 %) of the 151 IRBD patients evaluated between March and July 2023 developed clinically defined PD (n = 23), DLB (n = 24), or MSA (n = 3) at 6.2 ± 4.0 years after baseline CAS-J assessment. Compared to IRBD patients who were still disease-free (3.7 ± 2.8) or developed PD (4.3 ± 2.9) or DLB (4.6 ± 2.4), the CAS-J score was lower in patients with MSA (0, 1, 1) (Supplemental Fig. 1). Patients with constipation, defined as CAS-J score ≥ 2, converted to PD or DLB in a significantly shorter time duration than those without constipation (log-rank test, p < 0.001; Fig. 2). When adjusted for age and gender, Cox hazards analysis showed that CAS-J significantly predicted phenoconversion to PD or DLB (hazard ratio [HR] = 5.9, 95 % confidence interval [CI] = 1.8–19.1, p = 0.003).Fig. 2 Onset of PD or DLB in patients with isolated rapid eye movement sleep behavior disorder (Kaplan-Meier analysis). PD, Parkinson’s disease; DLB, dementia with Lewy bodies.

4 Discussion

In this study, patients with IRBD reported more frequent problems with defecation compared to age- and gender-matched paired controls. We quantified the bowel frequency and use of laxatives, as well as assessed the feeling of difficult defecation, using the CAS-J. Furthermore, > 60 % of men and women with IRBD experienced constipation. Men used laxatives less frequently than women. IRBD patients reported more frequent defecation difficulties than age- and gender-matched paired controls. The CAS evaluates the presence and severity of constipation. Chronic idiopathic constipation is one of the most common gastrointestinal disorders, with a global prevalence of 14 %. It is more common in women than in men, and its prevalence increases with age [15]. Our study revealed that constipation occurs more frequently in IRBD than in the general population.

Moreover, we compared the presence of constipation using CAS-J between IRBD patients and those who were disease-free or had developed PD or DLB. IRBD patients with a higher CAS-J score at baseline developed PD or DLB, whereas those with a lower CAS-J score developed MSA. The rate of progression to PD or DLB over time was lower in the group with a CAS-J score 0–1 compared to the group with a CAS-J score ≥ 2.

Previous studies have examined the association between constipation and subsequent PD risk [7]. Constipation is considered to be one of the primary early markers of PD [16] and DLB [17], but few studies have quantitatively assessed the defecation symptoms in individuals with IRBD [18], [19]. In a multicenter IRBD study, Cox proportional hazards analysis adjusted for age, gender, and center significantly predicted constipation outcomes (HR=1.67) [19]. However, the definition of constipation varied among studies as they used different criteria, such as the Movement Disorders Society Revised Unified Parkinson’s Disease Rating Scale [11], the Uniform MSA Rating Scale [20], the SCOPA-AUT [18], and the Rome Criteria [21]. In most studies, frequency and straining have been reported separately, when available. The prevalence of constipation varies with the definition used, which in turn depends on the questionnaire used [22]. CAS has been studied in adult cancer patients, pediatric patients, and pregnant women [9], [23]. Our study focused on the feeling of difficult defecation, which is included in the definition of constipation in the CAS-J. We performed a comprehensive semiquantitative assessment of functional constipation in IRBD patients.

In vivo staging of IRBD using 11C-donepezil positron emission tomography to assess cholinergic vagal innervation in the stomach demonstrated reduced colonic 11C-donepezil uptake in IRBD patients compared to healthy controls [24]. The same group demonstrated that the colonic transit time examined using radio-opaque markers and colonic volume assessed on abdominal computed tomography scans showed worsening in most IRBD patients over a 3-year period [4]. Furthermore, a recent study demonstrated reduced amplitude of the gastric peristaltic wave in IRBD, a prodromal stage of PD. In fact, the stomach is already markedly involved in IRBD patients several years before the involvement of substantia nigra and the onset of manifest PD [25]. The association between IRBD and constipation is strongly related to accelerated progression of cognitive impairment and motor symptoms [26], [27]. Furthermore, gender differences exist in neuropsychological test performances, with men having worse global cognition, speed-attention processing, verbal learning, and memory compared to women at early stages of PD. These findings suggest that men are more susceptible than women to the association between constipation and cognitive decline in patients with PD or IRBD [27]. In the current study, women with IRBD were more likely than men to experience abnormal bowel movements, highlighting the need to monitor the urge to defecate in men with IRBD. One possible mechanism for the aforementioned findings is that PD patients with marked gut dysbiosis may progress faster than those without gut dysbiosis [28]. The intestinal environment can have substantial effects on the activity of the central nervous system through the physiological contributions of the microbiota, regulation of the intestinal barrier function, and altered activity of peripheral neurons [29]. In IRBD patients, targeting the premotor intestinal stages of PD for therapeutic intervention may slow or halt disease progression to the central nervous system, which would significantly enhance the quality of life of IRBD patients. Therefore, it is essential to perform a comprehensive and accurate assessment of constipation in IRBD patients to facilitate therapeutic interventions.

Certain limitations of the present study should be acknowledged. First, the data were derived from a single center, and there was gender disparity in the IRBD patients. Second, although the diagnoses of PD and DLB were based on the standard clinical criteria, they lacked pathological confirmation. Finally, this study compared the disease-free group and disease group of IRBD patients but did not compare patients with age-matched healthy controls.

5 Conclusion

Our results emphasize the importance of evaluating the baseline CAS-J score in IRBD patients. These findings provide evidence for the usefulness of evaluating constipation using assessment questionnaires, a sensitive biomarker for the short-term risk of phenoconversion to PD or DLB in IRBD patients. Future studies should evaluate constipation combined with other known biomarkers of phenoconversion to optimize the short-term phenoconversion risk assessment for use with disease-modifying/neuroprotective therapies.

CRediT authorship contribution statement

Tomoyuki Miyamoto: Writing – review & editing, Writing – original draft, Visualization, Validation, Supervision, Software, Resources, Project administration, Methodology, Investigation, Funding acquisition, Formal analysis, Data curation, Conceptualization. Itsuo Nakajima: Supervision, Investigation, Data curation. Takuo Arikawa: Supervision, Investigation, Data curation. Masayuki Miyamoto: Writing – review & editing, Visualization, Project administration, Methodology, Investigation, Conceptualization.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Appendix A Supplementary data

The following are the Supplementary data to this article:Supplementary Data 1

CAS-J, Japanese version of the Constipation Assessment Scale; PD, Parkinson’s disease; DLB, dementia with Lewy bodies; MSA, multiple system atrophy.

Appendix A Supplementary data to this article can be found online at https://doi.org/10.1016/j.prdoa.2024.100269.
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