Faculty Bibliography

BACKGROUND:Fecal incontinence (FI) affects up to 1 in 4 patients with inflammatory bowel disease (IBD) and is associated with inflammation, surgeries, and altered rectal sensitivity. Ileal pouch-anal anastomosis (IPAA) is a surgical intervention for select IBD patients to avoid a permanent stoma. High-resolution anorectal manometry (HRAM) studies in IBD patients with FI demonstrate lower resting pressures and rectal sensory dysfunction. However, HRAM data in IBD patients with FI post-IPAA remains limited. We hypothesized patients with FI would have lower resting and squeeze pressures and rectal hypersensitivity compared to healthy controls and that these changes would be similar after IPAA. METHODS:Retrospective review of prospectively collected data was conducted on patients undergoing HRAM from 2017-2021 at a single urban academic medical center. Patient characteristics (age, gender, BMI, stool frequency, diabetes, pregnancy history) and surgical history (prior perianal surgery, index vs. re-do IPAA) were obtained. HRAM variables included rectoanal inhibitory reflex (RAIR), sphincter length, resting, squeeze, cough, and push pressures, sensation thresholds (first sensation, constant sensation, desire to defecate, urgency to defecate, max tolerable volume), and balloon expulsion test (BET). HRAM outcomes in IPAA patients with FI (IPAA-FI) were compared to non-IBD patients with FI (non-IBD-FI). HRAM data for both patient cohorts were also compared to existing normative data of healthy controls. Non-IBD patients with constipation and FI were excluded from analysis. An independent samples t-test was performed (p < 0.05) for continuous variables, and chi-square test was used for categorical variables. RESULTS:Fifty-six patients (66% female) were in the non-IBD-FI group. Eighteen patients (67% female) were in the IPAA-FI group. Average age in the IPAA-FI cohort was 44.8 ± 13.6 vs. 66.3 ± 14.4 in the non-IBD-FI group (p< 0.01). Sphincter length in the IPAA-FI group was 2.7 ± 1.1cm vs. 3.2 ± 0.6cm in the non-IBD-FI group (p=0.03). There was no significant difference in sensation thresholds or resting, squeeze, cough, and push pressures between the two groups. Urinary incontinence was observed in 5.6% of IPAA-FI patients vs. 44.6% of non-IBD-FI patients (p < 0.01). RAIR was present in 38.5% of IPAA-FI patients vs. 100% of non-IBD-FI patients (p < 0.01). Both patient cohorts had significantly shorter sphincter length, lower squeeze and push pressures, and lower sensation thresholds compared to normative data. Resting pressures for the IPAA-FI group was not significantly different compared to healthy controls. CONCLUSION/CONCLUSIONS:Overall, anorectal pressures and sensation are similar between IPAA-FI and non-IBD-FI patients. However, the underlying FI mechanism seems to differ. Higher rates of urinary incontinence in the non-IBD-FI cohort suggests global pelvic floor dysfunction compared to IPAA-FI patients who are younger and have post-operative neuromuscular dysfunction, as evidenced by shorter sphincter length and absent RAIR. Though rectal hypersensitivity and lower squeeze/push pressures are observed in both patient groups compared to healthy controls, normal resting pressure in IPAA-FI suggests that potentially different normative ranges are needed for this cohort to accurately assess post-surgical changes and guide pre-operative counseling.

Despite advancements in the assessment and management of functional neurological disorder (FND), the feasibility of implementing a new standard of care remains unclear. Chart reviews were performed for 100 patients with motor FND to investigate factors related to treatment adherence and clinical improvement over an average follow-up of 7 months. Of 81 patients who returned for follow-up, a history of chronic pain disorder inversely correlated with improvement. Of the 50 individuals newly referred for treatment, adherence correlated with improvement, while having abnormal neuroimaging inversely correlated with improvement. This study supports the feasibility of applying a new standard of care for FND.

The assessment of functional neurological disorders (FND) requires an interdisciplinary approach. The authors retrospectively reviewed charts for 100 outpatients with FND and used univariate and regression analyses to investigate neuropsychiatric associations with gender, illness duration, and work disability; secondary analyses evaluated for differences across motor FND subtypes. Men reported higher rates of cognitive complaints and functional weakness, whereas women endorsed increased past physical/sexual trauma. Number of self-reported medication allergies/sensitivities positively correlated with illness duration. Individuals with functional weakness compared with other motor FND subtypes exhibited lower rates of past psychiatric hospitalization and head trauma. This study supports the feasibility of integrating FND research.

