Neurostimulation for Paroxysmal Sympathetic Hyperactivity

Overseen By Jo Bergholte

Age: < 18

Sex: Any

Trial Phase: Academic

Sponsor: Medical College of Wisconsin

Disqualifiers: Intractable seizures, heart block, others

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

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: Up to 192 hours

20 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial is testing a new device called PENFS, which is worn on the ear and sends electrical signals to help control symptoms in children with severe brain injuries who suffer from PSH. The device aims to calm the overactive nervous system, potentially reducing the need for multiple medications and their side effects.

Will I have to stop taking my current medications?

The trial information does not specify whether participants need to stop taking their current medications. It is best to consult with the trial coordinators for specific guidance.

What data supports the effectiveness of the treatment Percutaneous Electrical Nerve Field Stimulation (PENFS) for Paroxysmal Sympathetic Hyperactivity?

Research on similar treatments, like electrical vagus nerve stimulation, shows promise in managing conditions with autonomic imbalance, such as heart failure, by reducing excessive sympathetic activity. This suggests that PENFS might also help in conditions like Paroxysmal Sympathetic Hyperactivity by modulating nerve activity. ^{1 2 3 4 5}

Is percutaneous electrical nerve field stimulation (PENFS) safe for humans?

PENFS, used in devices like Neuro-Stim, has been shown to have minimal adverse effects, such as minor bleeding, localized skin irritation, and rare infections at the site of use. It is considered a minimal-risk procedure by several institutions, making it generally safe for human use. ^{6 7 8 9 10}

How is the treatment for Paroxysmal Sympathetic Hyperactivity using PENFS different from other treatments?

PENFS (Percutaneous Electrical Nerve Field Stimulation) is unique because it is a non-invasive treatment that delivers electrical stimulation to the external ear to modulate central pain pathways, unlike other treatments that may involve drugs or invasive procedures. ^{6 11 12 13 14}

Research Team

Binod Balakrishnan, MD

Principal Investigator

Medical College of Wisconsin

Eligibility Criteria

This trial is for children aged 2-17 with moderate to severe PSH due to brain injury, who are not fully conscious (Glasgow Coma Scale < 15). It's not suitable for kids with ear issues, uncontrollable seizures, other implants like pacemakers, or those under 2 years old.

Inclusion Criteria

My pain severity is more than moderate.

You have a Glasgow Coma Scale score that is less than 15.

My child is between 2-17 years old and has PSH due to ASBI.

Exclusion Criteria

I have an ear deformity or severe skin irritation on my ear lobes.

I have seizures that medication cannot control.

Known pregnancy

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Application of the PENFS device over the external ear for continuous 120-hour periods

Up to 192 hours

Continuous monitoring during device application

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• PENFS

Trial Overview The study tests a non-drug treatment called PENFS. This device is applied to the ear and may calm overactive nervous systems in kids with PSH by stimulating nerve activity that can relax the body.

Participant Groups

Group I: Percutaneous Electrical Nerve Field Stimulation (PENFS) device application Experimental Treatment 1 Intervention

The peripheral neurostimulator, PENFS device, will be placed over the external ear of enrolled patients. The device will continuously stay in place for 120 hours.

PENFS is already approved in United States for the following indications:

Approved in United States as IB-Stim for:

• Functional abdominal pain associated with irritable bowel syndrome in adolescents 11-18 years of age

Who Is Running the Clinical Trial?

Medical College of Wisconsin

Lead Sponsor

Trials

645

Recruited

1,180,000+

Advancing a Healthier Wisconsin Endowment (AHW)

Collaborator

Trials

1

Recruited

20+

Children's Wisconsin

Collaborator

Trials

3

Recruited

500+

Findings from Research

Electrical vagus nerve stimulation (VNS) shows promise as a long-term therapy for chronic heart failure (HF) by potentially modulating parasympathetic activity, which has been less explored compared to sympathetic inhibition.

Animal studies suggest that VNS may positively influence factors related to HF, such as reducing proinflammatory cytokines and improving heart function, while the review also highlights trends in safety and efficacy for patients with advanced HF.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Electrical vagus nerve stimulation for the treatment of chronic heart failure. Sabbah, HN.[2021]

Neuromodulation therapies, such as spinal cord stimulation and vagus nerve stimulation, have shown promise in restoring autonomic balance in heart failure patients, which is crucial given the disease's association with sympathetic hyperactivity and parasympathetic hypoactivity.

