Assessment of rectal afferent neuronal function and brain activity in patients with constipation and rectal hyposensitivity

Background Blunted rectal sensation (rectal hyposensitivity: RH) is present in almost one‐quarter of patients with chronic constipation. The mechanisms of its development are not fully understood, but in a proportion, afferent dysfunction is likely. To determine if, in patients with RH, alteration of rectal sensory pathways exists, rectal evoked potentials (EPs) and inverse modeling of cortical dipoles were examined. Methods Rectal EPs (64 channels) were recorded in 13 patients with constipation and RH (elevated thresholds to balloon distension) and 11 healthy controls, in response to electrical stimulation of the rectum at 10 cm from the anal verge using a bipolar stimulating electrode. Stimuli were delivered at pain threshold. Evoked potential peak latencies and amplitudes were analyzed, and inverse modeling was performed on traces obtained to determine the location of cortical generators. Key Results Pain threshold was higher in patients than controls [median 59 (range 23–80) mA vs 24 (10–55) mA; P = 0.007]. Median latency to the first negative peak was 142 (±24) ms in subjects compared with 116 (±15) ms in controls (P = 0.004). There was no difference in topographic analysis of EPs or location of cortical activity demonstrated by inverse modeling between groups. Conclusions & Inferences This study is the first showing objective evidence of alteration in the rectal afferent pathway of individuals with RH and constipation. Prolonged latencies suggest a primary defect in sensory neuronal function, while cerebral processing of visceral sensory information appears normal.     

Rectal hyposensitivity is uncommon and unlikely to be the central cause of obstructed defecation in patients with high‐grade internal rectal prolapse

Background There are several causes of obstructed defecation one of which is thought to be internal rectal prolapse. Operations directed at internal prolapse, such as laparoscopic ventral rectopexy, may improve obstructed defecation symptoms significantly. It is not clear whether the obstructed defecation with internal prolapse is a mechanical phenomenon or whether it results changes in rectal sensitivity. This study aimed to evaluate rectal sensory function in patients with obstructed defecation and high‐grade internal rectal prolapse. Methods This study represents a retrospective review of a prospectively collected database of patients attending a tertiary referral pelvic floor unit. Patients with high‐grade (recto‐anal) intussusception formed the basis of this study. Rectal sensory function was determined by intrarectal balloon inflation. Three parameters (sensory threshold, urge to defecate and maximum tolerated volumes) were recorded. Abnormal sensitivity was defined as partial (one or two parameters abnormal) or total (all three abnormal). Key Results Four hundred and eight patients with high‐grade internal rectal prolapse both with and without obstructed defecation symptoms were studied. Two hundred and forty one (59%) had normal sensation. Eighteen (4%) had total hyposensitivity and three (1%) total hypersensitivity. A further 96 (24%) had partial hyposensitivity whilst 50 (12%) had partial hypersensitivity. Neither hypersensitivity nor hyposensitivity differed between patients with and without symptoms of obstructed defecation. Conclusions & Inferences Rectal hyposensitivity is relatively uncommon in patients with high‐grade internal rectal prolapse and obstructed defecation. Internal rectal prolapse may cause obstructed defecation through a mechanical process. It does not appear that rectal hyposensitivity plays a significant part in the pathological process.     

Rectal sensorimotor characteristics in female patients with idiopathic constipation with or without paradoxical sphincter contraction

Patients with chronic constipation fulfilling the Thompson criteria can show paradoxical sphincter contraction. Aim of this study was to evaluate rectal sensorimotor characteristics in patients with constipation with or without paradoxical sphincter contraction. Thirty female patients with chronic constipation and 22 female controls were investigated with anal manometry and rectal barostat. Paradoxical sphincter contraction was shown with manometry as a paradoxical increase of anal pressure during straining. Visceral sensitivity and compliance were tested by intermittent and continuous pressure-controlled distension. Patients were classified according to their sensations and compliance into normal, hypersensitive, reduced compliant, insensitive or excessive compliant rectum. Postprandial rectal response (PRR) and phasic volume events (PVEs) were registered for 1 h after a 600-kCal meal. Paradoxical sphincter contraction was found in 13 (43%) patients. In these patients, rectal sensitivity scores were higher (P = 0.045) than in patients without paradoxical contractions, but rectal compliance was not different. In 90% of patients an abnormal rectal sensitivity or compliance was found: excessively compliant in 35%, reduced compliant in 10%, hypersensitive in 27% and hyposensitive in 17%. Both patients with constipation (11%; P = 0.042) and controls (25%; P = 0.002) exhibited the presence of a postprandial rectal response. This response was not significantly different between idiopathic constipation, paradoxical sphincter contraction and controls. Patients with rectal hypersensitivity had lower response than other patients (P = 0.04). Patients with constipation had fewer basal PVEs compared controls (P = 0.03). Postprandial PVEs increased in both patients (P = 0.014) and controls (P < 0.001). Postprandial rectal response and PVE were not different in patients with or without paradoxical sphincter contraction. A total of 90% of female patients with idiopathic constipation show an abnormality in rectal sensation or compliance. The postprandial rectal response was comparable between patients with constipation and controls, however, PVEs were diminished. Patients with paradoxical sphincter contraction had higher rectal sensitivity but an unaltered compliance and postprandial rectal response. Future trials should investigate whether the classification of rectal abnormalities in patients with constipation has clinical importance.     

