Complex Partial Epilepsy Research Articles

Interictal metabolism and blood flow are uncoupled in temporal lobe cortex of patients with complex partial epilepsy.

We used positron emission tomography (PET) with 18F-2-deoxyglucose (FDG) and 15O water in 20 patients with complex partial seizures to compare glucose metabolism and blood flow in temporal lobe epileptic foci identified by ictal scalp-sphenoidal video-EEG telemetry. Glucose metabolism was measured 20 minutes after blood flow without moving the patient from the scanner. We also studied 11 patients with 99mTc-HMPAO single-photon emission computed tomography (SPECT). Both local cerebral metabolic rate of glucose (LCMRGlc) and regional cerebral blood flow (rCBF) were significantly decreased in temporal cortex ipsilateral to the EEG focus. However, LCMRGlc was reduced by 11.2% in inferior lateral and 11.1% in inferior mesial temporal cortex and rCBF by only 3.2% and 6.1%. The ratio of LCMRGlc to rCBF was significantly reduced in inferior lateral temporal cortex ipsilateral to the ictal focus (p < 0.009). Moreover, using standardized criteria, blinded raters found that 16 of 20 patients had focal FDG-PET hypometabolism, all in the epileptogenic region; 10 of 20 had focal 15O water PET hypoperfusion, but it was falsely lateralized in two of these 10; and five of 11 had focal 99mTc-HMPAO SPECT hypoperfusion, but it was falsely lateralized in two of these five. Our data suggest that interictal glucose metabolism and blood flow may be uncoupled in epileptogenic cortex.

A review of the preclinical pharmacology of tiagabine: a potent and selective anticonvulsant GABA uptake inhibitor.

We review the neurochemical and behavioral profile of the selective gamma-aminobutyric acid (GABA) uptake inhibitor, (R)-N-(4,4-di-(3-methylthien-2-yl)but-3-enyl) nipecotic acid hydrochloride [tiagabine (TGB), previously termed NNC 05-0328, NO 05-0328, and NO-328], which is currently in phase III clinical trials for epilepsy. TGB is a potent, and specific GABA uptake inhibitor. TGB lacks significant affinity for other neurotransmitter receptor binding sites and/or uptake sites. In electrophysiological experiments in hippocampal slices in culture, TGB prolonged the inhibitory postsynaptic potentials (IPSP) and inhibitory postsynaptic currents (IPSC) in the CA1 and CA3 produced by the addition of exogenous GABA. In vivo microdialysis shows that TGB also increases extracellular GABA overflow in a dose-dependent manner. Together these biochemical data suggest that the in vitro and in vivo mechanism of action of TGB is to inhibit GABA uptake specifically, resulting in an increase in GABAergic mediated inhibition in the brain. TGB is a potent anticonvulsant agent against methyl-6,7-dimethyoxy-4-ethyl-B-carboline-3-carboxylate (DMCM)-induced clonic convulsions (mice), subcutaneous pentylenetetrazol (PTZ)-induced tonic convulsions (mice and rats), sound-induced convulsions in DBA/2 mice and genetically epilepsy-prone rats (GEPR), and electrically induced convulsions in kindled rats. TGB is partially efficacious, against subcutaneous PTZ-induced clonic convulsions, and photically induced myoclonus in Papio papio. TGB is weakly efficacious in the intravenous PTZ seizure threshold test and the maximal electroshock seizure (MES) test and produces only partial protection against bicuculline (BIC)-induced convulsions in rats. The overall biochemical and anticonvulsant profile of TGB suggests potential utility in the treatment of chronic seizure disorders such as generalized clonic-tonic epilepsy (GTCS), photomyoclonic seizures, myoclonic petit mal epilepsy, and complex partial epilepsy.

