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PubMed1997

Hippocampal connexin 43 expression in human complex partial seizure disorder.

An increase in the cellular production of gap junction proteins and increased numbers of gap junctions in the neuronoglial syncytium of an epileptic focus have been proposed as a possible mechanism underlying synchronization of discharge. To study this issue, both Northern and Western blot analyses of the gap junction protein connexin 43 mRNA and protein abundance were performed on hippocampal tissue resected from patients presenting with a complex partial seizure disorder arising from the medial temporal area and the hippocampus in particular. Samples from 15 patients with medically intractable seizures were compared to those from 5 nonepileptic patients requiring temporal lobectomy in life-threatening situations. Six of the 15 epileptic patients underwent noninvasive electrographic recording, whereas the remaining 9 patients required intracerebral electrodes for extraoperative recording and therefore showed a more discrete focality than the noninvasive recordings. A decline in the mean levels of connexin 43 mRNA expressed predominantly in astrocytes was noted in the epileptic patient groups, particularly for those cases requiring intracranial electrode placement where ictal onset was more clearly established to be intrahippocampal. Quantitation of connexin 43 protein in both epileptogenic and nonepileptogenic hippocampal tissues showed no significant differences in expression. Although mean values for mRNA showed a decline, clinical outcomes postoperatively showed no correlation with either mRNA or protein expression individually in our epileptic population. The findings indicate that there is effectively no upregulation of mRNA and no increased production of connexin 43 protein in response to the development of epileptogenicity. Rather it appears the influence of gap junctions as a substrate of epileptogenicity in any mechanism(s) underlying synchrony or electrical propagation may be a function of the dynamic state (open versus closed) of the membrane-bound gap junction.

Adult↗
PubMed1999

Temporal lobectomy for intractable complex partial seizures in pediatric patients.

Fourteen children, 7 boys and 7 girls, who failed conventional medical treatment for complex partial seizures underwent anterior temporal lobectomy at Ramathibodi Hospital, Bangkok, Thailand, from July 1993 to June 1998. The mean age at onset of patients was 6.7 years old and the mean duration of seizures before surgery was 6.4 years. The age of patients at surgery ranged from 8 to 22 years old. These patients had had limited presurgical evaluation which included video-electroencephalography (EEG), magnetic resonance imaging (MRI) and single photon emission computed tomography (SPECT). All patients demonstrated concordant among clinical symptoms, EEG, MRI and SPECT on the same side of the temporal lobe. Ten and 4 patients had unilateral and bilateral temporal lobe lesions respectively. The operations were done on the left in 10 patients and on the right in 4 patients. Seizure free after 1/2-5 years of follow-up was obtained in 70 per cent of patients which included 9 of 10 patients with unilateral temporal lesion and 1 of 4 patients with bilateral temporal lesions. The rest of the patients showed marked reduction of seizures except for one patient with bilateral lesions in whom only 50-70 per cent reduction was obtained. Marked improvement of behaviour was also observed in 70 per cent of patients. Resected brain specimens revealed mesial temporal sclerosis, gliosis, tumors and cavernoma in 6, 5, 2 and 1 patients respectively.

Child↗
PubMed1994

Case report of an intracarotid amobarbital procedure performed for a deaf patient.

The intracarotid amobarbital procedure (IAP) was conducted with a profoundly deaf young man prior to right anteromedial temporal lobectomy for pharmacologically refractory partial complex seizures. The IAP required considerable modification in order to take into account the use of varying sign language methods and related issues. Visual memory, American Sign Language, signed English, and finger-spelling functioning were all assessed. The patient manifested left hemisphere dominance for all these abilities, performing well under right hemisphere anesthesia. In contrast, no ability to function on these tasks was detectable when the left hemisphere was anesthetized. This demonstrates that an intact left temporal lobe and related structures are sufficient to support sign language functioning. The development of a deaf adaptation of the IAP is of methodological significance, as the IAP is thereby rendered accessible for deaf patients.

Adult↗
PubMed1999

Dose-Response Study of Vigabatrin as add-on therapy in patients with uncontrolled complex partial seizures.

