Nov. 17, 2005

Epilepsy and Vagus Nerve Stimulation

Introduction

Epilepsy: Historical Viewpoints and Treatments
    Epilepsy, sometimes called “seizure disorder,” is not a mental illness, nor is it a disease. Rather, it is a neurological disorder that is characterized by recurrent seizures. People have tried to understand the nature of epilepsy since the time of the ancient Greeks, who called it epilepsia, literally meaning “to be seized by forces from without.” They termed it “the sacred disease,” because they believed that a person who experienced seizures was actually under the possession of a demon or evil spirit. Patricia Murphy, in the book Treating Epilepsy Naturally, quotes two neurologists’ explanation of the reasoning behind the Greeks’ view of epileptic seizures: “Only the gods could knock down a person, strip him of his reason, make his body thrash around and afterwards bring him round with no apparent ill effects” (16). Murphy continues by stating that the earliest known reference to epilepsy can be found on a tablet that was found in the region of the Persian Gulf and that dates back to roughly 2000 b.c.

    The first scientific paper on epilepsy was written by the famous Greek healer and “father of medicine,” Hippocrates of Cos. In the fifth century, he wrote:

[Epilepsy] appears to me nowise more divine nor more sacred than other diseases, but has a natural cause from which it originates. Men regard its nature and cause as divine from ignorance and wonder because it is not at all like to other diseases. (Hippocrates 154)

His proposition that epilepsy was not a spiritual condition but a physical one was not a viewpoint shared by many. Even as late as the 1800s, people still persisted in believing that epilepsy belongs to the realm of the supernatural, and accordingly, the treatments themselves tended to be little more than pseudoscientific nonsense. In the book Epilepsy: 199 Answers, Andrew Wilner—who is himself a neurologist and clinical neurophysiologist—describes the nature of these early “therapies” as useless and unpleasant inflictions. Some of these, he says, have included eating a raven’s egg or frog’s liver, drinking the blood of a gladiator, and drinking the bile of a dog upon killing the animal. One so-called remedy even went so far as to suggest that “the person who first saw the patient have a convulsion should urinate into his shoe, stir it and give it to the patient to drink” (25).

           Defining and Understanding Epilepsy

    Even neurologists would likely agree that coming up with a succinct, clear definition of epilepsy is quite a tall order. One of the reasons for this is that, according to Murphy, “the International Classification of Seizures identifies about forty types of epilepsy” (29). The Merriam-Webster Dictionary describes it as “any of various disorders marked by disturbed electrical rhythms of the central nervous system and typically manifested by convulsive attacks usually with clouding of consciousness” (“epilepsy”). Seizures can be defined as an abnormal electrical discharge of a group of neurons in the brain. However, a more specific understanding of neurons and the brain is useful. Murphy refers to what is called brain plasticity, or “the process by which the brain’s neural circuits are ‘wired’ and ‘rewired’” (26). Neurons, she says, have three components: a main cell body, an outgoing branch (axon) and an incoming branch (dendrite); these act as communication links with other nerve cells. Each neuron creates electrical nerve impulses, and each neuron is connected to hundreds of others by synapses. These communicate through neurotransmitters, which transmit chemical messages (27). Among other functions, these are what tell neurons to fire (or not to). Essentially, what happens during a seizure is due to an imbalance of neurotransmitters, and “groups of neurons in the brain become overstimulated” (Murphy 28). Two types of neurotransmitters exist: excitatory and inhibitory. If, shortly after the onset of a seizure, the inhibitory neurotransmitters manage to contain the excess discharges to one part of the brain, the person will likely suffer a less severe, petit mal (French, “small illness”) seizure—an “absence seizure.” The person generally has a momentary lapse of consciousness and appears to be in a light daze or stupor, is not aware of his surroundings and does not respond to stimuli for about three to ten seconds (Bazil 25).

    However, if the neurons are firing very rapidly, the inhibitory neurotransmitters may be temporarily unable to “restrain” the discharges, which spread throughout the brain and cause a grand mal (“great illness”), or “tonic-clonic,” seizure, in which the person loses consciousness and suffers a convulsion. The “tonic” phase may involve a strong increase in muscle tone, extreme hyperextension and nonsense vocalizations; the second, “clonic” phase most often involves involuntary twitching or jerking of limbs.

