Antiepileptic drugs: historical perspective, current therapy, and clinical investigations.
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Anticonvulsants↗
Biomedical subjects
R J Porter
Publications and source records attributed to R J Porter.
Mechanisms of action of new antiepileptic drugs.
Our understanding of how new antiepileptic drugs work mirrors what we know about how currently marketed antiepileptic compounds exert their action--that information is scarce and elusive. The mechanism of action of antiepileptic drugs is nevertheless inextricably linked to epileptogenesis itself, and investigations of several promising new compounds are underway to establish the levels at which these drugs act. Compounds act on synapses and membranes as well as affecting receptors, neurotransmitters, and peptides. The most extensive data are available on drugs that inhibit the action of GABA or its receptors, including new benzodiazepine-like agents and barbituric-acid derivatives. The few drugs that act by inhibiting the effects of excitatory amino acids are reviewed. Finally, the maximal electroshock test is an empirical method to determine the antiepileptic properties of a drug; several agents under development have been effective in this screening technique.
Acetamides↗
Shadowed and simple reaction times in stutterers and nonstutterers.
Stutterers may experience difficulties in preparing and executing responses. This study investigated these possibilities as well as the possibility that stutterers may experience difficulty in the selection of responses. Two reaction-time tasks were investigated: a shadowing response in which speakers exactly repeated vowel sequences they heard, and a simple response in which speakers said [u] regardless of the identity of the vowel stimulus. Two groups of six adult male subjects, stutterers and nonstutterers, participated. Stimuli consisted of vowel-vowel "syllables" whose initial duration (response foreperiod) was randomly varied from 500 to 1500 ms. Electromyographic (EMG) and acoustic measures were obtained for each response condition. The EMG response latencies, acoustic response latencies, and execution times (EMG latency less the acoustic response latency) were examined for the fluent responses. Results indicated stutterers were, on average, 34 ms slower on acoustic responses than nonstutterers regardless of the task or foreperiod. However, stutterers' and nonstutterers' EMG latencies were not significantly different. Further analysis indicated that the overall slower acoustic responses of stutterers were accounted for almost entirely by longer execution times. Stutterers' difficulties thus appear to lie after response initiation suggesting they have problems in coordination of gestures during execution of fluent responses.
Adolescent↗
Electroencephalographic studies of simple partial seizures with subdural electrode recordings.
We used subdural electrodes to study the EEG features of simple partial seizures in 7 patients. We detected epileptiform discharges in 61 of 68 subdurally recorded simple partial seizures compared with 6 of 55 simple partial seizures recorded with scalp electrodes (p less than 0.0001). The onset of 36 nonmotor simple partial seizures was detected only by the medial and basal temporal subdural electrodes, and the onset of 25 simple partial seizures with motor manifestations was recorded by subdural electrodes only from the lateral cortex of the posterior frontal lobe. There was a close correspondence between the area first involved in the epileptiform discharge during simple partial seizures and the area first involved during complex partial and secondary generalized tonic-clonic seizures. Subdural electrodes may be effective in localizing the onset and spread of simple partial seizures, including those that arise from the medial temporal lobe.
Adult↗
New antiepileptic drugs.
In contrast with the situation only a decade ago, a profusion of new potential AEDs has been introduced for world-wide clinical testing. Which, if any, of these compounds will be added to the physician's armamentarium against epileptic seizures is unknown, but the continuing flow of testable compounds augurs well for the future.
Anticonvulsants↗
Fear episodes due to limbic seizures with normal ictal scalp EEG: a subdural electrographic study.
The authors present the case of a 13-year-old girl with episodes characterized by either staring with preserved consciousness or fear in whom functional illness was suspected. Video-EEG telemetry revealed no changes during 30 of 32 attacks. Subdural electrode recordings revealed epileptiform discharges in 30 of 37 episodes. The discharge was always localized to the electrodes recording from the inferomedial temporal region, with electrodes over the lateral convexity of the same temporal lobe showing no background changes. Although the detailed pathophysiology of panic attacks remains to be clarified, the authors point out that their case and other epileptic case studies are consistent with the possibility that excessive neuronal activity in medial temporal lobe structures is a necessary element of the underlying mechanism.
