Defecation is an integrated somatovisceral process. Phenotypic Variation in Functional Disorders of Defecation

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1 GASTROENTEROLOGY 2005;128: Phenotypic Variation in Functional Disorders of Defecation ADIL E. BHARUCHA,* JOEL G. FLETCHER, BARB SEIDE,* STEPHEN J. RIEDERER, and ALAN R. ZINSMEISTER *Division of Gastroenterology and Hepatology, Department of Radiology, and Division of Biostatistics, Mayo Clinic and Mayo Foundation, Rochester, Minnesota Background & Aims: Although obstructed defecation is generally attributed to pelvic floor dyssynergia, clinical observations suggest a wider spectrum of anorectal disturbances. Our aim was to characterize phenotypic variability in constipated patients by anorectal assessments. Methods: Anal pressures, rectal balloon expulsion, rectal sensation, and pelvic floor structure (by endoanal magnetic resonance imaging) and motion (by dynamic magnetic resonance imaging) were assessed in 52 constipated women and 41 age-matched asymptomatic women. Phenotypes were characterized in patients by principal components analysis of these measurements. Results: Among patients, 16 had a hypertensive anal sphincter, 41 had an abnormal rectal balloon expulsion test, and 20 had abnormal rectal sensation. Forty-nine patients (94%) had abnormal pelvic floor motion during evacuation and/or squeeze. After correcting for age and body mass index, 3 principal components explained 71% of variance between patients. These factors were weighted most strongly by perineal descent during evacuation (factor 1), anorectal location at rest (factor 2), and anal resting pressure (factor 3). Factors 1 and 3 discriminated between controls and patients. Compared with patients with normal (n 23) or reduced (n 18) perineal descent, patients with increased (n 11) descent were more likely (P <.01) to be obese, have an anal resting pressure >90 mm Hg, and have a normal rectal balloon expulsion test result. Conclusions: These observations demonstrate that functional defecation disorders comprise a heterogeneous entity that can be subcharacterized by perineal descent during defecation, perineal location at rest, and anal resting pressure. Further studies are needed to ascertain if the phenotypes reflect differences in the natural history of these disorders. Defecation is an integrated somatovisceral process that requires increased abdominal pressure coordinated with relaxation of the external anal sphincter and pelvic floor muscles, particularly the puborectalis. Because symptoms of constipation alone are not adequate, anorectal testing is necessary to distinguish functional disorders of defecation from other causes of functional constipation (ie, slow transit constipation, irritable bowel syndrome). 1 Insufficient relaxation or paradoxical contraction of the external anal sphincter and/or puborectalis during defecation (ie, pelvic floor dyssynergia) can be recognized by manometry, electromyography, or barium proctography and is the most widely recognized cause of a defecatory disorder. 2 4 However, the specificity of pelvic floor dyssynergia to symptoms can be questioned because it is also observed in asymptomatic subjects. 5 7 In addition, methodological pitfalls limit the accuracy of barium proctography, which is the only established technique for visualizing anorectal motion in patients with symptoms of difficult defecation. 8,9 The bony landmarks necessary for evaluating anorectal motion are poorly visualized. The technique is poorly standardized, with inadequate normal values, and it involves radiation exposure. To overcome these limitations, dynamic pelvic magnetic resonance imaging (MRI) has been used to demonstrate a variety of anorectal and pelvic floor motion disturbances during real-time imaging of defecation in uncontrolled studies. 10,11 Controlled studies are necessary to ascertain the utility of dynamic MRI for recognizing disordered anorectal and pelvic floor motion in patients with symptoms of difficult defecation. In addition to pelvic floor dyssynergia, other reported disturbances in patients with difficult defecation include reduced rectal sensation, rectoceles, inadequate propulsive forces, and perineal laxity (manifested as excessive perineal descent). 2,12 14 It is unknown if these objective disturbances identify subgroups of patients with symptoms of difficult defecation. We aimed to evaluate anorectal function by manometry and MRI to test the hypothesis that detailed assessments of anorectal and pelvic floor functions would show phenotypic variability in patients with symptoms of difficult defecation. Abbreviations used in this paper: BMI, body mass index; MR, magnetic resonance; MRI, magnetic resonance imaging by the American Gastroenterological Association /05/$30.00 doi: /j.gastro

