Vagal Nerve Stimulation - A New Paradigm for Treating EpilepsyEpilepsy is a common neurological problem affecting over 1 percent of the population in the United States. In most cases, medications can be utilized to treat the symptom of epilepsy, seizures. However, in a smaller group of patients, 10-20 percent of individuals with epilepsy, medications will fail to control seizures or cause intolerable side effects. Over the past thirty years, epilepsy surgery has played a role for individuals with medically intractable seizures often rendering them significantly improved or cured of their seizures. There are patients who are not candidates for epilepsy surgery but have not responded to medications who would be candidates for another approach to treating their seizures. The University of Arizona Health Sciences Center through the Arizona Comprehensive Epilepsy Program is currently testing such a treatment, vagal nerve stimulation.The vagus nerve (10th cranial nerve) conducts electrical impulses in both directions between the brain and many body organs (i.e., heart and stomach). Its major function is to monitor and modulate the functions of visceral organs. In the 1950s, vagal nerve stimulation was observed to desynchronize the electroencephalogram (EEG) (1,2). Since seizures are synchronized electrical activity it was reasoned that vagal stimulation which desynchronized the EEG might inhibit seizures. Vagal nerve stimulation subsequently was shown to decrease the frequency and duration of seizures in a variety of animal models of epilepsy (3 - 6). Based on promising data from animals, several multi center, double blind, prospective, randomized and placebo controlled clinical trials were undertaken (7-10). These studies showed that vagal nerve stimulation was a safe and effective treatment to reduce the frequency of partial seizures which were refractory to medical therapy. The Arizona Comprehensive Epilepsy Program is participating in another study of the vagal nerve stimulator to assess the best stimulation parameters. In the current study, individuals with medically intractable epilepsy, who meet certain entry criteria and choose to participate, will have the stimulator (which is similar to a pacemaker) implanted in their chest with the lead (wire) wrapped around the vagus nerve in the neck (see diagram below). After allowing patients to heal from this short surgical procedure, the device will be turned on with one of two stimulation parameters. Patients will be carefully monitored in regard to seizure frequency and side effects through the 12 week trial. Patients who benefit from this treatment will be allowed to continue this treatment indefinitely. Those who receive the less effective stimulation will be switched to the more effective parameters and also be allowed to continue indefinitely. Based on previous studies, anticipated side effects include hoarseness, coughing and gastrointestinal complaints. The first of these devices used in Arizona was implanted in January 1996. Although this current study is closed to new participants, we will gladly provide further information about this and other epilepsy studies to any interested persons.
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References1. Dell P, Olson R. Projections thalamiques corticales et cerebelluses des afferences viscerales vagales. CR Soc Biol (Paris), 1951a; 145:1084-1088. 2. Dell P, Olson R. Projections (secondaires) mesencephaliques, diencephaliques, et amygdaliennes des afferentes viscerales vagales. CR Soc Biol (Paris), 1951b; 145:1088-1091. 3. McLachlan RS. Suppression of interictal spikes and seizures by stimulation of the vagus nerve. Epilepsia, 1993; 34(5):918-923. 4. Woodbury JW, Woodbury DM. Vagal stimulation reduces the severity of maximal electroshock seizures in intact rats: Use of a cuff electrode for stimulating and recording. Pace, 1991; 14:94-107. 5. Woodbury DM, Woodbury JW. Effects of vagal stimulation on experimentally induced seizures in rats. Epilepsia, 1990; 31(Suppl 2):S7-S19. 6. Lockard JS, Congdon WC, DuCharme LL. Feasibility and safety of vagal stimulation in monkey model. Epilepsia, 1990; 31(Suppl 2):S20-S26). 7. Ben-Menachem E, et al. Vagus nerve stimulation for treatment of partial seizures: 1. A controlled study of effect on seizures. Epilepsia, 1994; 35(3):616-626. 8. Ramsay RE, et al. Vagus nerve stimulation for treatment of partial seizures: 2. Safety, side effects, and tolerability. Epilepsia, 1994; 35(3):627-636. 9. George R., et al. Vagus nerve stimulation for treatment of partial seizures: 3. Long-term follow-up on first 67 patients exiting a controlled study. Epilepsia, 1994; 35(3):637-643. 10. Uthman BM, et al. Treatment of epilepsy by stimulation of the vagus nerve. Neurology, 1993; 43:1338-1345.