Fasting studies in cerebrospinal fluid and blood in children with epilepsy of unknown origin

Alterations in the cerebral energy supply are likely to cause cerebral function disturbances. Fasting is a suitable method for studying the energy metabolism. As the cerebrospinal fluid (CSF) compartment reflects the brain metabolism, data in CSF might give information about the metabolism of fuel substrates in brain. We compared the biochemical data on several fuel-related components in blood and CSF at the end of a 40-hours fast of epileptic children with unknown origin of epilepsy (aged 6-15 years) with the values of a reference group of children. In children with primary generalized epilepsy no abnormalities were found. In children with complex partial epilepsy many significant abnormalities were found, such as low blood lactate and alanine and low CSF ketones and CSF blood ratio for ketones. The possible significance of the observed abnormalities are discussed.

Temporal intermittent rhythmic delta activity in electroencephalograms.

Temporal intermittent rhythmic delta activity (TIRDA) has been reported to be highly specific for diagnosing complex partial epilepsy. Of 12,198 electroencephalographic (EEG) recordings performed at the Mayo Clinic between May 1, 1990 and May 1, 1991, 33 records from 27 patients (18 women and nine men; mean age, 41.5 years; range, 13-82 years) showed TIRDA. Clinical seizures were diagnosed in all patients, and complex partial epilepsy was well documented in 23. In a control group of 100 patients without TIRDA and matched for age and sex, generalized seizures were diagnosed in 25 and partial seizures in 15. Differences between TIRDA and control groups were highly statistically significant. Focal temporal sharp waves or spikes occurred in 23 patients with EEG recordings that contained TIRDA; three of these patients also exhibited generalized atypical spike-and-wave discharges. Four patients had TIRDA but no other epileptiform activity, although earlier EEGs of three of these patients contained spikes or sharp waves. These findings confirm earlier work, and we conclude that TIRDA represents an important epileptogenic abnormality.

Effects of Propofol Sedation on Seizures and Intracranially Recorded Epileptiform Activity in Patients with Partial Epilepsy

Case reports suggesting both pro- and anticonvulsant effect(s) of propofol have been published in recent years. The effects of sedative doses of propofol on epileptiform activities in patients suffering from intractable partial epilepsy were systematically investigated. Fourteen patients suffering from complex partial seizures were studied. Electroencephalogram (EEG) was recorded from intracranial electrodes implanted in the hippocampi and temporal neocortex. Propofol was given as a computer-controlled infusion in four steps to achieve target plasma propofol concentrations of 0.3, 0.6, 0.9, and 1.2 micrograms/ml. Each concentration was maintained for 30 min, and steady-state kinetics were confirmed by blood levels drawn at 10th and 30th min at each level. Between the 15th and 30th min of each concentration of propofol, EEG was analyzed for presence of electroencephalographic seizure activity and/or number of interictal spikes (IIS). Effects of propofol on IIS frequency at different electrode sites were compared using a two-way repeated measures analysis of variance. A value of P < 0.05 was considered significant. None of the patients developed a seizure during the 2 h of propofol infusion. No "false spikes" (spikes developing with propofol infusion in areas where no spikes were seen in baseline EEG) were seen. Although effects of propofol on IIS frequency were highly variable across patients and at different propofol doses in the same patient, there was no statistically significant effect of propofol on any electrode site with any of the doses studied. We were unable to demonstrate a significant change in epileptiform activity with sedative doses of propofol in patients suffering from complex partial epilepsy.

An intra-arterial electrode for intracranial electro-encephalogram recordings.

A new method for intracranial monitoring of brain electrical activity by means of an intra-arterial guide wire as electrode is described. We carried out intracranial electro-encephalography (EEG) using an insulated Seeker Lite-10 guide wire 18 times in 14 patients: ten times in 6 patients with cerebral arteriovenous malformation (AVM) before embolization, and another 8 times in 8 patients with epilepsy. In all cases, a 2-5 times stronger high voltage potential EEG compared with scalp EEG could be recorded. In 3 patients with complex partial epilepsy, intra-arterial (IA) EEG was recorded under subdural strip electrode monitoring, and IAEEG at the sphenoidal portion of the middle cerebral artery was compared with subdural electrode recordings. Frequent interictal spike discharges recorded with subdural electrodes in the lesional medial temporal lobe were simultaneously visible on IAEEG recording. This method is equivalent to that using a semi-invasive electrode, but ECoG recording can be performed at angiography. IAEEG is a method of electrode recording that has the possibility of clinical application.

