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Voice-over: Welcome to Spotlight on Migraine, hosted by the Association of Migraine Disorders. Join us for fresh perspectives by medical experts and advocates as we explore the spectrum of migraine and dig deeper into this complex disease.

This episode is brought to you by our generous sponsor, Lundbeck.

Dr. Shin C. Beh: I’ll be speaking on non-invasive vagus nerve stimulation in the treatment of acute vestibular migraine attacks.

The Latin meaning of the vagus is “wandering,” and it relates to the long course of the vagus nerve throughout the body. It begins in the brain stem, the largest of the cranial nerves, and extends throughout the entire body, innervating the respiratory system, the cardiovascular system, and the gastrointestinal system, among others. 

The efferent fibers of the vagus nerve come predominantly from two nuclei in the brain stem, which are the nucleus ambiguus and the dorsal motor nucleus of the vagus nerves. The afferent fibers terminate in three major areas, one being the nucleus tractus solitarius — this is the main relay station for all afferent vagus projections — the spinal nucleus of the trigeminal nerve, and area postrema. 

There are several fiber types in the vagus nerve. The A-fibers are the large myelinated fibers in general, the B is the small myelinated fibers, and C are unmyelinated fibers. Most of the fibers in the vagus nerve, about 60 to 80 percent, consist of C-type fibers.

Vagus nerve stimulation has a long history in neurology, going back to the 19th century, when J. L. Corning found that vagus nerve stimulation could stop epileptic seizures. At that time, however, the reasoning for it was that epilepsy arose from excess blood supply to the brain, and so his device was designed to compress the carotid arteries to reduce blood supply to the brain and stimulate the vagus nerves on both sides, with the goal of reducing cardiac output and cutting down the blood supply to the brain. Now, although the reasoning was wrong, the stimulation of the vagus nerve did help with the epileptic seizures.

And so, VNS, although it was found in the 19th century, it kind of fell out of favor until the late 80s, when experiments and animal models showed that, indeed, vagus nerve stimulation could stop epileptic seizures. And so, in the 90s, VNS devices were approved for the treatment of refractory epilepsy, which are seizures that are not responsive to medications. 

Typically, there was surgical implantation of a stimulator device with leads that are in the upper chest and leads wrapping around the left cervical vagus nerve. The devices administer a regular stimulation to the vagus nerve to reduce the number of seizures, and when a patient feels that a seizure is coming on, they can wave a magnetic wand over the device and stimulate the vagus nerve again to terminate a seizure. It is fairly effective. About 20 to 40 percent of people with a VNS device find that their seizure frequency is reduced by more than 50 percent.

Now, VNS use in migraine treatments was, like a lot of discoveries in science and medicine, serendipitous. So, in 2002, there was a case report of an adult patient who had a VNS device placed for refractory epilepsy, and although it did not help with his seizures, they found, interestingly, that it reduced the number of migraine attacks and was able to abort migraine attacks in this patient.

And so, eventually, this led to the development of the gammaCore device. So the gammaCore device is a non-invasive vagus nerve stimulator that is placed on the neck. And, as you well expect, surgical implantation of a vagus-nerve-stimulating device could be accompanied by multiple complications, and, therefore, a non-invasive device would be ideal. It’s easy to carry around and very safe to administer. The device stimulates predominantly the A- and B-type of fibers and spares the C-fibers and therefore causes much less pain and carries far less risk of heart issues, particularly arrythmias.

I know this is a very busy slide, but it basically summarizes all the studies that have been done in the treatment of headache so far utilizing the gammaCore device. And, as you can see, for migraine headaches and for cluster headaches, there are multiple studies that show that the gammaCore device actually really helps with these disorders. 

Nothing was done for vestibular migraine until very recently. What I did was I had a group of patients who had vestibular migraine — established patients, a well-known history of vestibular migraine — which I follow on a regular basis. These were about 18 patients, mean age of about 45 years. Fourteen of these patients, when they came to see me in the clinic, were in the midst of an acute vestibular migraine attack, and five of — four of them, rather, had been a really bothersome interictal dizziness. And we’ll talk about these two separate groups in a bit.

In the first group, those that came with an acute vestibular migraine attack, these were 14 patients, mostly women. They had not taken any medications — no rescue medications, no benzodiazepines, and no antiemetics — and in most of them who had woken up that morning in the midst of a vestibular migraine attack, and they had been seen in clinic that same day. So this group was seen within about six hours of their vestibular migraine attack starting. In two patients, while they were sitting in the waiting room, they suffered a vestibular migraine attack, and we could treat them within 15 minutes of the onset.

Before we treated them with the gammaCore device, they were asked to grade their vertigo and headache using the Visual Analog Scale, a scale of 1 to 10, 1 being the mildest pain and 10 being the worst ever pain or vertigo severity. We then administered a two-minute bilateral neck stimulation starting first on the right and then on the left with the gammaCore device in line with the PRESTO study performed by Dr. Tassorelli’s group. Fifteen minutes after treatment with the gammaCore, we asked them to grade the severity of their vertigo and headache again using the same Visual Analog Scale.

And so we found that in 13 of 14 patients, there was improvement in the severity of the vertigo. Two patients experienced complete resolution, and five patients reported an at least 50 percent reduction in the severity of their vertigo. So this table shows that before treatment, the mean severity was about 5.2, and after treatment, it’s about 3.1, meaning about a 46-something-percent change — of a reduction in the severity of their vertigo. All five patients who experience headache with their attacks of vestibular migraine reported improvement in the headache severity.

