Is the Afferent Pathway From the Rectum Impaired in Children With Chronic Constipation and Encopresis?

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1 GASTROENTEROLOGY 1995;109: Is the Afferent Pathway From the Rectum Impaired in Children With Chronic Constipation and Encopresis? VERA LOENING-BAUCKE* and THORU YAMADA* Departments of *Pediatrics and tneurology, University of Iowa, Iowa City, Iowa Background & Aims: Rectal sensations to balloon are impaired in children with chronic constipation and encopresis. The impairment of rectal sensation, which is often persistent and is related to nonrecovery, could be caused by a defect in the visceral afferent pathways. The aim of this study was to test whether the afferent pathway from the rectum is impaired in children with constipation and encopresis. Methods: Fifteen healthy children and 15 children with constipation and encopresis were studied. Cerebral evoked potentials (EPs) were studied by averaging results of 100 rectal s, which used 10, 20, and 30 ml air. EPs were recorded from Cz' to Fz. Results: Two different types of EPs were recorded in each control subject and each child with constipation and encopresis. One EP had an early onset and showed multiple positive and negative peaks. The other EP had a much later onset and was triphasic. Early-onset EPs were recorded with significantly smaller s than the late-onset EPs. N1 and P2 latencies of the early-onset EPs and NI, PI, and Nil latencies of the lateonset EPs were significantly prolonged in children with constipation and encopresis compared with controls. Conclusions: The prolonged latencies suggest a defect in the afferent pathway from the rectum in children with chronic constipation and encopresis. Afrequent and often persistent excretory disturbance in childhood is chronic constipation and encopresis. Constipation with or without encopresis (soiling of the underpants with feces secondary to overflow) represents a common problem in children, accounting for 3% of visits to our Pediatric Outpatient Clinic at the University of Iowa Hospitals and Clinics. Constipation in children is defined by a stool frequency of <3 per week, but constipation can be defined by the presence of a rectal fecal impaction with or without encopresis, even when the stool frequency is per week. Several studies using anorectal manometry have shown that rectal and sigmoidal sensations and rectal contractility to balloon are impaired in many of these children.l-6 The impairment of rectal sensation and rectal contractility are often persistent, related to nonrecovery, v and could be caused by changes in the viscoelastic proper- ties of rectal receptors, peripheral and central visceral afferent fibers, and synaptic transmission. Anorectal function studies provide information about the functional activity of the rectum and anal sphincters, but they provide only indirect information about the status of the nerves that innervate these structures. Efferent and afferent pathways are involved in mediating the reflexes influencing anal and rectal motility and in mediating sensations. An alteration in the efferent or afferent pathways from the rectum or the pelvic floor could be responsible for disorders of defecation, such as constipation and fecal incontinence. Investigations of the brain-gut interactions in humans have been very limited, because specific techniques were lacking. However, during the last years, we and other investigators have used and developed newer techniques that allow us to access the brain-gut axis in humans. We are able to investigate bidirectionally the neural pathways between the anal canal, spinal cord, and brain using magnetic stimulation of the brain and spine and electrical or mechanical stimulation of the anal canal and rectum The afferent neural pathways can be studied using evoked potential (EP) techniques. Cerebral EP recording is an objective tool for the evaluation of sensory disorders affecting the afferents from nerves and viscera and assesses nerves, the spinal cord, and the cerebral cortex. It offers a window into the development of sensation, perception, and cognition and, in pediatrics, provides information that is not available by any other means. We intended to test the hypothesis that the afferent nervous pathway from the rectum is impaired in children with chronic constipation and encopresis. Materials Subjects and Methods The study population consisted of 15 healthy children and 15 children with chronic constipation and encopresis. The healthy children were between 8 and 17 years of age (mean age, 13 years) and were cm tall (sitting height, Abbreviations used in this paper: EV, evoked potential by the American Gastroenterological Association /95/$3.00

