The Mechanism of Action of Vagus Nerve Stimulation for Refractory Epilepsy: The Current Status

Summary Vagus nerve stimulation (VNS) is a neurophysiologic treatment for patients with medically or surgically refractory epilepsy. Since the first human implant in 1989, more than 10,000 patients have been treated with VNS. The precise mechanism of action remains to be elucidated. Animal experiments with VNS were initially performed to demonstrate efficacy and safety preceding the clinical trials in human patients. Mechanism of action research involving animal experiments can provide essential clues. Animal experiments are often labor-intensive even in the hands of experienced researchers, however, and the results remain only a reflection of the complicated pathophysiologic systems of the human brain. Mechanism of action research in human patients treated with VNS is particularly challenging because of safety concerns, the large number of patients required, and the heterogenous nature of various small patient series. This study provides an overview of the progress that has been made in the past 10 years through neurophysiologic, neuroanatomic, neurochemical, and cerebral blood flow studies in animals and patients treated with VNS. Further elucidation of the mechanism of action of VNS may increase its clinical efficacy. It may also provide inspiration for the development of new therapeutic modalities for refractory epilepsy.

[1]  J. Zabara.  Inhibition of Experimental Seizures in Canines by Repetitive Vagal Stimulation , 1992, Epilepsia.

[2]  B. Uthman,et al.  Vagus nerve stimulation therapy for partial-onset seizures , 1998, Neurology.

[3]  H. R. Holmes,et al.  Brain natriuretic peptide-like immunoreactive innervation of the cardiovascular and cerebrovascular systems in the rat. , 1990, Circulation research.

[4]  R. Fernández-Mas,et al.  Vagus Nerve Prolonged Stimulation in Cats: Effects on Epileptogenesis (Amygdala Electrical Kindling): Behavioral and Electrographic Changes , 1999, Epilepsia.

[5]  Mikio Takaya,et al.  Vagus Nerve Stimulation Induces a Sustained Anticonvulsant Effect , 1996, Epilepsia.

[6]  A. Paintal,et al.  Vagal sensory receptors and their reflex effects. , 1973, Physiological reviews.

[7]  R H Hunt,et al.  Cerebral-evoked potential responses following direct vagal and esophageal electrical stimulation in humans. , 1993, The American journal of physiology.

[8]  T L Faber,et al.  Brain Blood Flow Alterations Induced by Therapeutic Vagus Nerve Stimulation in Partial Epilepsy: I. Acute Effects at High and Low Levels of Stimulation , 1998, Epilepsia.

[9]  A. Hamberger,et al.  Neurochemical effects of vagus nerve stimulation in humans , 1992, Brain Research.

[10]  O. Pompeiano,et al.  Synchronization of the EEG produced by low-frequncy electrical stimulation of the region of the solitary tract , 1961 .

[11]  T. Koeze,et al.  A SPECT study of the effect of vagal nerve stimulation on thalamic activity in patients with epilepsy , 2000, Seizure.

[12]  S. Krahl,et al.  Destruction of Peripheral C‐Fibers Does Not Alter Subsequent Vagus Nerve Stimulation‐Induced Seizure Suppression in Rats , 2001, Epilepsia.

[13]  S. Krahl,et al.  Locus Coeruleus Lesions Suppress the Seizure‐Attenuating Effects of Vagus Nerve Stimulation , 1998, Epilepsia.

[14]  M. Sterman,et al.  Afferent vagal stimulation: neurographic correlates of induced EEG synchronization and desynchronization. , 1967, Brain research.

[15]  E. Agostoni,et al.  Functional and histological studies of the vagus nerve and its branches to the heart, lungs and abdominal viscera in the cat , 1957, The Journal of physiology.

[16]  B. Uthman,et al.  Electrophysiological Studies of Cervical Vagus Nerve Stimulation in Humans: I. EEG Effects , 1992, Epilepsia.

