Pathophysiology Of Seizures Research Articles

Clinical trials of antiepileptic medications in newly diagnosed patients with epilepsy.

Results from add-on antiepileptic drug (AED) trials performed in patients with chronic refractory epilepsy cannot be directly extrapolated to newly diagnosed patients because of fundamental differences in disease characteristics between the two patient populations. This article reviews the results of randomized, controlled trials of AEDs as monotherapy in newly diagnosed patients, focusing on the newer drugs. None of the newer AEDs has shown superior efficacy when tested against established agents for the treatment of partial seizures and generalized tonic-clonic seizures, the most common seizure types. Some of the newer drugs have shown good tolerability, resulting in better overall effectiveness in the case of lamotrigine over carbamazepine and oxcarbazepine over phenytoin, whereas vigabatrin and remacemide were demonstrated to have inferior efficacy compared with carbamazepine. The difficulty in detecting differences in efficacy among the AEDs might be attributed to the strategies underlying their development and the characteristics of the patient population under investigation. A better understanding of the pathophysiology of seizures and its relationship to epileptogenesis, and the use of more innovative strategies to identify new molecular targets, are needed for the development of a new generation of more effective AEDs that are not merely antiseizure but will hinder or reverse the deleterious processes that underlie the genesis of refractory epilepsy.

Are the epilepsies disorders of ion channels?

Hughlings Jackson1 in 1870 first emphasised that “A convulsion is but a symptom” and that the pathophysiology of seizures is related to “a sudden temporary excessive discharge” of the brain. A century later neuroscientists demonstrated that seizures are due to excessive neuronal firing or “burst discharges” often caused by a paroxysmal depolarisation shift in the neuronal membrane. Although burst discharges are the hallmark of the epileptic neuron, the crucial question remains—what is the molecular dysfunction causing this membrane instability?

Gamma oscillation underlies hyperthermia-induced epileptiform-like spikes in immature rat hippocampal slices

BackgroundRecently a hyperthermic rat hippocampal slice model system has been used to investigate febrile seizure pathophysiology. Our previous data indicates that heating immature rat hippocampal slices from 34 to 41°C in an interface chamber induced epileptiform-like population spikes accompanied by a spreading depression (SD). This may serve as an in vitro model of febrile seizures.ResultsIn this study, we further investigate cellular mechanisms of hyperthermia-induced initial population spike activity. We hypothesized that GABAA receptor-mediated 30–100 Hz γ oscillations underlie some aspects of the hyperthermic population spike activity. In 24 rat hippocampal slices, the hyperthermic population spike activity occurred at an average frequency of 45.9 ± 14.9 Hz (Mean ± SE, range = 21–79 Hz, n = 24), which does not differ significantly from the frequency of post-tetanic γ oscillations (47.1 ± 14.9 Hz, n = 34) in the same system. High intensity tetanic stimulation induces hippocampal neuronal discharges followed by a slow SD that has the magnitude and time course of the SD, which resembles hyperthermic responses. Both post-tetanic γ oscillations and hyperthermic population spike activity can be blocked completely by a specific GABAA receptor blocker, bicuculline (5–20 μM). Bath-apply kynurenic acid (7 mM) blocks synaptic transmission, but fails to prevent hyperthermic population spikes, while intracellular diffusion of QX-314 (30 mM) abolishes spikes and produces a smooth depolarization in intracellular recording.ConclusionThese results suggest that the GABAA receptor-governed γ oscillations underlie the hyperthermic population spike activity in immature hippocampal slices.

Selection of antiepileptic drug polytherapy based on mechanisms of action: the evidence reviewed.

When monotherapy with antiepileptic drugs (AEDs) fails, combination therapy is tried in an attempt to improve effectiveness by improving efficacy, tolerability, or both. We reviewed the available studies (both animal and human) on AED polytherapy to determine whether AEDs can be selected for combination therapy based on their mechanisms of action, and if so, which combinations are associated with increased effectiveness. Because various designs and methods of analysis were used in these studies, it was also necessary to evaluate the appropriateness of these approaches. Published papers reporting on AED polytherapy in animals or humans were identified by Medline search and by checking references cited in these papers. Thirty-nine papers were identified reporting on two-drug AED combinations. Several combinations were reported to offer improved effectiveness, but no uniform approach was used in either animal or human studies for the evaluation of pharmacodynamic drug interactions; efficacy was often the only end point. There is evidence that AED polytherapy based on mechanisms of action may enhance effectiveness. In particular, combining a sodium channel blocker with a drug enhancing GABAergic inhibition appears to be advantageous. Combining two GABA mimetic drugs or combining an AMPA antagonist with an NMDA antagonist may enhance efficacy, but tolerability is sometimes reduced. Combining two sodium channel blockers seems less promising. However, given the incomplete knowledge of the pathophysiology of seizures and indeed of the exact mechanisms of action of AEDs, an empirical but rational approach for evaluating AED combinations is of fundamental importance. This would involve appropriate testing of all possible combinations in animal models and subsequent evaluation of advantageous combinations in clinical trials. Testing procedures in animals should include the isobologram method, and the concept of drug load should be the basis of studies in patients with epilepsy.