2 1200 BHARUCHA ET AL GASTROENTEROLOGY Vol. 128, No. 5 Patients and Methods Participants Between June 2000 and February 2003, 52 women with symptoms of obstructed defecation and 41 healthy, asymptomatic women consented to participate in this study, which was approved by the institutional review board of the Mayo Clinic. All subjects had a clinical interview and physical examination by an individual gastroenterologist, completed a validated bowel disease questionnaire focusing on disorders of evacuation and continence, 15 and underwent assessments of anorectal and pelvic floor functions. Healthy controls were recruited by public advertisement. Those who had any previous anorectal operations, including hemorrhoid procedures, or had sustained anorectal trauma during delivery (ie, grade 3 or 4 laceration) as documented by obstetric records were excluded from this study. Other exclusion criteria for controls included significant cardiovascular, respiratory, neurologic, psychiatric, or endocrine disease; symptom-based criteria for any functional gastrointestinal disorder as assessed by questionnaire; medications (with the exception of oral contraceptives or thyroid supplementation); and abdominal surgery (other than appendectomy or cholecystectomy). Patients were recruited from a specialized clinic devoted to gastrointestinal motility disorders. All patients had 2 or more symptom-based criteria for functional constipation. 16 The clinical examination included a rectal examination with an assessment of perineal descent during simulated evacuation; in 89 of 93 subjects, perineal descent during simulated evacuation was graded as normal, reduced, or increased by clinical examination, which was conducted before MRI. Procedures Questionnaire. The fecal incontinence and constipation assessment incorporated items from previously validated instruments and new questions. This assessment dealt predominantly with functional constipation, diarrhea, fecal incontinence, and irritable bowel syndrome. 15 Anorectal manometry, rectal balloon expulsion, and rectal sensation. Patients were instructed to evacuate the rectum after magnesium citrate enemas (Fleets, C.B. Fleet, Lynchburg, VA) about 1 hour before the test. Anorectal testing was conducted in the left lateral position by perfusion manometry. 17 Average resting and squeeze pressures in the anal canal and the weight necessary to facilitate rectal expulsion of a 50-mL balloon filled with warm water were summarized. Thresholds for first sensation and for constant urgency were recorded while an intrarectal balloon was inflated with air at a rate of 20 ml/5 seconds. Pelvic MRI. The anal sphincters were imaged with a disposable endorectal coil (MRInnervu; Medrad, Inc, Indianola, PA) before dynamic magnetic resonance (MR) proctography. 10 For imaging the anal sphincters, axial T2-weighted fast spin-echo images (field of view, 12 cm; repetition time, 4000 milliseconds; echo time, 105 milliseconds; 3.5-mm slice thickness/0-mm skip; matrix; 2 NEX) and corresponding T1-weighted spin-echo images (field of view, 12 cm; echo time/repetition time, minimum/400 milliseconds; 3.0-mm slice thickness/0.5-mm skip; matrix; 1 NEX) were acquired. Additional fast spin-echo images were acquired in the coronal plane. After removing the disposable endorectal coil, 120 ml of ultrasound gel was instilled into the rectum and a 4-element phased-array coil was placed around the pelvis. The volume of ultrasound gel was similar to that of barium paste used for barium proctography. An interactive single-shot, fast spinecho imaging technique 18 was used for dynamic MR proctography. Images were acquired with a field of view of cm, slice thickness of 5 mm, repetition time of milliseconds, echo time of 90 milliseconds, and matrix size of (half-nex). An oblique sagittal plane bisecting the anorectum was defined by selecting 3 points from axial images during real-time imaging. Images were then acquired every seconds during rest, squeeze, and defecation in the supine position. Using real-time image reconstruction, we could monitor the examination, ensure performance of desired maneuvers, and instruct patients. After the defecation sequence, patients were removed from the magnet and asked to empty the bladder and remaining rectal contents. Patients were then repositioned within the magnet to obtain additional dynamic sagittal images during the Valsalva maneuver. Finally, coronal images through the pelvic floor were obtained at rest and during the Valsalva maneuver. The same radiologist (J.G.F.), blinded to clinical data, analyzed anal sphincter appearance and pelvic floor motion in all patients with a standardized approach, 10 as summarized in the following text. To assess interobserver reproducibility, another reviewer also analyzed dynamic MR images in 27 randomly selected subjects (13 controls and 14 patients). Assessment of images by a radiologist. Anal sphincter appearance. Sphincters were characterized by their appearance (ie, normal, mild focal thinning, marked focal thinning, scar, tear, or atrophy), and the location of abnormalities around the anal canal circumference, and along its longitudinal axis (ie, from the most superficial aspect of the subcutaneous external anal sphincter to the anorectal junction). 10 Anorectal motion and rectal evacuation. Anorectal and pelvic floor motion from rest to squeeze and rest to defecation was recorded by images acquired every seconds; motion was analyzed by comparing single images at rest and during maximum excursion during squeeze and evacuation. Established definitions were used to measure the anorectal angle, anteroposterior and vertical motion of the anorectal junction, rectocele, and enterocoele size. 10,19,20 The anorectal angle was the angle between the central axis of the anal canal and the tangent to the posterior wall of the rectum. Vertical motion of the anorectal junction (ie, perineal motion) during squeeze and simulated defecation was measured in centimeters relative to the pubococcygeal line; descent below the line was represented as a positive value. Anteroposterior motion was measured parallel to the pubococcygeal line.

