Kindled seizures activate both branches of the autonomic nervous system.

Amygdaloid kindled seizures in the rat induce an abrupt elevation of blood pressure accompanied by a significant decrease in heart rate. The autonomic pharmacology of this response was examined in unanesthetized kindled rats. Muscarinic receptor blockade with atropine (1 mg/kg, intravenous (i.v.)) abolished the seizure-induced bradycardia. The seizure-induced hypertension was unaffected by beta-adrenergic blockade with timolol (1 mg/kg, i.v.), but was reduced by phentolamine (5 mg/kg, subcutaneous (s.c.)), an alpha-adrenergic receptor antagonist. A chemical sympathectomy was induced with 6-hydroxydopamine (100 mg/kg, i.v.), an agent that does not cross the blood-brain barrier. This eliminated the pressor response but did not completely block the seizure-induced bradycardia. The effectiveness of 6-hydroxydopamine was tested with tyramine (0.5 mg/kg, i.v.) an agent that releases endogenous catecholamines. These results indicate amygdaloid kindled seizures activate both branches of the autonomic nervous system. The bradycardia was mediated by the parasympathetic system; the pressor response was caused by an increase in peripheral resistance due to alpha-adrenergic receptor activation. More important, these findings show that kindling is a useful seizure model for future studies on the effect of seizures on cardiovascular function and possible mechanisms of seizure-related sudden unexplained death.

Definition of rational antiepileptic polypharmacy.

Rational polypharmacy is in its earliest stages of development and will require substantial additional development to realize its full potential. Indeed, despite the powerful appeal of the concept, clinical proof is not yet available that RP is superior to monotherapy. Important questions need to be addressed: 1. Will RP control seizures more effectively than monotherapy? 2. What data are needed to develop RP for a specific patient? 3. Will RP be cost effective? 4. Can RP be developed which will treat or prevent epilepsy while controlling seizures? Possible approaches to these questions could include: 1. The development of a data base for prospective use to monitor patients being treated at Epilepsy Centers using RP principles. 2. Use the data obtained from the above to construct more specific studies to compare identified combination therapies with monotherapy. 3. Prospectively compare in a placebo controlled, blinded study, the effect of the combination of an anti-ictal medication and a laboratory proven antiepileptic drug for prevention of the development of epilepsy in an at risk population such as head trauma or stroke.

Efficacy and safety of zonisamide: results of a multicenter study.

The safety and efficacy of zonisamide (ZNS), a new antiepileptic drug, was tested in 167 adult participants who entered a historical-controlled 16-week open label, multicenter study. The median percent reduction from baseline of partial seizures was 51.8% in the fourth month of the study (baseline median = 11.5 sz/month; treatment weeks 13-16 = 5.5 sz/month). Persons completing the efficacy study successfully were eligible for a long-term safety study; 113 entered this study. Adverse effects involved principally the CNS and were similar to those seen with other antiepileptic drugs. Four persons (3.7%) developed kidney stones and were withdrawn from the study 250-477 days after starting ZNS. Because of the high percentage of kidney stones, development of ZNS was stopped in the United States but was continued in Japan.

Syncope and seizures of psychogenic origin: identification with head-upright tilt table testing.

Psychogenic seizures and psychogenic syncope are common disorders but are difficult to identify. Head-upright tilt table testing has emerged as a promising means of evaluating vasovagally mediated syncope and convulsive syncope. Of a total of 42 patients evaluated by head-up tilt for recurrent syncope and 10 evaluated for recurrent idiopathic seizures, a total of 5 patients experienced syncope and 3 had tonic-clonic seizure activity unaccompanied by any significant changes in blood pressure, heart rate, transcranial Doppler cerebral blood flow velocity, and electroencephalographic monitoring. Psychiatric evaluation revealed that seven patients suffered from conversion reactions and one from probable malingering. We conclude that patients who pass out or convulse during head-upright tilt without any change in physiologic parameters can be presumed psychogenic in origin and may be referred for psychiatric evaluation without further expensive diagnostic studies.

Assessment of a computer program to detect epileptiform spikes.