Novel Role for the NMDA Receptor Redox Modulatory Site in the Pathophysiology of Seizures

Redox-active compounds modulate NMDA receptors (NMDARs) such that reduction of NMDAR redox sites increases, and oxidation decreases, NMDAR-mediated activity. Because NMDARs contribute to the pathophysiology of seizures, redox-active compounds also may modulate seizure activity. We report that the oxidant 5, 5'-dithio-bis(2-nitrobenzoic acid) (DTNB) and the redox cofactor pyrroloquinoline quinone (PQQ) suppressed low Mg(2+)-induced hippocampal epileptiform activity in vitro. Additionally, in slices exposed to 4-7 microM bicuculline, DTNB and PQQ reversed the potentiation of evoked epileptiform responses by the reductants dithiothreitol and Tris(2-carboxyethyl)phosphine (TCEP). NMDA-evoked whole-cell currents in CA1 neurons in slices were increased by TCEP and subsequently decreased by DTNB or PQQ at the same concentrations that modulated epileptiform activity. However, DTNB and PQQ had little effect on baseline NMDA-evoked currents in control medium, and PQQ did not alter NMDAR-dependent long-term potentiation. In contrast, in slices returned to control medium after low Mg(2+)-induced ictal activity, DTNB significantly inhibited NMDAR-mediated currents, indicating endogenous reduction of NMDAR redox sites under this epileptogenic condition. These data suggested that PQQ and DTNB suppressed spontaneous ictal activity by reversing pathological NMDAR redox potentiation without inhibiting physiological NMDAR function. In vivo, PQQ decreased the duration of chemoconvulsant-induced seizures in rat pups with no effect on baseline behavior. Our results reveal endogenous potentiation of NMDAR function via mass reduction of redox sites as a novel mechanism that may enhance epileptogenesis and facilitate the transition to status epilepticus. The results further suggest that redox-active compounds may have therapeutic use by reversing NMDAR-mediated pathophysiology without blocking physiological NMDAR function.

Cellular electrophysiological changes in the hippocampus of freely behaving rats during local microdialysis with epileptogenic concentration of N-methyl-D-aspartate

N-methyl-D-aspartate (NMDA) receptor dysfunctions are thought to be involved in the pathophysiology of seizures of hippocampal origin. While the cellular effects of excessive NMDA receptor stimulation have been widely studied in vitro, no data are available on the sequence of cellular electrophysiological events that follow the overstimulation of hippocampal NMDA receptors in awake, behaving subjects. Therefore, the present study addressed this problem. Intrahippocampal microdialysis with 500 μM NMDA was performed in freely behaving rats, and the electrical activity of single neurons in the dialysis area were monitored. In all recorded neurons ( n = 9), regardless of their type, NMDA induced a long-lasting electrical silence preceded in most cells by a brief but robust firing rate increase. During these firing rate increases, place cells lost the spatial selectivity of their discharges, and a gradual reduction in the amplitude of the action potentials was also observed. Remarkably, electroencephalographic (EEG) seizures developed exclusively after the appearance of cellular electrical silence in the recording/dialysis site. The NMDA-induced electrophysiological changes were reversible. This study demonstrates that the combined single-cell recording–intracerebral microdialysis technique can be readily used for inducing focal epileptiform events in the hippocampus and monitoring the induced cellular electrophysiological events in behaving animals.