3 May 2005 PHENOTYPES IN DEFECATORY DISORDERS 1201 Table 1. Demographic Characteristics, Anal Pressures, and Pelvic Floor Motion in Subjects Controls Patients P a Age (y) 43 2 NA NS BMI (kg/m 2 ) NA NS Vaginal deliveries NS Average anal resting pressure , 88 b 62 3 NS Average anal squeeze pressure , 192 b Rectal balloon expulsion (n) No external traction 33 NA, 100 b g traction 4 NA, 100 b g traction 4 NA, 100 b 41 First sensory threshold , 82 b 53 5 NS Urgency threshold , 280 b Anorectal angle change during evacuation ( ) c , 40.2 b Perineal descent during evacuation (cm) , 5.1 b NS Anorectal angle change during squeeze ( ) c , 13 b Perineal ascent during squeeze (cm) , 1.0 b NOTE. Values are mean SEM unless otherwise stated. NA, not applicable. a Test for association with group status (ie, patient or control). b 10th, 90th percentile values. c Negative value indicates reduction in angle during squeeze (or evacuation) compared with rest. Data Analysis The association between group status (ie, patient or control) and anal pressures, traction required for rectal balloon expulsion, rectal sensation, and pelvic floor motion indices (ie, angle change and vertical motion) was assessed by a logistic regression model, adjusting for age and body mass index (BMI) in each model. Pearson s 2 test or Fisher exact test assessed the association between anorectal descent during evacuation and anal resting pressure, rectal balloon expulsion test result (characterized as normal [ie, 100 g traction required] or abnormal [ie, 100 g required]), and presence of a rectocele ( 2 cm). Anal pressures, rectal balloon expulsion, rectal sensation, and anorectal motion by MRI were considered normal or abnormal based on the 10th 90th percentile range for asymptomatic controls. Fisher exact test assessed the association between perineal descent during evacuation as measured by clinical examination versus MRI. McNemar s test evaluated whether the clinical examination systematically underestimated or overestimated descent compared with MRI. Principal components analysis of anorectal functions. To assess whether patients could be clustered into subgroups by objective parameters of anorectal function, we used a principal components analysis of the partial correlation matrix (ie, adjusting out age and BMI). 21 The analysis adjusted for age and BMI because we sought to examine the variation in anorectal functions uncorrelated with age and BMI. Because we sought to characterize anorectal function at rest, during squeeze, and during evacuation, the 7 response variables selected for this analysis were average resting pressure, traction required for rectal balloon expulsion, change in anorectal angle from rest to squeeze, change in anorectal angle from rest to defecation, and location of the anorectal junction at rest, squeeze, and defecation. In the first step, the analysis constructed a score, which was the weighted linear combination of the 7 variables that accounted for the maximum between-subjects variance among all such linear combinations of these variables. This score was termed the first principal component score (or factor 1). A second linear combination was then constructed to account for the maximum possible remaining (between-subjects) variations and similarly a third linear combination. The principal component scores are subject to the constraint that they are uncorrelated with each other. For each patient, each score (or factor) is derived as a specific weighted linear combination of the 7 variables. The loading for a specific variable in a particular factor is the weight used for that variable in the given linear combination (factor). After these factors were computed, the (Pearson) correlation between each variable and the factor could be computed. The advantage of assessing the relationship between a variable and a factor by the correlation coefficient is that in contrast to the loadings, this approach can also examine the relationship with other variables not used for constructing the principal composite score. The correlation between bowel symptoms and the principal component scores was evaluated by Spearman s correlation coefficients. For these correlations, a Bonferroni correction for 3 comparisons (ie, 3 principal component scores) was applied; only correlations with a P value of.017 were considered significant. Thereafter, a multiple regression model was constructed to predict each principal component score using a combination of symptoms. For these analyses, symptoms were dichotomized to be consistent with Rome criteria, that is, never or infrequently (ie, 25% of the time) versus frequently (ie, 25% of the time), with 2 exceptions. First, the number of bowel movements was rated as reduced (ie, 3 bowel movements/week), normal (ie, between 3 bowel movements/ week and 3 bowel movements/day), or increased (ie, 3 bowel movements/day). Second, the time spent during the process of defecation was rated as normal (ie, 10 minutes) or excessive (ie, 10 minutes) based on data in the literature. 22

4 1202 BHARUCHA ET AL GASTROENTEROLOGY Vol. 128, No. 5 Figure 1. Sagittal dynamic MRI images of (left panel) normal puborectalis relaxation (subject 1) and (right panel) puborectalis contraction (arrow; subject 2) during rectal evacuation. In both subjects, evacuation was associated with perineal descent (2.6 cm in subject 1; 1.7 cm in subject 2) and opening of the anorectal junction. During evacuation, the anorectal angle increased by 36 in subject 1 and declined by 10 in subject 2. Results Clinical Features Demographic features were similar in patients and controls (Table 1). Consistent with the Rome II criteria, all patients reported 2 or more symptoms of functional constipation for 25% of the time. Symptoms included excessive straining during defecation (94%), hard stools (79%), sense of incomplete evacuation after defecation (79%), sense of anorectal blockage or obstruction (77%), infrequent stools (ie, 3 times per week; 