Hippocampal mossy fiber sprouting and synapse formation after status epilepticus in rats: Visualization after retrograde transport of biocytin

In complex partial epilepsy and in animal models of epilepsy, hippocampal mossy fibers appear to develop recurrent collaterals that invade the dentate molecular layer. Mossy fiber collaterals have been proposed to subserve recurrent excitation by forming granule cell-granule cell synapses. This hypothesis was tested by visualizing dentate granule cells and their mossy fibers after terminal uptake and retrograde transport of biocytin. Labeling studies were performed with transverse slices of the caudal rat hippocampal formation prepared 2.6-70.0 weeks after pilocarpine-induced or kainic acid-induced status epilepticus. Light microscopy demonstrated the progressive growth of recurrent mossy fibers into the molecular layer; the densest innervation was observed in slices from pilocarpine-treated rats that had survived 10 weeks or longer after status epilepticus. Thin mossy fiber collaterals originated predominantly from deep within the hilar region, crossed the granule cell body layer, and formed an axonal plexus oriented parallel to the cell body layer within the inner one-third of the molecular layer. When sprouting was most robust, some recurrent mossy fibers at the apex of the dentate gyrus reached the outer two-thirds of the molecular layer. The distribution and density of mossy fiber-like Timm staining correlated with the biocytin labeling. When viewed with the electron microscope, the inner one-third of the dentate molecular layer contained numerous mossy fiber boutons. In some instances, biocytin-labeled mossy fiber boutons were engaged in synaptic contact with biocytin-labeled granule cell dendrites. Granule cell dendrites did not develop large complex spines ("thorny excrescences") at the site of synapse formation, and they did not appear to have been permanently damaged by seizure activity. These results establish the validity of Timm staining as a marker for mossy fiber sprouting and support the view that status epilepticus provokes the formation of a novel recurrent excitatory circuit in the dentate gyrus. Retrograde labeling with biocytin showed that the recurrent mossy fiber projection often occupies a considerably greater fraction of the dendritic region than previous studies had suggested.

The relationship between seizure subtype and interictal personality

A wide variety of interictal personality traits has been associated with complex partial (CP) epilepsy. However, the specificity of these behavioural changes to CP epilepsy has been questioned in several controlled studies. To address this issue, we examined personality and behavioural characteristics in 467 Vietnam veterans 15 years post penetrating head injury. Of this sample, 238 (51%) had developed seizure disorders which were classified as follows: 39 simple partial (SP), 59 CP, 76 partial with secondary generalization (PG), and 64 generalized (G). Seizure patients were compared with two demographically matched control groups: 229 penetrating head-injured Veterans without seizures (PHI-C) and 84 uninjured veterans (UC). Dependent measures included self-report and examiner rating scales, and history of psychiatric treatment. Pre-injury intelligence, brain volume loss (CT scan), seizure frequency and duration of epilepsy served as covariates. We found statistically significant increases in interictal psychopathology in the CP, PG and G groups when compared with the two control groups (PHI-C and UC). No group differences were observed across seizure subtypes. These results suggest that interictal personality and behavioural abnormalities are not specific to individuals with CP seizures. Furthermore, the increased psychopathology in seizure groups when compared with the PHI-C group suggests that personality changes cannot be accounted for by structural brain damage alone.

