Abstract
Article abstract We assessed the long-term efficacy of vagus nerve stimulation (VNS) in 64 refractory epilepsy patients. After implantation, intermittent stimulation was delivered and seizure frequency and severity were counted. Average treatment time was 20 months. Nineteen of 47 patients with partial seizures, five of nine patients with idiopathic generalized seizures, and five of eight patients with Lennox–Gastaut syndrome had >50% seizure reduction. Side effects were mild. VNS is a safe and effective treatment for refractory epilepsy.
Vagus nerve stimulation (VNS) is a new therapy for the treatment of refractory epilepsy. The NeuroCybernectic Prosthetic (NCP) (Cyberonics; Webster, TX) has been approved for use in the United States, Europe, and other areas of the world. Registration has been based on the results of two double-blind controlled studies involving 367 patients with refractory partial seizures.1-3
We describe the results of up to 5 years of long-term follow-up at a single center in 64 patients not involved in sponsored clinical trials. Patients with partial seizures (PS), Lennox–Gastaut syndrome (LGS), or primary generalized seizures (PGS) were accepted as candidates for VNS to determine the patient types that will likely benefit.
Methods.
This is a prospective, open, long-term evaluation of patients receiving VNS between 1992 and the spring of 1997 at Sahlgrenska University Hospital (Göteborg, Sweden). Patients with PS (n = 47) were referred for VNS if surgical evaluation indicated that they would not benefit from resective surgery or if previous epilepsy surgery had failed. For the patients with PGS (n = 9) and LGS (n = 8), all were refractory to available antiepileptic drugs (AEDs).
Patients were being treated with one to four AEDs. The dosages were not changed during the first 6 months of VNS. If a new drug was added to improve efficacy, then evaluation of VNS efficacy was terminated.
The NCP system was implanted according to routine methodology.1 Ramping up of the NCP was done individually. After the first ramp-up, patients returned every other week to increase the current until an output current of 1.0 to 1.50 mA was reached. With unsatisfactory seizure control, rapid stimulation of 7 seconds on and 0.2 minutes off was tried.
All patients except seven were able to record their seizures on calendars, which were provided by the physician. Reduction of seizure frequency was calculated as the percent change in seizure rates during the last 3 months of VNS compared to 3-month baseline before implantation.
Estimates of the reduction of seizure severity was made subjectively by the patients, taking into account postictal alertness, length of seizures, injuries, and severity of the ictal state.
Standard EEGs and MRIs were performed in all 64 patients. In addition, in the patients with PS, ictal video-EEG recordings were done. Eighteen patients had previously undergone epilepsy surgery.
Results.
Average duration of stimulation with the NCP was 20 months (range, 3 to 64 months). The range of VNS stimulation was between 0.25 and 2.0 mA. The average battery life of the NCP was 41/2 years, depending on the stimulation parameters used. Stimulation intervals of 7 seconds on and 0.2 seconds off reduced battery life by up to 1 year. Eleven patients had their NCP removed owing to lack of efficacy.
Patients with partial seizures.
Clinically significant seizure reduction was defined as >50% reduction of seizures (responders). Overall, 19 of 47 patients (40.4%) were responders and 8 reported a >75% seizure reduction, with 1 seizure-free patient. Twenty-one were nonresponders, and seven reported a reduction of seizure frequency between 10 and 49%. The responders also experienced a corresponding reduction of >50% seizure severity.
Sixteen patients had a right-sided focus and 12 had a left-sided focus. Seventeen had bilateral foci and in two the focus could not be definitively located (table 1). Eight patients with right-sided foci and three with left-sided foci were responders. Seven patients with bilateral foci were responders. In the two patients with unknown seizure origin, one was a responder; the other had a modest reduction of 25%.
Seizure reduction according to seizure focus in partial seizure patients
Eighteen patients had epilepsy surgery before being implanted with the NCP. Five patients had a right temporal lobe resection but only one was classified as a responder. Of the three patients with a right basal frontal resection, one experienced a >75% seizure reduction, whereas the other two patients had a 75% reduction in seizure severity without a reduction in seizure frequency. The three patients with left anterior temporal lobe resections had a 20 to 25% reduction of seizure frequency, and very modest changes in seizure severity in two. One patient was operated on for a subarachnoida cysta with no improvement. Another patient had a right temporal oligodendroglioma removed and experienced a 50% seizure reduction with VNS.
Patients with LGS.
Five of the eight patients with LGS were responders in all seizure types. The seizure types that were most affected were generalized tonic-clonic seizures (GTCS) and absences. For two of the five responders, even the atonic seizures were significantly reduced. Five had previous callosotomies. Of these, one experienced a 25% seizure reduction and a 25% reduction in seizure severity. Another patient had a >50% seizure reduction and a 50% reduction in seizure severity. Two other patients had a 25% reduction in seizure severity alone. See table 2 for details.
Patients with Lennox–Gastaut syndrome: Monthly seizure frequency before and after vagus nerve stimulation
Patients with PGS.
Of the nine patients with PGS, six had typical absence epilepsy. Three patients had idiopathic generalized seizures with absences, GTCS, and myoclonic seizures. One patient died from sudden death shortly after implantation. He is not included in the efficacy analysis. Another patient with PGS died in status epilepticus. She had an excellent effect of VNS with >75% decrease in seizures. The NCP battery stopped and was replaced 2 months later. During that time and the following weeks, she had increased GTCs and finally status epilepticus.
Five of the eight patients were responders, and all the responders had absence epilepsy. Both absences and GTCs were dramatically reduced in four patients, who experienced a >75% seizure reduction. None of the three patients with unclassified idiopathic generalized epilepsy were responders (table 3).
Patients with primary generalized seizures: Seizure frequency before and after vagus nerve stimulation (VNS)
Adverse events.
Side effects were often mild and mostly related to the time on stimulation. One patient complained about the generator placement and it was moved twice without resolution. Hoarseness was reported in 11 and paresthesia in one. One patient had dyspnea. Four patients died, three in status epilepticus and one in sudden death. One patient developed a cord paresis after replacement of the lead. Three reported throat pain. Two patients became pregnant and have given birth to healthy babies.
Discussion.
VNS is an accepted therapy for treating seizures in refractory epilepsy patients. Although this study is an outcome design with limitations compared to randomized controlled studies, it nevertheless represents the experience of long-term follow-up of the largest population treated with VNS at any one center. Since the acceptance of VNS in Sweden as a therapeutic device, we have implanted patients with all types of epilepsy. Inclusion criteria are intractable seizures despite multiple trials with medication, no possibility of resective surgery, or failure to improve after surgery. Nevertheless, despite the refractoriness of this population, 44% experienced a large reduction in seizure frequency and severity over long periods of time. How the VNS will perform in less severely afflicted patients remains to be determined.
Acknowledgments
Disclosure
Drs. Ben-Menachem and Augustinsson have received honoraria and research grants for other studies from Cyberonics.
Acknowledgment
The authors thank Joyce Cramer, Yale Medical School, for reviewing this manuscript and for her helpful suggestions. C. Waldton of Dicamed contributed to this article by helping with organization of the data.
Footnotes
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See also pages 1117, 1166, and 1267
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