2 398 LOENING-BAUCKE AND YAMADA GASTROENTEROLOGY Vol. 109, No _+ 9 cm). The children with chronic constipation and encopresis were between 7 and 18 years of age (mean age, 11 years) and were 143 _+ 17 cm tall (sitting height, cm). The healthy children had no known neurological, gastrointestinal, or other diseases. They were not taking any medication and had no known family history of neurological disease, and the results of physical examination, including the neurological examination, were normal. The children with chronic constipation and encopresis were healthy except for problems related to their constipation, including > 1 soiling episode per week and fecal impaction. The study was approved by the Institutional Human Research Review Committee at the University of Iowa. Written informed consent was obtained from all subjects and their parents. Rectal Sensations Anorectal manometry was performed with a motility probe (model P31-D3; Sandhill Scientific, Littleton, CO). This motility probe is 5 mm in diameter and contains three intraluminal transducers spaced 5 cm apart. A latex balloon (2.5 X 3 cm), attached to the end of a 100-cm-long catheter, was tied along the silicone rubber tube of the motility probe. The outputs of the two pressure transducers and from the transducer attached to the balloon catheter were fed into the amplifiers of a recorder. The instrument has been described previously. 3'4'6 One of the transducers was placed into the rectum (6 cm) and a second into the anal canal (1 cm above the anal verge). The rectum was distended with the latex balloon with the base of the balloon placed 10 cm above the anal verge. Measurements were obtained with the children lying in a left lateral position. The balloon catheter was attached initially to a handheld syringe to study rectal sensations. We determined the minimal amounts of air (in milliliters) required to elicit a transient sensation of rectal balloon and the rectosphincteric reflex (>---5 mm Hg relaxation of anal pressure). We also determined the minimal amount of air (threshold) required to produce a strong, lasting urge to defecate (critical ), a sustained complete relaxation of the internal and external anal sphincters (constant anal relaxation), and rectal contractions of -->10 mm Hg (recorded 5 cm below the base of the rectal balloon).3 7 When the critical was reached, but constant relaxation or rectal contractions of -> 10 mm Hg had not yet occurred, the next higher was used as the of constant relaxation or rectal contractility. The latex balloon was placed into the rectum 10 cm above the anal verge. The balloon was attached to an air pump (Air Pump II; Wilson Cook Medical Corp., Winston-Salem, NC). This air pump delivered up to 30 ml of air at a speed of 1 ml/6 ms. The threshold of rectal sensation was determined initially three times at 1-mL increments and decrements. The smallest that was perceived two or more times was used as the threshold of rectal sensation. Rectal Stimulation for EP Recording For cerebral EP recording, we stimulated the rectum by inflating the latex balloon placed 10 cm above the anal verge with the air pump. The duration of full balloon inflation was 10 milliseconds, after which the balloon was fully deflated. The rectum was stimulated at a frequency of 6 inflations per minute (0.167 Hz). The pump produced a logic pulse (5 V, 0.01 milliseconds) at the beginning of each inflation cycle, which was used to trigger the EP recorder. Rectal s of 10, 20, and 30 ml air were used. Cerebral EPs EPs were recorded from 2 cm behind the vertex (Cz', international system 10-20) with the reference electrode attached to the forehead (Fz) using plate-shaped surface cup electrodes (13L71; Dantec Medical Inc., Santa Clara, CA). The ground was a third surface cup electrode attached to the midline of the posterior neck. Impedance of the active, reference, and ground cup electrodes was <5 k~. The Compact Four EP recorder (Nicolet Biomedical Instruments, Madison, WI) was used for recording and storage of data, analysis, and permanent printout. The artifact rejection function was used. The filter setting was Hz. We had previously determined that the filter setting of Hz did not significantly distort the latencies or amplitudes of the EP peaks of interest and appeared similar to the EP recorded with Hz except smoother. 