Abstract
Background:
Huntington’s disease (HD) patients often report anorectal dysfunction; however, in HD research no detailed analysis of these complaints has been published.
Objective:
To report anorectal dysfunction in a systematically studied cohort of HD subjects.
Methods:
In 54 HD patients (24 men) and 10 presymptomatic HD mutation carriers (2 men) and in 99 controls (44 men) a history of anal incontinence and constipation was obtained and data was compared accordingly. In HD mutation carriers a clinical neurologic assessment and in some cases anorectal manometry were performed.
Results:
Defecation urgency was reported by 28% of our HD mutation carriers, soiling in 18% and fecal incontinence in 28%. Severe anal incontinence (solid stools) was found in 0% men / 10% women, moderate (liquid stools) in 21% / 13%, and mild (flatus only) in 67% / 47% of our HD subjects. Compared to controls, anal incontinence was significantly more common in HD subjects (p < 0.001). Severe chronic constipation was found in 4.2% men / 0.0% women, moderate in 8.3% / 0.0%, and mild in 21% / 27% of HD subjects. Constipation was more common in HD men (p = 0.02) than in HD women (p = 0.144). Anorectal dysfunction was not reported by 54% of our HD subjects. Patients reporting incontinence or constipation were significantly more depressed (r = 0.53, p = 0.001). Upon anorectal manometry reduced resting anal pressure was found in 4 of 6 HD women.
Conclusions:
Our study demonstrated significant bowel dysfunction in HD patients. We propose these symptoms to be of central autonomic origin, although we cannot exclude effects of medication. These often neglected symptoms in HD subjects require greater attention from physicians.
INTRODUCTION
Huntington’s disease (HD) occurs in several brain regions whereby the enlarged protein huntingtin promotes apoptotic neuronal death. This results in cognitive, motor and personality disorders [1]. Recently, several studies have also demonstrated central autonomic dysfunction in HD [2–5]. Apart from bladder [4, 5] and sexual dysfunction [6–8], HD patients also frequently report symptoms of anorectal dysfunction. In a study of 1238 HD patients “difficulty with bowel control” was described in early stages as well as “loss of bowel control” in advanced stages of HD by 23% of the patients after more than 10 years of the disease [6]. However, in that study HD was not confirmed genetically, the level of the patient’s impairment was not evaluated according to the United Huntington’s Disease Rating Scale (UHDRS) [9], and bowel symptoms were not specified in detail [6]. A more recent study identified early abdominal fullness, anal incontinence and straining during defecation as more common in HD patients when compared to age and gender-matched controls [4]. Again, bowel symptoms (e.g., anal incontinence and chronic constipation) were not further specified, and no correlation between anorectal (dys)function and disease progression according to clinical scales such as the Total Functional Capacity Scale (TFC) [9] was determined.
The study’s aim was to examine anorectal (dys)function in a population of genetically confirmed HD patients, premanifest HD mutation carriers and controls using standard anal incontinence and chronic constipation questionnaires. We hypothesized that anorectal dysfunction is more common in HD subjects than in controls of similar age and is correlated with HD progression. In addition, anorectal manometry was performed on several HD patients with disturbing anorectal dysfunction.
MATERIALS AND METHODS
Patients
In the years 2008–2012, we sent an invitation letter to subjects from our records of genetically confirmed HD subjects (i.e.,≥36 CAG repeats in the huntingtin gene –inclusion criterion) to perform a prospective exploratory study. The study was planned to assess bladder, bowel and sexual (dys)function in HD patients and premanifest mutation carriers. Patients unable to independently manage using the toilet (e.g., bed ridden) were excluded (exclusion criterion). Subjects with disorders/conditions possibly affecting bowel function (e.g., spine injuries, severe diabetes, pregnancy), and severely ill subjects (e.g., heart failure, active cancer, cirrhosis of the liver) were also excluded (exclusion criteria). A group of control subjects of similar age and gender was recruited from HD patients’ relatives and spouses, medical staff and from a population of patients visiting general practitioners for unrelated minor health problems (e.g., flu, minor trauma, etc.). The National Ethics Committee of Slovenia approved the study, and, after a comprehensive explanation of the study protocol, all participating patients and controls gave their informed consent before entering the study.
