Vagus nerve stimulation | |
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Other names | Vagal nerve stimulation |
Vagus nerve stimulation (VNS) is a medical treatment that involves delivering electrical impulses to the vagus nerve. It is used as an add-on treatment for certain types of intractable epilepsy, cluster headaches, treatment-resistant depression and stroke rehabilitation.
VNS is used to treat drug-resistant epilepsy. [1]
In the United States, VNS is approved as adjunctive therapy for those 4 years of age or older with refractory focal onset seizures. In the European Union, VNS is approved as an adjunctive therapy for patients with either generalized or focal onset seizures without any age restrictions. [2] It is recommended that VNS is only pursued following an adequate trial of at least 2 appropriately chosen anti-seizure medications and that the patient is ineligible for epilepsy surgery. [3] This is because epilepsy surgery is associated with a higher probability of resulting in seizure freedom. [4] Patients who have poor adherence or tolerance of anti-seizure medications may be good candidates for VNS. [5]
VNS may provide benefit for particular epilepsy syndromes and seizure types such as Lennox-Gastaut syndrome, tuberous sclerosis complex related epilepsy, refractory absence seizures and atonic seizures. [6] [7] [8] [9] There are also reports of VNS being successfully utilized in patients with refractory and super-refractory status epilepticus. [10]
The UK National Institute for Health and Care Excellence (NICE) in the UK recommends VNS for cluster headaches. [11] device was used in these studies:
VNS is used to treat treatment-resistant major depressive disorder (TR-MDD). [12] The UK NICE guidance (from 2020) stated that "Evidence on its efficacy is limited in quality." and encouraged further research studies "in the form of randomised controlled trials with a placebo or sham stimulation arm." [13]
In 2021 the U.S. Food and Drug Administration approved the MicroTransponder Vivistim Paired VNS System (Vivistim System) to treat moderate to severe upper extremity motor deficits associated with chronic ischemic stroke. [14] [15]
Beyond its use in epilepsy and depression, VNS has shown potential benefits in treating other conditions such as inflammatory diseases. Ongoing research is exploring the broader applications of VNS in various medical fields. [16]
A meta-analysis of 74 clinical studies with 3321 patients found that VNS produced an average 51% reduction in seizures after 1 year of therapy. [17] Approximately 50% of patients had an equal to or greater than 50% reduction in seizures at the time of last follow-up. [17] Long-term studies have shown that response to VNS increases over time. For instance, a study that followed 74 patients for 10–17 years found a seizure frequency reduction of 50-90% in 38.4%, 51.4%, 63.6% and 77.8% of patients at 1-, 2-, 10- and 17-years following implantation, respectively. [18] Approximately, 8% have total resolution of seizures. [19] VNS has also been shown to reduce rates of sudden unexpected death in epilepsy (SUDEP) and to improve quality of life metrics. [20] [21] A number of predictors of a favorable clinical response have been identified including epilepsy onset > 12 years of age, generalized epilepsy type, non-lesional epilepsy, posttraumatic epilepsy and those who have less than a 10-year history of seizures. [17] [19] [22]
Long-term cognitive outcomes are at least stable following VNS. [23]
One study of children with epilepsy found that a post hoc analysis revealed a dose–response correlation for VNS. [24]
A 2022 narrative review concluded that "The use of VNS is an approved, effective and well-tolerated long-term therapy for chronic and treatment-resistant depression. Further sham-controlled studies over a longer observational period are desirable". [25] [26]
The review also found that, "Many studies and case series demonstrated the efficacy of VNS as an adjuvant procedure for TRD (treatment resistant depression). The effect occurs with a latency period of 3–12 months and possibly increases with the duration of VNS." [25] One study of only 10 weeks found no effect. [27]
A 2020 review concluded "Reviewed studies strongly suggest that VNS ameliorates depressive symptoms in drug-resistant epileptic patients and that the VNS effect on depression is uncorrelated to seizure response. [28]
In one study higher electrical dose parameters were associated with response durability. [29]
VNS may have positive wellbeing, mood and quality of life effects. [30] [31]
Studies have found improvements in standard patient-reported mood assessment scales in adult patients with epilepsy after using VNS, [3] and some have found no association between mood change and reduction in seizure frequency. [32] [33] Another study of epilepsy patients measured a general mood improvement, and suggested that VNS may improve unspecific states of indisposition and dysphoria. [34] Patients with comorbid depression have been found to have mood improvements with VNS therapy. [35]
Quality of life (QOL) improvement was also associated with VNS use. [36] One study of children with epilepsy found that better quality of life outcomes after VNS implantation were strongly associated with shorter duration of preoperative seizures and implantation at a young age. [37]
Anxiety reduction has been associated with VNS use. [38] [39] [40] Another study showed improvement in anxiety, depression and QOL scores that were not correlated with a reduction in seizure frequency. [41]
However these studies were small, and recommendations have been made that larger studies with randomised control groups be undertaken. [42]
In cardiac arrest VNS used in conjunction with cardiopulmonary resuscitation (CPR) has been shown to increase recovery time {return of spontaneous circulation) as well as reduce the number of shocks required when used in conjunction with cardioversion. [43] Numerous pre-clinical studies have shown the effectiveness of VNS in reducing atrial fibrillation and hypertension. [43]
Very small studies have shown possible efficacy of VNS for reduction of Sjogren's fatigue, [44] [45] and for bowel inflammatory disease. [46]
Piezoelectric BaTiO3 particles conjugated with capsaicin were designed as orally Ingested electrostimulators to activate the vagus nervers to combat obesity. This intervention has not yet been tested on the human body. [47]
The causes of VNS efficacy are not well understood.