PURPOSE: This placebo-controlled, randomized, double-blind, multicenter study examined the efficacy and safety of three daily doses of vigabatrin (VGB; 1, 3, or 6 g) as add-on therapy in 174 patients with previously uncontrolled complex partial seizures with or without secondary generalization. METHODS: A 12-week pretreatment assessment period was followed by drug therapy with a 6-week titration period and a 12-week maintenance phase. RESULTS: VGB doses of 3 and 6 g/day reduced median monthly frequency of seizures by 4.3 and 4.5 seizures, respectively, compared with 0.2 seizures for placebo (p = 0.0001). The percentages of patients classified as therapeutic successes (> or =50% reduction in seizure frequency) were 7% for placebo and 24, 51, and 54% for patients taking daily VGB doses of 1, 3, and 6 g, respectively; the comparison with placebo was significant for all treatment groups. The linear trend for dose response was highly significant (p< or =0.0001) for both median monthly seizure frequency and therapeutic success. Vigabatrin was well tolerated, causing no clinically significant changes in laboratory parameters, brain magnetic resonance imaging, evoked potentials, cognitive function, or psychosocial tests. Fatigue, drowsiness, and dizziness were the most common treatment-related adverse events in all treatment groups. Dropouts due to adverse events were higher in the 6-g/day group. CONCLUSIONS: VGB was significantly more effective than placebo as add-on therapy in reducing seizure frequency. VGB at 3 and 6 g/day produced the best efficacy: however, adverse events may limit the use of the 6-g/day dose in some patients.

Adult↗
PubMed2002

Investigation into the mechanisms of vagus nerve stimulation for the treatment of intractable epilepsy, using 99mTc-HMPAO SPET brain images.

Vagus nerve stimulation (VNS) has gained recognition as a treatment for refractory epilepsies where surgical treatment is not possible. While it appears that this treatment is effective in some patients, the mechanism of action is not clearly understood. The purpose of this study was to clarify findings of other positron emission tomography and single-photon emission tomography (SPET) investigations by measuring the acute effect of VNS on patients who have normal cerebral anatomy on magnetic resonance imaging and who have not previously been exposed to VNS. We investigated six subjects (two males and four females, mean age 29.5 years, range 21-39 years) with intractable epilepsy. One patient had primary generalised epilepsy causing generalised tonic-clonic seizures; the remaining five patients had localisation-related epilepsy causing complex partial seizures. SPET imaging was performed using 250 MBq of (99m)Tc-HMPAO and a four-scan paradigm - two with and two without stimulation. The stimulation began at VNS current levels of 0.25 mA and was increased according to the limit of patients' tolerance, usually defined by coughing or discomfort. The stimulating waveform was of continuous square wave pulses of 500 micro s duration at 30 Hz. Image analysis was by SPM99. Reduced perfusion during stimulation was observed in the ipsilateral brain stem, cingulate, amygdala and hippocampus and contralateral thalamus and cingulate. The study provides further evidence of the involvement of the limbic system in the action of vagal nerve stimulation.

Adult↗
PubMed2004

Vagal nerve stimulation technique: enhancing its efficacy and acceptability by augmentation with auto activation and deactivation mode of operation.

The purpose of this article is to search for an additional modus operandi to improve the functioning of currently deployed vagal nerve stimulation (VNS) technique that is being used as an adjunctive therapy for intractable epilepsy, mainly complex partial seizures (partial onset with secondary generalization). The efficacy and success of current VNS technique is variable and limited, which can be attributed (to a considerable extent) to its present modi operandi. The mechanism of anti-epileptic action of VNS that has been hypothesized in the article is found to conform to observations and results in a large number of studies including those on VNS itself. Based on this mechanism in controlling seizures, the author proposes an additional mode of operation of the VNS device, (an auto activation and deactivation mode), designed to work on a feedback mechanism, which would deliver VNS as and when the brain requires it to abort/arrest the impending focal attack and/or its generalization, thus eliminating the limitations associated with the current VNS device. This mode should enhance its acceptability, efficacy and success.

Brain↗
PubMed1995

[Complex partial seizures as cause of transient cardiac arrhythmia].