Preclinical studies and early clinical trials indicate that these neuromodulatory treatments are both safe and effective, offering new hope for managing heart failure, a condition with high mortality rates.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Interventional and device-based autonomic modulation in heart failure. Shen, MJ., Zipes, DP.[2015]

Electrical stimulation of the cervical sympathetic trunk at frequencies below 1 Hz did not trigger salivary secretion, but increasing the frequency to 10 Hz significantly enhanced salivary output, indicating a frequency-dependent response.

The study found that the increased salivary secretion during sympathetic stimulation was mediated by beta-adrenoceptors, as blocking these receptors with propranolol reduced the response, while blocking alpha-adrenoceptors did not affect it. This effect was reversible, diminishing one hour after propranolol administration.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Low-frequency subthreshold sympathetic stimulation augments maximal reflex parasympathetic salivary secretion in cats. Izumi, H., Karita, K.[2018]

Axonal modulation therapy (AMT) effectively blocks sympathetic stimulation to the heart in a porcine model, showing strong correlations between AMT intensity and reductions in heart rate and norepinephrine release, which are critical factors in cardiovascular disease.

AMT remains effective even after the removal of the left sympathetic chain, indicating its potential as a reversible treatment option for managing excess sympathetic activity associated with cardiovascular conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Scalable and reversible axonal neuromodulation of the sympathetic chain for cardiac control. Hadaya, J., Buckley, U., Gurel, NZ., et al.[2023]

Regulating autonomic tone in patients with heart failure with reduced ejection fraction (HFrEF) has shown potential benefits, including symptom improvement, reduced arrhythmic events, and lower mortality rates, based on various studies.

Several methods for autonomic regulation, such as parasympathetic nerve activation and spinal cord stimulation, have been explored, but their long-term effectiveness in treating HFrEF remains unproven, highlighting the need for further research.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Device Autonomic Regulation Therapy in Patients with Heart Failure with Reduced Ejection Fraction. N Williford, N., Statz, G., L Mann, D., et al.[2020]

The study involved 115 adolescents aged 11-18 with abdominal pain-related functional gastrointestinal disorders, showing that percutaneous electrical nerve field stimulation (PENFS) significantly reduced worst abdominal pain compared to a sham treatment after 3 weeks (median score reduction of 2.15, p<0.0001).

The effects of PENFS were sustained for an extended period, with significant improvements in pain scores and composite pain measures observed at follow-up, indicating that this non-invasive treatment is both safe and effective for managing abdominal pain in adolescents.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neurostimulation for abdominal pain-related functional gastrointestinal disorders in adolescents: a randomised, double-blind, sham-controlled trial. Kovacic, K., Hainsworth, K., Sood, M., et al.[2018]

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]

The Neuro-Stim System™ devices, used for pain relief through a minimally invasive procedure, have been deemed low-risk by various regulatory bodies, indicating a favorable safety profile.

In a study monitoring 1,207 devices and over 19,000 punctures, the incidence of adverse effects such as bleeding, dermatitis, and infections was quantified, providing valuable data on the safety of this neuromodulation technique.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Minimal adverse effects profile following implantation of periauricular percutaneous electrical nerve field stimulators: a retrospective cohort study. Roberts, A., Sithole, A., Sedghi, M., et al.[2020]

Invasive vagal nerve stimulation (VNS) significantly improves functional class, quality of life, and exercise capacity in patients with chronic heart failure and reduced ejection fraction, based on a systematic review of 1,263 patients across multiple studies.

Adverse effects from VNS were low, occurring in only 11% of patients, and there was no significant difference in mortality rates, indicating that VNS is a safe and effective treatment option for this condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Vagal Neuromodulation in Chronic Heart Failure With Reduced Ejection Fraction: A Systematic Review and Meta-Analysis. Sant'Anna, LB., Couceiro, SLM., Ferreira, EA., et al.[2021]

In a study of 30 children aged 8-18 with drug-refractory cyclic vomiting syndrome (CVS), 80% showed significant improvement in symptoms after 6 weeks of noninvasive auricular percutaneous electrical nerve field stimulation (PENFS), with benefits lasting an average of 113 days.