Adolescent↗
Cerebrospinal fluid pleocytosis following simple, complex partial, and generalized tonic-clonic seizures.
We observed postictal pleocytosis in 7 of 62 cerebrospinal fluid specimens obtained from 27 patients with epilepsy. Each patient had a known seizure disorder; none had any other cause for the pleocytosis. The maximum number of leukocytes was 12/mm3; the maximum number of erythrocytes was 190/mm3. Postictal pleocytosis was more common in samples obtained within 12 hours of the last seizure. Although previous studies have emphasized that pleocytosis is more common after repetitive generalized tonic-clonic seizures, we found increased leukocyte counts in cerebrospinal fluid after single simple, complex partial, or generalized tonic-clonic seizures.
Adolescent↗
Levels of catechols in epileptogenic and nonepileptogenic regions of the human brain.
Recent reports about tyrosine hydroxylase and alpha 1-adrenoceptors in epileptic foci have suggested increased regional catecholaminergic activity, which may serve a compensatory, inhibitory role. We measured levels of catechols, including the precursor 3,4-dihydroxyphenylalanine (DOPA) and the catecholamines dopamine (DA) and norepinephrine (NE), in surgically removed foci identified by electrocorticography and in nonepileptogenic sites from 23 patients with intractable temporal lobe epilepsy. The following values (mean +/- 1 SD) were obtained: DOPA = 142 +/- 60 ng/g of protein in the focus vs. 115 +/- 39 ng/g in the nonfocus (p less than 0.01); DA = 168 +/- 85 vs. 106 +/- 54 ng/g (p less than 0.001); and NE = 267 +/- 117 vs. 181 +/- 80 ng/g (p less than 0.001). The results are consistent with increased catecholaminergic activity in epileptic foci.
Adult↗
Clinical and electroencephalographic features of simple partial seizures.
The clinical and electroencephalographic features of 87 simple partial seizures in 14 patients were studied with video-EEG telemetry. The patients were able to respond to verbal stimuli during all seizures and, later, could clearly recall ictal events. To determine whether the EEG changes in simple partial seizures could be reliably observed, a reader blindly reviewed four EEGs of equal duration for each seizure. These EEGs consisted of one ictal and three nonictal recordings obtained at predetermined times before the seizure. There were 27 motor seizures (mean duration, 86 seconds; range, 2 to 250 seconds), all involving clonic movements of the head and/or upper extremities; 8 (30%) of these had a sensory component (pain in 6, paresthesia in 2). An EEG change, usually localized spikes or sharp waves over the contralateral or both rolandic regions, was identifiable in nine (33%) of the motor seizures. The 60 nonmotor seizures (mean duration, 63 seconds; range, 8 to 375 seconds) involved a variety of symptoms, including somatosensory/special sensory (3 seizures), autonomic (26 seizures), cognitive (1 seizure), affective (14 seizures), and mixed, or more than one category of nonmotor symptoms (16 seizures). In only nine (15%) of the nonmotor seizures was there an ictal EEG change, usually localized spikes or paroxysmal theta activity over the temporal region. Overall, among the 87 simple partial seizures, only 18 (21%) revealed ictal EEG changes. Thus, a normal EEG is common during simple partial seizures and does not exclude the diagnosis.
Adolescent↗
Cerebral glucose metabolism in the Lennox-Gastaut syndrome.
We used positron emission tomography with fluorine 18-labeled 2-deoxyglucose to study cerebral glucose metabolism in 10 patients with Lennox-Gastaut syndrome who had normal neuroradiological studies. The scans showed decreased metabolic rates relative both to those in the caudate nucleus and to normal control values in 3 patients whose seizures began before the age of 1, as well as in a patient with hyperprolinemia. No patient had a region of persistent focal hypometabolism. Metabolic rates increased in parallel with increased electroencephalographic discharges in 1 patient; 3 patients had lower metabolic rates when the electroencephalogram showed epileptiform discharges and while the patients were taking barbiturates.