    With regard to the pattern of activity, seizures can be described as either partial (focal) or generalized. Partial seizures involve a localized part of the brain; generalized ones involve the whole cortex. Partial seizures sometimes, but not always, involve altered consciousness and a feeling of confusion; in some cases, a partial seizure may simply evoke a particular sensory experience, such as perceiving a scent, hearing music or seeing bright lights flashing. Generalized seizures include both absence and tonic-clonic seizures (Bazil 17, 24-27, 30).

Background

           The Vagus Nerve and VNS Therapy

    Ziad Nahas, in an article published in the Psychiatric Times, explains that the vagus nerve is often referred to as the wandering nerve (69). In fact, the word “vagus” is from the medieval Latin vagus nervus, which literally translates as “wandering nerve.” It is not clear when the nerve was first considered potentially significant in the treatment of certain types of epilepsy, though some knowledge of its function has been known since at least near the turn of the century; the 1918 edition of Gray’s Anatomy describes the vagus nerve in some depth. According to an informational page on a Healthcommunities.com-sponsored Web site, the vagus nerve, also referred to as the tenth cranial nerve, the vagus nerve “has motor functions in the larynx,” stomach and heart, as well as “sensory functions in the ears and tongue” (neurologychannel).

    Over the past century, Nahas says, researchers have been able to prove that stimulation of the vagus nerve has a noticeable effect on the neuronal activity in the central nervous system, and such stimulation of the nerve can affect the nerve’s connections to certain seizure-prone regions of the brain. Alan Guberman, in an article from the Canadian Medical Association Journal, refers to Dr. Jacob Zabara, the contemporary founder of VNS (Vagus Nerve Stimulation) Therapy, who in 1985 “proposed that VNS might disrupt the hypersychronous brain electrical activity that underlies epileptic seizures” (Guberman 1165). That year, Zabara showed the anticonvulsant effect of VNS by giving vagal stimulation to dogs after seizures had been induced in them. Three years later, history was made: The first VNS device was implanted in a human being. Even today, the mechanism of action of stimulation is not well- understood. However, Dr. Carl Bazil, in his book Living Well With Epilepsy, says that one of the predominant theories is that the stimulus from the VNS device affects the brainstem:

In theory, the stimulus travels up the nerve into the base of the brain (nerves can conduct impulses in both directions). The stimulating impulse goes into the brainstem, where the “nucleus” of nerve cell bodies that make up the vagus nerve reside. These neurons will then “backfire” and send impulses to other brainstem structures to which they are connected. In this way, conduction in the brainstem is altered and … improves seizure control. (137)          

Who Could Benefit From VNS Therapy?

    According to The Epilepsy Foundation Web site, vagus nerve stimulation is primarily used on three types of epilepsy: partial seizures (60 percent of VNS users), generalized seizures (25 percent) and Lennox-Gastaut Syndrome (15 percent) (“Answer Place”). The last is a type of epilepsy that occurs in infancy and early childhood and is marked by frequent, multiple types of seizures (Wilner 120). It is very difficult to control.

    Additionally, according to the neurologychannel site, “[VNS Therapy] also may be recommended as a treatment for photosensitive epilepsy and epilepsy resulting from head injury” (neurologychannel). And Marc S. George, in his article titled “Vagus Nerve Stimulation: A New Tool for Brain Research and Therapy,” concurs with numerous other sources that another common use of VNS is in patients with refractive epilepsy, which is generally defined as persistent epileptic seizures that have not responded to at least two or three anticonvulsant medications (George 291). This is sometimes called pharmacoresistant therapy (Guberman 1165), which carries essentially the same definition.

Analysis

    It is well-established that, although many questions remain as to why VNS Therapy works, it has often proven effective. Guberman is among many who point out the fact that research studies that have proven, through such means as magnetic resonance imaging and photon emission tomography, that there have been well-confirmed effects of VNS on certain neuroanatomical connections and areas of the brain (1165).

    Though the first patient was implanted with the device in 1988, it was not until 1994 that the VNS Therapy became commercially available for the first time—in Europe. Originally named the Neuro-Cybernetic Prosthesis (Nahas 69), it was first approved in the United States in 1997 (George 290). Since then—although the device has not always been successful and still has some potential risks—many patients have been greatly helped by the vagus nerve stimulator. According to one source, over 32,000 people have received the VNS system (“Answer Place”).

Further Detail: Who Is a Good Candidate?