9 The sampling time was 1000 milliseconds. We averaged 50 stimulations twice to show the reproducibility of the findings. Then the two averages of 50 stimulations each were added, and latencies were measured from this combined average of 100 stimulations. Because of habituation, we paused for 1 minute after each 50 stimulations and for at least 10 minutes after each 100 stimulations. EPs have a complex wave form, consisting of successive peaks (upward N [negative]) and troughs (downward P [positive]). It has been generally accepted that the different peaks or components comprising the EP predominantly reflect sequential activation of neural generators excited by the ascending volley along the peripheral or central pathways. Short latency peaks are generated by fast-conducting fibers, and the longer latency peaks are mediated through polysynaptic pathways or slow-conducting fibers. The volley resulting from rectal stimulation has a variable degree of asynchrony, reflecting a spectrum of conduction velocities; this may be one of several factors accounting for the complexity of the EP. These peaks were evaluated by visual inspection and were designated as P1, N1, P2, N2, etc. (Figures 1A and 1B). Additional peaks, often small, were present only in a few subjects after P1 and before N1. To differentiate the two different EPs recorded after rectal stimulation, we designated roman numerals for the peaks of the second EP (NI, PI, NII, and PII) (Figure 1C). Again we recorded occassional small wavelets or peaks after PI and before NII. The EPs were analyzed by determining latencies. The latencies were measured as the time differences between the onset of the stimulus to the different peaks of the EP using an electronic cursor. Criteria for the existence of a particular peak was that the peak was repeatable, large, or consistently present in most of the subjects. Classification of a negative peak to either N1 or N2 depended on the proximity to the

3 August 1995 RECTAL AFFERENTS IN CHILDHOOD CONSTIPATION 399 A I0 ml B i0 ml P1 N1 P1 NI i i I I I I i i i i 100 ms/d i00 ms/d C D J /k ~ /~//~ 10 ml PI NI PI PI I I 1 I I I I I I I i00 ms/d i J J i I I I I I I io0 ms/d Figure 1. Cerebral EPs after rhythmical of the rectum with 10, 20, and 30 ml air. Early-onset EPs in (A) a 14-year-old healthy child and (B) a 12-year-old child with chronic constipation and encopresis. Late-onset EPs in (C) a 9-year-old healthy child and (D) an &year-old child with chronic constipation and encopresis. Each recording shows two averages of 50 stimulations. mean latency of either N1 or N2. All EPs were designated as early-onset EPs if the first positive peak had a latency of < 180 milliseconds (Figures 1A and B) and as late-onset EPs if the first negative peak had a latency of >180 milliseconds (Figures 1C and 1D). A significant delay (P < 0.05) in peak latency between controls and patients was considered to be abnormal. All subjects had breakfast, and studies were performed starting at approximately 10 AM. Studies were performed with the rectum empty of feces. If necessary, an enema was given before

4 400 LOENING-BAUCKE AND YAMADA GASTROENTEROLOGY Vol. 109, No. 2 testing. The EP studies were performed in a darkened, warm (24 C), and quiet room to facilitate relaxation. The subjects kept their eyes open during the EP recording. Earplugs and white noise were used to mask the noise from the pump. Statistical Analysis The statistical analysis included the Wilcoxon nonpaired rank sum test, Wilcoxon signed rank test for paired data, and regression analysis with significance accepted at 5% level. Results were expressed as mean _+ SD. Results Characterization of Subjects The ages of the healthy control children were similar to those of the patients (P > 0.1). Healthy children were significantly taller, and their mean sitting height was significantly greater than the height of children with chronic constipation and encopresis (P < 0.05). We measured sitting height because it more closely expresses the length of the neural pathway from the rectum than height. Healthy children reported at least 3 bowel movements/week (mean, 6 + 2/week). They reported no soiling or daytime wetting, 7% reported abdominal pain, and 7% had nighttime wetting. Patients reported from 0 to 17 bowel movements in the toilet per week (mean, 4 + 5/week). Patients reported soiling episodes/ week (range, 1-70). In addition, 70% of the patients complained of abdominal pain, 20% of daytime wetting, and 7% of nighttime wetting. Rectal Sensations The results of rectal sensations are shown in Table 1. Threshold s for rectal sensation, rectosphincteric reflex, critical, constant anal relaxation, and rectal contractility using the handheld syringe for were significantly larger in children with chronic constipation and encopresis than in healthy children (P < 0.05). The threshold s for rectal sensation using the air pump were similar in healthy children and children with chronic constipation and encopresis (P > 0.1). This implies that rectal receptors of controls and patients responded in