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Assessment of Rectal Afferent Neuronal Function Using Evoked Potentials in Patients With Constipation and Rectal Hyposensitivity – A Pilot Study
AGA Abstracts
report bowel symptom severity along a 10-cm visual analog scale. Results: Allele frequencies were found to be in Hardy-Weinberg equilibrium. Overall, a strong trend toward differences in ABHD6 genotypes was seen across study groups (χ2=10.6, p=0.09). While there was no significant difference in allele frequency between the IBS, UC and CD groups, minor allele homozygosity (G/G) was more common in the IBS, CD and UC groups when compared to healthy controls (p<0.004 for all). Additionally, ABHD6 heterozygosity (A/G) was more common in controls than in IBS, CD or UC groups (p>0.045 for each). Bowel symptoms trended towards greater subjective severity among minor allele carriers in a graded fashion (A/A: 4.3 ±0.6, A/G: 5.6 ±0.6, G/G: 6.1±0.8, p=0.08 across groups). Conclusion: The association of this ABHD6 polymorphism in endocannabinoid metabolism with three distinct gastrointestinal disorders adds to the growing body of evidence linking the endocannabinoid system to disruption of homeostasis in the gastrointestinal tract. While exact mechanism by which this polymorphism may contribute to the pathogenesis of IBS, UC and CD remains unclear, minor allele carriers demonstrate a dose effect in terms of subjective symptom severity. These findings warrant confirmation in larger, prospective studies; the full implication of this endocannabinoid polymorphism in disease pathogenesis needs to be further elucidated.
19 (34%) patients had colonic neuropathy, 15 (26%) colonic myopathy and 23 (40%) normal colonic motility. Of the 19 patients with colonic neuropathy, 15 were recommended colonic surgery; 10 underwent surgery with all reporting symptom improvement; 4/19 (21%) responded to aggressive non-surgical intervention. 11/15 (73%) with colonic myopathy and 17/23 (74%) patients with normal colonic manometry had symptomatic improvement with aggressive pharmacologic and/or biofeedback therapy(Table 1). Overall, 12 patients underwent colonic resection for refractory STC with all showing symptom improvement. Subsequently, 6/12 (50%) were diagnosed with small intestinal bacterial overgrowth requiring cyclical antibiotics. Patients with normal colonic motility or myopathy were much more likely to respond to aggressive non-surgical management (73%), as compared to patients with colonic neuropathy (21%) [p<0.005]. Conclusions: 24 hour ambulatory colonic manometry facilitates classification of colonic sensori-motor dysfunction in patients with STC. Those identified with normal motility or colonic myopathy were more likely to respond to aggressive pharmacologic and/or biofeedback intervention (73%), as compared to those with colonic neuropathy (21%). Patients with colonic neuropathy, if carefully selected, may be good candidates for colonic surgery with good outcomes. Hence, colonic manometry may be useful in guiding appropriate therapy for adults with STC.
Su1998
Su2000
Effects of Lubiprostone on Gastric Motor and Sensory Function in Patients With Chronic Idiopathic Constipation Brian E. Lacy, Burr J. Loew, Michael D. Crowell
Assessment of Rectal Afferent Neuronal Function Using Evoked Potentials in Patients With Constipation and Rectal Hyposensitivity - A Pilot Study Emma V. Carrington, Rebecca Burgell, Dina Lelic, Susan Surguy, Asbjørn M. Drewes, Qasim Aziz, Charles H. Knowles, S Mark Scott
Background: Lubiprostone is approved for the treatment of chronic idiopathic constipation (CC) in adult men and women. Prior studies have reported that some patients (Pts) develop mild nausea when treated with lubiprostone, although the mechanism is unknown. The aim of this study was to evaluate the effects of lubiprostone on gastric motor and sensory function in Pts with CC. Methods: Adult men and women meeting Rome III criteria for CC were eligible for inclusion in this prospective, open-label study. Demographics and 14 days of bowel symptoms were recorded prior to lubiprostone administration; all patients underwent a standardized 4-hr gastric emptying scan, nutrient drink test, and electrogastrography (EGG; both fasting and fed) before and at the end of a 7-day course of twice-daily (24 ug) lubiprostone. Adverse events were recorded. IRB approval was obtained. Data was entered into an Excel file and analyzed using paired samples T-test. Results: 19 Pts (84% female) were analyzed. The mean (SD) age was 42 (12.5) yrs; BMI = 26.6 (5.6) kg/m2; the mean duration of CC symptoms was 136 (91) months. The single most bothersome constipation symptom was straining or infrequent bowel movements (37% each), followed by hard stool (16%) or incomplete bowel movements (10%). All Pts had previously been treated with fiber products and stool softeners; most had been treated with MOM, stimulant laxatives, and polyethylene glycol (74-84%). Stool frequency (p = .029), straining (p = .028) and need for manual maneuvers (p = .001) were all improved with lubiprostone use during the study period. The % of radio-labeled meal retention was within normal limits both at 2hours pre- (27%) and post-medication (38.4%; p = .003) and 4-hours pre- (4%) and postmedication (5.1%; p = .122). No difference was noted in maximum tolerable volume (MTV) of the nutrient drink test pre- or post-medication (840 ml vs. 860 ml). Fasting and fed EGG recordings (frequency, power) were within normal limits and were not significantly different between the pre- and post-medication periods. The % of time with a normal 3 cpm rhythm decreased slightly from 92% in the pre-treatment period to 91% in the post-treatment period (p = 0.027). 