Noninvasive Continuous Monitoring of Cerebral Oxygenation Periictally Using Near‐Infrared Spectroscopy: A Preliminary Report

To report on the use of near-infrared spectroscopy (NIRS) to examine the changes in cerebral oxygenation in the periictal period in patients with seizures. Cerebral hemoglobin oxygen availability was monitored continuously and noninvasively with NIRS in three patients (one in the pediatric intensive care unit (ICU) and two in epilepsy-monitoring units) in conjunction with continuous EEG monitoring. Ictal events were recorded and compared with the pre-, intra-, and postictal periods for cerebral oxygen availability, as defined by oxygenated hemoglobin (HbO2), deoxygenated hemoglobin (Hb), and the redox state of cytochrome oxidase (cytox). Several important preliminary observations were made by using this technology. First, a preictal increase in cerebral oxygenation began between 1 and 2 h and >10 h before the ictal event. Second, despite adequate perfusion, based on an observed increased HbO2, reduction in cytox indicates a perfusion-metabolism mismatch during seizure activity. Third, continued seizure activity and even isolated ictal events were associated with decreased cerebral oxygen availability. Fourth, differences in cerebral oxygen availability were noted between different types of seizures (e.g., electrographic seizures were accompanied by rapid reductions in HbO2 and cerebral blood volume without reduction of cytox, whereas electroclinical seizures were characterized by marked increases in HbO2 with or without reduction of cytox). In this preliminary report on the use of NIRS for patients with seizures, we believe that NIRS allows continuous and noninvasive monitoring of changes in cerebral oxygenation periictally, thereby permitting investigations into the pathophysiology of seizures and the exploration of the potential of cerebral oximetry as a tool for seizure localization.

Association study of idiopathic primary generalized epilepsy (IGE)

s 429 with a 25year history of anticonvulsant drug-resistant complex partial seizures. Computer analysis of captured images revealed over 100 differentially regulated genes, some involved in neurotransmitter release, plasticity and signalling mechanisms. Other candidate genes were novel. Secondary validation with selected candidate clones re-gridded was undertaken by hybridizing newly constructed probes derived from further RNA samples from the same epileptic patient and control. This technology is an effective approach to analysing gene expression changes and may yield new targets from therapeutic intervention in epilepsy. Association study of idiopathic primary generalized epilepsy (IGE) A. Makoff*+, B. Chioza’i, N. Currant, F! Ashersod & L. Nashefsl *Department of Psychological Medicine, institute of Psychiatry, London, UK; t Department of Neuroscience, institute of Psychiatry, London, UK; $ Social Genetic & Developmental Psychiatry Research Centre, Institute of Psychiatry, London, UK; 5 Kent and Canterbury Hospital, Canterbury IKings College Hospital, London, UK Twin studies have demonstrated concordance rates of up to 95% for idiopathic generalized epilepsy (IGE) in monozygotic twin pairs. There are a few rare mendelian forms of IGE, but most show a complex pattern of inheritance. The relative risk for IGE among first-degree relatives is in the range 5-10 suggesting that association studies will be required to detect the expected small gene effects. We have collected an initial sample of 100 probands with IGE and 100 ethnically matched controls. Our initial studies have focused on the metabotropic glutamate receptor type 7 (mGluR7) and the (r4 nicotinic acetylcholine receptor subunit (nAchRo4). Mouse knockouts of mGluR7 result in an epileptic phenotype. Studies of a biallelic polymorphisms in mGluR7 are in progress. Mutations within nAchRo4 have been shown to cause the rare dendelian epilepsy autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE). An association study with a mixture of different IGE syndromes provides some evidence for association to nAchrcr4. The gene for nAchRo4 lies only 50 Kb from a voltage-sensitive potassium channel gene (KCNQ2) in which mutations cause one type of another mendelian epilepsy, benign familial neonatal convulsions (BFNC). We are currently utilizing polymorphisms in the nAchRa4 gene and KCNQ2 in our sample. Functional and structural findings in epilepsy demonstrated with diffusion weighted imaging U.C. Wieshamnn, MR. Symms & S.D. Shorvon Epilepsy Research Group, institute of Neurology, Queen Square, London, UK Diffusion weighted imaging (DWI) is a magnetic resonance imaging technique which is sensitive to molecular motion of water. Transient or permanent changes of the microstructural organization of tissue, for example, widening or shrinkage of the extracellular space cause diffusion changes which can be detected by DWI. We used DWI to investigate patients with epilepsy. In a patient with focal status we detected transient diffusion changes which were likely to reflect neuronal dysfunction. During the interictal stage we found an increased diffusion in structural lesions associated with epilepsy. These included hippocampal sclerosis, tumours and most forms of brain damage. These changes were associated with a reduced anisotropy of water diffusion which is likely to reflect a breakdown of the structural organization. A reduction of anisotropy was the predominant finding in cortical dysgenesis. In conclusion, DWI can show changes of water diffusion in focal status epilepticus. In addition, DWI provides information about the microstructure in lesions which may help to understand the pathophysiology of seizures.

