Complex Partial Epilepsy Research Articles

Biological profile of the metabolites and potential metabolites of the anticonvulsant remacemide

Remacemide hydrochloride ((±)-2-amino- N-(1-methyl-1,2-diphenylethyl)-acetamide hydrochloride or FPL 12924AA) is a novel compound undergoing clinical trials for patients with generalized tonic/clonic and complex partial epilepsy. Remacemide exhibits efficacy against maximal electroconvulsive shock (MES) in rodents and seizures elicited by N- methyl- d , l-aspartate (NMDLA) in mice. Using rat synaptic membrane fractions, remacemide was shown to possess relatively weak noncompetitive binding to the ionic channel site of the NMDA ( N- methyl- d-aspartic acid ) receptor complex. With the hypothesis that activity against NMDLA-elicited seizures might be reflected by transformation to a more active metabolic species, the aim of the present study was to evaluate potential pharmacological effects of the 9 identified metabolites of remacemide which were all found in human and dog urine. Moreover, specific entities were recognized in plasma (including the rat's), as well as dog and rat cerebrospinal fluid. Five putative metabolites were also examined. A major route of metabolic transformation of remacemide in rats yields the formation of a pharmacologically active more potent desglycine derivative, namely FPL 12495 (±). Potency over the parent compound is revealed in the MES test in mice and rats, the NMDA-induced convulsions/ mortality test in mice, and especially involving in vitro displacement of MK801 binding to the channel subsite of the NMDA receptor. The S isomer (FPL 12859) of this desglycinate is even more potent, while the R isomer is less potent than the corresponding racemate. Unlike the non-competitive NMDA antagonist, MK801, these desglycinates did not prevent kindled seizures. Three other identified metabolites show efficacy in the mouse and rat in vivo tests, namely the N-hydroxy-desglycinate (FPL 15053) and the p-hydroxy-desglycinates (FPL 14331 and FPL 14465). FPL 15053 exhibited modest activity in all tests. The only in vivo activity exhibited by the 2 p-hydroxy-desglycinates was evidenced in the MES test following i.p. and i.v. dosing. However, FPL 14331 was active in the MK801 binding assay. An oxoacetate metabolite, FPL 15455, failed to demonstrate any biological activity. Of potential metabolites tested 2 β-Miydroxy-desglycinates (FPL 14991 and FPL 14981) displayed modest activity in the MES test, however, only FPL 14981 prevented NMDLA-induced convulsions/mortality in mice and was 2-fold more active regarding MK801 binding. The hydroxy-methyl derivative of remacemide (FPL 13592) and its desglycinate (FPL 15112) prevented MES-induced convulsions only after i.v. administration; only the desglycine derivative displaced MK801 binding. FPL 14467 ( p-dihydroxy-desglycine) was inactive in vivo and weak in the MK801 binding assay. The discrepancy between in vivo/in vitro activities for many of the compounds is presumably due to pharmacokinetic factors.

The Anticonvulsant Effects of Vitamin E: A Further Evaluation

Vitamin E (d-alpha-tocopherol) has proven to be a useful adjunct to anticonvulsant drugs in clinical studies. Improvement has occurred even in patients with complex partial seizures, which are often resistant to drug therapy. In animals, vitamin E is effective against ferrous chloride seizures, hyperbaric oxygen seizures and penicillin-induced seizures. It has failed, however, to show anticonvulsant effects in the standard animal models used for drug screening--the maximal electroshock and threshold pentylenetetrazol tests. The present experiments were designed to further explore the anti-epileptic actions of vitamin E in animals. Three models related to complex partial epilepsy were used: 1) the development of amygdala-kindled seizures; 2) the development of electrically-induced status in kindled animals; and 3) the development of kainic-acid seizures. Vitamin E failed to produce significant effects in any of the models.

The neuroanatomy of panic disorder: The emerging role of the right parahippocampal region

Recent brain imaging and case report data suggest that a right temporal lobe abnormality, specifically involving the right parahippocampal region, may play an important role in the pathogenesis of some forms of panic disorder. The authors explore the interesting link between ictal fear in complex partial epilepsy, case reports of panic patients with focal temporal lobe pathology, and cocaine-induced panic. This is systematized into a proposed neuroanatomic theory of the pathogenesis of panic disorder involving the right temporal lobe and other brain regions.