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Since the mid-nineteenth century, when bromides were recognized to have anti-epileptic properties, an ongoing search for medicines to treat seizures has occurred. Despite vigorous research efforts, prior to 1993, no anti-epileptic drug (AED) had been approved since 1978, the year valproate was released. The goal of all AEDs has remained essentially unchanged for over one hundred years; effectively treat seizures with no side effects. Unfortunately, no medication treats all seizures effectively without some side effects. The new medications being discussed are no different except that their side effect profiles are much better than previously released medications. There is also some experimental evidence that these medications may be more effective in treating certain seizure types than older drugs. There are three medications which have come to market since 1993 and several which are in late stages of development and will likely come to market in the next couple of years.
Felbamate (Felbatol, Carter-Wallace) is a chemical cousin to the tranquilizer, meprobamate. This drug was approved by the Food and Drug Administration in July 1993 and is now available by prescription in the United States. This medication seems to be effective in treating both partial and generalized seizure types. The medication is available in 400 and 600 mg tablets and in suspension (600 mg/teaspoon). The long half-life of the drug will allow twice daily dosing, in the range of 1200-3600 mg per day. Although the medication can be used with other compounds, it will be best used as a single drug. This is because in the presence of other medications, the side effects are notable whereas as a single drug, the side effect profile is favorable. The side effects associated with felbamate tend to be mild and transient. These include nausea, headache, insomnia, loss of appetite and dizziness. The use of felbamate is now limited by the recognized idiosyncratic problems of aplastic anemia and hepatic failure.
Gabapentin (Neurontin, Parke-Davis) is a compound which was developed to work with a specific inhibitory system in the brain to prevent seizures. Although it doesn't interact with its intended target, it is an effective AED. This drug was released in early 1994 and is approved for treating partial seizures, both simple and complex, as an add-on medication. Gabapentin has a shorter half-life than felbamate and will require dosing three to four times daily. This medication has no important interactions with other AEDs and therefore is an ideal add-on drug. The side effects associated with this drug include dizziness and fatigue which typically are transient and can be minimized by gradually increasing the dose to the desired level. The drug has also been shown to be effective, in work done at the Arizona Health Sciences Center, in treating seizures associated with porphyria, a syndrome in which other seizure medications may worsen the disorder. Some data exist suggesting that this medication can be used as monotherapy in selected patients but this is still being investigated.
Lamotrigine (Lamictal, Burroughs-Wellcome) was released in early 1995. Much like gabapentin, it was originally developed with a specific chemical strategy in mind which didn't hold up but nevertheless it too is an effective AED. This drug is approved for use in treating both generalized and partial seizures, again as an add-on drug. The half-life of Lamotrigine is long and if used alone can in theory be taken once daily. When used with other drugs, it must be taken more than once daily. Like gabapentin, this drug seems to have few interactions with other AEDs and in addition to being used alone it can be used as an add-on compound. The side effects associated with this drug tend to be milder than older drugs. The side effects include dizziness, double vision, and fatigue. Lamotrigine has been available in parts of Europe for a decade and there is good data showing that it can be used in monotherapy.
Several other medications including vigabatrin, topiramate and tiagabine may be released in the near future. Although these medications increase the neurologist's (and primary care providers) armamentarium for treating epilepsy they are in no way a panacea. The first line drugs for treating epilepsy remain the old standards (i.e., phenytoin, carbamazepine and valproate). The newer drugs have a role when these drugs fail to control seizures or when the patient experiences adverse side effects. It seems that these new medications as a group are better tolerated than the older ones however this must be weighed against the high cost of the newer agents. For those of us committed to treating individuals with epilepsy, the new medications offer new hope for our patients with seizures.
David Labiner, M.D.
Director
Arizona Comprehensive Epilepsy Program
The University of Arizona College of Medicine