64%), and digital removal of stool from the rectum (50%). In addition to functional constipation, 16 patients (31%) also had symptom criteria (Rome II) for irritable bowel syndrome. The duration of symptoms was reported as 1 year (n 3), 1 5 years (n 15), 5 10 years (n 5), and more than 10 years (n 29). Anorectal Manometry and Rectal Balloon Expulsion Test The average anal resting pressure was similar in patients and controls (Table 1). However, 16 patients (31%) had a hypertensive anal sphincter, that is, the anal resting pressure was higher than the 90th percentile value for controls in this study, which was 88 mm Hg. The average squeeze pressure was lower in patients compared with controls (Table 1; P.001). The difference between anal pressure at rest and during squeeze was reduced (ie, lower than the 10th percentile) in 17 patients, 7 of whom had high resting anal sphincter pressures. Forty-one patients (79%) had an abnormal rectal balloon expulsion test result, requiring more than 100 g (ie, the 90th percentile value for controls) to expel the balloon (Table 1). Eighteen patients required g to expel the balloon, and 23 patients could not expel a rectal balloon despite 586 g of external rectal traction, the upper limit tested in the procedure. Rectal Sensation During rectal balloon distention, the average threshold for first sensation was comparable in patients and controls (Table 1). However, the threshold for constant urgency was higher (P.02) in patients compared with controls (Table 1). Thresholds for first sensation and/or constant urgency were increased (ie, 90th percentile) in 14 of 52 patients (27%) and reduced (ie, 10th percentile) in 6 patients (12%). MRI of Anorectal Motion in Controls In controls, rectal evacuation was generally associated with pelvic floor relaxation, manifested by widening of the anorectal angle and perineal descent (Figure 1 [left panel] and Table 1). However, in 7 controls, all younger than 45 years of age, the puborectalis indentation on the posterior rectal wall was more rather than less pronounced during rectal evacuation (Figure 1 [right panel]). In these 7 controls, the change in anorectal angle (mean change, 8 vs 22 in subjects with less pronounced puborectalis indentation) and descent during evacuation was smaller (mean descent, 1.7 cm vs 3.6 cm in subjects with less pronounced puborectalis indentation), suggesting that the puborectalis contracted instead of relaxed during evacuation. In controls, perineal descent was correlated (r s 0.48; P.0001) with change in anorectal angle during evacuation (Figure 2 [left panel]) and also correlated (r 0.34; P.03) with BMI. Similarly, perineal ascent was correlated (r s 0.67; P.0001) with narrowing of the anorectal angle during squeeze. The location of the anorectal junction at rest was correlated with age (r s 0.53; P.001) (Figure 2 [right panel]).

5 May 2005 PHENOTYPES IN DEFECATORY DISORDERS 1203 Figure 2. Comparison of change in (A) anorectal angle and perineal descent during rectal evacuation in controls and (B) location of anorectal junction at rest relative to the pubococcygeal line in controls. MRI of Anorectal Motion in Patients The average change in anorectal angle during evacuation and squeeze was reduced in patients compared with controls (Table 1). Perineal descent during rectal evacuation was normal in 44%, reduced in 35%, and increased in 21% of patients (Table 2). Increased perineal descent was associated (P.01) with a hypertensive anal sphincter, a normal rectal balloon expulsion test result, and a rectocele (Table 2 and Figure 3D). Seventeen of 41 controls (41%) and 19 of 52 patients (37%) had a rectocele 2 cm. In addition to reduced or increased perineal descent during evacuation, dynamic MRI also revealed abnormal (ie, reduced [n 18] or increased [n 4]) perineal elevation during squeeze in 42% of patients (Table 2). The augmentation in anal pressure during squeeze was weakly correlated (r s 0.2; P.04) with perineal elevation during squeeze. Taken together, 49 of 52 patients (94%) had one or more disturbances of anorectal motion (ie, angle change and/or vertical motion) during evacuation or squeeze. Can Objective Anorectal Parameters Identify Clusters in Patients? A principal components analysis incorporating selected response variables ascertained whether patients could be clustered into subtypes by objective criteria. Table 3 provides loadings on each factor and Pearson correlation coefficients for the 7 variables used for constructing these factors. Figure 4 also provides the Pearson correlation coefficients between variables that were not used for constructing these factors as well as the factors. This analysis revealed 3 composite scores, which cumulatively accounted for 71% of the residual variance (ie, after adjusting out effects of age and BMI) in the 7 response variables among subjects. The first composite score accounted for 29% of residual variation between patients. The variable loading values (Table 3) indicate that this score Table 2. Anal Pressures and Anorectal Motion in Patients With Normal, Reduced, and Increased Perineal Descent Normal descent Reduced descent Increased descent No. of patients Anal manometry and balloon expulsion Resting anal pressure a Increased, reduced 4, 2 5, 3 7, 0 Squeeze increment Increased, reduced 0, 12 0, 10 0, 7 Abnormal rectal balloon expulsion test a Anorectal motion during evacuation Anorectal angle change Increased, reduced 4, 5 0, 10 3, 1 No. of patients with impaired puborectalis relaxation Rectocele ( 2 cm) a Anorectal motion during squeeze Anorectal angle change Increased, reduced 2, 9 0, 11 0, 3 Perineal ascent Normal, 10; reduced, 10; increased, 2 Normal, 10; reduced, 7; increased, 1 Normal, 9; reduced, 1; increased, 1 NOTE. Values are number of patients with abnormal values relative to 10th 90th percentile values in controls. a P.01 for association between these parameters and patient status (ie, normal, reduced, or increased perineal descent).

