Scientific & Clinical Information

The vagus nerve is the 10th cranial nerve (also known as ‘the great wondering protector’). It is a parasympathetic nerve with breakline afferent and efferent sensory fibres and is the longest cranial nerve, with connections that allow control from high brain centres to key organs for maintaining the body’s balance (homeostasis). The vagus nerve has a wide range of reciprocal connections that allow for integration and responses to feedback signals in normal physiology.

VNS is a well-established clinical approach used for neuromodulation therapy for neurological and neuropsychiatric conditions, such as epilepsy and medication-resistant depression*, respectively.*

Invasive VNS (iVNS) was originally approved in the USA for the treatment of epilepsy (1997) and then for medication-resistant depression (2005). VNS has been now studied and applied for a range of conditions including headache, arthritis, asthma, pain, fibromyalgia, bipolar disorder and also aging-related diseases like dementia.

iVNS requires surgery that includes an incision in the patient’s neck (left side) conducted under general anaesthesia. An electrode is then inserted and attached around the vagus nerve. This is followed by insertion of an implanted pulse generator (IPG) under skin of the chest cavity of the patient.

iVNS is irreversible and has risks associated with surgery, such as infection (~3% of operations lead to device removal), nerve damage and voice alternations/ vocal cord paralysis, as well as device malfunctioning such as wire breakages and disconnections.

Medication resistant depression refers to patients not having adequate response to >4 anti-depressant treatments.

tVNS application holds a favourable risk-benefit ratio. The side effects experienced by users are typically ‘local’ i.e. at the site of electrode stimulation in the ear causing minor pain, redness or skin lesions. Other side effects can include 'systemic' effects where there are changes in the autonomic nervous system, which may manifest in the form of headaches, nausea or vertigo.

The general safety and tolerability of tVNS has been previously reviewed [1]. With the inclusion of 51 scientific studies and a total of 1322 subjects, the occurrence of side effects have been well-characterised. tVNS is a safe and well-tolerated treatment option.

[1] Redgrave et al Brain Stimul 2018;11(6):1225-1238

This pilot study was aimed to assess the safety and tolerability of tVNS as a treatment option for pharmaco-resistant epilepsy. Ten patients with pharmaco-resistant epilepsy (8 focal, 2 generalized epilepsies; mean age of 37.7 years; 6 female, 4 male) with a minimum of 4 seizures per month. The doses of medication were kept constant for the whole study period. tVNS was applied by themselves as part of their daily routines, where stimulation was performed for 1 hour in the morning, 1 hour at noon and 1 hour in the evening, over a period of 9 months. For seizure documentation during the study, patient diaries were used. Patients were asked to report their seizures, as well as tolerability, side effects and practicability of the tVNS device.

This study (cMPsE02) was a randomized, two-arm, parallel group, prospective, double-blind, actively controlled trial to assess the efficacy and safety of tVNS vs. control stimulation in patients with drug-resistant epilepsy. This study was conducted at 9 sites in Germany and 1 site in Austria between 2012 and 2014. A total of 76 adult epilepsy patients with different epilepsy syndromes were included.

The primary objective of this study was to demonstrate superiority of the add-on therapy of tVNS (25 Hz, n=39 patients) vs. active control (1 Hz, n=37 patients) in reducing seizure frequency over 20 weeks. The secondary objectives comprised of reduction in seizure frequency from baseline to end of treatment, sub-group analysis and safety evaluation.

Patients between 18-65 years of age were included in this study and suffered from epilepsy with focal and/or generalized seizures, with ≥ 3 seizures per month and not more than 21 consecutive seizure free days. Seizure frequency was assessed retrospectively prior to screening and prospectively during the baseline period. Patients had to be on a stable regimen of ≤3 anti-epileptic drugs (AEs) for at least 5 weeks prior to study enrollment. This AEs regimen had to be maintained throughout the study. Patients were randomized in a 1:1 ratio to treatment with either tVNS at high level (25 Hz) or low level (active control, 1 Hz) for 4 hours daily for a period of 20 weeks to the left auricular branch of the vagus nerve.

Unadjusted mean seizure reduction per 28 days at end of treatment was -2.9% in the 1 Hz group and 23.4% in the 25 Hz group (p=0.146) after 20 weeks compared to baseline. However, in contrast to the active controls, there was a clear significant reduction in seizure frequency in patients receiving 25 Hz tVNS who completed the full treatment period (n=26 patients, 34.2% reduction, p=0.034).

The average absolute changes in seizure frequency per 28 days were nearly -1 seizures per 28 days in the active control group (p=0.386) and -2 seizures per 28 days in the 25 Hz tVNS group (p=0.068). However, in those patients who completed the entire 20 weeks stimulation treatment, improvements were an average of -1.2 seizures per 28 days in the active control group and -3 seizures per 28 days in the 25 Hz group (p=0.031).

Patient treatment adherence was high with 84% in the active control group and 88% in the 25 Hz tVNS group.

The most common side effects were headache, pain at the ear, dizziness, vertigo, fatigue, nasopharyngitis and nausea. There was only 1 adverse event with possible relation to the trial causing a withdrawal, which was the occurrence of vestibular neuronitis.**

In conclusion, the results of this study showed that tVNS is a well-tolerated procedure with high treatment compliance rates in drug-resistant epilepsy patients. Although the superiority of 25 Hz tVNS treatment over 1 Hz active control tVNS was not proven, there was clear efficacy of 25 Hz tVNS treatment in patients who completed the entire 20 weeks treatment, with significant reduction in seizures compared to baseline.**

A 11-year old patient diagnosed with severe myoclonic epilepsy at an early age (so called 'Dravet syndrome'). The patient had therapy refractory fever related prolonged seizures with impairment of mental development. There was subsequent occurrence of further different seizure types.

