Non-invasive Vagal Neurostimulation (nVNS) in Adolescents With Postural Orthostatic Tachycardia Syndrome (POTS)

Project purpose: The investigators will study the use of non invasive vagal nerve stimulation in newly diagnosed adolescent patients with POTS to see if symptom management improves over 2 months. Surveys will include COMPASS-31. Child Functional Disability Inventory, and PHQ-9. Patient logs will evaluate headache frequency, exercise duration and VNS use.

Research objectives: The investigators hypothesize that:

Primary Aim 1. Use of noninvasive vagal nerve stimulation will decrease autonomic symptom intensity compared to control group.

Primary Aim 2. Use of noninvasive vagal nerve stimulator will improve child function.

Primary Aim 3. Heart rate elevation measured by head up tilt table test will decrease in the treatment group compared to the control group.

Secondary goals include:

Secondary Aim 1: To determine if utilization of noninvasive vagal nerve stimulation influences headache frequency

Secondary Aim 2: Determine if utilization of noninvasive vagal nerve stimulation will influence weekly duration of aerobic exercise.

Secondary Aim 3: Determine if utilization of noninvasive vagal nerve stimulator results in significant side effects, particularly depression, in adolescent patients.

• GammaCore intervention (Device), also known as external vagal nerve stimulator, non-invasive vagal nerve stimulator: Use of the vagal nerve stimulator, GammaCore, on the right side of the neck for two 2 minute stimulations performed 3 times a day
• STEPS management protocol (Other): STEPS is the acronym for the standard management program for our patients with POTS. It includes liberal use of salt, taking in 90-100 ounces of fluid, gradually increasing the duration of aerobic exercise, possible use of one of two prescription medications (metoprolol, and midodrine), and encouragement to set priority and goals

Primary outcomes

• The Change in Composite Autonomic Symptom Score (COMPASS-31) [Baseline; 8 Weeks]: The change in COMPASS-31 score from baseline to 8 weeks. COMPASS-31 measures autonomic dysfunction in patients with neurodegenerative diseases. It consists of 31 patient-reported questions assessing various symptoms, including orthostatic intolerance, vasomotor symptoms, and gastrointestinal issues. Total scores range from 0 to 100, with higher scores indicating more severe symptoms.
• The Change in Child Functional Disability Inventory Scores [Baseline; 8 Weeks]: The change in Child Functional Disability Inventory scores from baseline to eight weeks. The Child Functional Disability Inventory assesses the physical and psychosocial functioning of children due to their physical health. It consists of 15 items that measure activity limitations due to being sick or not feeling well. The total scores range from 0 to 60 with higher scores indicating greater perceived functional disability.
• The Change in Heart Rate (Beats Per Minute) in Head up Tilt Table Tests [Baseline; 8 Weeks]: The change in heart rate, measured in beats per minute (BPM), in the head up tilt table test (HUTT) from baseline to 8 weeks.

Secondary outcomes

• Change in the Number of Headaches Experienced by Adolescent Patients With POTS [Baseline; 8 Weeks]: The change in the number of headaches from baseline to 8 weeks experienced by adolescent patients with POTS.
• Change in Exercise Duration (Minutes) in Adolescent Patients With POTS [Baseline; 8 Weeks]: The change in the exercise duration (minutes) in adolescent patients with POTS from baseline to 8 weeks.
• Change in PHQ-9 Scores in Adolescent Patients With POTS [Baseline; 8 Weeks]: The change in the Patient Health Questionnaire 9-item (PHQ-9) scale score from baseline to 8 weeks. PHQ-9 is used to assess severity of depression. Scoring is calculated by assigning scores of 0, 1, 2, and 3 to the response categories, respectively, of "not at all," "several days," "more than half the days," and "nearly every day." Total score ranges from 0 to 27 where 0 is no depression, 1-4 is minimal depression, 5-9 is mild depression, 10-14 is moderate depression, and 15-19 is moderately severe depression and 20-27 severe depression.

Sex: All, ages: 12 Years to 19 Years, accepts healthy volunteers

Inclusion criteria:

1. Patient's age 12-19 years of age
2. Newly diagnosed POTS at Mayo Clinic in Rochester
3. Head up tilt table test results in a heart rate increase of 40 or more bpm
4. Consent is able to be obtained appropriately per age

Exclusion criteria:

1. POTS patients with orthostatic hypotension
2. POTS patients with vasovagal syncope
3. Use of medications other than midodrine or metoprolol
4. Inability to independently utilize the GammaCore device
5. Inability to independently complete surveys or patient logs
6. Patients receiving hormonal therapy other than birth control
7. Pregnancy
8. Prior neck surgery
9. Metallic implant present
10. Cardiac disorder
11. Presence of an eating disorder
12. Use of a feeding tube

Participant flow

Outcome results

• The Change in Composite Autonomic Symptom Score (COMPASS-31) (Primary), Mean, score on a scale: Standard Postural Orthostatic Tachycardia Syndrome management/ STEPS -5.40 +/- 6.82; STEPS + GammaCore Intervention (noninvasive vagal nerve stimulation) -5.94 +/- 10.89
• The Change in Child Functional Disability Inventory Scores (Primary), Mean, score on a scale: Standard Postural Orthostatic Tachycardia Syndrome management/ STEPS -2.92 +/- 8.60; STEPS + GammaCore Intervention (noninvasive vagal nerve stimulation) -3.40 +/- 11.76
• The Change in Heart Rate (Beats Per Minute) in Head up Tilt Table Tests (Primary), Mean, Beats per Minute (BPM): Standard Postural Orthostatic Tachycardia Syndrome management/ STEPS 47.50 +/- 6.45; STEPS + GammaCore Intervention (noninvasive vagal nerve stimulation) 58.14 +/- 28.94
• Change in the Number of Headaches Experienced by Adolescent Patients With POTS (Secondary), Median, Headaches: Standard Postural Orthostatic Tachycardia Syndrome management/ STEPS 1.00 (1.00 to 2.10); STEPS + GammaCore Intervention (noninvasive vagal nerve stimulation) 1.30 (0.70 to 3.10)
• Change in Exercise Duration (Minutes) in Adolescent Patients With POTS (Secondary), Median, Minutes: Standard Postural Orthostatic Tachycardia Syndrome management/ STEPS 25.00 (15.70 to 47.10); STEPS + GammaCore Intervention (noninvasive vagal nerve stimulation) 21.40 (8.60 to 45.70)
• Change in PHQ-9 Scores in Adolescent Patients With POTS (Secondary), Mean, score on a scale: Standard Postural Orthostatic Tachycardia Syndrome management/ STEPS 0.23 +/- 3.56; STEPS + GammaCore Intervention (noninvasive vagal nerve stimulation) -3.39 +/- 4.54

Adverse events

Time frame: Adverse events were collected from the time of informed consent through study completion, approximately 8 weeks.

Other adverse events by term

• Study Protocol and Statistical Analysis Plan (PDF, 2023-03-09)

• Lytitia Shea, MD, Principal investigator, Mayo Clinic