Sudden unexpected death in ‘epilepsy’—a missed opportunity to diagnose a long QT syndrome

s 429 with a 25year history of anticonvulsant drug-resistant complex partial seizures. Computer analysis of captured images revealed over 100 differentially regulated genes, some involved in neurotransmitter release, plasticity and signalling mechanisms. Other candidate genes were novel. Secondary validation with selected candidate clones re-gridded was undertaken by hybridizing newly constructed probes derived from further RNA samples from the same epileptic patient and control. This technology is an effective approach to analysing gene expression changes and may yield new targets from therapeutic intervention in epilepsy. Association study of idiopathic primary generalized epilepsy (IGE) A. Makoff*+, B. Chioza’i, N. Currant, F! Ashersod & L. Nashefsl *Department of Psychological Medicine, institute of Psychiatry, London, UK; t Department of Neuroscience, institute of Psychiatry, London, UK; $ Social Genetic & Developmental Psychiatry Research Centre, Institute of Psychiatry, London, UK; 5 Kent and Canterbury Hospital, Canterbury IKings College Hospital, London, UK Twin studies have demonstrated concordance rates of up to 95% for idiopathic generalized epilepsy (IGE) in monozygotic twin pairs. There are a few rare mendelian forms of IGE, but most show a complex pattern of inheritance. The relative risk for IGE among first-degree relatives is in the range 5-10 suggesting that association studies will be required to detect the expected small gene effects. We have collected an initial sample of 100 probands with IGE and 100 ethnically matched controls. Our initial studies have focused on the metabotropic glutamate receptor type 7 (mGluR7) and the (r4 nicotinic acetylcholine receptor subunit (nAchRo4). Mouse knockouts of mGluR7 result in an epileptic phenotype. Studies of a biallelic polymorphisms in mGluR7 are in progress. Mutations within nAchRo4 have been shown to cause the rare dendelian epilepsy autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE). An association study with a mixture of different IGE syndromes provides some evidence for association to nAchrcr4. The gene for nAchRo4 lies only 50 Kb from a voltage-sensitive potassium channel gene (KCNQ2) in which mutations cause one type of another mendelian epilepsy, benign familial neonatal convulsions (BFNC). We are currently utilizing polymorphisms in the nAchRa4 gene and KCNQ2 in our sample. Functional and structural findings in epilepsy demonstrated with diffusion weighted imaging U.C. Wieshamnn, MR. Symms & S.D. Shorvon Epilepsy Research Group, institute of Neurology, Queen Square, London, UK Diffusion weighted imaging (DWI) is a magnetic resonance imaging technique which is sensitive to molecular motion of water. Transient or permanent changes of the microstructural organization of tissue, for example, widening or shrinkage of the extracellular space cause diffusion changes which can be detected by DWI. We used DWI to investigate patients with epilepsy. In a patient with focal status we detected transient diffusion changes which were likely to reflect neuronal dysfunction. During the interictal stage we found an increased diffusion in structural lesions associated with epilepsy. These included hippocampal sclerosis, tumours and most forms of brain damage. These changes were associated with a reduced anisotropy of water diffusion which is likely to reflect a breakdown of the structural organization. A reduction of anisotropy was the predominant finding in cortical dysgenesis. In conclusion, DWI can show changes of water diffusion in focal status epilepticus. In addition, DWI provides information about the microstructure in lesions which may help to understand the pathophysiology of seizures.

Properties of human glial cells associated with epileptic seizure foci.

We studied physiological properties of glial cells from acute slices of biopsies from patients operated for intractable mesio-temporal lobe epilepsy using whole-cell patch-clamp recordings. Cells were filled with Lucifer Yellow (LY) during recordings to allow morphological reconstruction and immunohistochemical cell identification. Seizure-associated astrocytes had complex, arborized, highly branched processes giving them a stellate appearance, and cells stained intensely for the intermediate filament GFAP as previously reported for 'reactive' astrocytes. GFAP-positive astrocytes from epilepsy biopsies consistently expressed voltage-activated, TTX-sensitive Na+ channels that showed fast activation and inactivation kinetics. Unlike comparison astrocytes, derived from tissues that were not associated with seizure foci, these astrocytes expressed Na+ channels at densities sufficient to generate slow action potentials (spikes) in current clamp studies. In these cells, the ratio of Na+ to K+ conductance was consistently 3-4-fold higher than in comparison human or control rat astrocytes. Four of 17 astrocytes from epilepsy patients versus 14/14 from control rat hippocampus and four of five in comparison human tissue showed a lack of inwardly rectifying K+ currents, which in normal astrocytes are implicated in the control of extracellular K+ levels. These results suggest that astrocytes surrounding seizure foci differ in morphological and physiological properties, and that glial K+ buffering could be impaired at the seizure focus, thus contributing to the pathophysiology of seizures.