Genetic examination showed the patient had mutation in the SC-N1A. Exon 17 – mutation in the form of a heterozygous 1-base pair exchange c. C3521G ACT to AGT. The patient received mono- and combinative therapy with phenobarbital, valproate, ethosuximide, clonazepam, topiramate, siripentol, potassium bromide, zonegran, and lacosamide but resulted in continued occurrence of seizures. Initial success of potassium bromide treatment was stopped due to the side effects of bromoderma on the patient’s lower leg. A ketogenic diet was also terminated due to intolerance after 14 days

Treatment with tVNS (NEMOS®) began at 10 years 9 months of age. It was delivered in combination with zonisamide and phenobarbital. At that time, the patient suffered ~30 seizures per month, with regular administration of diazepam and/or midazolepam as an emergency drug, as well as oxygen during and after seizures. The effects of tVNS was well-tolerated and daily stimulation of 4 hours was well-adhered to. After 4 months, seizures were reduced by 57% from 30 per month to 13 per month. No side effects were observed.

This case report shows that tVNS is a useful and well-tolerated adjuvant therapeutic option for drug-resistant epilepsies.

A 24-year old patient suffered from seizures since the age of 11 and was treated since 2013. The patient presented focal bilateral tonic-clonic seizures with anxiety and dizziness, sometimes with auras, and always with automatisms. Upon epilepsy diagnosis, lamotrigine was given leading to seizure freedom for 18 months. With seizure recurrence, lamotrigine, levetiracetam and lacosamide were administered but did not achieve seizure freedom.

In June 2014, the patient was offered additional treatment with tVNS and since August 2014, the patient has been seizure free. tVNS stimulation began at 0.8 mA and was adjusted to 1.5 mA. tVNS treatment has been performed daily for 4 hours (mostly in a single session). Anxiety was reported 18 months after starting stimulation, with psychopathological evaluation being normal thereafter. Seizure freedom for the patient has led to psychosocial stabilization and the patient now is working as a household assistant and has acquired a driver’s license.

This reported case underscores the idea of an alternative approach as an add-on to regular pharmaceutical treatment. Long-term data on neurostimulation suggests increasing efficacy in patients with drug-resistant epilepsy, even in patients who do not immediately benefit from treatment and patience is worthwhile.

Original clinical data has suggested the effectiveness of tVNS® is on a comparable level to iVNS

[1] Bauer et al. Transcutaneous vagus nerve stimulation (tVNS) for treatment of drug-resistant epilepsy: A randomized, double-blind clinical trial (cMPsE02). Brain Stimulation, 2016; 9(3):356-363

[2] The vagus nerve stimulation study group: A randomized controlled trial of chronic vagus nerve stimulation for treatment of medically intractable seizure. Neurology, 1995; 45:224-30

[3] Handforth et al. Vagus nerve stimulation therapy for partial-onset seizures. A randomized active-control trial. Neurology, 1998; 51:48-55.

This study was a monocentric, prospective, double-blind, randomized, parallel group, controlled trial to assess the safety and efficacy of tVNS® treatment as a preventative therapy for chronic migraines. The study was conducted in a tertiary outpatient clinic in Germany (department of neurology, University of Munich) between March 2012 and July 2014.

Chronic migraine patients between 18-70 years with a diagnosis according to the ICHD-IIR, ≥15 headache days per month, a duration of disease ≥6 months, no migraine-prophylactic medication or stable migraine-prophylactic medication for ≥1 month. A total of 46 patients were randomized to receive 25 Hz (n=24, ITT) and 1 Hz (n=22) tVNS® stimulation for 4 hours daily over 3 months.

The primary outcome measure in this study was mean change in headache days per 28 days. A headache day was defined as a calendar day with a headache of ≥4 h duration, or a headache successfully aborted by acute headache medication or any other treatment known to be typically effective for the patient. Secondary outcome parameters were: i. % of ‘responders’ (subjects having at least 50% reduction of headache days per 28 days from baseline), ii. change in mean headache intensity, iii. change in days with acute medication intake per 28 days, iv. change in headache–related disability as assessed by Migraine Disability Assessment (MIDAS) and Headache Impact Test (HIT-6) questionnaires, v. number and type of adverse events.

Of 46 randomized patients, 40 completed the study (per protocol). Patients that received 1 Hz tVNS had significantly larger reduction in the headache days per 28 days than patients receiving 25 Hz tVNS (-7.0 ± 4.6, 36% reduction from baseline vs. -3.3 ± 5.4 days, 17% reduction from baseline; p=0.035, respectively). It was also found that 29.4% of patients receiving 1 Hz tVNS had a ≥50% reduction in headache days vs. 13.3% in the 25 Hz tVNS group. The number of days with intake of acute headache medication were significantly reduced in both groups. Headache intensity was not significantly changed in either treatment group and there were no differences.

HIT-6 and MIDAS scores were significantly improved in both groups. Among the patients treated with tVNS, there was high compliance, with the average number of stimulated hours per day being around 3.4 hours in all groups, corresponding to ~85% of the requested stimulation time.

No serious treatment related adverse events were found. Most adverse events were mild or moderate in severity and resolved without sequelae. The most frequent adverse events were mild or moderate pain at the site of stimulation, paresthesia or pruritus during or after stimulation, erythema, ulcer or scabbing.

In conclusion, treatment of chronic migraine by 1 Hz tVNS was safe and effective with a higher superiority than 25 Hz tVNS for reducing chronic migraines. tVNS treatment improves quality of life in chronic migraine patients and offers a patient compliant therapeutic option with good tolerability and safety. The efficacy of tVNS shown in this study is comparable to gold-standard medicative treatments used for migraine.