Methods
Bowel function questionnaires
All enrolled HD subjects and controls were asked about their bowel function. Afterwards, Slovenian versions of the anal incontinence [10] and chronic constipation questionnaires [11] were sent to them. Cognitively impaired patients were helped by spouses/accompanying persons in completing the questionnaires. The questionnaires include 18 questions covering five aspects of bowel function: consistency of feces (Q1), anal incontinence (six questions: Q2–7), sensation during defecation (Q8), pain and other associated problems (Q9), bowel and general medical conditions (Q10) and constipation (eight questions: Q11–18). Questions were scored 0–1 (Q8), 0–2 (Q16), 0–3 (Q2), 0–4 (Q3–7, Q11–15, Q17–18) [10]. More pronounced bowel dysfunction corresponded to a higher score for each question. Mild anal incontinence was defined as incontinence of flatus only (anal incontinence score: 1–5), moderate when incontinence of liquid stools occurred a few times per week (score: 6–10) and severe when daily incontinence of liquid or solid stools was present (score: 11–20). Perfect anal continence was scored 0. Patient constipation was defined as absent (constipation scores: 0 –4) with no evacuation problems, mild (score: 5–10) with rare and mild problems, moderate (score: 11–20) with more pronounced and frequent troubles or severe (score: 21–30) with continuous and very troublesome defecation [11].
Subjects were also asked about other medical conditions possibly influencing bowel function, e.g., spine injuries, sciatica, radiation therapy, pregnancies, deliveries (types and perineal injuries), diabetes, hemorrhoids, rectocele, bladder, uterus or rectum prolapse, etc.
Neurological evaluation
The total motor score (TMS) part of the UHDRS [9], ranging 0–124 points, was determined for all patients. HD patients were divided into four groups according to the TMS: (1) premanifest HD mutation carriers (0–4 points); (2) early stage HD patients (5–24 points); (3) intermediate stage HD patients (25–49 points); (4) late stage HD patients (≥50 points) [9]. The functional status of the HD patients was determined by total functional capacity index (TFC, range 0–13 where a higher value means better performance) (UHDRS 1996).
Evaluation of depression
Depression was evaluated using the Beck Depression Inventory questionnaire, a 21-item self-reported depression score, designed to assess symptoms and level of depression (range 0–63 where a higher value means more severe depression) [12].
Anorectal manometry
All HD patients reporting anorectal dysfunction were invited to undergo standard anorectal manometry testing. After a standard preparatory protocol, patients were put into the right lateral position and had the AR measurement catheter (ManoScantrademark, Given Imaging Ltd, Yoqneam, Israel) inserted into the rectum. Resting anal pressure, maximal voluntary squeeze pressure, the push/strain maneuver, cough maneuver, recto-anal inhibitory reflex (RAIR) and rectal volume sensory thresholds were measured. The results for mean anal resting pressure, maximum anal squeeze pressure and anal squeeze duration were analyzed using the ManoViewtrademark analysis system. We used the 10th and 90th percentiles of previously published age-matched values [13] as reference values.
Follow-up examination
Patients who entered the study in the first two years were invited to receive a follow-up examination. The interval between the first and follow up examination was 2–4 years.
Statistical analyses
Data was entered into a personal computer database (Excel; Microsoft Corporation, Redmond, WA, USA) and analyzed using a professional statistical package (GraphPad Prism version 5.00 for Windows, GraphPad Software, San Diego, CA, USA). They are given as mean±SD for basic and median±SD for the data on bowel functions obtained from the questionnaires. Data obtained from the bowel symptom questionnaire was compared separately to control groups of men and women. In addition, a pooled analysis of men and women combined was also performed using the t-test. Bowel symptom scores were correlated to age and gender, the number of CAG repeats, duration of the disease, level of depression, TFC and to TMS using the non-parametric Spearman correlation coefficient. In addition, post hoc analysis using Holm’s method was applied. Both the fecal incontinence index and constipation index were compared to controls of similar age, separately for men and women using the Mann-Whitney U-test. As some HD patients were examined twice, the data obtained during examination closer to the time of the anorectal manometry study was analyzed. Data obtained at the first and follow-up examinations was compared separately in men and women using the Wilcoxon matched-pairs signed rank test.