Simultaneous subdural grid and depth electrodes in patients with refractory complex partial seizures

Simultaneous implantation of intracerebral depth electrodes and subdural electrode grids is an extension of available techniques for invasive monitoring and seizure localization in epilepsy surgery candidates. This combined approach is described in 10 selected patients with refractory complex partial epilepsy, in whom previous intensive video/EEG monitoring with scalp or depth electrodes had indicated a lateralized seizure onset. All patients required subdural grids for further localization, functional mapping, or both. Ipsilateral depth electrodes were placed in mesial temporal or other regions through the same craniotomy. Four patients had seizures originating in the mesial temporal lobe, and the onsets were first seen in the temporal lobe depth electrodes. The other six patients had seizures beginning in lateral cortical structures, and the onsets were first seen in the subdural grid (overlying known structural lesions in four patients). The information from both electrode sources guided the surgical resections. All patients were improved after surgery; six are seizure-free with at least 12 months of followup. This preliminary experience indicates that simultaneous placement of depth and subdural grid electrodes is useful in localizing the site of seizure onset and in guiding surgical resections.

Middle Childhood Onset of Interictal Psychosis

The authors describe three children (mean age = 7.8 years) with complex partial epilepsy, left temporal lobe involvement, and interictal schizophrenia-like psychosis. As described in adults with complex partial epilepsy, these children met DSM-III criteria for schizophrenia, their affect was intact, and they demonstrated no negative signs of schizophrenia. Unlike adult epileptic patients, these children demonstrated psychotic symptomatology despite inadequate seizure control and after a short latency period. The possible role of early onset seizures, temporal lobe lesions, and kindling on the developing brain are discussed.

Epileptic Acquired Aphasia

The syndrome of acquired aphasia, dementia and behavior disorder in a child with partial complex epilepsy and continuous spike and waves during sleep is reported from the Service de Pediatrie, et Service de Neurologie, CHUV, Lausanne, Switzerland.

Acquired Aphasia, Dementia, and Behavior Disorder with Epilepsy and Continuous Spike and Waves During Sleep in a Child

Severe persistent neuropsychological disorders sometimes develop in the course of a focal epilepsy of unknown origin in previously normal children. Very frequent bilateral focal or generalized discharges are often noted on the sleep EEG records of these patients with no evidence of clinical seizures. The relation between these paroxysms and the observed deterioration remains unclear. We report a child with a partial complex epilepsy and severe disturbances of language, cognition, and behavior acquired in the early years of development who was followed for 15 years. A correlation between the evolution of the striking EEG abnormalities during sleep and the neuropsychological disorders could be established retrospectively. The observed sequence of onset and recovery of the aphasia, the dementia, and the "psychotic" behavior makes a direct causal relation between the deficits quite unlikely. Rather it suggests an association of independent symptoms with a specific language disorder becoming manifest in the course of the evolution. This child shows many of the main characteristics of the syndromes of "acquired aphasia with convulsive disorder" (Landau-Kleffner syndrome) and "epilepsy with continuous spike waves during sleep." Both syndromes describe probably different facets of a similar underlying, still unexplained cerebral dysfunction.

Increased AMPA-sensitive quisqualate receptor binding and reduced NMDA receptor binding in epileptic human hippocampus