Higher Cortical Dysfunctions and Image Diagnosis in a 9-Year-Old Girl with Complex Partial Epilepsy Caused by Focal Neural Migration Disorder

Higher Cortical Dysfunctions and Image Diagnosis in a 9-Year-Old Girl with Complex Partial Epilepsy Caused by Focal Neural Migration Disorder

FDG-PET and volumetric MRI in the evaluation of patients with partial epilepsy

We performed interictal FDG-PET- and MRI-based hippocampal volumetric measurements on 18 adult patients with complex partial epilepsy of temporal lobe origin in whom we had identified their ictal focus by video-telemetry EEG. Sixteen patients (89%) had regional hypometabolism, 11 (61%) had focal 1.5-tesla T2-weighted MRI (two structural abnormalities, nine hippocampal formation [HF] increased T2 signal), and nine (50%) had absolute HF atrophy ipsilateral to the temporal ictal focus. Ten (55%) had abnormal L/R HF ratios, nine ipsilateral to the EEG focus. All patients with abnormal MRI volumetric studies had focal PET abnormalities. Only seven had both abnormal HF volume ratios and T2 MRI (all increased HF T2 signal). There was a significant correlation between hippocampal volume and inferior mesial and lateral temporal lobe cerebral metabolic rate of glucose asymmetry index (p < 0.01), suggesting that hypometabolism may reflect hippocampal atrophy. PET is more sensitive than MRI volumetry in identifying the ictal focus but does not provide additional information when HF atrophy is present.

FDG-PET in children and adolescents with partial seizures: role in epilepsy surgery evaluation.

We used FDG-PET to measure interictal glucose metabolism in 16 children and adolescents (mean age 14.7 years) and complex partial seizures (CPS) (mean seizure onset age 5.0 years). Video-EEG localized the epileptic foci. Glucose metabolism was determined in 14 paired anatomic areas using a standard template. PET hypometabolism was defined as greater than 15% asymmetry. Nine of the 13 (69%) patients with a unilateral EEG focus had regional hypometabolism ipsilateral to the epileptogenic zone. Three subjects had bilateral EEG foci; all had nonfocal PET. MRI (15 patients) concurred with EEG and PET in two, and was normal in seven of nine with focal hypometabolism. One of seven patients with normal PET had a focal MRI abnormality. FDG-PET results are similar to those found in adults, but are present earlier in the natural history of CPS (9.7 vs 22.2 years duration epilepsy) than previously reported. The presence of FDG-PET hypometabolism may be associated with a poor response to drug treatment. PET can identify metabolic abnormalities associated with epileptic foci in children and adolescents and is useful in directing surgical intervention for the control of refractory complex partial epilepsy.

Ipsilateral subcortical atrophy associated with temporal lobectomy

Stereologic methods for determining the volume of cerebral structures in vivo via magnetic resonance imaging have identified unilateral hippocampal atrophy among patients with complex partial epilepsy of temporal lobe origin. Metabolic imaging has also identified altered metabolism in temporal as well as extratemporal regions among these patients. As the temporal cortex and subcortical nuclei of the limbic system are reciprocally connected with striatal projection fields, we examined the putamen nuclei for evidence of associated extratemporal volume asymmetry in patients before and after temporal lobectomy. There was no evidence of preoperative putamen volume asymmetry, but a significant post-operative decrement in ipsilateral putamen volume was observed. The magnitude of postsurgical putamen volume asymmetry was correlated with the duration of time since resection. Progressive degeneration of extratemporal projections of the temporal lobe may occur in association with temporal lobectomy.

Comparisons of MEG, EEG, and ECoG source localization in neocortical partial epilepsy in humans

In order to delineate the characteristics of epileptic spikes, 1946 different spikes were studied in 6 patients with complex partial epilepsy. Non-invasive MEG and EEG source analyses of interictal spikes were contrasted to ECoG localization, surgical outcome and presence of lesions on MRI. Results indicated that: (1) using the most frequent occurring spike topography patterns from a large sample of spikes improved goodness-of-fit values for both MEG and EEG localization, (2) when spike patterns could be appropriately matched on several successive MEG measurements to provide an adequate matrix (3 of 6 subjects), there was excellent agreement between MEG dipole sources and ECoG sources as well as surgical outcome and presence of MRI lesions, (3) EEG sources analyse also gave good results but not as consistently as MEG.

