Introduction

Parkinson’s disease (PD) is a neurodegenerative disorder. Prior to the manifestation of the motor-symptom of bradykinesia, non-motor symptoms like constipation frequently occur in the prodromal stadium (pPD). Therefore, involvement of the gastrointestinal (GI) tract, especially alterations of the enteric nervous system (ENS), in the pathogenesis can be assumed. Studying the GI tract with its ENS became the focus of research due to its good accessibility. Probe-based confocal laser-endomicroscopy (pCLE) allows to visualize structures of the GI tract in 1000-fold magnification. Therefore, pCLE seems to be a promising approach in the visualization of the ENS in vivo.

Aims & Methods

Aim: Visualization of the ENS by pCLE to create an imaging biomarker for the severity of PD in vivo compared to healthy controls (HC).
Patients with manifest PD and HC undergoing screening colonoscopy were included in this prospective trial. After removal of the mucosal surface with large biopsy forceps, label-free in vivo pCLE (Coloflex, Cellvizio) was performed in the rectum to visualize the ENS in vivo. Observation of neuronal structures in the submucosal plexus was performed with the help of tissue specific autofluorescence (AF). The specific AF was quantified per field of view and assigned to corresponding neuronal structures - small nerve fibre strands, big nerve fibre strands (NFS) and nerve cell bodies (NCB) (impressing as “cotton-balls”). To reliably compare our findings, we performed a direct comparison between conventional immunohistology and ex vivo pCLE. The results of in vivo pCLE were finally correlated to the severity of clinical symptoms.

Results

28 patients with PD and 15 healthy controls were included in this prospective trial. Age and sex distribution did not exhibit statistical differences. In PD we could observe a higher tissue AF in images with small NFS (AF_PD=2848±1889; AF_HC=972±811; p=0.007), with big NFS (AF_PD=22217±1940; AF_HC=687±702; p=0.008) and a larger diameter of nerve cell bodies (“cotton balls”) in PD patients (Diameter_PD=8.2±1.9µm; Diameter_HC=6.7±0.6µm; p=0.04). The total number of small nerves and ganglions in both groups did not differ (ns). Of note, a strong positive correlation of age and increasing accumulation of AF was observed in both groups (p=0.02). Specific morphological distinctions were not noticed. ENS phenotypes showed a strong correlation with clinical manifestation of symptoms (p=0.002).

Conclusion

Label-free pCLE allows reliable in vivo imaging of the ENS in vivo and differentiate between NFS and NCB. Patients with PD have increased AF of submucosal nerve components in comparison to HC. Furthermore, the severity of PD symptoms significantly correlates with increasing AF of ENS in the rectum and can therefore be used as an imaging biomarker for PD that potentially allows for diagnosis of pPD.

Introduction

Although urgency and sensation of incomplete evacuation are common symptoms in IBS, their relationship with other symptoms and gut physiology is still unclear.

Aims & Methods

We included IBS patients (Rome II-IV criteria) who participated in pathophysiology and treatment studies. The severity of urgency and sensation of incomplete emptying was graded using individual items of the Gastrointestinal (GI) Symptom Rating Scale-IBS (GSRS-IBS) and dichotomized into low (no to mild symptoms) and high symptom severity (moderate to severe symptoms). We investigated the association between these symptoms and the severity of other GI symptoms (GSRS-IBS), psychological distress (HADS), oro-anal transit time (OATT; radiopaque markers), rectal sensitivity (balloon distensions), and overlapping disorders of gut-brain interactions (DGBI) diagnosed using ROME questionnaire.

Results

We included 1084 patients with IBS (74% females, mean age 38±13 years; 33% IBS-C, 31% IBS-D, 14% IBS-M, and 22% IBS-U). High severity of urgency (55%) and sensation of incomplete evacuation (67%) were both highly prevalent. Among IBS subtypes, high severity of urgency was most prevalent in IBS-D and IBS-M (67 and 68% respectively) and sensation of incomplete emptying in IBS-C and IBS-M (73 and 75%). High severity of urgency was associated with more severe GI symptoms overall, except for constipation and hard stools, where the opposite pattern was seen (Table 1). The largest effect sizes among the GI symptoms were seen for diarrhea and loose stools. In addition, IBS patients with high severity of urgency demonstrated faster transit, rectal hypersensitivity and more severe psychological distress. For sensation of incomplete evacuation, the opposite pattern compared with urgency was seen for diarrheal and constipation symptoms, and with the largest effect sizes for constipation and hard stools. The sensation of incomplete evacuation was associated with slower OATT and more severe psychological distress, but not with rectal sensitivity. With increasing number of overlapping DGBI, there was a gradual increase in the severity of urgency (η²=0.026; p=0.003) and sensation of incomplete evacuation (η²=0.043; p<0.001).
Table 1. Characteristics of IBS patients with high vs low severity of urgency and sensation of incomplete evacuation, respectively.