Sacral nerve stimulation and rectal function: results of a prospective study in faecal incontinence

Abstract The mechanisms of action of sacral nerve stimulation (SNS) to treat faecal incontinence remain poorly understood. The aims of our study were: (i) to measure the effect of SNS on rectal function and (ii) to evaluate rectal function as a predictive factor of clinical response to SNS. Rectal function was studied before and 3 months after permanent SNS in 18 patients (17 women, mean age 58.5 years) with faecal incontinence, using an electronic barostat. Rectal sensitivity and volume variations were recorded during isobaric distensions. Three months after SNS, 14 patients had a significant improvement of faecal incontience symptoms and four had not. Baseline ‘maximal tolerated volume’ was significantly lower in the positive response group (210 ± 56 vs 286 ± 30 mL, P = 0.02). Baseline rectal compliance was lower in patients with a positive response than those without, although this difference did not reach significance (6.2 ± 3.2 vs 9.2 ± 2.9 mL mmHg^?1,P = 0.10). Rectal compliance was not significantly modified by SNS. Our results suggest that an increased rectal capacity as measured by the maximal tolerated volume may be a predictive factor of poor response to SNS in faecal incontinence. SNS does not significantly modify rectal function.     

Cortical processing of residual ano-rectal sensation in patients with spinal cord injury: an fMRI study

Abstract  Eleven paraplegic patients with complete traumatic spinal cord injuries (SCI) [according to American Spinal Injury Association (ASIA) criteria] at different levels (Th3–L3) were investigated during non-painful stimulation of the distal rectum and anal canal, using event related functional magnetic resonance imaging. Although a complete lesion was clinically diagnosed in all, four of them experienced reproducible sensations during anal and/or rectal stimulation. In six patients, individual data analysis revealed significant activation in the right secondary somatosensory cortex SII, the posterior cingular gyrus, the prefrontal cortex, and the left posterior cerebellar lobe during either anal or rectal stimulation or both. A Region of interest analysis using a data mask from healthy controls confirmed that SCI patients demonstrate cortical activation in areas similar to those activated in healthy volunteers, but to a less extensive degree. This supports the notion that the diagnosis of complete spinal cord transsection by ASIA criteria alone may be insufficient for assessment of 'completeness' of cord lesions, and that visceral sensitivity testing may be required in addition.     

Rectal visceral sensitivity in healthy volunteers: influences of gender, age and methods.

The barostat is a device that maintains a constant pressure within an air-filled polyethylene bag by means of a feedback mechanism. The system measures variations in rectal tone by recording changes in the intrarectal pressure and volume. Different procedures, such as ramp distension or intermittent distension, are used to test visceral sensitivity and rectal wall compliance. It is not quite clear which method is preferable and how the barostat measurements compare with those of the conventional latex balloon. In 28 healthy volunteers (11 males, mean age 36, range 22-67 years) rectal distension was performed in two ways: 1 Pressure-controlled distension, by both intermittent and ramp methods, with measurement on the Visual Analogue Scale (VAS, 0-5) at 8, 12, 16, 20, 24, 28, 32 and 36 mmHg. Hysteresis (comparing area under the curve during deflation and inflation with ramp pressure distension) and compliance were calculated. 2 Volume-controlled distension, with registration of first sensation, urge to defecate and maximal tolerated distension. This procedure was compared to conventional water-filled latex balloon distension. No differences were found between intermittent and ramp distension comparing VAS scores at the same pressures. Gender or age did not affect the VAS score. Males had larger volumes at the same pressures than females. Females had larger hysteresis than males. Older females had larger hysteresis than younger females. The pressure volume curves were S-shaped. Compliance at maximal tolerated distension (V/p) and maximal dynamic compliance (Delta V/Delta p) was higher in males than females. The polyethylene bag had higher MTV and MTP compared to the latex balloon. In conclusion, no differences were found in volumes, compliance or VAS between the intermittent and the ramp pressure-controlled inflation, indicating potential for simplification of the procedure. Males had larger rectal volumes and compliances; females had more pronounced hysteresis. A systemic difference was found between distension with the water-filled latex balloon and with the air-filled polyethylene bag. This should be taken into account when interpreting results.     

Normal proximal and delayed distal conduction in the pudendal nerves of patients with idiopathic (neurogenic) faecal incontinence.