6 1204 BHARUCHA ET AL GASTROENTEROLOGY Vol. 128, No. 5 Figure 3. Variations in anorectal and pelvic floor motion during evacuation in patients. (A) The pelvic floor was immobile during squeeze and evacuation. The anterior abdominal wall moved outward during evacuation, suggesting increased intra-abdominal pressure. (B) The puborectalis (white arrow) not only impeded evacuation but also perhaps precluded effective force transmission to the rectal segment above the anorectal junction. Observe the out-pouching of the anterior rectal wall or perhaps the anal canal (black arrow). (C) A patient in whom the anorectal junction was relatively low (ie, 2.5 cm below the pubococcygeal line) at rest, declining to 5.6 cm below this line during defecation. Despite normal descent and opening of the anorectal angle, only 5% of the rectal contents were expelled. (D) Excessive perineal descent during evacuation associated with a rectocele (arrow). defined a latent dimension that was positively correlated with perineal descent (ie, angle change [Ang ReDef], descent [Des ReDef]) from rest (Re) to defecation (Def) and negatively correlated with the balloon expulsion test (Bal Exp) (Figure 4A). A comparison of the factor 1 score in patients and controls suggests that a low score (ie, a value of 0.81) separated controls from 17 (of 18) patients with reduced perineal descent (Figure 5A). The second composite score accounted for 25% of the residual variation and implied a dimension positively correlated with anorectal location at rest (LocRest) and squeeze (LocSq) and negatively correlated with motion (ie, angle change, descent) from rest to defecation. However, this score did not discriminate controls from patients (Figure 5A). The third composite score accounted for 17% of the residual variation. This score was positively correlated (Figure 4B) with anal resting pressure (Res Pr) and anorectal motion (ie, angle change [Ang ReSq], descent [Des ReSq]) from rest to squeeze and negatively correlated with the anal pressure increment from rest to squeeze (Sq Res Pr). For this score, a value of 0.75 separated 40 (of 42) controls from 16 patients, 9 of whom had a hypertensive anal sphincter (Figure 5B). In contrast to anal pressures and indices of anorectal motion, rectal sensory thresholds were only weakly correlated with latent dimensions identified by principal components analysis. Several symptoms were correlated with the principal component scores (Table 4). However, in the multiple regression model, symptoms explained a relatively small proportion of the interindividual variation in these scores (ie, 21%, 18%, and 36% of the interindividual variation in the first, second, and third principal component scores, respectively). Interobserver Reproducibility for MRI Assessment of Pelvic Floor Motion All 5 MRI parameters used to construct principal component scores were significantly correlated between both observers who assessed MRI independently (Table

7 May 2005 PHENOTYPES IN DEFECATORY DISORDERS 1205 Table 3. Variable Loading and Correlation Coefficients for Principal Component Scores Variable Loading Factor 1 Factor 2 Factor 3 Correlation coefficient Loading Correlation coefficient Loading Correlation coefficient Balloon expulsion a b c Anal resting pressure c a Angle change from rest to defecation a a Angle change from rest to squeeze d a Anorectal location at rest a a Anorectal location at squeeze c a b Anorectal location during defecation a NOTE. The factor scores for each patient were computed by summing the products of the loading for a parameter and the value for that parameter in each patient. a P b P.001. c P.05. d P.01. 5). For some parameters (eg, location of anorectal junction at rest), values for both observers differed significantly (Table 5); however, the differences were relatively small. Comparison of Perineal Descent by Clinical Evaluation and MRI Perineal descent measured by clinical examination was strongly associated (P.001) with descent measured by MRI. Overall, the clinical examination and MRI agreed for characterizing perineal descent as normal, reduced, or increased in 66% of subjects (Table 6). Moreover, the clinical examination did not significantly underestimate or overestimate descent compared with MRI (P NS by McNemar s test). Anal Sphincter Morphology by MRI The anal sphincters were imaged by endoanal MRI in all controls and 50 of 52 patients. Two patients were uncomfortable with the endorectal coil. In 18 of 25 controls (72%) and 45 of 52 patients (87%), the internal and external anal sphincters appeared normal or revealed mild focal thinning only. Six controls and 4 patients had marked focal thinning, or a tear, or a scar involving the internal and/or external anal sphincters. One control and one patient had atrophy of the internal anal sphincter. No controls and only one patient had unilateral atrophy of the puborectalis muscle. Differences between controls and patients in anal sphincter morphology were not significant. Discussion The Rome II criteria reflect the traditional paradigm wherein functional disorders of defecation are defined by symptoms of constipation and pelvic floor dyssynergia. 16 However, clinical observations and case series suggest that patients with symptoms of difficult defecation may have other disturbances (eg, hypertensive anal sphincter, increased perineal descent, reduced or increased rectal sensation) Thus, the Rome II criteria may not completely account for the phenotypic variability in functional disorders of defecation. This study shows that functional disorders of defecation are a group of conditions that can be subcharacterized by measuring anorectal motion during evacuation, anorectal location at rest, and anal resting pressure using anal manometry and a sophisticated, dynamic MRI technique. Applying a principal components analysis to our data, 3 factors (or latent dimensions) emerged that best explained the total phenotypic variance. These factors were primarily weighted by perineal descent during evacuation, anorectal location at rest, and resting anal pressure. Perineal descent during evacuation (factor 1) and a hypertensive anal sphincter (factor 3) discriminated patients from controls. In addition to supporting the concept of phenotypic heterogeneity, these data enhance our understanding of defecatory disorders. Increased perineal descent during evacuation was associated with a hypertensive anal sphincter and with obesity. It is conceivable that this association is explained by a tendency for patients with a hypertensive anal sphincter to strain excessively during defecation, predisposing to pelvic floor weakness. We confirmed that external traction necessary to facilitate rectal balloon expulsion was inversely correlated with perineal descent. 26 Thus, external traction needed to expel a rectal balloon was lower in patients with significant perineal descent, suggesting weakness in the ligamentous or muscular support of the perineum. Interestingly, excessive descent was also associated with