The frequency and type of seizure-induced cardiac arrhythmias is presented in light of 36 partial-complex seizures recorded with simultaneous EEG/ECG. An average increase in heart rate of 35% (sinus tachycardia) was observed in 60% of patients (22/36). Bradycardia was demonstrated in 17% (6/36) due to AV-block in 3 cases, once due to sinus bradycardia and once due to bradycardia in the presence of atrial fibrillation. In one patient with a pacemaker spontaneous heart rhythm ceased. The average slowing of heart rate was 29% with a maximum of 62.5%. In the remaining 23% of patients (8/36), no change in heart rate was observed. These results, in conjunction with those of the literature, indicate that a primary epileptic origin needs to be included in the differential diagnosis of cardiac arrhythmias.

Adolescent↗
PubMed1992

Neurocardiac responses to vagoafferent electrostimulation in humans.

UNLABELLED: To determine if cardiac vagal tone is enhanced by vagal electrostimulation (VES), we examined the heart rate autospectrum (HRA) in eight patients with implanted stimulators for complex partial seizures. In four patients the VES was activated at 30 Hz and 500-msec pulse (HiStim group) compared to 2 Hz and 130-msec pulse for the LoStim group (n = 4). Continuous ECG and respiratory waveforms were recorded for 45 minutes every 8 hours (7-8 AM; 3-4 PM 11-12 PM) during resting supine wakeful epochs both before and 15 days after surgical implantation. From the HRA cardiac sympathovagal balance was expressed as the ratio of the low frequency (LF) power to the high frequency (HF) power. RESULTS: There were no presurgical differences between the groups in heart rate, its variance, or the energies contained in any autospectral band. The LoStim group showed no significant change in heart rate (HR), HF peak power, or LF:HF ratios during 2 weeks of VES. Conversely, in the HiStim group, the LF:HF peak power ratio (an expression of sympathetic dominance) decreased from 2.5 +/- 1.5 preimplant to 1.5 +/- 0.49 (P < 0.02) with VES. During VES there was a significantly higher HF power in the HiStim compared to LoStim group. No diurnal variations in HRA values were seen for either group. CONCLUSIONS: (1) A relationship exists between selective vagal nerve electrostimulation and the HRA; and (2) high stimulation frequency of the vagus nerve in man is associated with sustained augmentation of cardiac vagal tone throughout a 24-hour cycle.

Adult↗
PubMed1994

Dysembryoplastic neuroepithelial tumor. A tumor with small neuronal cells resembling oligodendroglioma.

Dysembryoplastic neuroepithelial tumor (DNT) is a clinicopathologically unique group of tumors, mostly located in the temporal lobe, associated with intractable complex partial seizure in young patients. We report two unusual cases with multifocal involvement of diverse sites in the central nervous system. Case 1 is that of a 50-year-old man with 9-year history of grand mal seizures, who died of acute myocardial infarction. Case 2 is that of a 10-year-old girl with intractable complex partial seizures and behavioral disorder. Postmortem examination in case 1 showed multifocal tumor in the left temporal lobe, third ventricle, and basal ganglia. Magnetic resonance imaging in case 2 showed tumor in the right temporal lobe, both thalami, right cerebellar hemisphere, and pons. Histologically, both tumors were characterized by a multinodular appearance with a predominant component of alveolar arrangement of oligodendroglial-like cells around delicate capillaries, with mucoid matrix containing floating ganglion cells. There were also astrocytic nodules resembling pilocytic astrocytoma in case 1, and a gangliocytoma-like area merging with surrounding cortical dysplasia in case 2. Ultrastructural examination showed ganglionic differentiation in the oligodendroglial-like cells in case 2. They possessed dense core neurosecretory granules and many slender neuritic processes with microtubules arranged in parallel and terminating in synaptic junctions. The periventricularly located tumor with nodular extension to the periphery suggests an origin from subependymal germinal matrix with nests of primitive neuroblasts arrested in their embryonal migration. DNTs are related to ganglioglioma based on their common location and clinical behavior and on the presence of both ganglionic and astrocytic cells. They are also related to pilocytic astrocytoma by morphological and behavioral similarity. Together with cerebral neuroblastoma and central neurocytoma, they form a spectrum of tumors harboring small neuronal cells. The differentiation of DNT from oligodendroglioma is important so as to avoid unnecessarily aggressive therapy.