[17]  D. Naritoku,et al.  Revision and removal of stimulating electrodes following long-term therapy with the vagus nerve stimulator. , 1999, Surgical neurology.

[18]  C. D. Thompson,et al.  Quantification in Patient Urine Samples of Felbamate and Three Metabolites: Acid Carbamate and Two Mercapturic Acids , 1999, Epilepsia.

[19]  A. Morales,et al.  Chronic Vagus Nerve Stimulation Increases the Latency of the Thalamocortical Somatosensory Evoked Potential , 1992, Pacing and clinical electrophysiology : PACE.

[20]  R. Fisher.  Emerging antiepileptic drugs. , 1993, Neurology.

[21]  A. Zanchetti,et al.  The effect of vagal afferent stimulation on the EEG pattern of the cat. , 1952, Electroencephalography and clinical neurophysiology.

[22]  Carter Lp,et al.  Vagus nerve stimulation activates central nervous system structures in epileptic patients during PET H2(15)O blood flow imaging. , 1998 .

[23]  M. Sterman,et al.  Cortical and subcortical patterns of response to afferent vagal stimulation. , 1966, Experimental neurology.

[24]  C. Nahmias,et al.  Regional Cerebral Blood Flow in Man Manipulated by Direct Vagal Stimulation , 1992, Pacing and clinical electrophysiology : PACE.

[25]  C. Fisher.  Basilar artery embolism after surgery under general anesthesia , 1993, Neurology.

[26]  G Van Hoey,et al.  Epilepsy surgery in Belgium, the experience in Gent. , 1999, Acta neurologica Belgica.

[27]  M. Salinsky,et al.  Vagus Nerve Stimulation Has No Effect on Awake EEG Rhythms in Humans , 1993, Epilepsia.

[28]  P. Rajna,et al.  Sensory Stimulation for Inhibition of Epileptic Seizures , 1989, Epilepsia.

[29]  D. Woodbury,et al.  Effects of Vagal Stimulation on Experimentally Induced Seizures in Rats , 1990, Epilepsia.

[30]  B. Uthman,et al.  Electrophysiologic Studies of Cervical Vagus Nerve Stimulation in Humans: II. Evoked Potentials , 1992, Epilepsia.

[31]  A. Kemeny,et al.  Slow Hyperpolarization in Cortical Neurons: A Possible Mechanism Behind Vagus Nerve Simulation Therapy for Refractory Epilepsy? , 2000, Epilepsia.

[32]  D. Naritoku,et al.  Regional induction of fos immunoreactivity in the brain by anticonvulsant stimulation of the vagus nerve , 1995, Epilepsy Research.

[33]  J. O. Foley,et al.  Quantitative studies of the vagus nerve in the cat. I. The ratio of sensory to motor fibers , 1937 .

[34]  K. Gale,et al.  Regulation of Limbic Motor Seizures by GABA and Glutamate Transmission in Nucleus Tractus Solitarius , 1999, Epilepsia.

[35]  K. Laere,et al.  Acute Single Photon Emission Computed Tomographic Study of Vagus Nerve Stimulation in Refractory Epilepsy , 2000, Epilepsia.

[36]  Erika E. Fanselow,et al.  Reduction of Pentylenetetrazole-Induced Seizure Activity in Awake Rats by Seizure-Triggered Trigeminal Nerve Stimulation , 2000, The Journal of Neuroscience.

[37]  J. Lockard,et al.  Feasibility and Safety of Vagal Stimulation In Monkey Model , 1990, Epilepsia.

[38]  K. Bough,et al.  A Ketogenic Diet Increases the Resistance to Pentylenetetrazole‐Induced Seizures in the Rat , 1999, Epilepsia.

[39]  T R Henry.  Functional imaging studies of epilepsy therapies. , 2000, Advances in neurology.

[40]  A. Hamberger,et al.  Effects of vagus nerve stimulation on amino acids and other metabolites in the CSF of patients with partial seizures , 1995, Epilepsy Research.