a similar manner to rapid but differently to slow and the absolute magnitude of the slow-distending stimulus. Cerebral EPs Two different cerebral EPs (early-onset and lateonset EPs) with different characteristics were recorded after rectal balloon in all control subjects and all children with chronic constipation and encopresis. The to produce an early-onset EP was 20 8 ml in control subjects and patients and was Table 1. Rectal Sensations and Contractility and Anal Responses to Balloon Distention Healthy children Children with constipation and encopresis Distention with handheld syringe Rectal sensation 18 _ _+ 16 a Rectosphincteric reflex 10 _ b Critical 120 _ _+ 118 b Constant anal relaxation 133 _ _+ 113 b Rectal contractility 60 _ _+ 86 b Rapid with air pump Rectal sensation NOTE. Results are means.+ SD. ap < bp < significantly smaller than the s producing a late-onset EP ( ml in controls and 26 6 ml in patients) (P < 0.01). Early-onset EPs. The early-onset EPs had an early large positive peak (P1) with a latency at around 100 milliseconds and multiple negative and positive peaks (Figure 1A and B; Table 2). The latencies of the early-onset EPs become shorter with larger s. P1 and P2 latencies of the early-onset EPs were not significantly different between healthy children and children with constipation and encopresis (P > 0.1), whereas N1 latency was significantly prolonged in children with constipation and encopresis (P < 0.05). Evaluating the relationship of the latencies of the early-onset EP to height and sitting height showed that P2 was significantly related to sitting height and height (P < 0.01) in the control subjects. When P1, N1, and P2 latencies were corrected to a standard height of 175 cm (latency/height 175), the N1 and P2 latencies were significantly prolonged in patients compared with controls (P < 0.01). Late-onset EPs. The late-onset EPs had a large negative peak (NI) at around 200 milliseconds, followed by a wide positive peak (PI) at around 330 milliseconds, followed by a wide negative peak (NII) at around 530 milliseconds (Figure 1C and D; Table 3). The latencies for NI, PI, and Nil were stable when the was increased. NI, PI, and NII latencies were significantly prolonged in patients with constipation and encopresis compared with healthy children (P < 0.05). Sitting height and height were significantly related to NI (P < 0.05) and PI latencies (P < 0.01) of the lateonset EP. When NI, P1, and Nil latencies were corrected

5 August 1995 RECTAL AFFERENTS IN CHILDHOOD CONSTIPATION 401 Table 2. Latencies of the Early-Onset EP Average Latencies (ms) P1 N1 P2 Healthy children Mean ± SD 20 ± _ _ _+ 36 Number Range Children with constipation and encopresis Mean ± SD 20 ± ± 33 a Number Range "P < to a standard height of 175 cm, the latencies in patients were significantly prolonged compared with controls (P < 0.01). Early- and late-onset EPs could be recorded in the same subject at the same rectal stimulation site. Often, an early-onset EP would be recorded with the smaller and a late-onset EP with the larger. Relationship of the EPs and Manometric Measurements Prolonged latencies did not correlate with abnormalities in anorectal functions as measured with slow using the handheld syringe for inflation, including the threshold s for rectal sensation, rectosphincteric reflex, critical, constant anal relaxation, and rectal contractility (P > 0.1). Discussion We recorded two types of cerebral EPs after rectal balloon in healthy children and children with constipation and encopresis. The P1 latency of the earlyonset EPs was similar (P > 0.1) in controls and patients, but N1 and P2 latencies of the early-onset EP were prolonged in patients (P < 0.01). The NI, PI, and NII latencies of the late-onset EPs were significantly prolonged in patients (P < 0.01). Our study suggests an impairment in the afferent pathway from the rectum in children with chronic constipation and encopresis. This impairment could be caused by changes in conduction velocities of the peripheral afferent fibers and/or central afferent projections and/or in increased synaptic conduction. Afferent activity from the gastrointestinal tract rarely reaches the level of consciousness and is primarily involved with regulatory processes and coordination of digestive function. However, visceral sensation does occur and can be subdivided into two functional categories: (1) nonpainful conscious sensations, which provide the individual with vague, emotionally colored sensations about the state of the gastrointestinal tract, such as fullness, hunger, satiety, or nausea; and (2) painful visceral sensation, which informs the individual about potential noxious events, t6 Different mechanoreceptors are located in the mucosa (parasympathetic mechanoreceptors), within the bowel wall (parasympathetic tension receptors), or primarily in the mesentery (splanchnic mechanoreceptors).17 Many afferent fibers can respond to more than one type of stimulus, and they can be multimodal or polymodal. Recording two types of EPs with different characteristics confirms results obtained after electrical rectal stimulation in healthy young adults. 