Vagal Nerve Stimulation for POTS

Overseen By Xichun Yu

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: University of Oklahoma

Must not be taking: Chronic medications

Disqualifiers: Hypertension, Cardiovascular disease, Pregnancy, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 8 weeks

80 Participants Needed

Trial Summary

What is the purpose of this trial?

The purpose of this study is to test the hypothesis that an antibody-mediated autoimmune reaction will cause symptoms of autonomic dysfunction in some patients with postural tachycardia syndrome (POTS). The investigators further hypothesize that electrical stimulation of the vagus nerve will improve POTS symptoms, autoimmunity and inflammation.

Will I have to stop taking my current medications?

The trial protocol does not specify if participants with POTS need to stop their current medications. However, healthy control subjects must not be on any chronic medications during the study.

What data supports the effectiveness of this treatment?

Vagus nerve stimulation (VNS) has been used effectively as a treatment for epilepsy, helping to reduce seizure frequency in many patients, although its effectiveness can vary. This suggests that VNS may have potential benefits for other conditions like POTS, even though specific data for POTS is not provided. ^{1 2 3 4 5}

Is vagal nerve stimulation safe for humans?

Vagal nerve stimulation (VNS) is generally considered safe, but it can have side effects. Surgical implantation can lead to infections and heart rate issues, while stimulation might cause voice changes, tingling, cough, headache, and throat pain. Non-invasive VNS is safer and more tolerable, reducing the need for surgery. ^{6 7 8 9 10}

How is vagal nerve stimulation treatment different from other treatments for POTS?

Vagal nerve stimulation (VNS) is unique because it involves using a small device to send electrical impulses to the vagus nerve, which is different from typical drug treatments. This method is already used for epilepsy and is considered low in adverse effects, offering a non-drug alternative for managing symptoms. ^{1 2 3 11 12}

Research Team

Stavros Stavrakis, MD

Principal Investigator

University of Oklahoma

Eligibility Criteria

This trial is for adults aged 18-80 with Postural Tachycardia Syndrome (POTS), characterized by a rapid heartbeat upon standing, without other causes of orthostatic tachycardia. Healthy controls must be non-smoking and not on chronic medications. Excluded are those with recent heart attacks, significant immune or blood disorders, pregnancy, pacemakers or cochlear implants, severe hypertension, history of vagotomy.

Inclusion Criteria

I understand and can follow the study's procedures and rules.

I either do not have health issues or have POTS with specific heart rate and blood pressure changes.

Able and willing to provide informed consent

Exclusion Criteria

Patients with active implants (such as a cardiac pacemaker, or a cochlear implant)

My blood pressure is higher than 150/100 mmHg.

I am currently pregnant or planning to become pregnant within the next 3 months.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either active vagal stimulation or sham stimulation for 2 months

8 weeks

Daily sessions

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Sham stimulation
• Vagal stimulation

Trial Overview The study aims to see if stimulating the vagus nerve can improve symptoms in POTS patients by potentially reducing autoimmune reactions and inflammation. Participants will receive either actual vagal stimulation or sham (fake) stimulation to compare effects.

Participant Groups

Group I: Vagal stimulation Active Control 1 Intervention

Vagal stimulation will be given at 20 Hz for 1 hour daily with the bipolar electrode attached to the tragus for 2 months.

Group II: Sham stimulation Placebo Group 1 Intervention

Sham stimulation will be given at 20 Hz for 1 hour daily with the bipolar electrode attached to the earlobe for 2 months.

Vagal stimulation is already approved in European Union, United States, United Kingdom for the following indications:

Approved in European Union as Vagus nerve stimulation for:

• Epilepsy
• Depression
• Cluster headaches

Approved in United States as Vagus nerve stimulation for:

• Epilepsy
• Treatment-resistant depression
• Stroke rehabilitation

Approved in United Kingdom as Vagus nerve stimulation for:

• Epilepsy
• Depression
• Cluster headaches

Who Is Running the Clinical Trial?

University of Oklahoma

Lead Sponsor

Trials

484

Recruited

95,900+

National Heart, Lung, and Blood Institute (NHLBI)

Collaborator

Trials

3,987

Recruited

47,860,000+

Findings from Research

The study identified a specific electrophysiological response called the larynx compound action potential (LCMAP) that occurs approximately 3 ms after vagus nerve stimulation (VNS), which can serve as an objective indicator of effective nerve activation.

