The US Drug and Medical Device Regulatory Authority (FDA) recently approved the first implant that treats rheumatoid arthritis by electrical impulses sent to the vagus nerve. Vagus nerve stimulation has been used for the past 30 years to treat drug-resistant epilepsy, depression, severe headaches, and stroke recovery.
Some implants have also been available in Europe even longer than in the United States, others, recently approved by the FDA, have not yet reached the continent.
What exactly is the vagus nerve?
The vagus nerve is one of the largest communication pathways between the brain and the rest of the body. It starts in the brain, goes down both sides of the throat and reaches the heart, lungs, stomach and intestines. It has about 200,000 fibers and is the longest of the 12 cranial nerves.
About 80 percent of these fibers transmit information to the brain in real time about what is happening in the body, and the rest conduct signals in the opposite direction, from the brain to the organs, according to Kevin Tracey, MD, neurosurgeon and president of the Feinstein Institutes for Medical Research at Northwell Health (New York, USA). This allows the brain to monitor and regulate processes such as heart rate, breathing, digestion.
The vagus nerve is the main pathway of the parasympathetic nervous system, the part that helps the body digest, keep inflammation under control, and return to a state of calm after an episode of stress.
Hence the medical interest in its stimulation. Nerves transmit information through electrical impulses, and their signals can be influenced by controlled impulses. Because the branches of the vagus nerve reach more organs, researchers hope that its stimulation could be used in more diseases, as Tracy Centanni, a neuroscience researcher at the University of Florida, told The New York Times.
In medical practice there are two types of vagus nerve stimulation devices. Some are surgically mounted implants, used for clear diagnoses and evaluated as medical devices. Others are non-invasive devices applied to the skin, usually around the neck or ear.
Conditions for which vagus nerve stimulation implants are used
The implants are placed under the skin in the neck or chest area and directly stimulate the nerve. The first such device, the VNS Therapy system, received FDA approval in 1997 as an adjunctive therapy for refractory epilepsy, meaning epilepsy that does not respond to medication. It is used in parallel with the medication, it does not replace it. In Europe, the device has been used even longer than in the US, having been approved for treatment-resistant epilepsy since 1994, three years before US approval, and since then more than 125,000 patients worldwide have received the implant.
The newer model, SenTiva, received CE marking (the authorization required to market the device on the European market) in 2018 for the treatment of drug-resistant epilepsy. Later, the system was also used in pediatric patients, including in European centers such as King's College Hospital in London.
In epilepsy, the therapy has one of the best documented uses. In a study of 454 patients, 37% of them saw a reduction in the frequency of seizures by half or more after one year, and after two to three years, the proportion reached 43%. In 2022, the eligibility criteria were extended to children from 4 years of age, for focal seizures, also called partial seizures.
Some newer models can detect the rapid changes in heart rate that often precede a seizure and automatically trigger additional pacing. The feature is especially useful for patients who do not realize they are having a seizure or who have seizures during sleep.
Depression
The same system was approved by the FDA in 2005 for treatment-resistant depression, defined as the failure of at least two adequate antidepressant treatments in the current depressive episode. In Europe, the Symmetry model is also available for this indication, which received CE marking for intractable depression in March 2020. The first patients received the implant in Great Britain, at Musgrove Park Hospital in Taunton, through a treatment plan developed together with the NHS, the British public health system.
In depression, stimulation works differently than in epilepsy. The device sends pulses at preset intervals without manual activation. Results appear slowly, sometimes after a few months or even a year.
Recovery after stroke
Another important use of vagus nerve stimulation was approved by the FDA in 2021. The Vivistim System is used in conjunction with medical rehabilitation in patients who have difficulty moving their arm after an ischemic stroke. The device sends impulses to the vagus nerve during exercise to help the brain better rebuild the connections involved in movement.
According to studies, it can be a therapeutic option including for limb paralysis caused by an ischemic vascular accident. Researchers have shown that vagus nerve stimulation combined with medical rehabilitation can improve upper limb function in patients with ischemic stroke sequelae. The method does not cancel the consequences of the vascular accident, but it can support the restoration of some movements when integrated into a rehabilitation program.
Unlike systems used for epilepsy and depression, Vivistim is currently only licensed in the US.