    As previously stated, VNS Therapy is most often used for people who suffer from particular types of epilepsy, such as those with Lennox-Gastaut Syndrome, and those who have generalized epileptic seizures. VNS Therapy is often a last-resort method when all others have failed. Says Patricia Dean in the article “Surgery for Epilepsy,” all people who “have not responded to medical or diet therapy” or who have experienced adverse side effects from medication “should be evaluated for surgery” (Dean). She goes on to say that the best candidate for a VNS implant is a person “for whom AEDs [antiepilepsy drugs] have failed and surgery would not, or has not, helped.” Some people simply do not wish to undergo traditional surgery, while others (for various reasons, such as health risks) may not be eligible candidates, making VNS Therapy an often-attractive alternative.

Method of Surgical Procedure

    The surgery itself is not considered a particularly dangerous, or even difficult, one. Some liken it to the procedure performed in the implant of a pacemaker. The patient receives general anesthesia, and a neurosurgeon performs the operation. According to Cyberonics’ Patient’s Manual, which is given to those who have received a VNS Therapy System, the surgery involves two implantable parts: the Pulse Generator and the Lead (“Patient’s Manual” 12). The former is a multiprogrammable, bipolar pulse generator and is placed in the anterior chest wall. It carries electrical signals to the left vagus nerve via implantable leads, which are “wrapped around the cervical portion” of the left vagus nerve (Nahas 69). Even more specifically, according to a page on the Cyberonics Web site, the system stimulates the nerve “in the neck area inside the carotid sheath … below where the superior and inferior cervical cardiac branches separate from the vagus nerve” (“Resource Center”). When the implantation is complete, the doctor uses what is called a Programming Wand (in conjunction with the computer and appropriate software), which is a sort of external programming system that allows for adjustment of the timing (frequency) and amount of stimulation the patient will receive (“Patient’s Manual 12-13). The surgery can last between 45 minutes and two hours; the patient is generally kept overnight and discharged the next day. The patient receives one or more Cyberonics Magnets, which can be passed over the stimulator to either briefly activate or deactivate it (“Patient’s Manual” 13, 15). However, the device itself functions 24 hours a day and delivers the pulses at fixed intervals, such as 30-second stimulations at 5-minute intervals (Guberman 1166).

Safety, Benefits and Statistics Regarding VNS Therapy

    As with practically all technologies, some risks do exist with the VNS device; however, many of these can often be mitigated or avoided altogether. Many people agree that the potential benefits far outweigh the risks (though people also agree that the possible hazards and contraindications cannot be entirely ignored). One question that tends to worry some people, according to The Epilepsy Foundation, is that the VNS device may be rejected by the body. However, the site says, this is not a problem, because the system is “made of titanium, a material that is widely used for pacemakers and does not trigger an immune response” (“Answer Place”). On a related note, the device is also not known to have any effects on, or interactions with, small appliances, cellular phones, antitheft devices or metal detectors (“Patient’s Manual” 50-51); most routine medical procedures, such as ultrasounds or x-rays, also should not interfere with the VNS (“Answer Place”).

    The VNS system is beneficial in other ways, as well. The “VNS Therapy Facts” page of the Cyberonics Web site discusses many other advantages. For one, the surgery is quick and has a low incidence of complications. Furthermore, VNS therapy “requires a surgical procedure and cannot be used without the unanimous agreement of a patient, prescribing physician, surgeon, hospital and payer,” so it will not be used without much consideration of its potential risks and benefits to the patient. Besides, physicians can easily monitor and control the VNS system (“Therapy Facts”). And Guberman points out that “VNS has the distinct advantage of not depending on patient compliance: It functions automatically around the clock” (1166), which means that a patient is not at the same risk of missing a dose if he were taking medications.

    A number of other articles and studies have been extremely useful in backing and supporting Cyberonics’ own research statistics regarding safety. One paper, titled “Quality of Life After Vagus Nerve Stimulation for Intractable Epilepsy,” was printed in a European journal of neurology. The study mainly looks at the results of the QOLIE-89, a quality-of-life evaluation that considers 17 factors or variables (such as effect on memory, language, emotional stability and energy/fatigue); the findings suggest a “clinically meaningful improvement” in about 25 percent of the patients, but at least some degree of positive change in nearly all of them (McLachlan 17-19). Another study, involving children with refractory epilepsy, found even stronger results. These included an overall reduction (over 50 percent) in seizure frequency, duration and severity, and other beneficial side effects were reported in anywhere from 75 and 90 percent of patients (Nagarajan 15). Yet another study, involving “pediatric patients with intractable epilepsy,” found a 78 percent mean decrease (range 30 to 99 percent) in seizure frequency (Farooqui 121). The study, along with countless other research projects, have been mostly consistent in showing a wide range of benefits of VNS Therapy, including but not limited to actual epileptic activity.