Brain Neoplasms↗
PubMed1998

Anticonvulsant effect of fosphenytoin in amygdala-kindled rats: comparison with phenytoin.

Phenytoin has been reported to exert variable anticonvulsant effects in the kindling model of complex partial seizures. Phenytoin is only water soluble at a pH of more than 10, and it has been suspected that poor absorption of the drug is responsible for its lack of effect in some experiments. Recently, fosphenytoin, a prodrug of phenytoin, has been developed by phosphorylating phenytoin which makes the drug water soluble at physiological pH while it is rapidly transformed to phenytoin after injection. This study examined the anticonvulsant profile and the absorption after intraperitoneal injection of fosphenytoin, compared to its parental drug phenytoin. The pharmacokinetic parameters of phenytoin and fosphenytoin were compared by determining plasma levels of phenytoin after i.p. injection of 50 mg/kg phenytoin or the equivalent dose of 84 mg/kg of fosphenytoin in non-kindled female Wistar rats. After both injections the maximal plasma concentration of phenytoin was about 30 microg/ml. The relative bioavailability of fosphenytoin was 83%. In contrast to phenytoin, failed injections resulting in non-detectable plasma concentration of phenytoin were almost absent after fosphenytoin. In fully kindled female Wistar rats, fosphenytoin dose-dependently increased the focal seizure (afterdischarge) threshold. Seizure severity and duration at threshold were reduced only after the highest does of fosphenytoin tested (84 mg/kg). Thus, fosphenytoin showed anticonvulsant properties similar to phenytoin in amygdala kindled rats. We conclude that fosphenytoin is an adequate and reliable substitute for the parenteral injection of phenytoin in experimental seizure models of rats.

Amygdala↗
PubMed1995

Cerebral and cerebellar diaschisis following carbamazepine therapy.

1. The regional cerebral blood flow was studied by SPECT in patients with partial epilepsy before and after 30 days of monotherapy with carbamazepine (CBZ). 2. Both a qualitative visual interpretation and a semiquantitative analysis of SPECT was performed. All patients underwent EEG, CT scan, and MRI studies. The CBZ serum concentrations were assayed. 3. After therapy, in three patients with focal epilepsy, both a crossed cerebral and cerebellar diaschisis were observed, with respect to the side of the epileptic focus in the opposite hemisphere. No morphologic changes were detected at MRI in the cerebral or cerebellar remote hypometabolic areas found at SPECT. 4. CBZ may have a depressant action on the corticopontocerebellar pathways and on the corticocallosal connections.

Adolescent↗
PubMed2002

So-called 'cryptogenic' partial seizures resulting from a subtle cortical dysgenesis due to a doublecortin gene mutation.

We report the case of a female suffering from resistant partial seizures, which were related to 'cryptogenic' epilepsy, as the cerebral cortex was considered normal on the initial MRI images. As her son is mentally retarded and has a pachygyria, the doublecortin gene, usually involved in band heterotopia or lissencephaly, was screened for mutations. A missense mutation was identified, shared by both the son and his mother, and a subtle discontinuous subcortical heterotopia was subsequently detected on the mother's MRI. The pathophysiology of epilepsy in this woman is discussed in the light of the role of doublecortin, not only in neuronal migration, but also in axonal growth and dendritic connectivity.

1-Alkyl-2-acetylglycerophosphocholine Esterase↗
PubMed1994

Brain single-photon emission tomography using technetium-99m bicisate (ECD) in a case of complex partial seizure.

The clinical application of technetium-99m bicisate (ethyl cysteinate dimer, ECD) for ictal and interictal studies of regional cerebral blood flow (rCBF) in a patient suffering from medically intractable simple and complex partial seizures is reported. The interictal study was performed 60 min p.i. and the ictal studies were performed at 60 min p.i. using an annular crystal single photon emission tomography (SPET) system dedicated for high-resolution brain SPET imaging. Visual evaluation of the studies was carried out, as well as semiquantitative measurement of regional tracer uptake. Magnetic resonance imaging (MRI) scans revealed atrophy of almost the complete left frontal lobe and the ventral parts of the left temporal lobe, including in part the temporomesial structures. The left parietal and occipital structures and the right hemisphere were normal. The interictal study showed a large perfusion defect involving the whole left frontal lobe as well as the left temporal lobe with remaining small areas of normal cortical tracer uptake. The ictal studies detected circumscribed hyperperfusion within the left mesial temporal lobe (ventral part of the hippocampus). Additionally an increase in perfusion could be seen within the entire remaining left temporal lobe. Semiquantitative evaluation of tracer uptake comparing both studies detected markedly increased uptake within the focus compared to the remaining left temporal lobe. On this basis the newly available tracer for studies of rCBF, 99mTc-bicisate, seems to be of value for the detection of epileptogenic foci. Additionally, the value of ictal rCBF studies in the presurgical evaluation of those patients presenting severe morphological alterations on MRI is clearly underlined by this case.