Adolescent↗
Localization of magnetic interictal discharges in temporal lobe epilepsy.
Three young adults with intractable complex partial seizures were studied by electroencephalography, magnetoencephalography, and electrocorticography. Interictal electroencephalographic (EEG) spikes for each patient were grouped according to their morphological characteristics and distribution across channels. Mapping of simultaneously recorded magnetoencephalographic signals produced dipolar patterns from which the three-dimensional locations of equivalent current dipoles were calculated, whereas the mapping of EEG spikes showed single regions of electronegativity. The magnetic spikes were localized to the anterotemporal lobe, and the EEG spikes were localized somewhat anterior or posterior to the magnetic spikes. The magnetoencephalographic findings corresponded well with intraoperative electrocorticographic and depth-electrode findings of discharging areas located over the lateral temporal lobe and on the basal and mesial surfaces of the temporal cortex.
Adult↗
Seizures during barbiturate withdrawal: relation to blood level.
We studied 21 patients with complex partial seizures during phenobarbital (PB) or primidone withdrawal. Blood levels were measured daily, and seizure frequency was monitored by nursing staff and EEG-video telemetry. Patients were monitored for one week of baseline and for five weeks after PB tapering was initiated (withdrawal). Most were observed for at least one week after levels were undetectable. When ranked seizure counts were averaged, there was a tendency for seizure rates to be highest as PB levels passed through the range 15 to 20 mg/l, compared with rates at higher or lower PB levels. There was little or no relation between the rate of PB withdrawal, other drug therapy, or initial PB level and the ratio of highest seizure frequency to mean seizure frequency. Patients withdrawing from PB may be most likely to experience an increase in seizure frequency when their PB blood level falls below 20 mg/l.
Humans↗
How to initiate and maintain carbamazepine therapy in children and adults.
Appropriate use of carbamazepine for the treatment of epilepsy is based on correct identification of the patient's seizure type. Carbamazepine is effective against partial seizures and against generalized tonic clonic seizures. Therapy should begin gradually, with initial doses increased slowly over 1 or 2 weeks, as tolerated. Side effects include fatigue, dizziness, ataxia, double vision, nausea, and vomiting. Most practitioners agree that, because of carbamazepine's relatively short half-life, the total dosage should be administered in at least two divided doses. This avoids too high a peak blood level that would occur with a single dose. Carbamazepine therapy is associated with the development of two hematologic conditions. Leukopenia, which may be transient or persistent, requires careful monitoring but is not cause for immediate discontinuation of therapy. Aplastic anemia occurs rarely but is potentially fatal, and therefore diligent monitoring of hematologic function is indicated. Aplastic anemia is an idiosyncratic, non-dose-related side effect that is most likely to occur within the first 3 or 4 months of initiating therapy. Once seizures are controlled, plasma levels of carbamazepine should be measured to establish optimum levels for individual patients being treated with this drug.
Adult↗
Effect of phenytoin on human cerebral glucose metabolism.
We used serial positron emission tomography scans with [18F]2-deoxyglucose to study the effect of phenytoin on human cerebral glucose metabolism in 10 patients with seizure disorders. Local CMRglu for each patient was measured in 10 regions of interest. EEGs were performed during each procedure to match scans for state of consciousness and exclude data from scans with ictal activity. Serial scans without a drug change were performed in six control patients. Metabolic rates were significantly lower in two cortical regions while patients were taking phenytoin. No significant changes on repeat scan were seen in the control population. Measured across all regions of interest, metabolic rates were 13% higher when patients were off phenytoin (p less than 0.02).
Adult↗
The effects of inflammatory bowel disease on pregnancy: a case-controlled retrospective analysis.