Now, we treated about four patients for very bothersome interictal type of dizziness. So these were patients with PPPD, or persistent postural perceptual dizziness. They were not in the midst of a vestibular migraine attack; however, they did mention that their PPPD dizziness was just much more bothersome that particular day when they were seen in clinic. And so we offered them a treatment with the gammaCore device, but all four of them reported no change whatsoever in the severity of their dizziness after treatment.

It’s very, very well tolerated. Only one patient described some neck discomfort, muscle tightness in the neck, but all the others found that the treatment was very well tolerated.

In another group of patients that I saw, these were four patients — established patients, again, with vestibular migraine — who were seen in the midst of an acute attack. These were established patients, and I had well-documented interictal-examination findings. So these were patients I’d examined a few times during the attack-free period, and I was familiar with what their exam findings were. None of them had taken any rescue medications, benzodiazepines, or antiemetics.

Before treatment, we had them grade the severity of their vertigo and headache, again using the same Visual Analog Scale, 1 being the mildest vertigo or headache, 10 being the most severe vertigo or headache ever. And also they had a bedside neuro-otologic examination performed with video goggles. Fifteen minutes after treatment with the gammaCore device — and they were treated the same way as in the previous one, with one two-minute stimulation on the right side of the neck and a second one on the left side of the neck. Fifteen minutes after treatment, we had them grade the vertigo and headache again and we also performed the same examination. 

So, in this patient population, we found that, very similar to the first one, the severity of vertigo did get better and the severity of the headache as well. So, in all four patients, they had a reduction in the severity of their vertigo. Two of the patients report complete resolution of vertigo and complete resolution of headache.

Now, the interesting part was in this case series of patients, all of them had abnormal findings during the attack of vestibular migraine. So, in Patient 1, there was spontaneous right-beating nystagmus with removal of fixation, Patient 2 had spontaneous up-beat nystagmus with removal of fixation, and Patient 3 had positional right-beating nystagmus in the Dix-Hallpike positions. So these were the findings during the vestibular migraine attack. After the vestibular migraine attack, which means after they had been treated with the gammaCore device, there was no nystagmus whatsoever.

This was the video recording of Patient 1, and during the attack, as you can see, this patient has right-beating nystagmus with removal of fixation. After treatment, upon cessation of the vestibular migraine attack, as you can see, the nystagmus has completely resolved and he’s back to his usual interictal examination findings. One more time, as you can see, there’s right-beating nystagmus there, and after treatment, the nystagmus has completely resolved.

Now, Patient 4 was a far more interesting patient. This was a patient who had a history of right vestibular neuritis to about two years prior to the onset of any vestibular migraine symptoms. And so, at baseline on examination, he has left-beating nystagmus. Let’s watch what happens during a vestibular migraine attack and after treatment with the gammaCore device. During the attack, you see there’s extremely mild left-beating nystagmus. After treatment, upon cessation of his vestibular migraine attack, you notice that the left-beating nystagmus has become much more brisk. 

And so, in this patient, the interesting finding here is that his vestibular migraine attack actually resulted in a reduction of the nystagmus that he usually has during the interictal period. So the possible hypothesis here is that changes brought about by a vestibular migraine actually opposed the left-beating nystagmus that he usually has on interictal examination. And so when the vestibular migraine attack stopped, his usual left-beating nystagmus came right back. And see one more time. During the migraine attack, we see very little left-beating nystagmus, but after the attack, nystagmus comes right back.

So the main question is, How does non-invasive vagus nerve stimulation abort acute vestibular migraine attacks? What could be the possible explanation for this? And so I think the answer boils down to the connections, right, the networks that exist in our brain stem. There are intimate connections between the vestibular system and the vagus system, and you can tell this from a lot of the manifestations that we see in patients. So anything that causes a patient to suffer vertigo is accompanied by nausea, vomiting, and a variety of vegetative autonomic type of symptoms. The person becomes very pale, very sweaty. They feel really clammy. 

Orthostatic reflexes are also due to vestibular-vagal network, so the vestibular system detects when you are upright, when you change position, and induces the appropriate changes in your blood pressure and in your pulse rate to accommodate that. And these are accomplished through the vestibular-vagal connections. 

The trigeminal, the vestibular, and vagus systems also are intimately connected, and I think it is the connections between the three systems that are responsible for the benefits that we see with non-invasive vagus nerve stimulation in vestibular migraine. So the evidence of the connections between the three systems can be see in nausea that happens during the migraine, the motion sickness that a lot of migraine sufferers experience, and how vestibular stimulation often can trigger a migraine headache.

There are numerous brain stem locations where the trigeminal, the vagus, and the vestibular systems meet and talk to each other. The biggest one is, of course, the nucleus tractus solitarius. This is a huge meeting place for all three systems. The dorsal motor nucleus of the vagus nerve is another location where all three systems tend to connect, and other locations include the rostro-ventro-lateral medulla, the reticular formation, and the locus coeruleus as well as the nucleus intercalatus in the lower part of the medulla.

Other potential ways that the vagus nerve stimulation suppresses vestibular migraine may be because of modulation of GABA, dopamine, and norepinephrine levels. Now, as you may know, migraine is associated with deficiencies or problems with the GABA levels, with dopamine levels, with the norepinephrine levels, and so the vagus nerve stimulation may influence migraine attacks by modulating the levels of these neurotransmitters. 

Another way that VNS can suppress inflammation is by inhibiting the release of pro-inflammatory cytokines and results in a reduction in migraine. And, as we know, neurogenic inflammation is one of the critical components of a migraine attack, and so the VNS may act on migraines — it may terminate migraines by suppressing this inflammatory response.

Thank you very much.

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