8 1206 BHARUCHA ET AL GASTROENTEROLOGY Vol. 128, No. 5 patients and controls. The weightings for this score suggest that when the anorectal junction was lower at rest, descent during evacuation was reduced. Therefore, it is necessary to consider the location of the anorectal junction at rest when using perineal descent during evacuation as a marker of pelvic laxity. Longitudinal studies will clarify whether anorectal location at rest and descent during evacuation represents different stages in the natural history of these disorders. For example, it is conceivable that in the initial stage of defecatory disorders, the pelvic floor is well supported at rest and descent Figure 4. Correlation between variables and (A) factors 1 and 2 and (B) factors 2 and 3. These plots incorporate the 7 response variables incorporated in the principal components analysis (which are demarcated by square boxes) and other measured parameters. The correlation reflects the contribution of a given variable to a factor, that is, a higher correlation (maximum 1) suggests a greater contribution of the variable to that principal component. The parameters were assessed by MRI (angle measurements are in open circles, and anorectal junction motion is shown as filled circles), anal manometry and rectal balloon expulsion (open squares), and rectal sensation (open triangles). The legend for parameters that had the highest weighting (positive or negative) in each score is in bold. Ang, angle; Loc, location; Des, perineal motion (ie, ascent or descent of anorectal junction relative to pubococcygeal line); AP, anteroposterior motion; Re, Rest; Sq, squeeze; Def, defecation; Bal Exp, balloon expulsion; Pr, pressure. For example, DesReSq indicates perineal motion during squeeze relative to at rest. obesity, which is a recognized risk factor for cystocele, uterine prolapse, and rectocele. 27 The second factor (anorectal location at rest) did not discriminate between patients and controls. One explanation is that the distribution of values for the second score represents a latent dimension that is comparable in Figure 5. Distribution of principal component (PC) scores (A) 1 and 2 and (B) 1 and 3 in controls and patients. For each subject, the principal component scores were derived by summing the product of the loading for a parameter (shown in Table 3) and the value for that parameter for all 7 variables. A shows that a PC 1 score of 0.81, represented by a line parallel to the y-axis, discriminated controls from 17 of 18 patients with reduced perineal descent. The PC 2 score ranged from 2.1 to 3.1 in controls. This score did not discriminate between patients and controls. For PC 3, a score of 0.75, represented by the line parallel to the x-axis, separated 40 of 42 controls (with a PC 3 score 0.75, ie, situated below this line) from 16 patients.

9 May 2005 PHENOTYPES IN DEFECATORY DISORDERS 1207 Table 4. Association Between Symptoms and Latent Dimensions Identified by Principal Components Analysis Symptoms Component 1 correlation coefficient (partial R 2 ) Component 2 correlation coefficient (partial R 2 ) Component 3 correlation coefficient (partial R 2 ) Rome II symptoms for constipation No. of bowel movements 0.46 a (0.1) (0.1) Hard stools 0.38 a (0.04) 0.28 b (0.07) 0.17 Sense of anal blockage during 0.29 b b defecation Excessive straining during 0.28 b a defecation Anal digitation during defecation Sense of incomplete evacuation (0.05) 0.34 a (0.03) after defecation Abdominal distention (0.05) 0.29 b Rome II Criteria for IBS (0.07) Other symptoms Abdominal pressure during a (0.05) defecation Use of different positions (0.05) 0.34 c during defecation Time spent during defecation 0.31 c a Mucus 0.28 b 0.22 (0.06) 0.36 a Abdominal pain NOTE. Partial R 2 only provided for symptoms that were useful for predicting interindividual variation in the corresponding principal component. a P.001, b P.017, c P.005, for Spearman correlation coefficient of the symptom and the principal component. during evacuation is either normal or reduced. With continued straining, the pelvic floor becomes weaker and descends excessively during evacuation but remains well supported at rest. Eventually, the pelvic floor is poorly supported and the anorectal junction is lower even at rest. Previous studies have used similar methods (ie, cluster analysis or principal components analysis) to identify subgroups among patients with functional gastrointestinal disorders. 28,29 Guthrie et al categorized patients with irritable bowel syndrome into subgroups using predetermined parameters (ie, physiologic parameters, physical and psychological symptoms). 30 In contrast to the cluster analysis used by Guthrie et al, our analysis was not designed to segregate patients into 2, 3, or 4 selected subgroups. Instead, we sought to ascertain whether the joint distribution of relevant parameters of anorectal function could be summarized by latent dimensions that maximally accounted for variation between patients. Although principal components analysis does not account for every possible phenotype, it does represent patterns of disordered functions. Table 5. Interobserver Reproducibility for Anorectal Measurements by MRI Parameter Mean: observer 1 Mean: observer 2 Mean difference (95% confidence interval) between raters 1 and 2 Correlation coefficient (Spearman) Were differences significant? a Anorectal angle at rest ( ) ( 2.4, 4.1) 0.63 b No Anorectal angle during squeeze ( ) ( 7.1, 0.12) 0.70 c No Anorectal angle during evacuation ( ) ( 7.1, 6.0) 0.24 No Anorectal angle change from rest to ( 8.0, 0.9) 0.59 d Yes squeeze ( ) Anorectal angle: change from rest to ( 7.7, 5.0) 0.60 d No evacuation ( ) Anorectal location at rest e (0.2, 0.7) 0.76 c Yes Anorectal location during squeeze e (0.1, 0.5) 0.83 c Yes Anorectal location during evacuation e (0.5, 1.4) 0.80 c Yes a Differences were compared by paired t test or signed rank test depending on normality of distribution of differences. b P.001. c P d P.01. e Anorectal junction location (cm) reflects perpendicular distance from pubococcygeal line: positive and negative values indicate location below and above this line, respectively.