PENFS not only reduced the frequency and duration of CVS episodes but also decreased nausea and disability scores, with no serious side effects reported, indicating it is a safe and effective treatment option for pediatric patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Percutaneous Electrical Nerve Field Stimulation for Drug-Refractory Pediatric Cyclic Vomiting Syndrome. Karrento, K., Venkatesan, T., Zhang, L., et al.[2023]

In a study of 83 patients with chronic headaches, peripheral nerve field stimulation (PNFS) led to an average pain reduction of 4.8 points on a scale of 0 to 10, with 41 out of 60 implanted patients experiencing over 50% pain relief after an average follow-up of 12.9 months.

PNFS also resulted in significant reductions in medication use (83% of patients decreased their analgesic intake), disability, and depression levels, indicating its potential as an effective and reversible treatment option for chronic headache conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Peripheral nerve field stimulation for chronic headache: 60 cases and long-term follow-up. Verrills, P., Rose, R., Mitchell, B., et al.[2022]

High-frequency sphenopalatine ganglion (SPG) stimulation has shown promise as a treatment for chronic cluster headache (CCH), effectively aborting attacks in some patients, based on initial studies.

Due to the moderate rate of long-term side effects and the introduction of a commercially available SPG neurostimulator, standardized patient selection and care protocols are recommended to maximize treatment efficacy and safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Stimulation of the sphenopalatine ganglion in intractable cluster headache: expert consensus on patient selection and standards of care. Jürgens, TP., Schoenen, J., Rostgaard, J., et al.[2022]

Peripheral nerve stimulation and peripheral nerve field stimulation are effective methods for managing neuropathic pain by delivering electrical stimulation to targeted nerves or painful areas.

Careful patient selection through inclusion/exclusion criteria and psychological screening is crucial, as only those showing significant improvement during a trial are considered for permanent implantation, while also being aware of potential risks like infection and device failure.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Peripheral nerve/field stimulation for chronic pain. Petersen, EA., Slavin, KV.[2014]

Auricular neurostimulation therapy using percutaneous electrical nerve field stimulation (PENFS) significantly reduced abdominal pain in adolescents with irritable bowel syndrome (IBS), with 59% of patients experiencing a 30% or more reduction in pain severity compared to 26% in the sham group.

PENFS also improved overall wellbeing, as indicated by a symptom response scale, with 82% of patients reporting improvement versus only 26% in the sham group, and no significant side effects were reported, highlighting its safety as a noninvasive treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of Auricular Neurostimulation in Adolescents With Irritable Bowel Syndrome in a Randomized, Double-Blind Trial. Krasaelap, A., Sood, MR., Li, BUK., et al.[2021]

References

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

Electrical vagus nerve stimulation for the treatment of chronic heart failure. [2021]

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

Interventional and device-based autonomic modulation in heart failure. [2015]

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

Low-frequency subthreshold sympathetic stimulation augments maximal reflex parasympathetic salivary secretion in cats. [2018]

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

Scalable and reversible axonal neuromodulation of the sympathetic chain for cardiac control. [2023]

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

Device Autonomic Regulation Therapy in Patients with Heart Failure with Reduced Ejection Fraction. [2020]

6. Netherlands pubmed.ncbi.nlm.nih.gov

Neurostimulation for abdominal pain-related functional gastrointestinal disorders in adolescents: a randomised, double-blind, sham-controlled trial. [2018]

7. England pubmed.ncbi.nlm.nih.gov

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

8. New Zealand pubmed.ncbi.nlm.nih.gov

Minimal adverse effects profile following implantation of periauricular percutaneous electrical nerve field stimulators: a retrospective cohort study. [2020]

9. Switzerland pubmed.ncbi.nlm.nih.gov

Vagal Neuromodulation in Chronic Heart Failure With Reduced Ejection Fraction: A Systematic Review and Meta-Analysis. [2021]

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

Percutaneous Electrical Nerve Field Stimulation for Drug-Refractory Pediatric Cyclic Vomiting Syndrome. [2023]

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

Peripheral nerve field stimulation for chronic headache: 60 cases and long-term follow-up. [2022]

12. England pubmed.ncbi.nlm.nih.gov

Stimulation of the sphenopalatine ganglion in intractable cluster headache: expert consensus on patient selection and standards of care. [2022]

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

Peripheral nerve/field stimulation for chronic pain. [2014]

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

Efficacy of Auricular Neurostimulation in Adolescents With Irritable Bowel Syndrome in a Randomized, Double-Blind Trial. [2021]