Mechanisms which may account for the efficacy of VNS include:
There is evidence that VNS results in cortical desynchronization in epilepsy patients who had a favorable clinical response relative to those who did not. [48] [49] [50] This makes sense given that seizures consist of abnormal hypersynchronous activity in the brain.
Multiple lines of evidence suggest that inflammation plays a significant role in epilepsy as well as associated neurobehavioral comorbidities such as depression, autism spectrum disorder and cognitive impairment. [51] There is evidence that VNS has an anti-inflammatory effect through both peripheral and central mechanisms. [52] [46]
VNS can change the activity of several neurotransmitter systems involving serotonin, norepinephrine and GABA. [53] [54] These neurotransmitters are involved in both epilepsy and other neuropsychiatric conditions such as depression and anxiety.
VNS may alter the functional connectivity in several brain regions and enhance synaptic plasticity to reduce excitatory activity involved in seizures. [55] [56] It has also been shown to change the functional connectivity of the default mode network in depressed patients. [57]
VNS may influence the vagus nerve, which plays a role in the gut-brain axis. [58] [59]
Some believe that indirect stimulation of the thalamus may be a key mechanism in VNS efficacy. [30]
A large 25-year retrospective study of 247 patients found a surgical complication rate of 8.6%. [60] The common adverse events included infection in 2.6%, hematoma at the surgical site in 1.9% and vocal cord palsy in 1.4%. [60]
In some rare cases where the VNS is not effective, surgery may be necessary to remove the VNS system. The surgery may remove both the generator and the lead. [61]
The most common stimulation related side effect at 1 year following implantation are hoarseness in 28% and paraesthesias in the throat-chin region in 12%. [62] At the third year the rate of stimulation related adverse effects decreased substantially with shortness of breath being the most common and occurring in 3.2%. [62] In general, VNS is well tolerated and side effects diminish over time. Also, side effects can be controlled by changing the stimulation parameters.
One small study found sleep apnea in as many as 28% of adults with epilepsy treated with VNS. [63]
Another small study found significant daytime drowsiness, which could be relieved by reducing the stimulation intensity. [41]
Because vagal tone can reduce heart rate, VNS carries the risk of bradycardia (excessively slow heart rate, and even of stopping the heart. [43]
A range of side effects are possible but rare. [25]
The device consists of a generator the size of a matchbox that is implanted under the skin below the person's collarbone. Lead wires from the generator are tunnelled up to the patient's neck and wrapped around the left vagus nerve at the carotid sheath, where it delivers electrical impulses to the nerve. [64]
Implantation of the VNS device is usually done as an out-patient procedure. The procedure goes as follows: an incision is made in the upper left chest and the generator is implanted into a little "pouch" on the left chest under the collarbone. A second incision is made in the neck, so that the surgeon can access the vagus nerve. The surgeon then wraps the leads around the left branch of the vagus nerve, and connects the electrodes to the generator. Once successfully implanted, the generator sends electric impulses to the vagus nerve at regular intervals. The left vagus nerve is stimulated rather than the right because the right plays a role in cardiac function such that stimulating it could have negative cardiac effects. [12] [65] The "dose" administered by the device then needs to be set, which is done via a magnetic wand; the parameters adjusted include current, frequency, pulse width, and duty cycle. [12]
The intravenous VNS system produced by LivaNova has stated default settings for use in depression of output power 1.25mA, frequency 20 Hz and pulse width 250 μs, with operation occurring for 30 seconds every 5 minutes (giving a work cycle of 10%). [25]
External devices work by transcutaneous stimulation and do not require surgery. Electrical impulses are targeted at the vagus nerve in the neck, or aurical (ear), at points where branches of the vagus nerve have cutaneous representation. GammaCore is recommended by The National Institute for Health and Care Excellence (NICE) for cluster headaches. [66]