Retrospective analysis of 82 pregnancies in women with either ulcerative colitis or Crohn's disease suggested that, in general, neither disease had a major effect on pregnancy outcome. The birth-weights of babies born to women with inflammatory bowel disease were marginally lower than those born to women in a control group matched for age and parity, but the difference was statistically significant only in women with Crohn's disease. In both disease groups there was a higher frequency of low haemoglobin levels in pregnancy than in the matched control groups. There were no statistically significant effects of ulcerative colitis or Crohn's disease on duration of pregnancy, mode of delivery or raised blood pressure and/or proteinuria. In the absence of a relapse, a diagnosis of inflammatory bowel disease should not influence obstetric management.
Adolescent↗
Barbiturates reduce human cerebral glucose metabolism.
We studied the effect of barbiturates on local cerebral glucose metabolism by performing positron emission scans before and after withdrawal of phenobarbital or primidone. The postwithdrawal scan showed a significant increase (mean, 37%) in seven of eight cortical regions tested. Patients who had serial scans without a drug change showed a nonsignificant tendency for metabolic rates to go down on the second scan (mean decrease, 7%). Addition or deletion of a single drug other than barbiturate did not change metabolic rates on repeat scans. The depression in cerebral glucose metabolic rate due to phenobarbital, if confirmed, may have bearing on the adverse neuropsychological effects of the drug.
Adult↗
Neuroimaging in refractory partial seizures: comparison of PET, CT, and MRI.
We compared the results of x-ray CT, magnetic resonance imaging (MRI), and positron emission tomography (PET) using 18F 2-deoxyglucose in 36 patients with partial seizures. Seventeen patients had localized epileptic discharges on surface EEG. MRI showed an abnormality in 9, CT in 4, and PET in 13 of 14 patients who had the test. Nineteen patients had nonlocalizing EEG discharges. MRI showed an abnormality in 11, CT in 10, and PET in 8 of 12. MRI is more sensitive than CT in detecting structural lesions underlying PET hypometabolism.
Adolescent↗
New wave of research in the epilepsies.
The epilepsies affect at least 1 to 2 million people in the United States and 20 to 40 million people worldwide. Because the causes and basic mechanisms of the epilepsies have only started to unravel, there is still no cure for the disease. The purpose of this chapter is to present the new routes of navigation in epilepsy research, the salient theories on mechanisms of epilepsies, and their cogency to cause (generation of seizures) and effects (epileptic cell damage). In particular, it advances a comprehensible picture of the major cellular events involved in the generation, arrest, or spread of partial epileptic seizures; it also questions the major molecular events involved in the transmission and use of genetic information in the generalized epilepsies. In reviewing the many theories on mechanisms of epilepsies, this chapter establishes the connections between neurosciences, molecular genetics, and the epilepsies. The knowledge gained from such connections will certainly bear on the diagnosis of the subvarieties of epilepsies and is already promoting new methods of treatment of the disease. Indeed, it is this fusion between molecular genetics, neurosciences, and the clinical epilepsies that provides the excitement and new ferment in research of the epilepsies. This chapter also advances a conceptual blueprint for priority challenges in epilepsy research. It calls attention to the primary goal, namely, understanding the mechanisms of human epilepsies. In the most common of human epilepsies, namely, temporal lobe epilepsy, a priority challenge is to analyze paroxysmal depolarization shifts in hippocampal slices in vitro, slices excised from known sites of epileptogenicity. Parallel experiments exploring biochemical membrane abnormalities in neuronal and glial membranes isolated from the hippocampal seizure focus would be especially valuable. The role of kindling and the mirror focus in human temporal lobe epilepsy must be resolved. A second important goal is the search for polymorphisms of restriction endonuclease patterns in monogenic epilepsies in order to localize the abnormal gene to a specific chromosome. Because of the recent successful applications of positron emission tomography (PET), single-photon-emission computed tomography, and nuclear magnetic resonance computed tomography (NMR-CT), ion transport pathways, neurotransmitter systems, and metabolic processes may be constructed within the functioning brains of epileptic patients.(ABSTRACT TRUNCATED AT 400 WORDS)
Animals↗