Epilepsy in the developing brain: lessons from the laboratory and clinic.

Children with epilepsy present unique challenges to the clinician. In addition to having differences in clinical and EEG phenomena, children differ from adults in regard to etiological factors, response to antiepileptic drugs (AEDs), and outcome. It is now recognized that the immature brain also differs from the mature brain in the basic mechanisms of epileptogenesis and propagation of seizures. The immature brain is more prone to seizures due to an imbalance between excitation and inhibition. gamma-Aminobutyric acid (GABA), the major CNS inhibitory neurotransmitter in the mature brain, can lead to depolarization in the hippocampal CA3 region in very young rats. There are also age-related differences in response to GABA agonists and antagonists in the substantia nigra, a structure important in the propagation of seizures. These age-related differences in response to GABAergic agents provide further evidence that the pathophysiology of seizures in the immature brain differs from that in the mature brain. Although prolonged seizures can cause brain damage at any age, the extent of brain damage after prolonged seizures is highly age dependent. Far less histological damage and fewer disturbances in cognition result from prolonged seizures in the immature brain than from seizures of similar duration and intensity in mature animals. However, detrimental effects of AEDs may be greater in the immature brain, than in the mature brain. These lessons from the animal laboratory raise questions about the appropriateness of current therapeutic approaches to childhood seizure disorders.

Infantile Spasms and West Syndrome

Infantile Spasms and West Syndrome , a multiauthored book by an international group of faculty, addresses one of the most intriguing, confusing, and controversial epileptic disorders unique to infants in early childhood. Infantile spasms (IS) are defined as the combination of epileptic spasms and diffuse spike activity occurring in infants; West syndrome is defined as the combination of infantile spasms and hypsarrhythmia, with or without cognitive impairment. The incidence of IS is one in every 2000 to 4000 infants. The book contains a foreword, overview, five chapters, references, and index. The first chapter, titled Background, gives historical perspectives, definitions of various epileptologic terms used throughout the book, a detailed review of epidemiology of West syndrome and IS, and basic pathophysiology of seizures as a function of age. Sections of this chapter are difficult to read as they are saturated with information at times loosely related to the main subject. A summary

New antiepileptic drugs

Notwithstanding pharmacokinetics has greatly increased the rational approach to the drug treatment of epilepsies, about 25% of the patients do not respond to the therapy. Therefore, a great effort has been made to discover new antiepileptic drugs effective in refractory seizures. On the basis of increased knowledge of seizure pathophysiology two principal groups of drugs have been developed: the first enhancing brain GABA activity (vigabatrin); the second inhibiting excitatory amino-acids (lamotrigine and felbamate). Oxcarbazepine has the same mechanism of action as carbamazepine, whereas gabapentin's mechanism is still uncertain. The major clinical indications of these new antiepileptic drugs are represented by partial complex seizures. Side effects (mostly regarding the central nervous system) appear mild, and clinical interactions have little importance. The role of therapeutic drug monitoring for these substances is at present not well established.

Experimental models of epilepsy in young animals.

Seizures occur more frequently early in life. Some of these early seizures may eventually become epilepsy. Others are reactive seizures due to excessive environmental stimuli that, in any other age group, might not have elicited a similar response. To understand the developmental aspects of seizures and epilepsy in humans, it is important to study these processes in animals of equivalent ages. In this paper, we describe several animal models of developmental seizures, including their electroclinical manifestations and their validity in respect to human epileptic syndromes. There are several factors that may account for the increased seizure susceptibility of the immature brain, including the delayed development of effective systems or synaptic networks that are involved in the suppression of seizures. A better insight of the basic pathophysiology of seizures as a function of age in animal models will lead to the development of new therapeutic approaches for the treatment of age-specific epileptic disorders in humans.

Metabolic and degenerative diseases associated with epilepsy.