This study compares an automated spike detection program to a group of 6 electroencephalographers. Since group members varied in experience, an expertise factor was devised to weight their scoring. EEGers underscored epileptiform events on 6 records in a manner analogous to the computer's storage of EEG segments. A summation of expertise factors was determined for every event. This sum was normalized and interpreted as a probability the event would be called a spike by a given EEGer. The performance of each scorer and of the computer at different amplitude thresholds was analyzed based on this probability. Higher rated scorers identified more subtle events. Lowering the threshold of the computer program produced a comparable increase in sensitivity. The increase in total events detected by the computer was linear over the range studied. While the proportion of false positive detections increased with lowering threshold, our readers have not found a moderate number of these distracting. We conclude that the computer system, while not as specific as an EEGer, can be as sensitive and can be a reliable screening editor for large amounts of monitoring data. On balance it is more effective than an EEGer for this limited purpose.

Single photon emission computed tomography in epilepsy.

Functional brain imaging by either single photon emission computed tomography (SPECT) or positron emission tomography (PET) is now a well-established technique in the diagnosis and evaluation of the epilepsies. Perhaps only in stroke have these emerging technologies proven of greater significance. Scalp, cortical, or depth electroencephalographic (EEG) data previously have been the gold standards for the localization and subcharacterization of epileptic activity in the human brain. Yet, they are fraught with difficult interpretations, technical difficulties, and limitations in sampling accuracy. Both SPECT and PET have localizing power approaching that of combined scalp and depth EEG. In the following discussion, a brief overview of the results of PET investigations in epilepsy is presented as background and comparative material for the concurrent and, more recently, dominant role of SPECT in evaluating patients with seizure activity. SPECT results in the interictal state in partial and generalized seizure activity are reviewed followed by an analysis of the role of ictal SPECT imaging in epilepsy. Next, relationships among interictal hypoperfusion (or hypometabolism) and computed tomography, magnetic resonance imaging, neuropathology, clinical severity, and cognitive function are discussed. The role of perfusion or metabolism imaging in the management of antiepileptic pharmacotherapy is also discussed, and the potential for receptor imaging in the evaluation of the epilepsies is examined. Finally, application in pediatric epilepsy are presented.

Kindled seizures elevate blood pressure and induce cardiac arrhythmias.

The effect of kindled seizures on the cardiovascular system was examined in amygdaloid kindled rats. The most prominent cardiovascular response during a generalized kindled seizure was an abrupt 50% increase in mean arterial pressure (MAP) lasting 20-30 s after initiation of the seizure. Superimposed on this change in blood pressure (BP) was a profound bradycardia characterized by a rate about half that recorded before stimulation. Changes in heart rate (HR) and BP observed during amygdaloid kindled seizures were similar to those observed during secondary spontaneous seizures. These effects apparently are independent of the kindling stimulus because stimulus-induced cardiovascular changes were not present at the beginning of the kindling process. These results suggest that the kindling seizure model is useful to study the underlying mechanisms of seizure-induced cardiac arrhythmias and possibly the clinical phenomenon of sudden unexplained death in epileptic patients.

Cognitive function and regional cerebral blood flow in partial seizures.

Patients with partial seizures have cognitive function impairments that have been attributed to the toxic side effects of anticonvulsants and structural cerebral damage. However, even when these factors are absent, neuropsychological (NP) deficits have been demonstrated, although of milder degree than in structurally brain-damaged patients. Assessment of cerebral metabolism using positron emission tomography and cerebral blood flow with single photon emission computed tomography (SPECT) reveals focal physiologic deficits in structurally normal areas. Using both SPECT and NP assessment with the Halstead-Reitan Battery, we evaluated 50 patients with partial seizures. Comparison of the location of visually identified regional cerebral blood flow (rCBF) deficits in these patients with the location of the NP deficits revealed a significant correlation. Additional analyses indicated that rCBF quantification in visually identified areas of hypoperfusion was significantly lower than in "normal" areas and that quantified NP variables significantly discriminated patients with and without visual rCBF deficits in temporal and frontal brain regions.