9-~1 We have several theories to explain the two different EPs. The early-onset EP was produced by a smaller and showed polyphasic waves, and the latencies shortened when the rectal was increased, suggesting that the early-onset EP may be caused by desynchronized afferent volleys produced by inadequate rectal. With an adequate of rectal, we recorded a late-onset EP that had a simple triphasic wave form with a large positive peak around 330 milliseconds, suggesting that more synchronized afferent volleys were stimulated. The two EPs could be caused by stimulation of two different fiber populations, with the smaller stimulating low-threshold, faster-conducting fibers, resulting in the early-onset EP. Larger s may stimulate high-threshold, slower-conducting fibers, resulting in the late-onset EP. The fibers that convey information from the rectum to the spinal cord are principally unmyelinated C fibers and thinly myelinated A delta fibers. Conduction velocities for A delta fibers range from 2.5 to 30 m/s. Our calcu- Table 3. Latencies of the Late-Onset EP Average Latencies (ms) NI PI Nil Healthy children Mean ± SD 27 _~ ~- 34 Number Range Children with constipation and encopresis Mean ± SD 26 ± ± 22 a 370 ± 32 b a Number Range ap ~ bp < 0.01.

6 402 LOENING-BAUCKE AND YAMADA GASTROENTEROLOGY Vol. 109, No. 2 lated conduction velocities are 4 and 8 m/s, both in the range of A delta fibers. Sacral parasympathetic fibers in the pelvic nerve convey sensory information (e.g., fullness and/or pressure). *s Somatosensory anorectal afferents in the pudendal nerve 19 also contribute to the transmission of these physiological sensations. 9'2 It is possible that the balloon used in the present study simultaneously activated visceral afferent fibers in the pelvic nerve and somatic afferent fibers in the pudendal nerve. The balloon was placed and stayed 10 cm above the anal verge in the rectum, an area not innervated by the pudendal nerve. However, during rectal, relaxation of the internal anal sphincter and simultaneous contraction of the external sphincter occur (the rectosphincteric reflex), and the external anal sphincter is innervated by the pudendal nerve. The lumbar splanchnic nerves also innervate the rectum and internal anal sphincter and have been shown to convey information about pain. 2~ However, balloon in the present experiments was not painful. Subjects reported that balloon produces sensation that felt like gas. Therefore, we do not believe that the lumbar splanchnic nerve was activated by the stimulus. During the last few years, a number of different techniques were introduced to study the afferent pathways to obtain objective information on subjective visceral sensations. In particular, EP studies provide a useful approach to the study of sensory function and have been used in the investigation of central or peripheral neurological diseases. Recent studies showed the clinical use of EPs in the study of human visceral sensations. EPs can be recorded after electrical stimulation of the urinary bladder and urethra, rectosigmoid colon, 8'9 rectum, 9-11 anal canal, 12'13 and esophagus Mechanical stimulation provided by balloon is a classical stimulus for the production of gastrointestinal sensation and rectal sensation. Cerebral EPs have been successfully recorded after balloon stimulation of the rectum 14'15 and esophagus) 1-34 Most of these studies were performed in healthy controls. Patient groups studied after electrical or mechanical esophageal stimulation were patients with noncardiac chest pain, 33 patients with diabetic neuropathy, 29 and epileptic subjects. 3 The only other EP study using mechanical rectal stimulation in healthy adults is by Collet et al., 14 who first showed that the afferent pathway from the rectum can be stimulated with a rectal balloon. Mean P1 latency 14 was 123 milliseconds, very similar to our mean P1 latency of 128 milliseconds in adults) 5 Mean latency of the early-onset EP for our healthy children with a shorter height and sitting height was 104 milliseconds. To our knowledge, this is the first report on results of EP after mechanical rectal stimulation in children with chronic constipation and encopresis. Mechanical stimulation has several advantages. In our study, it gave clearer cortical EPs with higher amplitudes and better defined peaks than maximal electrical rectal stimulation (P < 0.01). 