3 Pts (16%) reported AEs; 2 had mild nausea and 1 had a mild headache. No SAEs were reported. Conclusions: Twice-daily lubiprostone does not alter 4-hr gastric emptying in men and women with chronic constipation. Satiation, as measured by a nutrient drink test, was also unchanged by lubiprostone, as were 2 separate EGG parameters. Although the 2hr gastric emptying time was slightly delayed after twice-daily treatment with lubiprostone compared to baseline, the 2-hr time fell within normal limits. The cause of nausea, which develops in some CC patients treated with lubiprostone, does not appear to reflect alterations in gastric motor or sensory function.
Introduction Impaired rectal sensation (rectal hyposensitivity: RH) is present in one quarter of patients with chronic intractable constipation. The mechanisms contributing to its development are not fully understood, but may reflect afferent neuronal disruption or dysfunction. This study aimed to demonstrate the feasibility of rectal evoked potentials (EPs) as a tool to evaluate the integrity of sensory innervation in patients with constipation and RH in comparison to healthy controls. Methods Rectal EPs (recording site Cz) were recorded in 9 patients with constipation and RH to balloon distension and 4 healthy controls in response to electrical stimulation (4 sets of 50 stimuli, 0.2 Hz frequency, 0.2 ms pulse width) of the rectum at 10 cm from the anal verge using a specialized bipolar stimulating electrode. Stimuli were delivered at reported pain threshold. EP peak latencies were analysed. Results Pain threshold to electrical stimulation was higher in patients than controls (median 43 [range 22-80] mA vs. 29 [10-44] mA, ns). Median latency to the first negative peak was 159 ms [118-167] in subjects with RH compared to 108.5 ms [102-118] in control subjects, (P=0.003) suggesting prolonged neuronal conduction velocities either peripherally or centrally in the patient group. Conclusions Rectal EPs are a feasible tool to assess integrity of the rectal afferent pathway. Prolonged latencies in constipated patients with rectal hyposensitivity suggest a primary defect in sensory neuronal function. Further investigation is required to confirm these findings. Su2001 Reproducibility of Methane and Hydrogen Values in Constipated Patients With Methanogenic Flora Kalyani Meduri, Ashok Attaluri, Jessica Valestin, Robert W. Summers, Satish S. Rao Background: Methanogenic flora has been shown to be associated with constipation and slow colonic transit and has been implicated in its pathogenesis. However, whether methane production is reproducible in patients with chronic constipation is not known. Aim: To examine the reproducibility of methane and hydrogen production during lactulose breath tests in constipated patients. Methods: Patients with chronic constipation (ROME III) and methanogenic flora (baseline CH4 > 3ppm) were enrolled into this clinical mechanistic study. All patients had lactulose breath tests done on two different days separated by about 30 days. All patients were on a standardized restricted diet the day before the breath test. After an overnight fast, patients consumed 10 grams of lactulose in 100cc of water. Breath samples were collected at baseline and every 15 minutes for 5 hours. Samples were analyzed for hydrogen and methane. Intra class correlation coefficients (ICC) and coefficients of variation (CV) for each test were calculated for baseline, peak and area under the curve (AUC) of hydrogen and methane production. Results: 16 patients (M:F=2:14) participated. The mean baseline, peak values and AUC for hydrogen and methane, as well as the ICC and CV values are shown in the table. There was excellent intra-subject reproducibility (ICC) for methane values and fair reproducibility for hydrogen values. However, there was a high degree of inter-subject variance (CV) with each test Conclusions: There is a high degree of reproducibility of methane production with lactulose breath testing in patients with chronic constipation, suggesting that methane assessment may be a valuable biomarker for constipation. Also, there is significant inter-subject variability indicating variable bacterial population/fermentation capability. Further studies are needed to validate our findings particularly with other breath tests and in other patient populations. Acknowledgement: Takeda Pharmaceutical research grant.
