B. J. Wilder

Efficacy and Safety of Vagus Nerve Stimulation in Patients With Complex Partial Seizures

Summary: A clinical trial of chronic intermittent vagal stimulation in five patients suggests that the procedure may be safe and effective as adjunctive treatment of medically intractable seizures of partial onset. Patients tolerated well the implantation of the neurocybernetic prosthesis and the vagal stimulation without serious physiological or lifestyle changes. Stimulation of the vagus nerve either reduced the seizure frequency or decreased the duration or intensity of seizures. Adverse side effects were limited to a tingling sensation in the throat and hoarseness during stimulation. A major complication was mechanical interruption of the wire‐electrode circuitry, with consequent cessation of stimulation. The small number of patients and the relatively short follow‐up period make this a pilot study, but the results are promising.

Electrophysiological Studies of Cervical Vagus Nerve Stimulation in Humans: I. EEG Effects

Summary: Evidence from studies of experimental animals indicates that electrical stimulation of the vagus nerve alters EEGs under certain stimulus parameters. We report EEG effects of electrical stimulation of the vagus nerve in 9 patients with medically intractable seizures as part of a clinical trial of chronic vagal stimulation for control of epilepsy. The mechanism of action of the vagal antiepileptic effect is unknown, and we believed that analysis of electrophysiologic effects of vagal nerve stimulation would help elucidate the brain areas affected. The left vagus nerve in the neck was stimulated with a programmable implanted stimulator. Stimulation at various stimulus frequencies and amplitudes had no noticeable effect on EEG activity whether the patient was under general anesthesia, awake, or asleep, but vagus nerve stimulation may interrupt ongoing ictal EEG activity.

A double‐blind study comparing carbamazepine with phenytoin as initial seizure therapy in adults

Carbamazepine was compared with phenytoin in a double-blind study. Of 87 patients, data on 70 patients were complete and used for analysis. Thirty-five patients were treated with each drug. The incidence of major side effects, minor side effects, and complete control (85%) was the same in both groups. A mild but significant elevation of WBC count was found before initiation of drug treatment in the patients presenting with generalized convulsive seizures. Sporadically, elevations in SGOT and LDH were seen; WBC counts below 4,000 were reported, but these were not clinically significant.

Vagus Nerve Stimulation in Humans: Neurophysiological Studies and Electrophysiological Monitoring

Summary: Evidence from studies of experimental animals indicates that electrical stimulation of the vagus nerve alters behavioral and electrographic seizure activity. We report on effects of electrical stimulation of the vagus nerve in five patients with medically intractable seizures as part of a clinical trial of chronic vagal stimulation for control of epilepsy. The mechanism of action of the vagal antiepileptic effect is unknown, and it is hoped that analysis of electrophysiological effects of vagal nerve stimulation will help elucidate which brain areas are affected. Stimulation of the left vagus nerve in the neck was accomplished with a programmable implanted stimulator. Effects of stimulus amplitude, duration, and rate were studied. Noncephalic reference recording of the vagus‐nerve‐evoked potential showed some unusual properties: a scalp negative component occurred with latency of 12 ms, very high amplitude (up to 60 μV), and widespread scalp distribution. Field distribution studies indicate that this potential is generated in the neck, in the region of the stimulating electrodes. Muscle paralysis confirms this observation. Stimulation at various frequencies had no noticeable effect on electroencephalographic (EEG) activity regardless of whether the patient was under general anesthesia, awake, or asleep.

Neurochemical effects of vagus nerve stimulation in humans

An implanted stimulating device chronically stimulated the left cervical vagus nerve in epileptic patients. Cerebrospinal fluid concentrations of free and total gamma-aminobutyric acid, homovanillic acid, 5-hydroxyindoleacetic acid, aspartate, glutamate, asparagine, serine, glutamine, glycine, phosphoethanolamine, taurine, alanine, tyrosine, ethanolamine, valine, phenylalanine, isoleucine, vasoactive intestinal peptide, beta-endorphin, and somatostatin were measured before and after 2 months of chronic stimulation in six patients. Significant increases were seen in homovanillic acid and 5-hydroxyindoleacetic acid in three patients, and significant decreases in aspartate were seen in five patients. These changes were associated with a decrease in seizure frequency.

Electrophysiologic studies of cervical vagus nerve stimulation in humans. II: Evoked potentials

Summary: Evidence from studies of experimental animals indicates that electrical stimulation of the vagus nerve not only can alter the EEG but evokes activity in specific brain areas. We report effects of electrical stimulation of the vagus nerve in 9 patients with medically intractable seizures as part of a clinical trial of chronic vagal stimulation for control of epilepsy. The left vagus nerve in the neck was stimulated with a programmable implanted stimulator. Effects of stimulus amplitude, duration, and rate were studied. Noncephalic reference recording of the vagus nerve evoked potential showed some unusual properties: a scalp negative component occurred with a latency of 12 ms, very high amplitude (60 μV), and widespread scalp distribution. Field distribution studies indicated that this potential was myogenic in origin and generated in the region of the stimulating electrodes in the neck area. Chemically induced muscle paralysis confirmed this observation. Bipolar scalp recording showed several small‐amplitude topographically distinct potentials occurring in 30 ms. No effect, either acute or chronic, could be detected on pattern‐reversal evoked potentials, auditory brainstem evoked potentials, auditory 40‐Hz potentials, or cognitive evoked potentials.

Treatment of four siblings with progressive myoclonus epilepsy of the Unverricht-Lundborg type with N-acetylcysteine.