Adult↗
PubMed1997

Tiagabine therapy for complex partial seizures. A dose-frequency study. The Tiagabine Study Group.

OBJECTIVE: To evaluate the efficacy and safety of 2 regimens of tiagabine as add-on therapy for patients with complex partial seizures (CPSs) that are refractory to other treatment. DESIGN: Randomized, double-blind, placebo-controlled, add-on, parallel-group trial with an 8-week baseline period, 12-week experimental period (4 weeks of dose titration and 8 weeks of fixed-dose therapy), and 4-week termination period. SETTING: Twenty-six centers throughout the United States. PATIENTS: Three hundred fifty-one patients were enrolled, 318 were entered in the double-blind period, and 271 completed the study. INTERVENTIONS: Tiagabine, 16 mg 2 times per day (106 patients); tiagabine, 8 mg 4 times daily (105 patients); and placebo (107 patients). The doses of tiagabine were titrated in 3 steps to the fixed dose. MAIN OUTCOME MEASURE: The median change in the 4-week rate of CPSs from baseline to experimental period. RESULTS: The median change from baseline was -1.6 CPSs per 4 weeks in the group of patients who were given tiagabine 2 times per day, and it was -1.2 CPSs in the group of patients who were given tiagabine 4 time per day (P = .06 and P = .02, respectively, compared with placebo). The 4-week seizure frequency was reduced by 50% or more in 31% of the patients who were given tiagabine 2 times per day and in 27% of the patients who were given tiagabine 4 times per day vs 10% of the placebo-treated patients (P < or = .001 for each tiagabine-treated group compared with the placebo group). The most frequent adverse events involved the central nervous system and occurred in comparable proportions in the 3 treatment groups. Similar proportions of patients discontinued the study prematurely for adverse events. CONCLUSIONS: Tiagabine administered 2 and 4 times daily as add-on pharmacotherapy was effective in reducing CPSs in patients with epilepsy whose conditions were refractory to treatment with other antiepileptic agents, and it was well tolerated.

Adolescent↗
PubMed1993

Evaluation of the effects of vigabatrin on cognitive abilities and quality of life in epilepsy.

We evaluated the psychological effects of the antiepilepsy drug vigabatrin in a randomized multicenter double-blind placebo-controlled parallel group study that compared 3 grams oral vigabatrin with placebo as daily add-on therapy in patients with focal epilepsy whose complex partial seizures were difficult to control. Testing at baseline and after 12 weeks of vigabatrin (n = 83) or placebo (n = 85) used eight measures of cognitive abilities and three of mood and adjustment. The vigabatrin and placebo groups were highly similar at entry into the study. At the end of the study, there were no differences between the vigabatrin and placebo groups on any cognitive variable or on any measure of mood and adjustment. Analysis of the results related to relief from seizures demonstrated only chance findings. In a similar manner, there were no relationships between vigabatrin serum levels at the end of the study and changes on measures of abilities and adjustment. Vigabatrin appears to be a useful antiepilepsy drug with little impact upon tests of either cognitive abilities or quality of life.

Adaptation, Psychological↗
PubMed1991

Effect of long-term vigabatrin therapy on selected neurotransmitter concentrations in cerebrospinal fluid.