Su1999 Clinical Utility of Ambulatory Colonic Manometry in Adults With Slow Transit Constipation: Can Underlying Pathophysiology Guide Therapy? Siddharth Singh, Sarah Heady, Jessica Valestin, Satish S. Rao Background: Severe slow transit constipation (STC) is characterized by colonic sensorimotor dysfunction. Current treatment for adults with severe STC is empirical with failure of medical therapy forming the basis for surgery. While colonic manometry is routinely used to guide therapy in children with chronic constipation, whether a pathophysiologicallybased therapy is useful in adults with STC is not known. Aims: To investigate whether colonic manometry is useful in guiding therapy in adult patients with STC. Methods: Consecutive adults with refractory STC (>20% radioopaque marker retention) referred to a specialized center underwent 24-hr ambulatory colonic manometry with a 6 sensor probe placed colonoscopicaloy and other standard colorectal tests. Patients were classified as having normal motility or colonic neuropathy or myopathy based on the absence or attenuated response of 2 out of 3 manometric features: High amplitude propagated contractions (HAPCs), gastrocolonic response, waking response. Based on these tests, pharmacologic management, biofeedback therapy and/or surgical interventions were recommended. Patients were followed clinically for at least 1 year or via telephone interview to assess symptomatic response to treatment(s) and clinical outcome. Results: 57 patients (48 females) with severe STC (median follow up 4 yrs, range 1-17 yr; 36 with co-existent dyssynergic defecation) were evaluated;
AGA Abstracts
S-530
report bowel symptom severity along a 10-cm visual analog scale. Results: Allele frequencies were found to be in Hardy-Weinberg equilibrium. Overall, a strong trend toward differences in ABHD6 genotypes was seen across study groups (χ2=10.6, p=0.09). While there was no significant difference in allele frequency between the IBS, UC and CD groups, minor allele homozygosity (G/G) was more common in the IBS, CD and UC groups when compared to healthy controls (p<0.004 for all). Additionally, ABHD6 heterozygosity (A/G) was more common in controls than in IBS, CD or UC groups (p>0.045 for each). Bowel symptoms trended towards greater subjective severity among minor allele carriers in a graded fashion (A/A: 4.3 ±0.6, A/G: 5.6 ±0.6, G/G: 6.1±0.8, p=0.08 across groups). Conclusion: The association of this ABHD6 polymorphism in endocannabinoid metabolism with three distinct gastrointestinal disorders adds to the growing body of evidence linking the endocannabinoid system to disruption of homeostasis in the gastrointestinal tract. While exact mechanism by which this polymorphism may contribute to the pathogenesis of IBS, UC and CD remains unclear, minor allele carriers demonstrate a dose effect in terms of subjective symptom severity. These findings warrant confirmation in larger, prospective studies; the full implication of this endocannabinoid polymorphism in disease pathogenesis needs to be further elucidated.
19 (34%) patients had colonic neuropathy, 15 (26%) colonic myopathy and 23 (40%) normal colonic motility. Of the 19 patients with colonic neuropathy, 15 were recommended colonic surgery; 10 underwent surgery with all reporting symptom improvement; 4/19 (21%) responded to aggressive non-surgical intervention. 11/15 (73%) with colonic myopathy and 17/23 (74%) patients with normal colonic manometry had symptomatic improvement with aggressive pharmacologic and/or biofeedback therapy(Table 1). Overall, 12 patients underwent colonic resection for refractory STC with all showing symptom improvement. Subsequently, 6/12 (50%) were diagnosed with small intestinal bacterial overgrowth requiring cyclical antibiotics. Patients with normal colonic motility or myopathy were much more likely to respond to aggressive non-surgical management (73%), as compared to patients with colonic neuropathy (21%) [p<0.005]. Conclusions: 24 hour ambulatory colonic manometry facilitates classification of colonic sensori-motor dysfunction in patients with STC. Those identified with normal motility or colonic myopathy were more likely to respond to aggressive pharmacologic and/or biofeedback intervention (73%), as compared to those with colonic neuropathy (21%). Patients with colonic neuropathy, if carefully selected, may be good candidates for colonic surgery with good outcomes. Hence, colonic manometry may be useful in guiding appropriate therapy for adults with STC.
