VNS Prospective Neuromodulation of Autonomic, Immune and Gastrointestinal Systems

Study Overview
=================
Brief Summary
-----------------
Vagal nerve stimulation is a neurosurgical procedure consisting of implantation of an impulse generator battery with leads placed into the vagus nerve in the neck. This procedure was FDA approved for epilepsy in the 1990s and is commonly performed as an outpatient surgery. The mechanism of efficacy is not well understood; however it is increasingly recognized that electrical stimulation of the vagus nerve may impact other organ systems in the body including the immune, gastrointestinal and autonomic systems. The primary objective of this study is to characterize the pre- and post-operative bowel habits and gut microbiome of patients implanted with vagal nerve stimulator (VNS) for epilepsy. Secondary objectives of this study include: (1) to characterize the pre- and post-operative autonomic profile, (2) characterize the pre- and post-operative immune profile, and (3) to elucidate whether gut microbiota changes are related to VNS efficacy for epilepsy.

Official Title
-----------------
Prospective Non-randomized Single-arm Trial of Efferent Neuromodulation of Autonomic, Immune and Gastrointestinal Systems by VNS in the Epilepsy Population

Conditions
-----------------
Autoimmune Diseases, Epilepsy, Autonomic Dysfunction, Inflammatory Bowel Diseases

Intervention / Treatment
-----------------
* Device: Vagal nerve stimulation (VNS)


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Undergoing VNS implantation for the first time as a treatment for epilepsy Documented follow up with a Louisville-based neurologist in the past 1 year or documented ability to follow to travel to Louisville for outpatient medical care Exclusion Criteria: Previous treatment with VNS Current pregnancy (contraindication to surgery) History of chemotherapy Treatment with cholinergic or anticholinergic medication in the past month or during the study period Pre-existing cardiac arrythmia or presence of cardiac pacemaker/defibrillator Treatment with immunomodulator in the past month or during the study period Treatment with steroids in the past month or during the study period History of cancer

Ages Eligible for Study
-----------------
Minimum Age: 0 Years
Maximum Age: 60 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Other
Intervention Model: Single Group Assignment
Interventional Model Description: Prospective single-arm with internal control group
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Patients undergoing device implantation<br>Patients undergoing device implantation with vagal nerve stimulator (VNS) for epilepsy | Device: Vagal nerve stimulation (VNS)<br>* Implantation with vagal nerve stimulator for epilepsy<br>* Other names: Cyberonics VNS;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Metagenomic microbiome profile | Stool and saliva specimens will be used to generate metagenomic profiles of gut flora populations. Pre- and post-VNS gut profiles will be compared. It is important to note that the genomic profile of all gut flora is the outcome, rather than the presence or absence of any specific type of bacteria. | 1 year | 
| Bowel movement frequency | A brief clinical questionnaire regarding the frequency and consistency of bowel movements will be administered. This will be done pre- and post-VNS implantation in each patient. Any medications to manage diarrhea and constipation will be carefully recorded as well as their efficacy. | 1 year | 
| Abdominal pain | A brief clinical questionnaire regarding the frequency, severity and location of abdominal pain. This will be done pre- and post-VNS implantation in each patient. Any medications to manage abdominal pain will be carefully recorded as well as their efficacy. | 1 year | 
| Immune Profile 1 - Flow cytometric profiling of cell populations | One milliliter of whole blood from each subject will be aliquoted into separate tube and directly stained with fluorochrome-conjugated antibodies to investigate the cellular composition of the blood. Subtypes of lymphocytes, monocytes and granulocytes will be defined by set phenotypic marker expression | 1 year | 
| Immune Profile 2 - Ex vivo stimulation of cells in whole blood | Up to 10 ml of the whole blood will be cultured in 24-well tissue culture plates in the presence and absence of innate immune cell activators, such as TLR ligands, LPS, CpG ODN, poly I:C or flagellin, or adaptive immune activators such as anti-CD3/anti-CD28 beads, PHA or recall antigens. Culture supernatants and cells will be harvested at the needed time points and analyzed via MSD and qPCR, respectively. | 1 year | 
| Inflammatory Profile 1 - Meso Scale Discovery (or MSD) analysis for pro-inflammatory cytokines/chemokines | Serum electrochemiluminescence detection analysis of the following cytokines/chemokines: IFNg, IL-1ß, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-13, TNFα. Units in Picograms/ml or Nanograms/ml depending on the specific chemokine/cytokine | 1 year | 
| Inflammatory Profile 2 - Meso Scale Discovery (or MSD) analysis for metabolic hormones | Serum electrochemiluminescence detection analysis of the following hormones: GLP-1, insulin, Glucagon, Leptin. All in picograms/mL. | 1 year | 
| Inflammatory Profile 3 - Metabolomics for Short Chain Fatty acids (SCFAs) | Short Chain Fatty Acids (SCFAs) in both feces and serum will be derivatized, extracted in organic solvent and analyzed using Gas chromatography-mass spectrometry (GC-MS) to determine the levels of short-chain fatty acids. To the microbial community SCFAs are a necessary waste product, required to balance redox equivalent production in the anaerobic environment of the gut. SCFAs are saturated aliphatic organic acids that consist of one to six carbons of which acetate (C2), propionate (C3), and butyrate (C4) are the most abundant (≥95%). Acetate, propionate, and butyrate are present in an approximate molar ratio of 60:20:20 and will be measured in picomoles/mL. | 1 year | 
| Inflammatory Profile 4 - Intestinal inflammation and permeability markers | sCD163 (nanograms/mL), sCD14 (micrograms/mL), CRP (mg/L), and I-FABP (picograms/mL) are markers of intestinal inflammation and permeability and will be measured using an enzyme-linked immunosorbent assay (ELISA) performed on cell-free supernatants such as plasma, serum and urine. The units of measurement | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Epilepsy severity | Patients will keep a log of seizure type, keeping careful track of the frequency of each type, how long each seizure lasts and what medical interventions are taken to stop each seizure. | 1 year | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
epilepsy, vagal, autoimmune, autonomic, inflammatory bowel disease, immune