Based on results from the kindling model of epilepsy, we hypothesized that enhanced binding of radioligands to the NMDA receptor and decreased binding to the alpha-amino-3-hydroxy-5-methyl-4- isoxazolepropionate (AMPA)-sensitive quisqualate (ASQ) receptor would be found within epileptic hippocampi of humans with complex partial epilepsy (CPE). To test these hypotheses, we used tissue that was surgically removed from patients with intractable CPE, and control tissue that was obtained at autopsy. We used autoradiographic techniques to measure ASQ receptor binding (with 3H-AMPA as the radioligand) and binding to 2 sites on the NMDA receptor/channel complex: the agonist recognition site (with 3H-glutamate) and the phencyclidine (PCP) binding site that resides within the NMDA channel [with 3H-N-(1-[thienyl]cyclohexyl) piperidine (TCP) in the presence of saturating concentrations of NMDA and glycine]. Measurements of receptor binding were corrected for pathologic alterations in neuronal density. Contrary to our expectations, ASQ receptor binding was significantly increased (100%; p less than 0.02) in the dentate gyrus stratum moleculare in patients with CPE (n = 8), and it was unchanged in other hippocampal regions. In nearby sections from the same specimens, binding was significantly decreased to the agonist recognition site of the NMDA receptor in the stratum oriens of area CA3 (46%; p less than 0.05) and was also decreased to the PCP site in the stratum radiatum and stratum oriens of CA3 (44% and 74%, respectively; p less than 0.05). The increase in ASQ receptor binding may contribute to hyperexcitability in these epileptic patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Processing of Words and Faces by Patients with Left and Right Temporal Lobe Epilepsy

Tests of word and face processing were given to patients with complex partial epilepsy focussed on the left or right temporal lobe, and to non-epileptic control subjects. The left TLE group showed the greatest impairment on object naming and on reading tests, but the right TLE group also showed a lesser impairment relative to the normal control subjects on both tests. The right TLE group was selectively impaired on distinguishing famous from non-famous faces while the left TLE group was impaired at naming famous faces they had successfully recognized as familiar. There was no significant difference between the three groups on recognition memory for words. The implications of the results for theories of the role of the temporal lobes in word and face processing, and the possible neural mechanisms responsible for the deficits in TLE patients, are discussed.

Processing of words and faces by patients with left and right temporal lobe epilepsy.

Tests of word and face processing were given to patients with complex partial epilepsy focussed on the left or right temporal lobe, and to non-epileptic control subjects. The left TLE group showed the greatest impairment on object naming and on reading tests, but the right TLE group also showed a lesser impairment relative to the normal control subjects on both tests. The right TLE group was selectively impaired on distinguishing famous from non-famous faces while the left TLE group was impaired at naming famous faces they had successfully recognized as familiar. There was no significant difference between the three groups on recognition memory for words. The implications of the results for theories of the role of the temporal lobes in word and face processing, and the possible neural mechanisms responsible for the deficits in TLE patients, are discussed.

EEG dipole modeling in complex partial epilepsy

Visual inspection and qualitative impressions of clinical EEG abnormalities are being replaced by quantitative characterization of scalp voltage fields and dipole modeling of underlying cerebral sources. Three approaches have been used in the analysis of focal spikes of complex partial epilepsy. 1) Instantaneous, single dipole, inverse solutions for the voltage topography of the spike peak have revealed two distinct equivalent dipole configurations in the brain lobe beneath the negative extreme-radial and oblique (mixed radial and tangential). Only radial dipoles have been found for frontal and fronto-central spikes, while either type have been found for temporal and occipital spike foci. 2) Dipole stability can be assessed by an inspection of sequential instantaneous solutions encompassing the spike complex or by calculating the standard deviation of dipole location (x,y,z) and orientation (elevation, azimuth) parameters during this period. Two-thirds of spike dipoles of the radial type and essentially all of the oblique equivalent dipoles were found to be stable, whereas one-third of the radial dipoles were unstable in position or orientation. 3) Spatio-temporal analysis can identify multiple underlying sources and their potentials. Modeling separate radial and tangential dipoles over the course of the spike has revealed a composite character for spike fields with oblique dipoles and often has defined leads or lags in activity that suggested propagation between infero-mesial and lateral temporal cortex. Correlations with clinical and intracranial EEG data suggest that patients with mesial temporal sclerosis have spikes with oblique and stable equivalent dipoles; patients with discrete cortical lesions have spikes with radial and stable dipoles; patients with extensive or multi-focal cortical insults have spikes with radial and unstable dipoles.