Su1998
Su2000
Effects of Lubiprostone on Gastric Motor and Sensory Function in Patients With Chronic Idiopathic Constipation Brian E. Lacy, Burr J. Loew, Michael D. Crowell
Assessment of Rectal Afferent Neuronal Function Using Evoked Potentials in Patients With Constipation and Rectal Hyposensitivity - A Pilot Study Emma V. Carrington, Rebecca Burgell, Dina Lelic, Susan Surguy, Asbjørn M. Drewes, Qasim Aziz, Charles H. Knowles, S Mark Scott
Background: Lubiprostone is approved for the treatment of chronic idiopathic constipation (CC) in adult men and women. Prior studies have reported that some patients (Pts) develop mild nausea when treated with lubiprostone, although the mechanism is unknown. The aim of this study was to evaluate the effects of lubiprostone on gastric motor and sensory function in Pts with CC. Methods: Adult men and women meeting Rome III criteria for CC were eligible for inclusion in this prospective, open-label study. Demographics and 14 days of bowel symptoms were recorded prior to lubiprostone administration; all patients underwent a standardized 4-hr gastric emptying scan, nutrient drink test, and electrogastrography (EGG; both fasting and fed) before and at the end of a 7-day course of twice-daily (24 ug) lubiprostone. Adverse events were recorded. IRB approval was obtained. Data was entered into an Excel file and analyzed using paired samples T-test. Results: 19 Pts (84% female) were analyzed. The mean (SD) age was 42 (12.5) yrs; BMI = 26.6 (5.6) kg/m2; the mean duration of CC symptoms was 136 (91) months. The single most bothersome constipation symptom was straining or infrequent bowel movements (37% each), followed by hard stool (16%) or incomplete bowel movements (10%). All Pts had previously been treated with fiber products and stool softeners; most had been treated with MOM, stimulant laxatives, and polyethylene glycol (74-84%). Stool frequency (p = .029), straining (p = .028) and need for manual maneuvers (p = .001) were all improved with lubiprostone use during the study period. The % of radio-labeled meal retention was within normal limits both at 2hours pre- (27%) and post-medication (38.4%; p = .003) and 4-hours pre- (4%) and postmedication (5.1%; p = .122). No difference was noted in maximum tolerable volume (MTV) of the nutrient drink test pre- or post-medication (840 ml vs. 860 ml). Fasting and fed EGG recordings (frequency, power) were within normal limits and were not significantly different between the pre- and post-medication periods. The % of time with a normal 3 cpm rhythm decreased slightly from 92% in the pre-treatment period to 91% in the post-treatment period (p = 0.027). 3 Pts (16%) reported AEs; 2 had mild nausea and 1 had a mild headache. No SAEs were reported. Conclusions: Twice-daily lubiprostone does not alter 4-hr gastric emptying in men and women with chronic constipation. Satiation, as measured by a nutrient drink test, was also unchanged by lubiprostone, as were 2 separate EGG parameters. Although the 2hr gastric emptying time was slightly delayed after twice-daily treatment with lubiprostone compared to baseline, the 2-hr time fell within normal limits. The cause of nausea, which develops in some CC patients treated with lubiprostone, does not appear to reflect alterations in gastric motor or sensory function.