OBJECTIVE:Adverse early-life events are predisposing factors for functional neurological disorder (FND) and post-traumatic stress disorder (PTSD). Cingulo-insular regions are implicated in the biology of both conditions and are sites of stress-mediated neuroplasticity. We hypothesised that functional neurological symptoms and the magnitude of childhood abuse would be associated with overlapping anterior cingulate cortex (ACC) and insular volumetric reductions, and that FND and PTSD symptoms would map onto distinct cingulo-insular areas. METHODS:This within-group voxel-based morphometry study probes volumetric associations with self-report measures of functional neurological symptoms, adverse life events and PTSD symptoms in 23 mixed-gender FND patients. Separate secondary analyses were also performed in the subset of 18 women with FND to account for gender-specific effects. RESULTS:Across the entire cohort, there were no statistically significant volumetric associations with self-report measures of functional neurological symptom severity or childhood abuse. In women with FND, however, parallel inverse associations were observed between left anterior insular volume and functional neurological symptoms as measured by the Patient Health Questionnaire-15 and the Screening for Somatoform Symptoms Conversion Disorder subscale. Similar inverse relationships were also appreciated between childhood abuse burden and left anterior insular volume. Across all subjects, PTSD symptom severity was inversely associated with dorsal ACC volume, and the magnitude of lifetime adverse events was inversely associated with left hippocampal volume. CONCLUSIONS:This study reveals distinct cingulo-insular alterations for FND and PTSD symptoms and may advance our understanding of FND. Potential biological convergence between stress-related neuroplasticity, functional neurological symptoms and reduced insular volume was identified.

BACKGROUND AND OBJECTIVE/OBJECTIVE:Although many patients present with functional neurological symptoms (FNS), few US clinics offer specialized FNS care, and data on clinic attendees remain limited. We determined predictors of initial attendance, symptom burden, and FNS subtype in the first patients referred to our Functional Neurological Disorders Clinic for suspected FNS. METHODS:We reviewed the charts of 62 consecutive patients (46 women, 16 men). Regression analyses investigated predictors of keeping the first scheduled clinic appointment. For the 49 patients who did keep that appointment, regression analyses examined neuropsychiatric factors associated with symptom burden and motor FNS subtypes. RESULTS:The odds of not keeping the first appointment were 10.4 times greater for patients referred from the emergency department than from other sources. The patients who kept their appointment reported a symptom burden that was significantly associated with a past FNS-related emergency department visit and a diagnosis of another medically unexplained somatic syndrome. The number of FNS findings on neurological examination also correlated with a history of an FNS-related emergency department visit. Patients with psychogenic non-epileptic seizures reported cognitive complaints and prior psychiatric hospitalizations significantly more often than did patients with other FNS. One fourth of all patients had two or more motor FNS. CONCLUSIONS:In our FNS cohort, patients were less likely to keep an initial clinic appointment if they were referred from the emergency department than from other sources. Patients with psychogenic non-epileptic seizures were more likely to report cognitive symptoms and past psychiatric hospitalizations than patients with other FNS.

Proopiomelanocortin (POMC) is a multivalent prohormone that can be processed into at least 7 biologically active peptide hormones. Processing can begin in the trans-Golgi network (TGN) and continues in the secretory granules of the regulated secretory pathway (RSP). Sorting of POMC into these granules is a complex process. Previously, a membrane-associated form of carboxypeptidase E (CPE) was shown to bind to POMC and facilitate its trafficking into these granules. More recently, secretogranin III (SgIII) was also found to affect POMC trafficking. Here, we show by RNA silencing that CPE and SgIII play a synergistic role in the trafficking of POMC to granules of the RSP in AtT20 cells. Reduction of either protein resulted in increased constitutive secretion of POMC and chromogranin A, which was increased even further when both proteins were reduced together, indicative of missorting at the TGN. In SgIII-reduced cells, POMC accumulated in a compartment that cofractionated and colocalized with syntaxin 6, a marker of the TGN, on sucrose density gradients and in immunocytochemistry, respectively, indicating an accumulation of this protein in the presumed sorting compartment. Regulated secretion of ACTH, as a measure of sorting and processing of POMC in mature granules, was reduced in the SgIII down-regulated cells but was increased in the CPE down-regulated cells. These results suggest that multiple sorting systems exist, providing redundancy to ensure the important task of continuous and accurate trafficking of prohormones to the granules of the RSP for the production of peptide hormones.