Asperger's Syndrome and Ligamentous Laxity

Two autistic girls and one autistic man in whom Asperger's syndrome coexists with lifelong ligamentous laxity and muscular incoordination are described. Two had cranial circumferences at or above the 90th percentile as children, two have complex partial epilepsy, one has a colloid cyst of the third ventricle, and one had evidence of Sotos syndrome. Echocardiography was performed in the two girls and both had evidence of increased aortic compliance. It is suggested that all three suffer from a Marfan-like disorder of connective tissue and, more speculatively, that this has led to anomalous development of midline brain structures with consequent social handicaps characteristic of Asperger's syndrome.

Induction of c‐fos mRNA Expression by Afterdischarge in the Hippocampus of Naive and Kindled Rats

Periodic induction of focal electrical seizure [afterdischarge (AD)] is an absolute prerequisite for the development of kindling, an animal model of complex partial epilepsy. Once established, it is a permanent condition. The mechanism(s) that translate ADs, which last tens of seconds, into life-long alterations in the CNS is unclear. Cellular immediate-early genes have been implicated in the conversion of short-term stimuli to long-term alterations in cellular phenotypes by regulating target gene expression. We have investigated the contribution of one such early gene, c-fos, to this process. The relationship between ADs and expression of c-fos gene in the rat hippocampus, a key structure in kindling development, was studied by analysis of mRNA levels. The low constitutive expression of c-fos mRNA in the hippocampus was not altered by kindling. There was an "all-or-none" relationship between induction of c-fos and the duration of AD. The threshold for induction was approximately 30 s of AD. Above-threshold ADs induced c-fos in both naive and kindled animals to the same extent and with identical temporal profiles. Although the expression of c-fos is unchanged with kindling, c-fos may nonetheless contribute to many long-term changes of kindling, both adaptive and epileptogenic.

Side-effects of drugs in epileptic patients

Drug therapy in patients suffering from various forms of epilepsy aims at the administration of such dosages of antiepileptic drugs as to produce significant reduction of seizures without the occurrence of serious side-effects. To assess these side-effects 75 patients (48 males, 27 females) with epilepsy, attending an out-patient clinic were studied prospectively and data were collected regarding diagnosis, drug use and side-effects. Primarily generalized epilepsy and partial complex epilepsy with secondary generalization are the most prevailing categories. 69% (52) Of the patients are treated with monotherapy, with carbamazepine as the drug most frequently prescribed (30/52). Side-effects were scored after examining and questioning the patient with the help of a standard questionnaire. A distinction was made between groups of side-effects, being systemic, anamnestic, dermatological, neurological or miscellaneous. Also, haematological and biochemical changes were looked for. In the monotherapy group 26/52 (50%) of the patients showed side-effects (23 patients with 1, 2 with 2, 1 with 3 side-effects), and in the polytherapy group 15/23 (65%) (8 patients with 1, 7 with 2 side-effects). Adverse drug reactions were hardly related to the plasma concentration category. Between 50-60% of the patients at sub-therapeutic and low-therapeutic plasma levels complained of side-effects. No clear relationship between the clinical efficacy and the side-effects could be established. The clinical custom, among others, to titrate the dose according to the disappearance or appearance of side-effects seems open for discussion.

Cognitive Effects of Anticonvulsants

The neuropsychological effects of carbamazepine, phenobarbital, and phenytoin in 15 patients with partial complex epilepsy were investigated at the Department of Neurology, Medical College of Georgia, Augusta, GA.

Detection of epileptiform activity by different noninvasive EEG methods in complex partial epilepsy

The diagnostic utility of different noninvasive electrode placements for deriving the electroencephalogram and detecting interictal epileptiform discharges was compared. Anterior temporal and nasopharyngeal electrodes in combination with routine scalp electrodes detected over 97% of the spikes, whereas recording from only standard electrode placements detected 58%. Minisphenoidal and surface sphenoidal electrodes were generally not helpful. In some circumstances, however, the use of surface sphenoidal electrodes provided important confirmatory information. In no case did the minisphenoidal electrodes provide unique information, and their use seems unjustified, although the inclusion of other nonstandard electrodes in the recording montage is important to increase the yield.