James L. Corning (1855-1923) was an American neurologist who developed the first device for stimulating the vagus nerve towards the end of the 19th century. [67]
At this time a widely held theory was that excessive blood flow caused seizures. [67]
In the 1880s Corning designed a pronged instrument called the “carotid fork” to compress the carotid artery for the acute treatment of seizures. In addition, he developed the “carotid truss” for prolonged compression of the carotid arteries as a long-term preventative treatment for epilepsy. Then he developed the “electrocompressor” which allowed for the compression of the bilateral carotid arteries as well as electrical stimulation of both the vagus and cervical sympathetic nerves. The idea was to reduce cardiac output and to stimulate cervical sympathetic nerves to constrict cerebral blood vessels. Corning reported dramatic benefits however it was not accepted by his colleagues and ultimately was forgotten. [67]
In the 1930s Biley and Bremer demonstrated the direct influence of VNS on the central nervous system. [68] In the 1940s and 1950s vagal nerve stimulation was shown to affect EEG activity. [69]
In 1985 neuroscientist Jacob Zabara [70] proposed that VNS could be used to treat epilepsy. [71] He then demonstrated its efficacy in animal experiments. [72] The first human was implanted with a VNS for the treatment of epilepsy in 1988. [73]
In 1997, the US Food and Drug Administration's neurological devices panel met to consider approval of an implanted vagus nerve stimulator (VNS) for epilepsy, requested by Cyberonics (which was subsequently acquired by LivaNova). [64]
The FDA approved an implanted VNS for TR-MDD in 2005. [12]
In April 2017, the FDA cleared marketing of a handheld noninvasive vagus nerve stimulator, called "gammaCore" and made by ElectroCore LLC, for episodic cluster headaches, under the de novo pathway. [74] [75] In January 2018, the FDA cleared a new use of that device, for the treatment of migraine pain in adults under a 510(k) based on the de novo clearance. [76] [77]
In 2020, electroCore's non-invasive VNS was granted an Emergency Use Authorization for treating COVID-19 patients, given Research has shown this pulse train causes airways in the lungs to open its anti-inflammatory effect. [78]
Because the vagus nerve is associated with many different functions and brain regions, clinical research has been done to determine its usefulness in treating many illnesses. These include various anxiety disorders, [79] obesity, [80] [81] alcohol addiction, [82] chronic heart failure, [83] prevention of arrhythmias that can cause sudden cardiac death, [84] autoimmune disorders, [85] [86] irritable bowel syndrome, [87] [88] [89] Alzheimer's disease, [90] [91] Parkinson's disease, [92] hypertension, [93] [94] several chronic pain conditions, [95] inflammatory disorders, fibromyalgia and migraines. [96] [97]
A 2022 study showed that chronic VNS showed strong antidepressant and anxiolytic effects, and improved memory performance in an Alzheimer's Disease animal model. [98]
Epilepsy is a group of non-communicable neurological disorders characterized by recurrent epileptic seizures. An epileptic seizure is the clinical manifestation of an abnormal, excessive, and synchronized electrical discharge in the neurons. The occurrence of two or more unprovoked seizures defines epilepsy. The occurrence of just one seizure may warrant the definition in a more clinical usage where recurrence may be able to be prejudged. Epileptic seizures can vary from brief and nearly undetectable periods to long periods of vigorous shaking due to abnormal electrical activity in the brain. These episodes can result in physical injuries, either directly, such as broken bones, or through causing accidents. In epilepsy, seizures tend to recur and may have no detectable underlying cause. Isolated seizures that are provoked by a specific cause such as poisoning are not deemed to represent epilepsy. People with epilepsy may be treated differently in various areas of the world and experience varying degrees of social stigma due to the alarming nature of their symptoms.
The vagus nerve, also known as the tenth cranial nerve, cranial nerve X, or simply CN X, is a cranial nerve that carries sensory fibers that create a pathway that interfaces with the parasympathetic control of the heart, lungs, and digestive tract.