    Perhaps one of the most intriguing aspects of vagus nerve stimulation—aside from the actual effect on epileptic seizures, of course—is what may have been an unintentional side effect of the stimulation. Extensively discussed in Mark George’s paper, VNS apparently can cause significant positive “mood effects” in epilepsy patients; that is, many of them reported a change in general attitude and mood. “Results demonstrated increased brain blood flow” in certain parts of the brain (such as the rostral medulla, thalamus and post-central gyrus) contralateral to the device, as well as decreased bilateral blood flow in the hippocampus, amygdala and cingulated gyrus (George 292). George summarizes with the statement that “VNS changes in activity of the brainstem, limbic system and other CNS areas are compatible with antidepressant activity.” He believes that VNS effects changes in levels of serotonin, norepinephrine and glutamate, all of which are “neurotransmitters implicated in the pathogenesis of major depression” (292).

Compared to Other Treatments

    Because VNS itself does not involve drugs or medications, there is no risk of the systemic toxicity sometimes associated with AEDs, nor does VNS cause some of the side effects that AEDs do, including liver failure, bone loss and rash (“Therapy Facts”). In fact, the safety advantages over AEDs are some of the most frequently cited reasons to use VNS Therapy. In Avenues, the Cyberonics newsletter, one article says that this is especially important for women who have epilepsy and are pregnant, because they have to “balance seizure control against the use of [AEDs] during pregnancy.” It can allow for a reduction of the amount of medicine a patient has to take (“Safety Advantages”).

    While many studies, including those since discussed, have done well to establish the comparative safety of vagus nerve stimulation to antiepileptic drugs, other research has shown that, in a noticeable number of cases, VNS Therapy can actually be even more effectively used in conjunction with AEDs (as opposed to being a complete substitute for them). “It [VNS] can be combined with antiepileptic drug therapy without adding sedative side effects,” for example, according to one study (Shields S62). A brief article on the two as complementary treatments says that one of the problems found with epileptic patients is that they may have more than one type of seizure—but because certain drugs are only meant to treat certain types of seizures, problems arise when drug interactions occur. Patients with VNS systems have to keep taking whatever epilepsy medications they are currently on, the article says, because it can be an invaluable way to reduce the number of drugs one has to take, making the combination a safer and more effective approach “for epilepsy patients [who] do not respond adequately to their epilepsy medications” (“Complementary”).

Risks of VNS Therapy

    For all the great things that VNS is doing for people, it is imperative to also consider (both on a patient-by-patient basis and in a broader scope) the level of potential for the associated risks associated with the therapy and surgery. To begin with, Guberman reports that there is a slight risk (in 0.1 percent of cases to date) of complications from surgery, including “wound infection” and “transient vocal chord paralysis” (1166). Also, he says, the leads in the neck could occasionally break. The Patient’s Manual says that there have been very rare instances in which the Pulse Generator or Lead has moved or “come through the skin” (43). Other surgical complications, though some are mostly just standard risks of surgery, include infection, pain at the site of incision, tissue reactions (such as inflammation), blood clotting, “pockets of fluid or fibrous tissue around the implanted devices” and minor surgical scars (“Patient’s Manual” 44). Cyberonics adds, “During the intraoperative Lead Test, rare incidents of bradycardia and/or asystole have occurred” (“Resource Center”). According to the neurologychannel site, other possible risks are surgical injury to the carotid artery or internal jugular vein.

    Some other risks involving the VNS itself (not the surgical procedure) exist; of course, device malfunction is a potential (though presumably unlikely) concern; it could be responsible for painful stimulation, direct current stimulation, neck pain or breathing problems (“Patient’s Manual” 45), all of which might cause nerve damage. Multiple sources also warn against excessive stimulation, as degenerative nerve damage from this has been observed in laboratory tests. The Resource Center warns that the device “may affect the operation of other implanted devices, such as cardiac pacemakers and implantable defibrillators,” both of which could cause the “inappropriate … responses” from the VNS Pulse Generator or cause it to have problems detecting the Cyberonics Magnet (when it is passed over the VNS).

