Elsevier

Autonomic Neuroscience

Volume 235, November 2021, 102840
Autonomic Neuroscience

Transcutaneous vagus nerve stimulation in the treatment of drug-resistant epilepsy

https://doi.org/10.1016/j.autneu.2021.102840Get rights and content

Highlights

  • TaVNS shows promising results concerning reduction of seizure frequency and seizure severity in PWE.

  • Adverse effects of taVNS are mild or moderate and mostly reversible.

  • Randomized double-blind clinical trials are needed for assessing efficacy and safety of taVNS in greater detail.

  • Mode of action is not fully understood yet.

Abstract

Epilepsy is a common chronic neurological disease with a high burden of illness. Invasive vagus nerve stimulation (iVNS) is a well-established treatment option in patients with epilepsy (PWE). More recently, transcutaneous vagus nerve stimulation (tVNS) was introduced, an alternative option which is particularly interesting because it does not require surgery and is instantaneously removable. Here, we thoroughly reviewed clinical data on efficacy and safety of tVNS in epilepsies.

Five prospective trials in 118 patients with drug-resistant epilepsies and 3 randomized controlled trials in 280 patients with drug-resistant epilepsies were carried out. Study protocols were heterogeneous in terms of patients' characteristics, used device, stimulation parameters, study duration and endpoints. Seizure reduction amounted up to 64%, with responder rates (seizure reduction ≥50%) up to 65%. Seizure freedom was reached in up to 24%, and even to 31% in a small pediatric study group. Seizure severity scores were provided in 4 studies, showing significant improvement in two of them. Adverse side effects were mostly headache, ear pain and skin alteration and rated as mild to moderate. Drowsiness might be depend on stimulation intensity. Quality of life scores reflecting burden of illness showed significant improvement in two studies.

Efficacy and safety of tVNS in PWE has to be interpreted as promising. Multicenter randomized double-blind clinical trials with standardized stimulation protocols and long-term follow-up studies are necessary to finally assess tVNS treatment outcome in drug-resistant epilepsies.

Introduction

An epileptic seizure is defined as a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain (Fisher et al., 2005). Seizures might occur due to acute brain illness (e.g. acute symptomatic seizure due to brain hemorrhages or systemic infection) as well as a symptom of a chronic illness, i.e. epilepsy. According to the recent proposal of the International League against Epilepsy, epilepsy is a disease of the brain with at least two unprovoked (or reflex) seizures, or one unprovoked (or reflex) seizure and a probability of further seizures of at least 60% occurring over the next 10 years or diagnosis of an epilepsy syndrome (Fisher et al., 2014). With a prevalence of 0.5 to 1%, epilepsy is one of the most common neurological diseases with about 50 million patients worldwide (GBD Neurology Collaborators, 2019; World Health Organization, 2019). Although two thirds of affected subjects achieve seizure-freedom with the first two appropriately chosen antiseizure medication (ASM), the other third requires extensive therapy attempts in order to achieve seizure-freedom or at least an acceptable seizure control (Kwan and Brodie, 2000). Failure of two tolerated and appropriately chosen and used ASM (whether as monotherapies or in combination) to achieve sustained seizure freedom is the recent definition of drug-resistance in epilepsy (Kwan et al., 2010). Unfortunately, newly developed ASMs have not resulted in a significantly higher rate of seizure-free patients, even though the tolerability and interaction profile of newer ASM seems to be more favorable (Chen et al., 2018). For some patients resective epilepsy surgery is a hope for seizure freedom or seizure reduction (Baud et al., 2018), nevertheless anesthesia and operation risk as well as postoperative deficits in cognition and vision have to be considered. For those who are not suitable or not willing to undergo resective surgical intervention or in whom surgical intervention failed, alternative treatment options are necessary.

