Analysis of RR variability in drug-resistant epilepsy patients chronically treated with vagus nerve stimulation

Vagus nerve stimulation (VNS) has been suggested as an adjunctive treatment for drug-resistant epilepsy when surgery is inadvisable. The overall safety profile of VNS seems to be favorable as only minor adverse effects have been described. The purpose of this study was to determine if cardiac vagal tone is eventually modified by short- and long-term VNS. The effects of short- and long-term VNS were evaluated in seven subjects with intractable epilepsy. Autonomic cardiac function has been carried out by means of a 24-h analysis of RR variability at baseline (t(0)), 1 month (t(1), short-term VNS) and 36 months after VNS initiation (t(2), long-term VNS). Frequency- and time-domain parameters were calculated. Periodic cardiological and neurological evaluations were performed.Clinically relevant cardiac effects were not observed throughout the study. Despite the limited number of patients and the variety of data among them, for all the patients, a common trend towards a nocturnal decrease in the high-frequency (HF) component of the spectrum was observed after long-term VNS (mean+/-S.D.: 40+/-18 normalized units (nu) at t(0), 38+/-17 nu at t(1), 18+/-10 nu at t(2); p<0.05 of t(2) vs. either t(0) or t(1)). The day-to-night changes in the power of low-frequency (LF) and HF components were significantly blunted after long-term VNS (LF day-to-night change: +16+/-13 nu at t(0) and +15+/-8 nu at t(1) vs. +3+/-13 nu at t(2), p<0.02; HF day-to-night change: -18+/-13 nu at t(0) and -13+/-11 nu at t(1) vs. +3+/-12 nu at t(2), p<0.003). No significant changes were observed with regard to the time-domain parameters of the heart rate variability. Throughout the neurological follow-up, one subject became seizure-free, three experienced a seizure reduction of >50%, two patients of <50% and one had no changes in his seizure frequency. Our findings suggest that long-term VNS might slightly affect cardiac autonomic function with a reduction of the HF component of the spectrum during night and a flattening of sympathovagal circadian changes, not inducing, however, clinically relevant cardiac side effects.

[1]  A. Atkinson,et al.  Diphenylhydantoin as an antiarrhythmic drug. , 1974, Annual review of medicine.

[2]  R S Fisher,et al.  Reassessment: Vagus nerve stimulation for epilepsy , 1999, Neurology.

[3]  Josemir W Sander,et al.  Incidence of sudden unexpected death in an adult outpatient cohort with epilepsy at a tertiary referral centre. , 1995, Journal of neurology, neurosurgery, and psychiatry.

[4]  L. D. Blumhardt,et al.  ELECTROCARDIOGRAPHIC ACCOMPANIMENTS OF TEMPORAL LOBE EPILEPTIC SEIZURES , 1986, The Lancet.

[5]  Paul Schraeder,et al.  Sudden Unexplained Death in Epilepsy: Observations from a Large Clinical Development Program , 1997, Epilepsia.

[6]  T. Tomson,et al.  Carbamazepine induced bradycardia - a problem in general or only in susceptible patients? A 24-h long-term electrocardiogram study , 1992, Epilepsy Research.

[7]  A. Malliani,et al.  Cardiovascular Neural Regulation Explored in the Frequency Domain , 1991, Circulation.

[8]  J. M. Van Buren,et al.  Some autonomic concomitants of ictal automatism; a study of temporal lobe attacks. , 1958 .

[9]  E. Fallen,et al.  Neurocardiac Responses to Vagoafferent Electrostimulation in Humans , 1992, Pacing and clinical electrophysiology : PACE.

[10]  W. Hauser,et al.  ECG abnormalities in patients with epilepsy , 1987, Neurology.

[11]  A. Damato,et al.  The antiarrhythmic actions of carbamazepine (Tegretol). , 1970, The Journal of pharmacology and experimental therapeutics.

[12]  A. Porta,et al.  Relationship between spectral components of cardiovascular variabilities and direct measures of muscle sympathetic nerve activity in humans. , 1997, Circulation.

[13]  M. Turiel,et al.  Power Spectral Analysis of Heart Rate and Arterial Pressure Variabilities as a Marker of Sympatho‐Vagal Interaction in Man and Conscious Dog , 1986, Circulation research.

[14]  D. Zipes,et al.  Bradycardia and Asystole with the Use of Vagus Nerve Stimulation for the Treatment of Epilepsy: A Rare Complication of Intraoperative Device Testing , 1999, Epilepsia.

[15]  F. Sharbrough,et al.  The Ictal Bradycardia Syndrome , 1996, Epilepsia.

[16]  A. Malliani,et al.  Heart rate variability. Standards of measurement, physiological interpretation, and clinical use , 1996 .

[17]  F. Vale,et al.  Ventricular asystole during vagus nerve stimulation for epilepsy in humans , 1999, Neurology.

[18]  Maromi Nei,et al.  EKG Abnormalities During Partial Seizures in Refractory Epilepsy , 2000, Epilepsia.

[19]  H. Akaike.  Fitting autoregressive models for prediction , 1969 .

[20]  E. Kasarskis,et al.  Carbamazepine-induced cardiac dysfunction. Characterization of two distinct clinical syndromes. , 1992, Archives of internal medicine.

[21]  Steven C Schachter,et al.  Vagus nerve stimulation therapy summary: Five years after FDA approval , 2002, Neurology.

[22]  M G Frei,et al.  Left Vagus Nerve Stimulation with the Neurocybernetic Prosthesis Has Complex Effects on Heart Rate and on Its Variability in Humans , 2001, Epilepsia.

[23]  C. Whitty,et al.  Sino‐Auricular Heart Block as an Epileptic Manifestation , 1954, Epilepsia.

[24]  S. Quint,et al.  Heart period variability during vagal nerve stimulation , 1998, Seizure.

[25]  C. D. Binnie,et al.  Vagus nerve stimulation for epilepsy: a review , 2000, Seizure.

[26]  D. Wilkins.  Reassessment: vagus nerve stimulation for epilepsy. , 2000, Neurology.

[27]  Mario Mariani,et al.  Alteration of Cardiac Function in Patients with Temporal Lobe Epilepsy: Different Roles of EEG‐ECG Monitoring and Spectral Analysis of RR Variability , 1997, Epilepsia.

[28]  HELMUT GRUBER,et al.  CHRONISCHE ELEKTROSTIMULATION: AUSWIRKUNGEN AUF DIE MORPHOLOGIE DES NERVEN , 1990 .

[29]  G. Breithardt,et al.  Heart rate variability: standards of measurement, physiological interpretation and clinical use. Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology. , 1996 .

[30]  R. Fincham,et al.  Bradycardia and syncope as manifestations of partial epilepsy. , 1990, Journal of the American College of Cardiology.

[31]  F W Sharbrough,et al.  Ictal tachycardia during temporal lobe seizures. , 1983, Mayo Clinic proceedings.

[32]  T. C. Erickson.  CARDIAC ACTIVITY DURING EPILEPTIC SEIZURES , 1939 .

[33]  A. Malliani,et al.  Spectral analysis of heart rate variability in the assessment of autonomic diabetic neuropathy. , 1988, Journal of the autonomic nervous system.

[34]  W. Hauser,et al.  Epilepsy, Vagal Nerve Stimulation by the NCP System, All‐Cause Mortality, and Sudden, Unexpected, Unexplained Death , 2000, Epilepsia.