Transcranial magnetic stimulation (TMS) is a noninvasive form of brain stimulation in which a changing magnetic field is used to induce an electric current at a specific area of the brain through electromagnetic induction. An electric pulse generator, or stimulator, is connected to a magnetic coil connected to the scalp. The stimulator generates a changing electric current within the coil which creates a varying magnetic field, inducing a current within a region in the brain itself.
Deep brain stimulation (DBS) is a surgical procedure that implants a neurostimulator and electrodes which sends electrical impulses to specified targets in the brain responsible for movement control. The treatment is designed for a range of movement disorders such as Parkinson's disease, essential tremor, and dystonia, as well as for certain neuropsychiatric conditions like obsessive-compulsive disorder (OCD) or neurological disorders like epilepsy. The exact mechanisms of DBS are complex and not entirely clear, but it is known to modify brain activity in a structured way.
A corpus callosotomy is a palliative surgical procedure for the treatment of medically refractory epilepsy. The procedure was first performed in 1940 by William P. van Wagenen. In this procedure, the corpus callosum is cut through, in an effort to limit the spread of epileptic activity between the two halves of the brain. Another method to treat epilepsy is vagus nerve stimulation.
Lennox–Gastaut syndrome (LGS) is a complex, rare, and severe childhood-onset epilepsy syndrome. It is characterized by multiple and concurrent seizure types including tonic seizure, cognitive dysfunction, and slow spike waves on electroencephalogram (EEG), which are very abnormal. Typically, it presents in children aged 3–5 years and most of the time persists into adulthood with slight changes in the electroclinical phenotype. It has been associated with perinatal injuries, congenital infections, brain malformations, brain tumors, genetic disorders such as tuberous sclerosis and numerous gene mutations. Sometimes LGS is observed after infantile epileptic spasm syndrome. The prognosis for LGS is marked by a 5% mortality in childhood and persistent seizures into adulthood.
The auricular branch of the vagus nerve is often termed the Alderman's nerve or Arnold's nerve. The auricular branch of the vagus nerve supplies sensory innervation to the skin of the ear canal, tragus, tympanic membrane and auricle.
In the field of neurology, temporal lobe epilepsy is an enduring brain disorder that causes unprovoked seizures from the temporal lobe. Temporal lobe epilepsy is the most common type of focal onset epilepsy among adults. Seizure symptoms and behavior distinguish seizures arising from the medial temporal lobe from seizures arising from the lateral (neocortical) temporal lobe. Memory and psychiatric comorbidities may occur. Diagnosis relies on electroencephalographic (EEG) and neuroimaging studies. Anticonvulsant medications, epilepsy surgery and dietary treatments may improve seizure control.
Frontal lobe epilepsy (FLE) is a neurological disorder that is characterized by brief, recurring seizures arising in the frontal lobes of the brain, that often occur during sleep. It is the second most common type of epilepsy after temporal lobe epilepsy (TLE), and is related to the temporal form in that both forms are characterized by partial (focal) seizures.
Treatment-resistant depression (TRD) is major depressive disorder in which an affected person does not respond adequately to at least two different antidepressant medications at an adequate dose and for an adequate duration. Inadequate response has most commonly been defined as less than 25% reduction in depressive symptoms following treatment with an antidepressant. Many clinicians and researchers question the construct validity and clinical utility of treatment-resistant depression as currently conceptualized.
Juvenile myoclonic epilepsy (JME), also known as Janz syndrome or impulsive petit mal, is a form of hereditary, idiopathic generalized epilepsy, representing 5–10% of all epilepsy cases. Typically it first presents between the ages of 12 and 18 with myoclonic seizures. These events typically occur after awakening from sleep, during the evening or when sleep-deprived. JME is also characterized by generalized tonic–clonic seizures, and a minority of patients have absence seizures. It was first described by Théodore Herpin in 1857. Understanding of the genetics of JME has been rapidly evolving since the 1990s, and over 20 chromosomal loci and multiple genes have been identified. Given the genetic and clinical heterogeneity of JME some authors have suggested that it should be thought of as a spectrum disorder.
Responsive neurostimulation device is a medical device that senses changes in a person's body and uses neurostimulation to respond in the treatment of disease. The FDA has approved devices for use in the United States in the treatment of epileptic seizures and chronic pain conditions. Devices are being studied for use in the treatment of essential tremor, Parkinson's disease, Tourette's syndrome, depression, obesity, and post-traumatic stress disorder.