Different methods of neurostimulation for seizure control are available. Invasive methods as deep brain stimulation of the anterior thalamus (DBS) (Fisher et al., 2010) or brain responsive (closed loop) neurostimulation (RNS) (Nair et al., 2020) and invasive (classical) vagus nerve stimulation (iVNS) were investigated in several trials (Overview in (Boon et al., 2018)). Due to their invasive nature, anesthesia and operation risk are inherent to all of these treatment opportunities and, if failing, reoperation is necessary. IVNS was approved in the 1990s and more than 100.000 patients with drug resistant epilepsy were implanted to date (Fisher et al., 2020), thus leading to broad experience: efficacy, determined by responder rate (subjects in whom seizure frequency is reduced by at least 50%) amounts up to 60% and seizure freedom was found in up to 8% of implanted PWE (Morris et al., 2013; Elliott et al., 2011; Englot et al., 2016). The overall complication rate ranges from 2.5 to 12%; they can be of technical (as cable break) or surgical nature (for example infection, hematoma, and vocal cord palsy). Surgical complication rate amounts up to 8.6.% (Révész et al., 2016), fortunately most complication symptoms recover well. Apart from operation risk and complication rate, iVNS displays limitations in MRI suitability and need regular onsite appointments for device check.

Given these restrictions and risks, transcutaneous vagus nerve stimulation (tVNS), the non-invasive external stimulation method, is an interesting alternative.

Section snippets

Transcutaneous vagal nerve stimulation in epilepsy patients

Different devices are available for transcutaneous vagal nerve stimulation, transcutaneous cervical VNS (tcVNS), percutaneous auricular VNS (paVNS) and transcutaneous auricular VNS (taVNS). Studies performed in PWE were carried out with the taVNS.

A proof of concept trial with taVNS over 9 months in 10 adult PWE showed a reduction of seizure frequency in 5 of 7 patients at 9 month follow-up. None of them reached seizure freedom; none of them was rated to be a responder (at least 50% reduction of

Quality of life, cognitive and emotional outcome, usability and handling

Not only seizures, but also side-effects from ASM, co-morbidities, and social consequences of seizures increase the burden of this illness on those affected. Therefore, simply counting seizure does not reflect benefit or risk of an intervention. For example good seizure control with negative cognitive effects leads to lower quality of life which reflects everyday living. Of course, there is no question that each additional seizure can be associated with an increased risk of health problems, but

Prediction of seizure reduction by taVNS

All types of intervention – including ASM, epilepsy surgery or neurostimulation - require valid data on outcome features when counseling PWE. Hence, personalized medicine and good medical practice is based on the combination of individual predictor assessment.

Some of the above mentioned studies provide correlations between outcome and patient features. Most studies did not find a correlation between seizure reduction and age (He et al., 2013; Rong et al., 2014b; Aihua et al., 2014), gender (He

taVNS and electrophysiology with focus on electroencephalography

Epilepsy is a clinical diagnosis and seizures usually are counted by patients and caregivers. To date, seizure counts are mostly provided with the help of paper diaries. However, new electronic and digital solutions with different wearable technologies, at least for tonic-clonic seizures, offer new possibilities of seizure registration. Diaries are subject of under- and overestimation, mal-compliance of documentation as well as false documentation by inaccurate event estimation (Hoppe et al.,

Conclusions

TaVNS studies in epilepsy yielded promising results PWE, with improved seizure control and severity. Quality of life increased in most patients (even if seizure control did not improve). Adverse effects are mild or moderate, mostly reversible and well tolerated. Handling is good and usability seems to be dependent on suggested daily stimulation time. Taking into account the currently available data, it remains unclear which patients benefit most from taVNS.

Available studies differ in used taVNS

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Declaration of competing interest

RvW has received fees as a speaker, consultant or travel support from Arvelle, Cerbomed, Desitin, GW pharmaceuticals, Eisai and UCB. RS has received fees as a speaker or consultant from Arvelle, Angelini, Bial, Desitin, Eisai, LivaNova, Novartis, UCB Pharma and UnEEG, and grants from the Deutsche Forschungsgemeinschaft (DFG), the Bundesministerium für Bildung und Forschung (BMBF), the Bundesministerium für Gesundheit, and the Marga and Walter Boll Stiftung.

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