RESULTS
Study population
A total of 82 HD patients and 15 premanifest HD mutation carriers were invited to participate in the study. Of these, 27 HD patients and 5 HD mutation carriers did not respond to the invitation, and 1 female HD patient was excluded due to her inability to ambulate. Finally, 54 HD patients (24 men) and 10 premanifest HD mutation carriers (2 men) were examined. The main demographic data, disease data, UHDRS motor score, TFC, and depression scores are presented in Table 1. According to TMS, 19 patients (8 men) exhibited early stage HD, 20 (8 men) intermediate, and 15 (8 men) late stage. In terms of medications, antidepressants were taken regularly by 35 HD patients, neuroleptics by 22, central acetylcholine-esterase inhibitors by 20, benzodiazepines by 6, and tetrabenazine by 5 HD patients. Seven HD patients did not regularly use any medication, while a single medication was taken by 19 patients, 2 medications by 15, 3 medications by 12, and 4 medications by 1 HD patient.
General data of Huntington’s disease (HD) patients, premanifest HD mutation carriers and controls included in the study
Except for subject number, mean values and standard deviation are shown. The premanifest HD mutation carriers group consisted of 8 women and 2 men. Patient and control ages were similar for both men (p = 0.16) and women (p = 0.08). For constipation, the subject’s personal opinion is shown. TFC –total functional capacity; TMS –total motor score (i.e., motor part of Unified Huntington’s Disease Rating Scale (UHDRS) [9]. The Beck Depression Inventory (BDI) questionnaire was completed by 19 HD men, 19 HD women, 9 premanifest HD mutation carriers and 88 controls (51 women and 37 men).
The control group consisted of 44 men (mean age: 43 years, range: 23–68 years), and 55 women (mean age: 49 years, range: 31–83 years). The majority of controls were recruited in general practitioners’ clinics (65 subjects): 25 were members of the medical staff, and 9 were HD patients’ genetically negative family members. The patient and control groups were of similar age (men: p = 0.16; women: p = 0.08). Control subjects participated anonymously by dropping the filled-in questionnaires into a box or sending it in by mail. Of the control group a total of 39 men and 52 women also completed the Beck Depression Inventory.
Bowel symptoms
From a total of 10 premanifest HD mutation carriers 1 reported fecal soiling, 7 reported incontinence of flatus only, 1 reported urgency for defecation, and 2 reported complete anal continence. None of them reported incontinence for liquid or solid stools. According to the constipation index, none of the premanifest mutation carriers were constipated, although 1 female carrier regarded herself as constipated due to a feeling of incomplete evacuation. In addition, 2 female carriers reported abdominal bloating, 1 male and 1 female reported feelings of incomplete evacuation, 1 male felt pain during defecation, and 1 female felt abdominal pain.
Anal incontinence and constipation questionnaires were completed by all 54 of the included HD patients and 99 controls. Anal incontinence was more common in the HD group, with a median incontinence index for HD women of 2.5 (range 0–13) and controls of 2 (range 0–5) (p = 0.0004) and with a median incontinence index for HD men of 4 (range 0–8) and controls of 1 (range 0–7) (p = 0.0001). A detailed analysis is shown in Table 2. By contrast, using the constipation questionnaire for men and women combined, the only difference in HD patients compared to controls was time spent in the lavatory (p = 0.01). In addition, some significant differences were found upon separate analysis between HD men and women with their controls (see Table 3). The median constipation index for HD men was 3 (range 0–13) and for controls 1 (range 0–9) (p = 0.0021). For HD women, the median index was 2 (range 0–10) and for controls 3 (range 0–14) (p = 0.144). HD patients also reported associated problems such as incomplete defecation (28%), straining on defecation (35%), rectal pain (15%), the sensation of rectal prolapse (15%), abdominal cramps (19%), bloating (24%), rectal bleeding (13%), mucous discharge (7%), urinary incontinence (25%), hemorrhoids (17%) and episodic diarrhea (7%).