The latency of the response in the external anal sphincter muscle following transcutaneous stimulation of the cauda equina at the L1 vertebral level was measured in nine women with neurogenic faecal incontinence (mean 7.3 SD 0.7 ms) and 11 normal subjects (mean 5.6 SD 0.6 ms) (p = 0.01). There was no difference in conduction velocity between the L1 and L4 vertebral levels thus supporting the suggestion that conduction delay in faecal incontinence occurs distally.     

Electromyography of the external anal sphincter in patients with Parkinson's disease and multiple system atrophy: Frequency of abnormal spontaneous activity and polyphasic motor unit potentials

Electromyographic studies of the external anal sphincter muscle have received increasing attention in the differential diagnosis of patients with parkinsonism. Based on the fact that the external anal sphincter muscle is partly innervated by fibers that originate in Onuf's nucleus in the segments S2–S4 of the spinal cord, an increased duration of the motor unit potentials (MUPs) and an increased polyphasia may reflect neuronal loss of these lower motor neurons characteristic for multiple system atrophy. We report the results of anal sphincter electromyography in 15 patients with clinically probable multiple system atrophy (MSA) and 10 patients with Parkinson's disease (PD). There was no significant difference between patients with MSA and patients with PD concerning the duration of MUPs, mean number of phases, and rate of polyphasic motor potentials. There was a tendency for a longer mean duration and increased polyphasia in patients with MSA compared to patients with PD. Spontaneous activity was recorded in 11 of 15 patients with MSA occurring especially in patients with MSA of the striatonigral type, but not in patients with PD. In this study, the duration of MUPs and the rate of polyphasia were unreliable criteria in the electrophysiological differential diagnosis of patients with parkinsonism. Abnormal spontaneous activity, although difficult to detect, is a more specific marker for neuronal degeneration of Onuf's nucleus occurring in patients with MSA. © 1997 John Wiley & Sons, Inc. Muscle Nerve 20:1167–1172, 1997     

Autonomic neuropathy in patients with HIV: Course, impact of disease stage, and medication

The purpose of this article is to examine the prevalence, degree, and natural course of pupillary neuropathy (PANP), cardiovascular autonomic neuropathy (CANP), and sensorimotor neuropathy (SNP) and to study the impact of disease stage and medication on neuropathy in 61 consecutive patients with HIV. PANP, CANP, and SNP were assessed by standardized test procedures. Overall prevalence of PANP, CANP, and SNP were 66%, 15%, and 15%, respectively. The maximal pupillary area (pupillary measure, p<0.0001) and the lying-to-standing ratio (cardiovascular measure, p<0.0001) were abnormal as compared with control subjects. The changes in CD4+ T-lymphocytes and respiratory sinus arrhythmia percentile during 2 years of follow-up correlated significantly (r=0.758, p=0.007). Patients with CANP were more often in an advanced disease stage than patients without CANP (p=0.004). SNP, but not PANP or CANP, was associated with the intake of the neuropathogenic drugs dideoxycytidine, dideoxyinosine, and 2,3 didehydro-2,3 dideoxythymidine (p<0.05). Autonomic and sensorimotor neuropathy are frequent in patients with HIV, and progression of CANP may put patients at risk for unexpected cardiorespiratory arrest.     

Clinical evaluation of ganaxolone in pediatric and adolescent patients with refractory epilepsy

PURPOSE: A pilot study of the safety, tolerability, dose range and potential efficacy of ganaxolone for the treatment of refractory epilepsy in pediatric and adolescent subjects. METHODS: We report the results of a nonrandomized, nonblinded, open-label, dose-escalation trial of ganaxolone in pediatric subjects (5-15 years) suffering from refractory epilepsy. Subjects received an oral suspension of ganaxolone in a 1:1 complex with beta-cyclodextrin in a dose escalation (1 mg/kg, b.i.d. to 12 mg/kg t.i.d.) schedule over 16 days. This was followed by a maintenance period for 8 weeks. Subjects that showed significant response were eligible for a compassionate use extension period. RESULTS: Fifteen subjects enrolled, eight completed the trial and three continued in the open-label compassionate-use extension period. All subject exhibited refractory partial or generalized epilepsy. In an intent-to-treat analysis, four (25%) were considered substantial responders (>or=50% reduction in seizure frequency), two (13%) were considered moderate responders (between 25 and 50% reduction in seizure frequency) and the remainder were considered nonresponders (<24% reduction). Three subjects entered the extension phase, one remained essentially seizure-free for over 3.5 years of ganaxolone administration. Ganaxolone was tolerated well. A total of 17 adverse events were reported in 10 patients, all were considered mild to moderate in severity. Somnolence was the most frequently (nine) reported adverse event. CONCLUSIONS: This pilot study is consistent with other clinical studies indicating that ganaxolone has anticonvulsant activity in humans. The results of this study encourage the further study of ganaxolone as an antiepileptic therapy.