Conclusion

Urgency and sensation of incomplete evacuation are common in IBS and predominantly associated with bowel habits. These symptoms are associated with transit, rectal hypersensitivity, overlapping DGBI and psychological distress supporting the relevance of gut-brain interactions in the pathophysiology of IBS symptoms.

Clinical Case Summary

Background: Syphilis is a chronic systemic infection caused by the spirochete Treponema pallidum, often referred to as "the great imitator" due to its ability to affect nearly any organ. Syphilitic hepatitis, or "luetic jaundice," is a rare manifestation, indicating spirochete dissemination to the liver.
Case Report: A 26-year-old female was admitted to the hospital with fever (39.5 °C), fatigue, sweating, tremor, dark urine, pale stools, and significant weight loss (15 kg over two months). She also reported lower extremity muscle and joint pain, cough and slowing of speech. On examination, she had icteric skin, a generalized maculopapular rash, and enlarged cervical lymph nodes. No history of alcohol or drug use was noted.
Laboratory tests revealed elevated levels of both cytolytic and cholestatic liver enzymes, along with increased bilirubin an elevated C-reactive protein.
Abdominal ultrasound and contrast CT showed hepatomegaly, hilar and retroperitoneal lymphadenopathy and splenomegaly.
Viral hepatitis markers (HBsAg, HBV PCR, HCVAb, HCV PCR, anti-HAV IgM, anti-HEV IgM) and antibodies for CMV, EBV, HIV, HSV-1,2 were negative. Wright-Hedelson test for brucellosis and serological markers for autoimmune hepatitis were negative while IgG and cerulopasmin levels were within normal range. Given systemic findings and history, syphilis was considered. Serologic tests were positive for Treponema pallidum (ELISA, TPHA, MRP). Liver biopsy revealed mild active hepatitis. The diagnosis of ^secondary syphilitic hepatitis was made. The patient was started on antimicrobial therapy. During follow-up, liver function tests normalized, and systemic symptoms resolved.
Conclusion: This case underscores the importance of considering syphilis in the differential diagnosis of unexplained hepatitis. Although rare, syphilitic hepatitis should be considered in patients with liver enzyme elevations and nonspecific symptoms, particularly when no clear alternative diagnosis is found.

References

1) Malvar G, Cardona D, Pezhouh MK, Adeyi OA, Chatterjee D, Deisch JK, Lamps LW, Misdraji J, Stueck AE, Voltaggio L, Gonzalez RS. Hepatic Secondary Syphilis Can Cause a Variety of Histologic Patterns and May Be Negative for Treponeme Immunohistochemistry. Am J Surg Pathol. 2022 Apr 1;46(4):567-575. doi: 10.1097/PAS.0000000000001848. PMID: 34864775.
2)Supronowicz Ł, Rogalska M. Syphilitic hepatitis. Clin Exp Hepatol. 2024 Mar;10(1):9-13. doi: 10.5114/ceh.2024.136235. Epub 2024 Mar 12. PMID: 38765910; PMCID: PMC11100338.
3)Al Dallal HA, Narayanan S, Alley HF, Eiswerth MJ, Arnold FW, Martin BA, Shandiz AE. Case Report: Syphilitic Hepatitis-A Rare and Underrecognized Etiology of Liver Disease With Potential for Misdiagnosis. Front Med (Lausanne). 2021 Nov 29;8:789250. doi: 10.3389/fmed.2021.789250. PMID: 34912834; PMCID: PMC8666961.
Figure 1: Histological images of the liver biopsy
Figure 2: Abdominal CT images
Figure 3: Images of maculopapular rash