Symptoms of anal incontinence in 54 Huntington’s disease (HD) patients and 99 controls
Frequencies in 24 HD/42 control men and 30 HD/53 control women are shown. Frequency of bowel movements: 0 = 1–2 per 1–2 days, 1 = 2 per week, 2 = 1 per week, 3 = <1 per week; frequency of Difficulty (painful evacuation effort), Completeness (feeling of incomplete evacuation), Pain (abdominal pain): 0 = never, 1 = rarely, 2 = sometimes, 3 = usually, 4 = always; Time (minutes in the lavatory): 0 = <5, 1 = 5–10, 2 = 10–20, 3 = 20–30, 4 = >40; Failure (unsuccessful evacuations per 24 h): 0 = never, 1 = 1–3, 2 = 3–6; History (years of constipation): 0 = 0, 1 = 1–5, 2 = 5–10, 3 = 10–20, 4 = >20; Assistance (type of assistance): 0 = without assistance, 1 = stimulative laxatives, 2 = digital assistance or enema. * = pooled men and women where p < 0.05. Pooled men and women were non-significant except for Time in the lavatory (p = 0.01). Significant p-values (p < 0.05) are in bold, significant problems in controls are underlined, and in comparison to the incontinence questionnaire, 4 controls did not complete the constipation questionnaire for unknown reasons.
Results of constipation questionnaire in 54 Huntington’s disease (HD) patients and 95 controls
Frequencies in 24 HD/42 control men and 30 HD/53 control women are shown. Frequency of bowel movements: 0 = 1–2 per 1–2 days, 1 = 2 per week, 2 = 1 per week, 3 = <1 per week; frequency of Difficulty (painful evacuation effort), Completeness (feeling of incomplete evacuation), Pain (abdominal pain): 0 = never, 1 = rarely, 2 = sometimes, 3 = usually, 4 = always; Time (minutes in the lavatory): 0 = <5, 1 = 5–10, 2 = 10–20, 3 = 20–30, 4 = >40; Failure (unsuccessful evacuations per 24 h): 0 = never, 1 = 1–3, 2 = 3–6; History (years of constipation): 0 = 0, 1 = 1–5, 2 = 5–10, 3 = 10–20, 4 = >20; Assistance (type of assistance): 0 = without assistance, 1 = stimulative laxatives, 2 = digital assistance or enema. * = pooled men and women where p < 0.05. Pooled men and women were non-significant except for Time in the lavatory (p = 0.01). Significant p-values (p < 0.05) are in bold, significant problems in controls are underlined, and in comparison to the incontinence questionnaire, 4 controls did not complete the constipation questionnaire for unknown reasons.
After a median interval of 3 years (range 2–4 years), we performed a follow-up examination of 23 HD patients (12 men) and 4 premanifest HD mutation carriers (1 man). In a majority of HD patients, anal incontinence scores either remained unchanged or increased. However, improvement was observed in 9 HD patients (3 men and 6 women, Table 4). No dynamics were observed in premanifest HD mutation carriers. Similarly, constipation scores increased or remained stable in the majority of the patients; although, improvement was detected in 5 HD patients (2 men and 3 women) (Table 4).
Findings in the 23 Huntington’s disease patients who were examined two times
Mean values and standard deviation are shown for basic patient’s data and median for bowel function data. The interval between both examinations varied from 2 to 4 years, mean 3 years. * –significant difference (p < 0.05) between both examinations. TFC –total functional capacity; BDI –Beck Depression Inventory; TMS –total motor score (motor part of the Unified Huntington’s Disease Rating Scale).
Anorectal manometry
While all 26 HD patients (11 men) with bowel symptoms were invited, only 6 women with pronounced anorectal problems consented to anorectal manometry. All patients reported urgency and had an anal incontinence index and/or constipation index above the mean value for HD women (i.e., 2.0 for constipation and 2.5 for incontinence). Reduced resting anal pressure was the main finding in 4 patients, and reduced anal squeeze pressure was found in 2 of the 6 HD women.