The finding of increased activity of the enzyme extracellular superoxide dismutase in four siblings with progressive myoclonus epilepsy of the Unverricht-Lundborg type (PME-UL) prompted the addition of antioxidants to these patients treatment regimen. After 6 months treatment with vitamin E, selenium, riboflavin, and zinc, there was some improvement in patient awareness and speech. N-acetylcysteine (NAC) is a sulfhydryl antioxidant that increases cellular glutathione and the activity levels of several antioxidant enzymes and has additional actions that contribute to its demonstrated efficacy in preventing or decreasing damage in models of neuronal toxicity. We treated the affected siblings with 4 to 6 grams a day of NAC in addition to the other antioxidants and magnesium. There has been a marked decrease in myoclonus and some normalization of somatosensory evoked potentials with NAC treatment. The patients were treated with NAC for up to 30 months with continued beneficial effects. NAC may prevent further deterioration in the clinical course of patients with PME-UL and may be indicated in other neurodegenerative conditions where excess free radical activity may contribute to disease progression. NEUROLOGY 1996;47: 1264-1268.

Vagal Stimulation for Control of Complex Partial Seizures in Medically Refractory Epileptic Patients

Chronic intermittent stimulation of the vagus nerve is a new method currently being tested for the treatment of medically intractable complex partial seizures (CPS). We have studied the effects of vagal stimulation in nine patients with CPS for 4–16 months to determine its safety and efficacy. With the patients maintained on constant dosages of antiepileptic drugs, we recorded the electroencephalogram and electrocardiogram, and performed clinical laboratory tests and gastric analysis over a 6‐week baseline period. The neurocybernetic prosthesis (NCP) was then implanted and connected to two spiral electrodes wound around the left vagus nerve. After a 4‐week placebo period, vagal stimulation was started. Stimulation parameters were increased stepwise at monthly intervals until patients were being stimulated for 30‐second periods at 20‐50 Hz with 1‐2 mA of current at 250‐500‐μsec pulses. A second 4‐week placebo period was added 3 months after the implantation. Thereafter, vagal stimulation was resumed and self‐stimulation with magnetic activation was allowed for a 1‐minute period at the onset of an aura. Six patients had a significant reduction in the frequency, intensity, or duration of seizures. All patients tolerated the implantation and stimulation well and none reported pain, discomfort, or important changes in their daily activities, sleep habits, eating, swallowing, or breathing. There were no remarkable changes in blood pressure or heart rate.

Lack of Interaction of Gabapentin with Carbamazepine or Valproate

Summary: Gabapentin (GBP) studies were conducted in patients with epilepsy receiving carbamazepine (CBZ, n= 12) or valproate (VPA, n = 14) monotherapy. The effects of GBP coadministration on steady‐state CBZ or VPA concentrations and of these antiepileptic drugs (AEDs) on GBP pharmacokinetics were investigated. GBP (400 mg) was coadministered every 8 h for 3% days with CBZ or for 5 1/3 days with VPA. GBP was well tolerated. Mean steady‐state plasma CBZ/CBZ‐10, ll‐epoxide (CBZ‐E) and serum VPA concentrations before, during, and after GBP administration were not significantly different. Mean steady‐state GBP pharmacokinetic parameters during CBZ or VPA coadministration were similar to steady‐state parameters reported in healthy subjects. Thus, no pharmacokinetic interaction exists between CBZ or VPA and GBP. No dosage adjustment is necessary when GBP and CBZ or VPA are coadministered.

Phenytoin Prodrug: Preclinical and Clinical Studies

Summary: The currently available phenytoin (PHT) solution has many disadvantages stemming from poor aqueous solubility of PHT. A novel approach to solve the problem has been the synthesis of a phosphate ester of PHT (PHT prodrug ACC‐9653). This water‐soluble compound is metabolized rapidly into P04 and PHT. A four center open‐label, baseline‐controlled study of 43 patients with epilepsy maintained on oral twice‐daily PHT monotherapy was performed to evaluate the safety and pharmacokinetic profile of the prodrug. Patients received an i.v. or i.m. dose of ACC‐9653 at a dose equivalent to the patients morning dose of PHT. Intravenous dosages were infused at a rate of 75 mg/min, and i.m. dosages were given as one or two injections. After a period of 6 days, during which patients were again maintained with oral PHT, they were given a dose of ACC‐9653 via whichever route they had not yet received. The Tmsx of the prodrug averaged 5.7 and 36 min (0.095 and 0.606 h) after i.v. and i.m. administrations, respectively. The elimination half‐life of ACC‐9653 (conversion from prodrug to PHT) after i.v. and i.m. administration was 8.4 and 32.7 min (0.140 and 0.545 h), respectively, and both were independent of the dose. The plasma clearance of ACC‐9653 was not dependent on dose or route of administration and averaged 19.8 ± 1.16 and 17.8 ± 0.83 L/h after i.v. and i.m. administrations, respectively. The area under curve ratio of PHT after i.m. and i.v. ACC‐9653 was 1.17 ± 0.13 which was not significantly different from 1. These findings indicate that both i.v. and i.m. administrations of ACC‐9653 maintained stable levels of PHT. Unlike i.v. PHT infusion, serious cardiovascular and respiratory adverse reactions were not observed during the administration of i.v. ACC‐9653. Postural hypotension was reported in two patients. Paresthesia was the most frequent adverse experience reported during the i.v. infusion of ACC‐9653. The tingling sensation was transient and localized to the groin, lower back, abdomen, head and neck regions. Phlebitis, tissue necrosis, induration, cording and sclerosis were not observed in this patient population following either i.m. or i.v. ACC‐9653 administration. In summary, PHT plasma levels in patients with epilepsy who were receiving chronic oral PHT monotherapy were maintained by the i.m. or i.v. administration of ACC‐9653. Both i.v. and i.m. ACC‐9653 were well tolerated by the patients as evidenced by the absence of serious cardiovascular events, laboratory variable abnormalities, or adverse experiences.