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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new non-drug treatment called Percutaneous Electrical Nerve Field Stimulation (PENFS) for children with Paroxysmal Sympathetic Hyperactivity (PSH) following a severe brain injury. PSH can cause symptoms like a fast heart rate, high blood pressure, and sweating. The PENFS device, placed on the ear, may help calm the nervous system by stimulating a nerve pathway to reduce these symptoms. Children aged 2 to 17 with moderate PSH and a specific brain injury status might be suitable for this trial. The goal is to determine if PENFS can effectively relieve PSH symptoms and improve quality of life without medications. As an unphased trial, this study provides a unique opportunity to explore a novel treatment option that could enhance the quality of life for children with PSH.

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 prior data suggests that the PENFS device is safe for treating PSH?

Research has shown that the Percutaneous Electrical Nerve Field Stimulation (PENFS) device is generally safe. In a study involving over 1,200 patients, researchers reported no serious side effects. Some minor issues, such as slight bleeding or skin irritation at the placement site, were noted but are uncommon. Infections at the site are also rare. PENFS is non-invasive, meaning it doesn't require surgery, which usually makes it safer than surgical treatments. This device has been used for other conditions with symptoms similar to Paroxysmal Sympathetic Hyperactivity (PSH), indicating its potential for safe use in this case as well. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Most treatments for Paroxysmal Sympathetic Hyperactivity (PSH) focus on controlling symptoms with medications like beta-blockers and sedatives. However, the Percutaneous Electrical Nerve Field Stimulation (PENFS) device introduces a new approach by using electrical stimulation to target nerve activity through the external ear. This method is unique because it offers a non-drug, potentially less invasive option that could continuously modulate nerve signals for up to 120 hours. Researchers are excited about PENFS due to its potential to provide sustained symptom relief without the side effects commonly associated with medications.

What evidence suggests that the PENFS device is effective for treating Paroxysmal Sympathetic Hyperactivity?

Research has shown that the Percutaneous Electrical Nerve Field Stimulation (PENFS) device can significantly reduce symptoms of nervous system disorders. In one study with children who had cyclic vomiting syndrome, 80% experienced a significant improvement in symptoms after six weeks. PENFS boosts the activity of the parasympathetic nervous system, calming the body's stress responses. In animal studies, PENFS reduced nervous system activity by 36% in just five minutes. These findings suggest that PENFS, which participants in this trial will receive, could help manage symptoms of Paroxysmal Sympathetic Hyperactivity (PSH) by calming an overactive nervous system. ^{2 4 5 6 7}

Who Is on the Research Team?

Binod Balakrishnan, MD

Principal Investigator

Medical College of Wisconsin

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

Citations

1. withpower.com withpower.com/trial/phase-hyperkinesis-4-2022-ffd89

Neurostimulation for Paroxysmal Sympathetic Hyperactivity 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 ...

2. ibstim.com ibstim.com/efficacy/

Efficacy IB-Stim treatment resulted in at least a 30% improvement in worst pain at the end of 3 weeks in 59% (16/27) vs 26% (6/23) in the active and sham groups, ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11852813/

a randomized, double-blind, sham-controlled pilot study - PMC This study aims to investigate the effectiveness and practicality of combining transcranial direct current stimulation (tDCS) with medication to treat PSH.

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10869640/

Percutaneous Electrical Nerve Field Stimulation (PENFS) in ... Improvements in abdominal pain, nausea, and functional disability were sustained at 6-12 months and benefits in anxiety and catastrophizing ...

5. ctv.veeva.com ctv.veeva.com/study/percutaneous-neurostimulation-to-treat-paroxysmal-sympathetic-hyperactivity-in-children

Percutaneous Neurostimulation to Treat Paroxysmal ... PENFS was shown to decrease central sympathetic nervous system activity by 36% within 5 minutes of being placed in the ear of a rat model.

6. ibstim.com ibstim.com/safety-profile/

Safety Profile for IB-Stim Safety of percutaneous electrical nerve field stimulation has also been reported in a separate study of over 1200 patients with no serious ...

7. eurjmedres.biomedcentral.com eurjmedres.biomedcentral.com/articles/10.1186/s40001-025-02564-w

Diagnosis and management of paroxysmal sympathetic ... This article summarizes the articles on PSH in recent years, mainly discussing the research history and terminology of PSH, etiology and pathogenesis, ...