Correlations
Correlations between patients’ basic characteristics, total motor score (TMS), Total Functional Capacity index (TFC), Beck Depression Inventory (BDI) score and bowel dysfunction are shown in Table 5. Older patients had more problems with continence: age correlated to the level of incontinence (r = 0.28, p = 0.041) and fecal incontinence index (r = 0.29, p = 0.036). However, no correlation was found between the BDI score and age (r = 0.238, p = 0.152).
Correlations between patients’ basic characteristics, total motor score (TMS), Total Functional Capacity index (TFC), Beck Depression Inventory score (BDI) and bowel dysfunction. Significant correlations are printed in bold.
The strongest correlations were observed between the BDI score and the level of incontinence (r = 0.47, p = 0.003), fecal incontinence index (r = 0.51, p = 0.001) and constipation index (r = 0.53, p = 0.001). Post hoc analysis using Holm’s method demonstrated significance only for the Beck depression score with the incontinence index (p = 0.04) and constipation index (p = 0.02). Statistical correlation was also found between the constipation index and level of incontinence (p = 0.015) and between the constipation index and incontinence index (p = 0.011). Medication showed no effect on the consistency of stools, level of incontinence, fecal incontinence index and constipation index. The closest relationship was found between acetylcholinesterase inhibitors and the fecal incontinence index (p = 0.08), the adjusted p-value, however, showed no difference.
DISCUSSION
According to our knowledge, this is the first study focused in detail on bowel dysfunction in HD patients and premanifest HD mutation carriers. A general description of bowel dysfunction in genetically confirmed HD patients has been published [4]. However, the questionnaire used in that study (SCOPA-OUT) [14] included only 3 questions on bowel dysfunction (2 on constipation and 1 on incontinence). By contrast, in our present study we used specific comprehensive inventories, i.e., an anal incontinence questionnaire including 12 questions (Table 2) [10] and chronic constipation questionnaires including 8 questions (Table 3) [11]. Our study confirmed that anal incontinence in HD patients is more common and more severe (p < 0.0001) compared to the controls (Fig. 1A). Our findings additionally emphasize previous reports [4]. Complete anal continence (for flatus, liquid and solid stools) was reported by 12% of HD men and 30% of HD women vs. 45% of male and 33% of female controls. Interestingly, several of our HD patients reported incontinence for liquid stools with no concomitant incontinence for flatus (Fig. 1B). Other patients, however, reported incontinence for solid stools but no incontinence for liquid stools because they never experienced liquid stools. In our HD patient group anal incontinence had a strong negative effect on the patient’s quality of life (Table 2), as previously reported [15]. We also observed strong correlation of anal incontinence (r = 0.47, p = 0.003) and incontinence index (r = 0.51, p = 0.001) with the Beck depression score. In the same HD patient cohort these correlations were much stronger for anal incontinence than for urinary incontinence [5], which probably relates to the more severe social consequences of anal incontinence.
A. Comparison of bowel dysfunctions in 54 Huntington’s disease (HD) patients (P) and 99 controls (C) of similar age and gender distribution. Bowel dysfunction was more pronounced in HD patients. P values < 0.05 are printed in bold. B. Anal incontinence problems in 54 Huntington’s disease (HD) patients (P) and 99 controls (C). P values < 0.05 are printed in bold. Note that the graph shows only the occurrence of some problem and not the severity. Patients and controls have similar occurrence of incontinence for flatus, but their severity is different (Table 2).
By contrast, although constipation was more common in HD men compared to controls (p = 0.002), we found no difference between HD women and controls (p = 0.144) nor for pooled HD men and women compared to controls (Table 3 and Fig. 1A). It is known that in general population constipation affects a greater proportion of women than men [16]. Interestingly, the opposite was observed in our HD population. Accordingly, we found constipation less pronounced in HD women compared to controls (see Table 3 and Fig. 1A). Constipation was found to advance with age (r = 0.287, p = 0.036), which is in line with previous reports [16]. We also found borderline correlation between the constipation index and TMS (r = 0.263, p = 0.055) as well as more solid feces in patients with higher TMS scores (r = –0.272, p = 0.047). This can probably be explained either by increased constipation due to disease progression and/or due to reduced patient mobility [17]. No difference in the anal incontinence index or constipation score was found in the 23 HD patients’ (12 men) follow-up examinations after 2–4 years (Table 4), which contrasts with the clear progression in bladder dysfunction observed in the same HD patient cohort [5].