Regional cerebral function and blood flow: complementary single photon emission computed tomography of the brain using xenon-133 and [123I]iodoamphetamine.

Regional cerebral function and blood flow can be imaged using isopropyl[123I]iodoamphetamine (IMP), or 133Xe (DSPECT), respectively. Both of these essentially non-invasive, quantitative, methods are suitable for many nuclear medicine laboratories. This study assessed the in vivo information about intracerebral disease provided by IMP and DSPECT techniques to determine the optimal diagnostic use of these modalities. Single photon emission computed tomograms of 53 subjects were acquired using similar displays for IMP and DSPECT data. Lobar tracer distributions were graded by three experienced observers and analyzed using a kappa statistic to eliminate chance agreements. Overall, both IMP and DSPECT had similar patterns. However, while similar, one or the other technique often displayed abnormalities not present on both. Although technical factors may account for some differences between the modalities, a case of arteriovenous malformation proves that discordant findings can result directly from tracer localization properties. Thus at least some discordances provide truly complementary diagnostic information lacking in either single study taken alone.

Clinical utility of a Bayesian dosing program for phenytoin.

We performed two studies to assess the clinical utility of a Bayesian regression analysis computer program for phenytoin (PHT). In a randomized prospective study of 40 epileptic patients, the dosing program was significantly more accurate (p = 0.002) and less biased (p = 0.02) than a group of physicians at hitting a target PHT serum-concentration. Initial serum PHT concentrations that were not steady state were associated with the largest dosing errors by physicians but did not affect the accuracy of the dosing program. In a second study, we used the dosing program to predict 91 serum concentrations in 31 patients with PHT toxicity after the drug was stopped (initial concentration 26-69 micrograms/ml). The program predicted serum concentrations with a mean error of 3.49 +/- 0.29 micrograms/ml without significant tendency to over- or underpredict. We conclude that this dosing program may aid clinicians by improving dosing accuracy and predicting serum concentrations in patients with PHT toxicity.

Anterior temporal electrodes in complex partial seizures.

Anterior temporal (AT) and sphenoidal (SP) electrodes as well as standard 10-20 electrodes were used to evaluate patients with recent onset complex partial seizures. A total of 58 epileptiform foci were found in 80 patients. AT electrodes significantly improved detection of foci in comparison with 10-20 electrodes. SP electrodes resulted in a small, non-significant increase in detection in comparison to AT electrodes. AT electrodes may be substituted for basal electrodes for the purpose of diagnosis in the majority of patients with recent onset complex partial seizures.

Endurance of the kindling effect is independent of the degree of generalization.

The endurance of the effect of amygdaloid kindling was studied in rats kindled to stages 1-4, then left unstimulated for 45 days prior to resumption of kindling. Afterdischarge duration and behavioral stages upon resumption of kindling revealed retention of the full kindling effect. Endurance of the localized effect of kindling appears to be independent of the degree of generalization prior to interruption of kindling.

Acoustic analysis of affective prosody during right-sided Wada Test: a within-subjects verification of the right hemisphere's role in language.

A within-subjects study of the affective characteristics of voice was carried out in patients undergoing a Wada Test (WT). All patients became densely aphasic after the left-sided WT and lost the ability to impart affect into speech after the right-sided WT. The affective changes in voice induced by the Wada test were acoustically analyzed by computer-assisted techniques and compared to data obtained pre-Wada and post-Wada. The statistical results, using a one-way analysis of variance for repeated measures, confirmed robustly the current view that the right hemisphere modulates dominantly the affective components of language. The results are also evaluated in light of recent clinical and acoustical data regarding the organization of language in speakers of tone languages, thus, allowing the authors to address issues concerning universal principles of brain-language-behavioral relationships.

Causes of treatment failure with antiepileptic drugs vary over time.

The V.A. Epilepsy Cooperative Study Group evaluated monotherapy with carbamazepine, phenobarbital, phenytoin, and primidone in a total of 622 patients with previously untreated partial seizures. In the 24 months following onset of treatment, 223 patients failed treatment. Analysis of these failures reveals that the majority occurred during the first 6 months with equal contributions to failure from systemic toxicity, neurotoxicity, and seizures. The contribution of systemic toxicity to failure was significantly less in the next 18 months. An increase in the contribution of seizures to failure was seen in this latter period.