Direct measurement of extracellular lactate in the human hippocampus during spontaneous seizures.

The effect of clinical, spontaneous-onset seizures on extracellular fluid lactate was investigated by the method of lactography, the in vivo on-line measurement of lactate levels using microdialysis. Studies of experimental animals have suggested that generation of extracellular lactate as measured by microdialysis is an index of local glucose utilization and is dependent on the activity of neurons under physiological conditions. Patients with medically refractory complex partial epilepsy underwent stereotactic implantation of combination depth electrode/microdialysis probes into both hippocampi for 7-16 days. During spontaneous complex partial seizures with secondary generalization, extracellular lactate levels rose by 91 +/- 32%. Moreover, this increase persisted for 60-90 min. During a unilateral hippocampal seizure that did not propagate to the contralateral hippocampus, the increase in lactate content was restricted to the side of seizure activity. Between seizures, extracellular lactate levels correlated with the frequency of interictal spikes. In summary, these data suggest that brief clinical seizures increase nonoxidative glucose metabolism significantly as measured by the generation of extracellular lactate. Furthermore, the increase in extracellular lactate levels is limited to the site of seizure activity. Lactate is transported extracellularly via a lactate/proton cotransporter, therefore, the rise in extracellular lactate level may mediate the drop in pH0 associated with seizure activity. As acidification of the extracellular compartment has an inhibitory effect on neuronal excitability, the rise in extracellular lactate content may be a mechanism of seizure arrest and postictal refractoriness. Moreover, extracellular lactate may also mediate the decreased seizure susceptibility associated with frequent interictal spikes.

Dual-isotope autoradiographic measurement of regional blood flow and benzodiazepine receptor availability following unilateral middle cerebral artery occlusion.

Single-photon emission tomography (SPET) imaging in patients with complex partial epilepsy has shown that the seizure focus is characterized by both decreased interictal blood flow and decreased uptake of the benzodiazepine (BZ) receptor tracer iodine-123 iomazenil. The purpose of this study was to examine the confounding effect of decreased flow on iomazenil uptake. The left middle cerebral artery of four rats was occluded, and the animals were simultaneously injected with 25 microCi of iodine-125 iomazenil and 500 microCi of the blood flow tracer [123I]iofetamine (N-isopropyl-p-iodoamphetamine). All rats, including two sham, were sacrificed 1 h after injection, a time when uptake of both agents is nearly maximal. Control experiments showed that arterial occlusion for 1 h did not affect the total number of BZ binding sites. Using a dual autoradiographic technique, the uptake of both [123I]iofetamine and [125I]iomazenil was measured in more than 200 regions showing variable levels of reduced flow and expressed as a percentage of the contralateral homotypic area. The straight line fit of % [125I]iomazenil (y axis) versus % [123I]iofetamine (x axis) in all 200 regions had a slope of 0.74. Insofar as the rat is an accurate model of human subjects with epilepsy, these studies suggest that decreased flow to the epileptogenic focus will linearly exacerbate the decrease in uptake secondary to neuropathologic loss of BZ receptors. Thus, for localization of seizure focus, a single SPET image of [123I]iomazenil in an epileptic patient may have greater sensitivity than a comparable blood flow image, because the former is enhanced by both decreased flow and a loss of BZ receptors.

Mechanism of epilepsy.

Epilepsy is a collection of diverse disorders that together affect approximately 1% of the general population. Current therapies are largely symptomatic and are aimed at controlling seizures in affected individuals. This review focuses on emerging insights into mechanisms underlying the most common form of epilepsy--complex partial epilepsy--and also addresses progress in molecular genetic approaches. Such developments will hopefully lead to more effective therapies.