LCMAP was successfully recorded in 11 out of 21 rats immediately after surgery, while others required a recovery period, suggesting that monitoring LCMAP could help determine the optimal timing for increasing VNS therapy in patients with refractory epilepsy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Repeated assessment of larynx compound muscle action potentials using a self-sizing cuff electrode around the vagus nerve in experimental rats. El Tahry, R., Mollet, L., Raedt, R., et al.[2011]

In a study of 138 patients with refractory epilepsy, vagus nerve stimulation (VNS) led to a significant average reduction of 51% in monthly seizure frequency over a mean follow-up of 44 months, demonstrating its efficacy as an adjunctive treatment.

The responder rate, defined as patients experiencing at least a 50% reduction in seizures, was 59%, with 9% of patients achieving complete seizure freedom, indicating that VNS can provide substantial benefits for many patients with difficult-to-treat epilepsy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Vagus nerve stimulation for refractory epilepsy: a Belgian multicenter study. De Herdt, V., Boon, P., Ceulemans, B., et al.[2007]

In a retrospective study of 62 patients treated with vagus nerve stimulation (VNS) for epilepsy, only 6 patients experienced significant seizure reduction, indicating that while VNS can be beneficial, it may not be effective for the majority of patients.

Contrary to its reputation for low adverse effects, the study found that only 9 patients had no adverse effects, with some experiencing severe and even life-threatening complications, highlighting the need for careful monitoring throughout the treatment process.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Vagus nerve stimulation therapy in epilepsy patients: long-term outcome and adverse effects: a retrospective analysis]. Carius, A., Wintermantel, A.[2022]

In a study of 61 patients with intractable epilepsy, the output current of vagus nerve stimulation (VNS) did not correlate with the percentage reduction in seizure frequency, indicating that higher current levels are not necessarily more effective.

Interestingly, about 20% of patients who initially did not respond to VNS experienced significant seizure reductions when the output current was increased, suggesting that adjusting current levels may benefit some non-responders.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Vagus nerve stimulation for epilepsy: is output current correlated with acute response? Bunch, S., DeGiorgio, CM., Krahl, S., et al.[2007]

A prediction model for the efficacy of vagus nerve stimulation (VNS) in children with drug-resistant epilepsy (DRE) was developed using clinical and EEG synchronization features from 88 children, achieving an accuracy of 75.7% in a discovery cohort.

The model identified significant differences in brain activity patterns, specifically higher interictal awake phase lag index (PLI) in responders compared to non-responders, suggesting that these features can help predict which children are likely to benefit from VNS therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A prediction model integrating synchronization biomarkers and clinical features to identify responders to vagus nerve stimulation among pediatric patients with drug-resistant epilepsy. Ma, J., Wang, Z., Cheng, T., et al.[2022]

Vagal nerve stimulation (VNS) is considered a safe alternative therapy for epilepsy, although it can have rare but significant complications.

The study highlights cases of four patients who were implanted with VNS without prior video-EEG monitoring, suggesting a need for better guidelines on the necessity of this monitoring before VNS implantation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Video EEG monitoring prior to vagal nerve stimulator implantation. Attarian, H., Dowling, J., Carter, J., et al.[2019]

In a review of 111 patients who received vagus nerve stimulation (VNS) for refractory epilepsy, three cases of intraoperative bradycardia were observed during device testing, but no adverse cardiac events occurred postoperatively.

Despite the initial bradycardia during testing, all three patients experienced reduced seizure frequency after starting VNS therapy, indicating that VNS is safe and effective for managing epilepsy even when bradycardia is noted during the procedure.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cardiac responses of vagus nerve stimulation: intraoperative bradycardia and subsequent chronic stimulation. Ardesch, JJ., Buschman, HP., van der Burgh, PH., et al.[2022]

In a study of 48 patients with intractable partial epilepsy, vagus nerve stimulation (VNS) demonstrated a significant reduction in seizure frequency, with a 26% decrease after 1 year, 30% after 5 years, and 52% after 12 years of treatment.

The side effects of VNS were generally mild to moderate, indicating that it is a safe and tolerable option for patients with difficult-to-treat epilepsy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effectiveness of vagus nerve stimulation in epilepsy patients: a 12-year observation. Uthman, BM., Reichl, AM., Dean, JC., et al.[2019]

Vagus nerve stimulation (VNS) is effective for treating refractory epilepsy and depression, but traditional methods involve surgical implantation, which carries risks such as infection and bradycardia.