Comparative cognitive effects of anticonvulsants

We investigated the neuropsychological effects of carbamazepine, phenobarbital, and phenytoin in 15 partial complex epilepsy patients treated with each drug for 3 months, using a randomized double-blind, triple crossover design. Neuropsychological evaluation at the end of each treatment period included Digit Span, Selective Reminding Test, Digit Symbol, Finger Tapping, Grooved Pegboard, Choice Reaction Time, P3 evoked potential, and Profile of Mood States. Employing anticonvulsant blood levels and seizure frequencies as covariates, the only significant difference was for Digit Symbol. Performance with phenobarbital was significantly worse than with the other 2 anticonvulsants despite phenobarbital's having had the lowest overall blood levels. Our data show that patients receiving carbamazepine, phenobarbital, and phenytoin have comparable neuropsychological performance on most measures. The results suggest that the differential cognitive effects of anticonvulsants may be subtle.

MR imaging in patients with intractable complex partial epileptic seizures.

Detailed neurologic studies, high-field-strength MR imaging, and CT scanning were performed preoperatively in 53 patients with intractable complex partial seizures who underwent surgical treatment for epilepsy. Macroscopic structural (tumoral or vascular) lesions were found in 28% of patients. The remainder had pathologic findings consistent with mesial temporal gliosis. Tumors were found in 22% of the patients and were benign or of low-grade malignancy in every case. MR was accurate in the preoperative diagnosis of structural lesions, including very small occult tumors and cryptic vascular malformations. In patients with mesial temporal gliosis, there was correlation between the MR observation of a unilaterally dilated anterior temporal horn and the EEG-identified seizure focus and side of temporal lobectomy. However, MR demonstrated T2-weighted signal abnormalities correlating with the epileptogenic focus in only 8% of cases of mesial temporal gliosis. MR provided useful information in 28% of patients who underwent surgery for refractory complex partial epilepsy. MR obviated invasive EEG monitoring in 93% of the patients with structural lesions. MR was useful in only 8% of the patients with pathologic changes of mesial temporal gliosis.

Spike voltage topography and equivalent dipole localization in complex partial epilepsy

The EEG of 45 patients with complex partial epilepsy was recorded from standard and supplementary inferior temporal electrode sites for 2 or more days via cable telemetry onto video (VHS) tape (22-25 channels, common reference). Epochs with "temporal spikes" were read into a topographic EEG device where individual spikes were visually identified and averaged in sums of 8-32. Analysis of spike voltage topography revealed two distinct patterns - dipolar, Type 1 and non-dipolar, Type 2. One or the other spike type predominated in all but two patients. Application of source modeling techniques (3 shells, single dipole, 6 parameters) to the spike topography data revealed that both spike types had similar equivalent dipoles in terms of location and orientation, except for vector elevation. However, calculated dipoles for Type 1 spikes were more stable over the course of the spike peak. Correlations with clinical data and intracranial EEG suggest that Type 1 spikes originate in mesial temporal structures, while Type 2 spikes arise from temporal or frontal neocortex. Spike voltage topography and equivalent dipole localization appear to be useful in the presurgical evaluation of patients with focal epilepsy.

Excitotoxic Amino Acid Receptors in Human Complex Partial Epilepsy

It has long been recognized that mesial temporal sclerosis is the most common pathologic finding in temporal lobes removed for the treatment of medically refractory complex partial epilepsy. The regions of the hippocampus most vulnerable contain the highest densities of excitatory amino acid receptors in the brain. We used receptor autoradiography to determine the density of N-methyl-D-aspartate (NMDA) and kainic acid (KA) receptors from 5 patients undergoing such surgery and compared the findings with 6 specimens obtained at postmortem. A 2-fold increase in the density of NMDA receptors and an increased density of KA receptors was found in entorhinal cortex in epileptic specimens. Loss of NMDA and KA receptor density was apparent in the sclerotic regions CA3 and CA1, but not in other areas of the hippocampus or dentate gyrus. These findings suggest that damage in the hippocampus may result, at least in part, from the presence of aberrant excitatory circuits in the entorhinal cortex.