Ten patients, suffering from drug-resistant complex partial seizures were treated for a period of up to 3 years with vigabatrin (Sabril). Vigabatrin is a novel antiepileptic agent, whose action is based on the inhibition of gamma-aminobutyric acid (GABA) aminotransferase, the enzyme responsible for the catabolism of the neurotransmitter GABA. Samples of lumbar cerebrospinal fluid were obtained from the patients prior to commencing vigabatrin therapy, and thereafter at 6 months, 1 year, 2 years, and up to 3 years following the initiation of vigabatrin treatment. The influence of vigabatrin on the cerebrospinal fluid concentrations of free and total GABA, homocarnosine, homovanillic acid, 5-hydroxyindoleacetic acid, and 3-methoxy-4-hydroxyphenylethylene glycol, as well as of the drug itself, was assessed. All patients demonstrated a clinical response to vigabatrin, and the drug was well tolerated over the entire observation period. Mean (+/- SD) reduction of seizure frequency was 65% +/- 23% (range, 26% to 100%) when comparing the end of the treatment period to the previgabatrin baseline. The cerebrospinal fluid concentrations of both free and total GABA and of the dipeptide homocarnosine showed approximately 2- to 5-fold increases over baseline values, with free GABA and homocarnosine being the more sensitive variables. Cerebrospinal fluid concentrations of homovanillic acid, 5-hydroxyindoleacetic acid, and 3-methoxy-4-hydroxyphenylethylene glycol were not altered in a significant manner over the observation period. These findings support the concept that the effects of vigabatrin are restricted to an effect on GABA catabolism and do not extend to the neurotransmitters dopamine and norepinephrine. Clinical efficacy and elevation of GABA and homocarnosine concentration were sustained over the period of observation.

Adult↗
PubMed1989

Magnetic resonance imaging in refractory focal epilepsy with normal CT scans.

One hundred patients suffering from focal epilepsy with complex partial seizures refractory to medical treatment and showing no abnormality at CT were explored by MRI with an 0.5 Tesla magnet. MRI detected an abnormality in 25 patients with, in 17 of them, good correlation between MRI and clinical as well as electroencephalographic findings. Abnormal morphology and signal was found in 5 patients, with positive CT results on reexamination of previous CT images or on new CT scans in 4 of them. There was a diffuse temporal lobe high-intensity signal in 3 cases and a localized high-intensity signal in 9 cases (temporal lobe 4, occipital lobe 3, frontal lobe 1, fronto-parietal and parietal lobes 1). Thus, in 13% of the cases MRI demonstrated a lesion that had not been detected at CT, and the location of the lesion was concordant with clinical and electroencephalographic data.

Adolescent↗
PubMed1998

Intra- and interobserver variability of MRI-based volume measurements of the hippocampus and amygdala using the manual ray-tracing method.

We studied the intra- and interobserver variability of volume measurments of the hippocampus (HC) and the amygdala as applied to the detection of HC atrophy in patients with complex partial seizures (CPE), measuring the volumes of the HC and amygdala of 11 normal volunteers and 12 patients with presumed CPE, using the manual ray-tracing method. Two independent observers performed these measurements twice each using home-made software. The intra- and interobserver variability of the absolute volumes and of the normalised left-to-right volume differences (deltaV) between the HC (deltaV(HC)), the amygdala (deltaV(A)) and the sum of both (deltaV(HCA)) were assessed. In our mainly right-handed normals, the right HC and amygdala were on average 0.05 and 0.03 ml larger respectively than on the left. The interobserver variability for volume measurements in normal subjects was 1.80 ml for the HC and 0.82 ml for the amygdala, the intraobserver variability roughly one third of these values. The interobserver variability coefficient in normals was 3.6% for deltaV(HCA), 4.7% for deltaV(HC) and 7.3% for deltaV(A). The intraobserver variability coefficient was 3.4% for deltaV(HCA), 4.2% for deltaV(HC) amd 5.6% for deltaV(A). The variability in patients was the same for volume differences less than 5% either side of the interval for normality, but was higher when large volume differences were encountered, is probably due to the lack of thresholding and/or normalisation. Cutoff values for lateralisation with the deltaV were defined. No intra- or interobserver lateralisation differences were encountered with deltaV(HCA) and deltaV(HC). From these observations we conclude that the manual ray-tracing method is a robust method for lateralisation in patients with TLE. Due to its higher variability, this method is less suited to measure absolute volumes.

Adolescent↗