Rheumatoid arthritis
The most recent approval is the SetPoint system, for treating rheumatoid arthritis. The device is the size of a bean and is implanted in the left side of the neck on an outpatient basis. It sends electrical impulses into the vagus nerve for one minute a day and activates the body's natural anti-inflammatory reflex. The patient doesn't have to do anything other than recharge the implant for a few minutes a week, and the battery has a shelf life of up to ten years.
The idea stemmed from Dr. Kevin Tracey's research into the connection between the vagus nerve and inflammation. If certain signals sent through this nerve can reduce the inflammatory response, then its electrical stimulation could be used to limit inflammation in diseases such as rheumatoid arthritis. This mechanism involves the vagus nerve sending signals to the brain and the brain further influencing the spleen. The desired result is the reduction of some inflammatory proteins, especially the tumor necrosis factor, TNF, involved in joint destruction.
The approval was based on the RESET-RA clinical trial, a randomized trial that included 242 adults with moderate or severe rheumatoid arthritis. Participants had not responded sufficiently to biological drugs or targeted synthetic therapies. The published data showed that about three-quarters of them, 182 people, saw an improvement in symptoms after implantation without the need for additional therapy.
Like Vivistim, SetPoint currently has FDA approval in the US, but no European CE marking.
Non-invasive prescription devices
Medically approved non-invasive vagus nerve stimulation devices are applied to the neck or ear without the need for any surgery. This category is evaluated by the FDA to a less stringent standard of safety and effectiveness than implants. The best known is the gammaCore, a portable device that is applied to the neck above the path of the vagus nerve and can be used by the patient at home.
The indications of the device were gradually expanded. It received its first FDA approval in 2017 for the acute treatment of episodic cluster headache pain, then in January 2018 for the acute treatment of migraine pain in adults. Also in 2018, it was also authorized for the prevention of cluster headaches in adults, being the first and only product approved for the prevention of this condition.
More recently, the FDA expanded indications for migraine in adolescents 12 to 17 years of age and then for paroxysmal hemicrania and continuous hemicrania in adults, becoming the first treatment, drug or device approved for these rare forms of headache.
In Europe, gammaCore is CE marked for the acute treatment and prevention of primary headache, and in England and Scotland it is also approved for cluster headache, being one of the few vagus nerve stimulation devices reimbursed by a European public health system. In addition to gammaCore, the FDA has also cleared several noninvasive devices that can reduce opioid withdrawal symptoms: NSS-2 Bridge, Drug Relief, Sparrow, and NET.
What is freely available online
The problem arises with devices that anyone can buy online, without a prescription and without a doctor's recommendation. Many look, at first glance, like non-invasive medical devices. Worn in the ear or around the neck, they produce tingling, small electrical impulses and sometimes a perceptible change in heart rate.
However, these sensations do not automatically mean that the vagus nerve is being effectively stimulated. Michael Kilgard, director of the Texas Biomedical Device Center at the University of Texas Dallas, USA, explained to The New York Times that they can occur simply because a weak current passes through the skin. In other words, the fact that the user feels something does not prove that the device is influencing the vagus nerve in the promised way.
Kristl Vonck, a neuroscientist at the University of Ghent, Belgium, points out that these consumer products are not well regulated and, in order to be marketed, do not need to prove that they actually work. To be sold as wellness gadgets, many eschew clear medical promises and use wording that is difficult to verify. They say they support energy, sleep, memory, or the gut-brain connection, without proving that they treat disease or measurably alter vagus nerve activity. Some companies rely on small studies with high margins, and others borrow the language of serious research as a marketing technique.
The Cleveland Clinic notes that commercial externally applied devices cannot reach the frequencies and voltages used by implanted devices because their signals must pass through the skin and muscles of the neck and are not precise enough to access and regulate the specific activity of the vagus nerve. The long-term effects of these commercial devices are not yet fully known.
Overall, the immediate risks appear low. The devices may cause tingling, local discomfort or a slight reddening of the skin, but the batteries are usually too weak to cause burns. The more serious problem is not necessarily the electric shock, but the confidence these sensations can create. Dr. Kilgard said he has encountered patients who have bought such gadgets and put off treatments with proven effectiveness. For many, the fact that they immediately feel something new, different, can be enough to believe that the device is working.
