Edward J. Hammond

Effects of vagus nerve stimulation on amino acids and other metabolites in the CSF of patients with partial seizures

Electrical stimulation of the vagus nerve (VNS) is a new method for the treatment of patients with medically intractable epilepsy. Sixteen patients, ten of whom participated in a larger multicenter double-blind trial on the efficacy of VNS in epilepsy, and six who participated in pilot studies, consented to participate in the present study. Ten patients received HIGH stimulation and six patients LOW stimulation for the 3-month trial. Cerebrospinal fluid (CSF) samples (16 ml) were collected both before and after 3 months of VNS. Amino acid and neurotransmitter metabolites were analyzed. Four patients responded to VS with more than a 25% seizure reduction after 3 months. Mean and median concentrations of phosphoethanolamine (PEA) increased in responders and decreased in nonresponders. Free GABA increased in both groups but more so in the nonresponders. After 9 months of VS (6-9 months on HIGH stimulation) 4 of 15 patients had more than 40% seizure reduction. There were significant correlations between seizure reduction and increases in asparagine, phenylalanine, PEA, alanine and tryptophan concentrations. Comparison between patients with HIGH or LOW stimulation showed a significant increase in ethanolamine (EA) in the HIGH group and a decrease in glutamine in the LOW group. All patients regardless of response or stimulation intensity showed significantly increased total and free GABA levels. A decrease in CSF aspartate was marginally significant. Other trends were decreases in glutamate and increases in 5-hydroxyindoleacetic acid. Chronic VNS appears to have an effect on various amino acids pools in the brain.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

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.

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.

Effects of Intracortical Injection of Blood and Blood Components on the Electrocorticogram

Summary: Long term effects of the intracortical implantation of blood and blood products on the electrocorticogram were studied in cats and guinea pigs. Focal epileptiform paroxysmal discharges developed after implantation of whole blood, hemolyzed erythrocytes, methemoglobin, ferritin, ferrous chloride, ferric chloride, fibrinogen, hemin, and cottonoid. In each group recurrent paroxysmal discharges became more prominent and more frequent after several months, suggesting a physiological change caused by a breakdown product of blood. The lesions were characterized by varying degrees of cell loss, iron deposition and glial proliferation. It is thought that posttraumatic epilepsy, which is frequently accompanied by extravasation of blood into the brain, might share a similar physiopathogenesis.

Absence of cortical white matter changes in three patients undergoing long-term vigabatrin therapy

Chronic administration of the experimental antiepileptic drug vigabatrin (gamma-vinyl GABA) to animals has been shown to cause dose-dependent neuropathological changes characterized by a microvacuolation in specific white matter tracts. This finding has led to some concern as to whether similar pathologic changes might occur in patients taking this medication. Here we report on analysis of tissue specimens taken during neurosurgery from three patients undergoing chronic vigabatrin therapy (4 g/day). The first patient, a 34-year-old woman, had taken vigabatrin for 2 years prior to surgery, the second, a 50-year-old man, had taken the drug for 1 year, and a 34-year-old man had taken the drug for 5.3 years. For comparison, similar specimens were taken from three other patients not taking vigabatrin who were undergoing surgery for intractable epilepsy. Specimens from each subject were prepared in an identical manner and examined with light and electron microscopy. All specimens were examined in a blinded fashion. There was some minor nonspecific myelinic splitting seen in both controls and vigabatrin-treated patients but there was no evidence for any drug-induced lesions similar to that seen in experimental animals.

Immunofluorescent Evidence for a Specific Binding Site for Phenytoin in the Cerebellum

Summary: The regional distribution of phenytoin in the brains of experimental animals was studied using the indirect fluorescent antibody technique. Using antibodies directed against phenytoin, we observed a specific pattern of staining the Purkinje and granule cell layers of the cerebellum. An identical pattern of staining was seen in phenytoin‐treated and untreated animals. Several control procedures and studies indicated that the observed pattern was not caused by nonspecific staining or autofluorescence. The distinctive staining pattern obtained using this technique can be attributed to the high molecular specificity of antigen‐antibody reactions and a discrete binding site for phenytoin in the vicinity of cerebellar Purkinje and granule cells.