New non-invasive VNS systems eliminate the need for surgery, improving safety and tolerability, and allowing patients to administer stimulation on demand, potentially expanding its use in various medical conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Surgically implanted and non-invasive vagus nerve stimulation: a review of efficacy, safety and tolerability. Ben-Menachem, E., Revesz, D., Simon, BJ., et al.[2022]

In a study of 24 children undergoing intermittent vagal nerve stimulation over a total of 61 patient years, 15 adverse events were reported, with 13 likely related to the device, indicating a need for careful monitoring during treatment.

Despite the occurrence of adverse events, vagal nerve stimulation was generally well tolerated, and unlike standard drug therapies, these events did not typically require stopping the treatment, although they sometimes led to unexpected surgeries.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse events in children receiving intermittent left vagal nerve stimulation. Murphy, JV., Hornig, GW., Schallert, GS., et al.[2019]

In a study of 14 epilepsy patients with vagal nerve stimulators, those who experienced a 50% or greater reduction in seizures (responders) had lower preoperative connections between the left hippocampus and both the left and right thalamus compared to non-responders, suggesting these connections may help predict treatment outcomes.

The study found that varying the stimulation current (up to 1.5 mA) and duration (up to 3 months) did not significantly alter hippocampal-thalamic connectivity, indicating that these parameters may not be critical for immediate changes in brain function.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The effect of vagal nerve stimulation on hippocampal-thalamic functional connectivity in epilepsy patients. Zhu, J., Xu, C., Zhang, X., et al.[2021]

In a study of 6 patients with drug-resistant epilepsy over 4 years, vagus nerve stimulation (VNS) led to an overall 60% reduction in seizure frequency, with one patient becoming seizure-free, indicating its potential efficacy as a treatment.

The effectiveness of VNS appeared to improve over the first 3 years, with optimal outcomes associated with stimulation currents of 1.5-2.0 mA, suggesting that careful adjustment of stimulation parameters can enhance treatment results.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Vagus nerve stimulation (VNS) in the treatment of drug-resistant epilepsy. A 4-year follow-up evaluation of VNS treatment efficacy]. Koszewski, W., Bacia, T., Rysz, A.[2015]

References

1. Netherlands pubmed.ncbi.nlm.nih.gov

Repeated assessment of larynx compound muscle action potentials using a self-sizing cuff electrode around the vagus nerve in experimental rats. [2011]

2. England pubmed.ncbi.nlm.nih.gov

Vagus nerve stimulation for refractory epilepsy: a Belgian multicenter study. [2007]

3. Germany pubmed.ncbi.nlm.nih.gov

[Vagus nerve stimulation therapy in epilepsy patients: long-term outcome and adverse effects: a retrospective analysis]. [2022]

4. Denmark pubmed.ncbi.nlm.nih.gov

Vagus nerve stimulation for epilepsy: is output current correlated with acute response? [2007]

5. England pubmed.ncbi.nlm.nih.gov

A prediction model integrating synchronization biomarkers and clinical features to identify responders to vagus nerve stimulation among pediatric patients with drug-resistant epilepsy. [2022]

6. United States pubmed.ncbi.nlm.nih.gov

Video EEG monitoring prior to vagal nerve stimulator implantation. [2019]

7. Netherlands pubmed.ncbi.nlm.nih.gov

Cardiac responses of vagus nerve stimulation: intraoperative bradycardia and subsequent chronic stimulation. [2022]

8. United States pubmed.ncbi.nlm.nih.gov

Effectiveness of vagus nerve stimulation in epilepsy patients: a 12-year observation. [2019]

9. England pubmed.ncbi.nlm.nih.gov

Surgically implanted and non-invasive vagus nerve stimulation: a review of efficacy, safety and tolerability. [2022]

10. United States pubmed.ncbi.nlm.nih.gov

Adverse events in children receiving intermittent left vagal nerve stimulation. [2019]

11. United States pubmed.ncbi.nlm.nih.gov

The effect of vagal nerve stimulation on hippocampal-thalamic functional connectivity in epilepsy patients. [2021]

12. Poland pubmed.ncbi.nlm.nih.gov

[Vagus nerve stimulation (VNS) in the treatment of drug-resistant epilepsy. A 4-year follow-up evaluation of VNS treatment efficacy]. [2015]