9'1 In addition, subjects did not report discomfort during balloon stimulation, whereas electrical stimulation had to be performed with maximal tolerable intensity, staying just below the pain level. Using mechanical stimulation has one disadvantage. The trigger pulse to the EP recorder has to be preset. In our study, the trigger pulse was set at the onset of. The pressure in the balloon started to increase 20 milliseconds after triggering balloon inflation and the EP recorder. The maximal pressure was reached in 120 milliseconds for 10-mL and in 200 milliseconds for 30-mL. The response of hollow viscera to is affected by the pressure- curve, the viscoelastic properties of the rectal wall. '8 A significant number of patients with encopresis had an altered threshold of rectal sensation when a rectal balloon was inflated by a handheld syringe. This is most likely caused by changes in the viscoelastic properties of rectal receptors. Threshold s of rectal sensation to rapid balloon were similar in controls and patients, indicating that viscoelastic properties were not influencing the response of the rectal receptors to rapid. Rapid balloon was used for EP recording. Similar s in controls and patients produced early-onset EPs or late-onset EPs. Therefore, the longer latencies measured in children with chronic constipation and encopresis are real and not due to the necessity to use larger balloon s. The prolonged latencies found in our patients after rectal mechanical stimulation suggest a decrease in the conduction velocities of slow-conducting afferent fibers or increased synaptic delay and suggest a defect in the afferent pathway from the rectum in children with chronic constipation and encopresis. Further studies will be necessary to evaluate the peripheral and central part of this pathway to determine a possible location for the defect. References 1. Loening-Baucke V. Factors determining outcome in children with chronic constipation and faecal soiling. Gut 1989;30: Meunier P, Marechal JM, de Beaujeu MJ. Rectoanal pressures and rectal sensitivity studies in chronic childhood constipation. Gastroenterology 1979; 77: Loening-Baucke V. Sensitivity of the sigmoid colon and rectum in children treated for chronic constipation. 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7 August 1995 RECTAL AFFERENTS IN CHILDHOOD CONSTIPATION Loening-Baucke V. Persistence of chronic constipation in children after biofeedback treatment. Dig Dis Sci 1991;36: Loening-Baucke VA. Abnormal rectoanal function in children recovered from chronic constipation and encopresis. Gastroenterology 1984;87: Loening-Baucke V. Modulation of abnormal defecation dynamics by biofeedback treatment in chronically constipated children with encopresis. J Pediatr 1990;116: Frieling T, Enck P, Wienbeck M. Cerebral responses evoked by electrical stimulation of rectosigmoid in normal subjects. Dig Dis Sci 1989; 34: Loening-Baucke V, Read NW, Yamada T. Further evaluation of the afferent pathways from the rectum. Am J Physiol 1992;262:G927-G Loening-Baucke V, Read NW, Yamada T. Cerebral evoked potentials after rectal stimulation. Electroencephalogr Clin Neurophysiol 1991;80: Meunier P, Collet L, Duclaux R, Chery-Croze S. Endorectal cerebral evoked potentials in human. 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Cerebral-evoked potential responses following direct vagal and esophageal electrical stimulation in humans. Am J Physiol 1993; 264:G486-G Castell DO, Wood JD, Frieling T, Wright FS, Vieth RF. Cerebral electrical potentials evoked by balloon of the human esophagus. Gastroenterology 1990; 98: Smout AJPM, DeVore MS, Castell DO. Cerebral potentials evoked by esophageal in humans. Am J Physiol 1990;259: G955-G Smout AJPM, DeVore MS, Dalton CB, Castell DO. Cerebral potentials evoked by oesophageal in patients with non-cardiac chest pain. Gut 1992;33: DeVault KR, Beacham S, Streletz U, Castell DO. Cerebral evoked potentials: a method of quantification of central nervous system response to esophageal pain. Dig Dis Sci 1993; 38: Received September 19, Accepted March 8, Address requests for reprints to: Vera Loening-Baucke, M.D., Department of Pediatrics, University of Iowa Hospitals and Clinics, 200 Hawkins Drive, Iowa City, Iowa Supported by the Children's Miracle Network Telethon and grant MO1-RR-O0059 from the General Clinical Research Center Program, Division of Research Resources, National Institutes of Health. Presented in part at the American Gastroenterological Association meeting in Boston, Massachusetts, May 19, 1993, and published in abstract form (Gastroenterology 1993;104:A544).