Brain source imaging of focal and multifocal epileptiform EEG activity

Brain electric source analysis (BESA) of the scalp EEG has been used to identify multiple equivalent current sources in the brain during during interictal spikes and seizure onset. To obviate the need for fitting dipole sources to every EEG segment, a new method has been developed on the basis of multiple fixed dipoles, each designed to emphasize functional imaging of particular cortical areas. "FOCUS" can quickly display EEG in various montages including new "sources montages" which provide a high sensitivity for source currents near each dipole while largely suppressing contributions from other brain areas. By comparing this "source EEG" to routine digital EEG in patients with complex partial epilepsy, we have observed that "FOCUS" can more readily determine whether an epileptiform discharge is consistent with a discrete or multifocal generator, characterize likely cerebral source(s), differentiate between spikes and seizures of mesio-basal versus lateral temporal or frontal origin, and estimate the presence and direction of propagation from source potential timing differences. Improved non-invasive EEG evaluations of partial epilepsy will undoubtedly result from this advance.

Nonepileptic seizures and childhood sexual and physical abuse.

Nonepileptic seizures (NES) must be distinguished from epilepsy to avoid the adverse effects of unnecessary antiepileptic drugs and to initiate appropriate psychiatric treatment. A higher frequency of prior sexual abuse has been suspected in NES, although no prospective controlled study has compared patients with NES and epilepsy. A series of patients with conversion disorder presenting as epilepsy and 140 patients with complex partial epilepsy (CPE) without evidence of conversion were selected from a series of consecutive admissions to a comprehensive epilepsy center. The groups did not differ with respect to age, years of education, race, or marital status, but the percentage of women was greater in the conversion NES group (73.2%) than in the CPE control group (50.7%; p < 0.002). The frequency of a history of sexual or physical abuse was greater in the NES group (32.4%) than in the CPE controls (8.6%; p < 0.000). Severity of sexual but not physical abuse was significantly greater in the NES group relative to controls (p < 0.05). There was a trend for a closer relationship of the perpetrator of sexual abuse to the victim among the NES patients compared with CPE controls (p < 0.1). These results support the impression that childhood abuse is more common among patients with conversion NES than with epilepsy, and suggests that in some cases childhood abuse may be a contributory pathogenetic factor.

The neuropathology of temporal lobe epilepsy.

Complex partial epilepsy arising in the temporal lobe has been associated with several types of pathologic lesions including Ammon's horn sclerosis, malformations, neoplasms, and inflammatory scars from infarcts or infection. These lesions are usually situated at various sites in the medial temporal lobe, so that one of the enigmas of attempting to understand the pathogenesis of TLE pertains to the clinical manifestation of a single epileptic disorder which is associated with dissimilar lesions at dissimilar sites. Recent demonstrations of an alteration in temporal lobe anatomy, i.e. malformations of the normal circuitry of the temporal lobe and foci of microdysgenesis, have given rise to the hypothesis that insults which occur during a critical period of brain development could alter the connections within the hippocampus and predispose it to increased excitability and seizurogenesis. Such a hypothesis forces us to reconsider TLE in reference to risk factors which may act as "teratogens" and produce these malformations. These malformations may range from a subtle alteration in the neurotransmitters of the dentate gyrus to large areas of cortical dysplasia or the hamartomatous neoplasms seen in TLE. A reevaluation of the neuroanatomical disruptions created by the various lesions may allow us to define a minimal optimal surgical resection for each lesion; or, the definitions of neurotransmitter deficits may lead to alternative pharmacologic therapies. As neuropathologists we have the exciting opportunity to participate in the definition of the neuropathology of temporal lobe epilepsy.

The role of electrocorticography for epilepsy surgery in children with complex partial epilepsy

The role of electrocorticography for epilepsy surgery in children with complex partial epilepsy