10 1208 BHARUCHA ET AL GASTROENTEROLOGY Vol. 128, No. 5 Table 6. Comparison of Perineal Descent During Evacuation Measured by Clinical Examination and MRI MRI Clinical examination Reduced Normal Increased Reduced (n 21) Normal (n 58) Increased (n 10) In our study, symptoms alone were not useful for predicting these objectively defined combinations of anorectal function parameters, extending previous studies showing that symptoms suggestive of outlet delay (eg, a frequent feeling of anal blockage during defecation) do not distinguish functional disorders of defecation from constipation due to irritable bowel syndrome or slow colonic transit. 1,25 Consistent with other studies, some patients also had reduced or increased rectal sensation. 31 However, rectal sensation was not significantly associated with any factor from the principal components analysis. Pelvic floor motion was abnormal not only during evacuation but also when patients squeezed their pelvic floor muscles. Combined disturbances of pelvic floor motion during squeeze and evacuation support the concept that pelvic floor dysfunction is attributable to impaired central coordination, rather than structural abnormalities, because endoanal MRI infrequently revealed anal sphincter or puborectalis injury. Impaired pelvic floor motion during squeeze may be useful for corroborating the diagnosis of pelvic floor dysfunction, particularly in patients who have normal anal pressures, rectal balloon expulsion, and perineal descent during evacuation. In these patients, results of anorectal tests during evacuation may be normal because patients compensate for pelvic floor dysfunction by straining. In contrast to pelvic floor motion during evacuation, motion during squeeze is not influenced by intra-abdominal pressure or pelvic floor laxity. Moreover, patients may be less inhibited about squeezing the pelvic floor muscles as opposed to expelling contents from the rectum. Anorectal and pelvic floor motion were visualized in real time (ie, every seconds) with a novel dynamic MRI technique. The normal range for anorectal and pelvic floor motion was determined by considering all asymptomatic subjects, regardless of puborectalis function during evacuation. Thus, the normal range for anorectal motion (ie, angle change and descent) during evacuation evaluated by MRI in asymptomatic controls was wider than previously reported for barium defecography. 19 By avoiding radiation exposure, visualizing the pelvic floor and bony landmarks directly, MRI appears to overcome some limitations of barium defecography. 8 Moreover, in contrast to barium defecography, interobserver agreement for parameters of anorectal motion used for constructing principal component scores was excellent. 32 For some parameters (eg, location of anorectal junction at rest), differences between both observers were statistically significant but unlikely to be clinically significant. Similar to previous studies with defecation proctography, dynamic MRI revealed contraction instead of relaxation of the puborectalis muscle during evacuation in some asymptomatic subjects. 7,33 Even though the range of normal values was wide, dynamic MRI identified disturbances of evacuation and/or squeeze in 94% of patients. Anal sphincter defects and/or atrophy were observed in 60% of patients with fecal incontinence 34 but only 13% of patients with a rectal evacuation disorder in this study. Dynamic MR assessment of pelvic floor motion can be completed in 20 minutes and at lesser expense by eliminating anal sphincter imaging. Defecating in the supine position is a potential limitation to imaging anorectal and pelvic floor motion by dynamic MRI. However, a previous study found few differences in the detection of clinically relevant findings between supine MR and seated MR using open-configuration magnets, with the exception of detecting rectal intussusceptions, for which seated MRI was superior. 35 What are the implications of these findings for clinical practice? Anal manometry and an abnormal balloon expulsion test result suffice to confirm the diagnosis of an evacuation disorder in most patients with typical symptoms and reduced perineal descent (ie, 1 cm) at clinical examination. Indeed, in our study, the clinical examination was reasonably accurate for characterizing perineal descent as normal, reduced, or increased compared with MRI. Although clinical examination and MRI disagreed in 34% of subjects, disagreements between examination and MRI were not systematic and typically differed by only one stage. Thus, only one of 21 subjects with reduced descent by clinical examination had increased descent by MRI. Conversely, only one of 10 subjects with increased perineal descent by clinical examination had reduced descent by MRI. However, one-stage disagreements may be clinically meaningful in patients in whom routine diagnostic tests (eg, anorectal manometry and rectal balloon expulsion) do not confirm the clinical suspicion of a rectal evacuation disorder, for example, in patients who do not have florid perineal descent (ie, perineal ballooning) on physical examination. In these patients, MRI may facilitate diagnosis because a physical examination may not accurately characterize perineal descent, the rectal balloon expulsion test result may be normal, 24 and perineometry may underestimate descent, as has been suggested by prior comparisons with defecog-