Cerebral location of international 10-20 system electrode placement.

We employed CT scanning to correlate scalp markers placed according to the international 10-20 system with underlying cerebral structures. Subjects were 12 normal volunteers. Measurements included assessment for cranial asymmetry to determine the effect of skull asymmetry on cortical location of electrodes. Results were correlated with the cortical histological map of Brodmann. Primary cortical locations agree well with previously published data and provide cortical localization in greater detail than previous studies. Variability of cortical electrode location was substantial in some cases and not related to cranial asymmetry. The results indicate that CT scanning or other neuroimaging techniques which reveal detailed cerebral anatomy would be potentially highly useful in defining the generators of electrocerebral potentials recorded from the scalp.

Quantification of intracerebral steal in patients with arteriovenous malformation.

Eleven patients with angiographically and/or pathologically proved arteriovenous malformations (AVMs) were studied using dynamic, single-photon-emission computed tomography (DSPECT). Quantification of regional cerebral blood flow in structurally normal areas remote from the AVM disclosed areas of decreased flow compared with normal controls in eight of 11 patients examined. Areas of hypoperfusion correlated with altered function as manifested by epileptogenic foci and impaired cognitive function. Dynamic, single-photon-emission computed tomography provides a noninvasive technique to monitor quantitatively hemodynamic changes associated with AVMs. Our findings suggest that such changes are present in the majority of patients with AVMs and that they may be clinically significant. The potential application of regional cerebral blood flow imaging by DSPECT in the management of patients with AVMs is discussed.

Lorazepam: a controlled trial in patients with intractable partial complex seizures.

Lorazepam was studied in a double-blind, placebo-controlled, crossover trial in eight patients with frequent partial complex seizures refractory to therapy with a combination of standard anticonvulsant drugs. Concomitant antiepileptic drugs were maintained at therapeutic serum levels throughout the study, and concentrations of lorazepam were monitored. Following an 8-week baseline observation, patients were randomly assigned to placebo or lorazepam (1 mg BID). The dose was increased biweekly until seizures stopped or unacceptable side effects occurred. Eight weeks later, patients were crossed over, and the same escalating dose paradigm was followed. When seizure frequency during the last 2 weeks of each treatment was compared, seven of eight patients had fewer seizures on lorazepam, and the eighth had decreased seizure duration (a significant difference: p less than 0.01, two-tailed sign test). Blood level data suggest a narrow therapeutic window, with seizure improvement occurring at concentrations of 20-30 ng/ml and side effects at greater than 33 ng/ml. Lorazepam appears to be a useful adjunct in refractory partial complex seizure therapy. It should not be stopped abruptly, as an increase in seizure frequency may result.

Single-proton tomographic study of regional cerebral blood flow in epilepsy. A preliminary report.

Regional cerebral blood flow (rCBF) may be measured with a single-photon-emission computed tomograph (SPECT) after inhalation of xenon 133. Our SPECT studies of rCBF in a group of 18 patients with seizure disorders, when compared with studies in 32 normal control subjects, have shown enhanced flow to an active seizure focus and ischemia of brain areas in certain subjects between seizures. Thus, SPECT determination of rCBF has demonstrated a number of findings recently observed with positron-emission tomography and may become a useful modality in the study of patients who have epilepsy.

Single-photon tomographic determination of regional cerebral blood flow in epilepsy.

Using a single-photon emission computed tomographic scanner (SPECT) the authors determined regional cerebral blood flow (rCBF) with inhaled xenon-133, a noninvasive procedure. Studies were performed in 40 normal individuals, and these were compared with rCBF determinations in 51 patients with seizure disorders. Although positive results were obtained in 15 of 16 patients with mass lesions, the group of principal interest comprised 25 patients suffering from "temporal lobe" epilepsy. Only one of these had a positive x-ray computed tomogram, but 16 had positive findings on rCBF study. These findings included increased local blood flow in the ictal state and reduced flow interictally.