We found a different evolution of fecal incontinence and constipation: fecal incontinence had two peaks. The first at TFC 7 is probably a consequence of fecal urgency and might outline progressive deregulation between cortical and brainstem autonomic centers [18]. The second is probably a consequence of decreased mobility in the advanced disease. In contrast, constipation increased with disease progression and could be at least partly explained by decreased mobility in the advanced disease [17]. We have chosen the motor criterion on account of its easy applicability to our HD patients. It was also reported to represent the strongest characteristic to defining the clinical stage of the disease [19].
Four of our HD women reported recurrent diarrhea that spontaneously disappeared, pointing to probable central autonomic dysregulation [2, 3]. One of our female HD patients underwent repeated gastrointestinal examinations, but no organic cause of intractable diarrhea was found. Although cancer is not often observed in HD patients [20], HD and colorectal cancer might share similar epigenetic mechanisms (e.g., demethylation) [21], therefore some vigilance is prudent.
Three of the other HD patients reported losing stools without notice, possibly pointing to frontal lobe dysfunction [22]. We also found a high prevalence of defecation urgency reported by 28% of our HD patients, which complements the high prevalence of urinary urgency (affecting 54% of men and 40% of women) in the same population of HD patients [5]. Although no impairment of gastric emptying has been found in early HD patients (Shoulson stage I/II), such a disorder cannot be excluded in more advanced HD patients who were also enrolled in our study [23].
To objectivize anorectal function with bowel symptoms, we performed anorectal manometry in 6 HD women. The most common finding was reduced resting anal pressure, found in 4 (67%) of the 6 subjects. This finding is in line with our previous results, which show decreased tonic activity and/or decreased voluntary activation in 81% of HD patients on needle electromyography of the external anal sphincter muscle [24]. In the absence of Onuf’s nucleus degeneration these findings point to a central dysregulation, probably of both the internal smooth and external striated anal sphincter muscles [24].
These findings in our HD patients might also be at least partially due to centrally acting medications: Centrally active acetylcholine-esterase inhibitors were used by 20 of our HD patients. Although diarrhea is a well-known side effect of these medications, we found no difference in fecal incontinence (p = 0.08) and the constipation index (p = 0.30) between patients taking and not taking these medications. This might be explained by the concomitant use of several other centrally acting medications; i.e., antidepressants, neuroleptics, benzodiazepines and tetrabenazine. Neuroleptics in particular are well known for causing constipation [25].
A recognized limitation of our study is a possible bias in the recruitment of HD patients and controls. We cannot exclude the possibility that patients with sacral dysfunctions (including bowel problems) more often decided to participate than those without. Furthermore, only patients with bowel problems were invited to anorectal manometry. Similarly, recruitment of controls could be troubled by the inclusion of subjects with atypical lifestyle and eating habits, as only a few patients’ relatives responded to our invitation.
The study’s strengths, however, were the inclusion of genetically confirmed HD patients and the use of standard clinical scales, e.g., UHDRS and detailed anorectal function questionnaires.
In conclusion, in HD patients of both genders we found more common anal incontinence, and in HD men we also found more common constipation compared to the controls. Furthermore, bowel symptoms had a greater effect on the daily life of HD women. The majority of tested symptomatic HD patients also had decreased anal resting tone. Bowel dysfunction in HD, therefore, appears to be primarily related to progressive degeneration and dysregulation of the basal ganglia and frontal lobes.
CONFLICT OF INTEREST
The authors have no conflict of interest to report.
Footnotes
ACKNOWLEDGMENTS
The authors wish to thank the general practitioners Mojca Pibernik, MD and Polona Rudolf, MD for providing us with data for the control group. The study was supported by the Republic of Slovenia Research Agency, Grant No. P3-0338.