11 May 2005 PHENOTYPES IN DEFECATORY DISORDERS 1209 raphy. 36 In addition to characterizing disordered squeeze or evacuation, dynamic MRI also shows generalized pelvic organ prolapse (eg, cystocele), which is associated with increased perineal descent. An additional benefit of MRI is that patients are able to review images of evacuation with their physician, enhancing their understanding of their disorder and the need for pelvic floor retraining. In a small uncontrolled study, symptom improvement after pelvic floor retraining was influenced by perineal descent during evacuation; perineal descent 4 cm predicted a poor response. 37 Controlled studies are necessary to ascertain the response to pelvic floor retraining among phenotypes. We perceive that these findings are representative of women with symptoms of difficult defecation, but the findings need to be confirmed in a different group of subjects (men and women) to document their generalizability. Colonic motor responses to physiologic (eg, a meal) and pharmacologic (eg, neostigmine) stimuli were not evaluated by intraluminal techniques (eg, barostat manometry) to identify coexistent colonic inertia. We cannot exclude the possibility that some patients with an evacuation disorder also had colonic motor dysfunction. 38 Because we did not measure anal pressures during simulated evacuation, we cannot compare features of dyssynergia assessed by MRI with manometry. References 1. Grotz RL, Pemberton JH, Talley NJ, Rath DM, Zinsmeister AR. Discriminant value of psychological distress, symptom profiles, and segmental colonic dysfunction in outpatients with severe idiopathic constipation. Gut 1994;35: Rao SS, Welcher KD, Leistikow JS. Obstructive defecation: a failure of rectoanal coordination [comment]. Am J Gastroenterol 1998;93: Preston DM, Lennard-Jones JE. Anismus in chronic constipation. Dig Dis Sci 1985;30: Karlbom U, Edebol Eeg-Olofsson K, Graf W, Nilsson S, Pahlman L. 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12 1210 BHARUCHA ET AL GASTROENTEROLOGY Vol. 128, No. 5 ferentiates subgroups of patients with severe irritable bowel syndrome. Gut 2003;52: Harraf F, Schmulson M, Saba L, Niazi N, Fass R, Munakata J, Diehl D, Mertz H, Naliboff B, Mayer EA. Subtypes of constipation predominant irritable bowel syndrome based on rectal perception. Gut 1998;43: Muller-Lissner SA, Bartolo DC, Christiansen J, Ekberg O, Goei R, Hopfner W, Infantino A, Kuijpers HC, Selvaggi F, Wald A. Interobserver agreement in defecography an international study. Z Gastroenterol 1998;36: Bartram CI, Turnbull GK, Lennard-Jones JE. Evacuation proctography: an investigation of rectal expulsion in 20 subjects without defecatory disturbance. Gastrointest Radiol 1988;13: Bharucha AE, Fletcher JG, Harper CM, Hough D, Daube JR, Stevens C, Seide B, Riederer SJ, Zinsmeister AR. Relationship between symptoms and disordered continence mechanisms in women with idiopathic faecal incontinence. Gut 2005;54: Bertschinger KM, Hetzer FH, Roos JE, Treiber K, Marincek B, Hilfiker PR. Dynamic MR imaging of the pelvic floor performed with patient sitting in an open-magnet unit versus with patient supine in a closed-magnet unit. Radiology 2002;223: Oettle GJ, Roe AM, Bartolo DC, Mortensen NJ. What is the best way of measuring perineal descent? A comparison of radiographic and clinical methods. Br J Surg 1985;72: Harewood GC, Coulie B, Camilleri M, Rath-Harvey D, Pemberton JH. Descending perineum syndrome: audit of clinical and laboratory features and outcome of pelvic floor retraining. Am J Gastroenterol 1999;94: Dinning PG, Bampton PA, Andre J, Kennedy ML, Lubowski DZ, King DW, Cook IJ. Abnormal predefecatory colonic motor patterns define constipation in obstructed defecation. Gastroenterology 2004;127: Received July 20, Accepted February 2, Address requests for reprints to: Adil E. Bharucha, MD, Clinical and Enteric Neuroscience Translational and Epidemiological Research Program, Mayo Clinic, 200 First Street SW, Rochester, Minnesota bharucha.adil@mayo.edu; fax: (507) Supported in part by US Public Health Service/National Institutes of Health grants R01 HD38666 and R01 HD41129 and by General Clinical Research Center grant RR00585 from the National Institutes of Health in support of the Physiology Laboratory and Patient Care Cores. The authors thank Amy Luedtke for secretarial support and Dr Michael Camilleri for critically reviewing the manuscript.