Identifying the specific etiology of epilepsy is often difficult. The search for the cause often leads the clinician to suspect inborn errors of intermediary metabolism and other degenerative metabolic diseases. Although these uncommon diseases are often difficult to determine, a correct diagnosis is critical for treatment and genetic counseling. A review of the relevant biochemistry will aid in understanding the pathophysiology of seizures in these conditions. The stream-lined approach to the initial laboratory evaluation that is offered will enable the clinician to screen for most metabolic and degenerative diseases that are associated with epilepsy.

Effects of morphine and D-Ala2-D-Leu5-enkephalin in the seizure-susceptible El mouse.

Opioid agonists were used to investigate the modulation of seizures in the seizure-susceptible El mouse. Morphine and D-Ala2-D-Leu5-enkephalin (DADLE) were injected subcutaneously or intracisternally as prototypic agonists for mu and delta opioid receptors. Systemic or intracisternal injection of both morphine and DADLE decreased the incidence of seizures and the seizure score in El mice in a dose-dependent manner. The anticonvulsant effects of morphine and DADLE were reversed by naloxone (2 mg/kg, s.c.). This implies that opioid agonists have anticonvulsant properties which are mediated by mu and delta opioid receptors. In conclusion, a deficit in endogenous opioid peptides, which act as anticonvulsants may play a significant role in the etiology or pathophysiology of seizures in the El mouse.

An analysis of various environmental and specific sensory stimuli on the seizure activity of the Mongolian gerbil

Mongolian gerbils were subjected to different environmental and specific sensory stimuli to determine the ability of these stimuli to provoke seizures. None of the specific sensory stimuli, somatosensory, olfactory, auditory or visual, were effective in inducing convulsions. This finding does not implicate dysfunctions of the specific sensory pathways in seizure genesis in gerbils. In contrast, several novel environmental stimuli that exposed the animals to a difficult exploratory task (i.e., Y-maze, dish rack, etc.) could trigger seizures, and this suggests that the pathophysiology of epileptiform events in gerbils may have a unique association with exploratory behavior. However, the frequency, latency and severity of the seizures showed no correlation with each other, indicating that these parameters are probably determined by independent factors. Taken together with previous studies on the electrophysiology of the dentate gyrus during exposure to novel experiences, and the anatomical abnormalities found in the hippocampus of the seizure-sensitive gerbil, these behavioral data provide further support for a significant role of the hippocampus in the pathophysiology of seizures in this model of genetic epilepsy.

In vivo 1H spectroscopy of the human brain following electroconvulsive therapy

Recent advances in the methodology of magnetic resonance spectroscopy now permit localized proton (1H) spectroscopy of the human brain in clinical magnetic resonance systems. In this study, localized 1H spectroscopy was used to observe directly the stimulation of brain metabolic activity in patients undergoing electroconvulsive therapy (ECT) and to compare results obtained before and after treatments. Persistent increases in lactate were expected on the basis of animal data but these increases were small and equivocal 1 hour after ECT. In contrast, a large increase in a lipid signal from before to after ECT was observed in 5 patients when short echo times were used. We postulate that a significant portion of this lipid signal is related to maximal activation of the phosphatidylinositol system (increased levels of diacylglycerol and free fatty acids) have generalized inhibitory effects potentially relevant to both the clinical pathophysiology of seizures and the efficacy of ECT in major affective disorders.

Anticonvulsant Therapy in Small Animals

This article includes an overview of the pathophysiology of seizures and a discussion of the mechanism of action of anticonvulsants based on the targeted physiologic processes. The commonly used anticonvulsants are classified and reviewed by chemical group. The concept, indications, and benefits of therapeutic monitoring of serum anticonvulsant concentrations are presented. The use of anticonvulsant agents for treatment of status epilepticus is addressed.

The role of serotonin in the pathophysiology of myoclonic seizures associated with acute imipramine toxicity

Article abstract Seizures are a well-known manifestation of imipramine toxicity, but the pathophysiology of these seizures is unknown. Since myoclonic seizures can be generated in guinea pigs with 5-hydroxytryptophan, the precursor of serotonin, and since imipramine has been observed to decrease the reuptake to serotonin in the brain, an attempt was made to potentiate 5-hydroxytryptophan-induced myoclonus in guinea pigs with imipramine. Subthreshold doses of 5-hydroxytryptophan together with 35 mg per kilogram of imiparmine consistently led ?o myoclonic seizures in the animals. Antagonists of norepinephrine, dopamine, and acetylcholine all failed to block the potentiation of 5-hydroxytryptophan-induced seizures with imipramine. These results are consistent with the hypothesis that imiprarnine acts via serotonergic mechanisms in the brain to produce myoclonic seizures.