    Two especially important precautions must be taken, according to both The Epilepsy Foundation and Cyberonics. One of these is that the patient must not have other medical conditions that the device could affect; for example, “people who have had certain other throat operations or disorders.” But perhaps the biggest warning is against using short-wave diathermy or therapeutic ultrasound diathermy, both of which are said to present a “significant risk.” Diathermy is used to “promote healing by heating deep muscular tissues with high-frequency electrical currents,” according to the Foundation. Diathermy is very dangerous to the VNS, because diathermy could cause the implant to heat up, “causing pain and … damage to surrounding nerves and tissue,” which could in turn lead to “loss of vocal cord function, or even death, if veins or arteries in the neck are damaged” (“Answer Place”; “Patient’s Manual”). People who are getting MRI scans should also notify the technicians, as only certain scanners are safe to the functioning of the implant.

    Some people experience lesser symptoms, most commonly including dyspnea, voice alteration or hoarseness, paresthesia, dyspepsia, shortness of breath and vomiting (George 290-1), though Cyberonics says that these symptoms may gradually lessen (or go away altogether) after a few days, weeks or months, depending on how well the body “acclimates” to the device. These problems can also be quickly adjusted (in most cases) by having the doctor to adjust how much stimulation is delivered or in what frequency. “In severely mentally retarded children who need assistance for feeding,” reports Guberman, there is some evidence that the risk of aspiration may be increased during stimulation” (1166).

    VNS has been known to occasionally have side effects that cause sleep disturbances, such as sleep apnea. One study, headed by Mary Marzec, looks almost exclusively at the effects of VNS on sleep-related breathing. She says that in a pilot study, a connection was established between VNS and “decreased respiratory airflow and effort during sleep” (930). She goes on to extensively discuss the findings, with a focus on the AHI, or Apnea-Hypopnea Index, which is calculated by taking the total number of episodes of either (apnea or hypopnea) and dividing by the number of hours of sleep; Marzec reports that 31 percent of the people studied reached “clinically significant levels” of AHI (933). She also adds that all subjects were observed to have some “decreases in airflow and effort coinciding with VNS activations.” In the conclusion, she does not warn against the use of VNS but instead says that she recommends further research to ensure that more serious problems will not be caused (934).

Conclusions

    Vagus nerve stimulation is not without its limitations, and it is not proven effective in everyone; in fact, it still has a long way to go. In a way, it is unfortunate that an even more comprehensive discussion of its risks is not possible here. One of the biggest drawbacks to VNS—stated almost unanimously, even by Cyberonics—is that the device does not generally become particularly effective until a year or two following its implantation. It is considered an invasive surgery, and various cost estimates range from $15,000 to $25,000, though most medical insurance will cover the cost. All told, it seems that this is a technology that does have risks but that is still comparatively safe and effective. Having a family member who used to have epilepsy makes it easy to say that nobody wants to have epilepsy or have to see someone suffer from it because of how many problems it causes. For people who have never seen an epileptic seizure, especially of the grand mal variety, it can be a surreal, frightening experience to watch.

    That a device the size of a small pocket-watch can help to control what may be described as a sort of “power surge” of the brain goes to show just how far technology and science have come—a far cry from believing that a person foaming at the mouth and shaking was being given messages from the gods, and a far better treatment than exorcising a person or giving them random animal parts to digest. Where will VNS be five, ten, twenty, fifty years from now? It has helped lead to the beginnings of the “next level” of neurology, including deep brain stimulation, an even more complex area of treatment. There is still the world to learn about how the brain works, and hopefully one day science will have come far enough that everything from epilepsy and psychological disorders will just seem like a bad dream.

    In the meantime, one of the best things we can do is not make the same mistake others did in the past—isolate people or otherwise make them out to be “less equal” than everyone else. For whatever reason, disabled persons often were treated as little more than a dumb, feeble person, a “freak of nature” or a lab rat. If we make the same mistakes as others who have gone before us did in how we treat those who are afflicted, then for whatever advancements technology may bring, we would be no better than even the most primitive people. Society is better measured by how it treats its people than by how fast or strong the technology may be.

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