Introduction Impaired rectal sensation (rectal hyposensitivity: RH) is present in one quarter of patients with chronic intractable constipation. The mechanisms contributing to its development are not fully understood, but may reflect afferent neuronal disruption or dysfunction. This study aimed to demonstrate the feasibility of rectal evoked potentials (EPs) as a tool to evaluate the integrity of sensory innervation in patients with constipation and RH in comparison to healthy controls. Methods Rectal EPs (recording site Cz) were recorded in 9 patients with constipation and RH to balloon distension and 4 healthy controls in response to electrical stimulation (4 sets of 50 stimuli, 0.2 Hz frequency, 0.2 ms pulse width) of the rectum at 10 cm from the anal verge using a specialized bipolar stimulating electrode. Stimuli were delivered at reported pain threshold. EP peak latencies were analysed. Results Pain threshold to electrical stimulation was higher in patients than controls (median 43 [range 22-80] mA vs. 29 [10-44] mA, ns). Median latency to the first negative peak was 159 ms [118-167] in subjects with RH compared to 108.5 ms [102-118] in control subjects, (P=0.003) suggesting prolonged neuronal conduction velocities either peripherally or centrally in the patient group. Conclusions Rectal EPs are a feasible tool to assess integrity of the rectal afferent pathway. Prolonged latencies in constipated patients with rectal hyposensitivity suggest a primary defect in sensory neuronal function. Further investigation is required to confirm these findings. Su2001 Reproducibility of Methane and Hydrogen Values in Constipated Patients With Methanogenic Flora Kalyani Meduri, Ashok Attaluri, Jessica Valestin, Robert W. Summers, Satish S. Rao Background: Methanogenic flora has been shown to be associated with constipation and slow colonic transit and has been implicated in its pathogenesis. However, whether methane production is reproducible in patients with chronic constipation is not known. Aim: To examine the reproducibility of methane and hydrogen production during lactulose breath tests in constipated patients. Methods: Patients with chronic constipation (ROME III) and methanogenic flora (baseline CH4 > 3ppm) were enrolled into this clinical mechanistic study. All patients had lactulose breath tests done on two different days separated by about 30 days. All patients were on a standardized restricted diet the day before the breath test. After an overnight fast, patients consumed 10 grams of lactulose in 100cc of water. Breath samples were collected at baseline and every 15 minutes for 5 hours. Samples were analyzed for hydrogen and methane. Intra class correlation coefficients (ICC) and coefficients of variation (CV) for each test were calculated for baseline, peak and area under the curve (AUC) of hydrogen and methane production. Results: 16 patients (M:F=2:14) participated. The mean baseline, peak values and AUC for hydrogen and methane, as well as the ICC and CV values are shown in the table. There was excellent intra-subject reproducibility (ICC) for methane values and fair reproducibility for hydrogen values. However, there was a high degree of inter-subject variance (CV) with each test Conclusions: There is a high degree of reproducibility of methane production with lactulose breath testing in patients with chronic constipation, suggesting that methane assessment may be a valuable biomarker for constipation. Also, there is significant inter-subject variability indicating variable bacterial population/fermentation capability. Further studies are needed to validate our findings particularly with other breath tests and in other patient populations. Acknowledgement: Takeda Pharmaceutical research grant.
Su1999 Clinical Utility of Ambulatory Colonic Manometry in Adults With Slow Transit Constipation: Can Underlying Pathophysiology Guide Therapy? Siddharth Singh, Sarah Heady, Jessica Valestin, Satish S. Rao Background: Severe slow transit constipation (STC) is characterized by colonic sensorimotor dysfunction. Current treatment for adults with severe STC is empirical with failure of medical therapy forming the basis for surgery. While colonic manometry is routinely used to guide therapy in children with chronic constipation, whether a pathophysiologicallybased therapy is useful in adults with STC is not known. Aims: To investigate whether colonic manometry is useful in guiding therapy in adult patients with STC. Methods: Consecutive adults with refractory STC (>20% radioopaque marker retention) referred to a specialized center underwent 24-hr ambulatory colonic manometry with a 6 sensor probe placed colonoscopicaloy and other standard colorectal tests. Patients were classified as having normal motility or colonic neuropathy or myopathy based on the absence or attenuated response of 2 out of 3 manometric features: High amplitude propagated contractions (HAPCs), gastrocolonic response, waking response. Based on these tests, pharmacologic management, biofeedback therapy and/or surgical interventions were recommended. Patients were followed clinically for at least 1 year or via telephone interview to assess symptomatic response to treatment(s) and clinical outcome. Results: 57 patients (48 females) with severe STC (median follow up 4 yrs, range 1-17 yr; 36 with co-existent dyssynergic defecation) were evaluated;
AGA Abstracts
S-530