A vagal maneuver is an action used to stimulate the parasympathetic nervous system by activating the vagus nerve. The vagus nerve is the longest nerve of the autonomic nervous system and helps regulate many critical aspects of human physiology, including heart rate, blood pressure, sweating, and digestion through the release of acetylcholine. Common maneuvers that activate the vagus nerve include the Valsalva maneuver and carotid sinus massage, which can serve diagnostic or therapeutic functions.
Epilepsy is a neurological condition of recurrent episodes of unprovoked epileptic seizures. A seizure is an abnormal neuronal brain activity that can cause intellectual, emotional, and social consequences. Epilepsy affects children and adults of all ages and races, and is one of the most common neurological disorders of the nervous system. Epilepsy is more common among children than adults, affecting about 6 out of 1000 US children that are between the age of 0 to 5 years old. The epileptic seizures can be of different types depending on the part of the brain that was affected, seizures are classified in 2 main types partial seizure or generalized seizure.
Cortical stimulation mapping (CSM) is a type of electrocorticography that involves a physically invasive procedure and aims to localize the function of specific brain regions through direct electrical stimulation of the cerebral cortex. It remains one of the earliest methods of analyzing the brain and has allowed researchers to study the relationship between cortical structure and systemic function. Cortical stimulation mapping is used for a number of clinical and therapeutic applications, and remains the preferred method for the pre-surgical mapping of the motor cortex and language areas to prevent unnecessary functional damage. There are also some clinical applications for cortical stimulation mapping, such as the treatment of epilepsy.
Neuromodulation is "the alteration of nerve activity through targeted delivery of a stimulus, such as electrical stimulation or chemical agents, to specific neurological sites in the body". It is carried out to normalize – or modulate – nervous tissue function. Neuromodulation is an evolving therapy that can involve a range of electromagnetic stimuli such as a magnetic field (rTMS), an electric current, or a drug instilled directly in the subdural space. Emerging applications involve targeted introduction of genes or gene regulators and light (optogenetics), and by 2014, these had been at minimum demonstrated in mammalian models, or first-in-human data had been acquired. The most clinical experience has been with electrical stimulation.
Drug-resistant epilepsy (DRE), also known as refractory epilepsy, intractable epilepsy, or pharmacoresistant epilepsy refers to a state in which an individual with a diagnosis of epilepsy is unresponsive to multiple first line therapies. Based on the 2010 guidelines from the International League against Epilepsy (ILAE), DRE is officially diagnosed following a lack of therapeutic relief in the form of continued seizure burden after trialing at least two antiepileptic drugs (AEDs) at the appropriate dosage and duration. The probability that the next medication will achieve seizure freedom drops with every failed AED. For example, after two failed AEDs, the probability that the third will achieve seizure freedom is around 4%. Drug-resistant epilepsy is commonly diagnosed after several years of uncontrolled seizures, however, in most cases, it is evident much earlier. Approximately 30% of people with epilepsy have a drug-resistant form. Achieving seizure control in DRE patients is critical as uncontrolled seizures can lead to irreversible damage to the brain, cognitive impairment, and increased risk for sudden unexpected death in epilepsy called SUDEP. Indirect consequences of DRE include seizure related injuries and/or accidents, impairment in daily life, adverse medication effects, increased co-morbidities especially psychological, and increased economic burden, etc.
Fabrice Bartolomei is a French neurophysiologist, and University Professor at Aix-Marseille University (AMU), leading the Service de Neurophysiologie Clinique of the Timone Hospital at the Assistance Publique - Hôpitaux de Marseille, and he is the medical director of the ‘Centre Saint-Paul - Hopital Henri Gastaut’. He is the coordinator of the clinical network CINAPSE that is dedicated to the management of adult and pediatric cases of severe epilepsy and leader of the Federation Hospitalo-Universitaire Epinext. He is also member of the research unit Institut de Neurosciences des Systèmes.
Julian Koenig is a German neuroscientist who is tenured associated professor of biological child and adolescent psychiatry at University of Cologne. Koenig is co-editor of European Child & Adolescent Psychiatry, affiliate editor of the Journal of Child Psychology and Psychiatry, and consulting editor of Psychophysiology.
Interventional Psychiatry is a subspecialty within the field of psychiatry, focusing on the use of procedural and device-based treatments to manage mental health disorders, particularly those resistant to conventional therapies such as pharmacotherapy and psychotherapy. This field integrates neuromodulation methods with targeted pharmacological interventions, providing options for patients who have not responded to traditional treatments.