Anticonvulsant and antiarrhythmic effects of nifedipine in rats prone to audiogenic seizures

Calcium ion participates in the regulation of neural transmission and the presynaptic release of neurotransmitters. It is also involved in epileptic events, cardiac arrhythmias and abnormal conduction of stimuli. The purpose of the present study was to evaluate the effects of nifedipine, a calcium channel blocker, on epileptic seizures and on reperfusion arrhythmias in rats prone to audiogenic epileptic seizures (Wistar audiogenic rats, WAR) and in normal Wistar rats (N = 6/group). The seizure severity index was applied after an intraperitoneal injection of 20 or 40 mg/kg nifedipine (N20 and N40 groups, respectively). The Langendorff technique was used to analyze cardiac function, as well as the incidence and severity of the reperfusion arrhythmias after ligature and release of the left coronary artery in rats treated or not with nifedipine. We found that nifedipine treatment decreased seizure severity (0.94 ± 0.02 for WAR; 0.70 ± 0.10 for WAR + N20; 0.47 ± 0.08 for WAR + N40) and increased the latent period (13 ± 2 s for WAR; 35 ± 10 s for WAR + N20; 48 ± 7 s for WAR + N40) for the development of seizures in WAR. Furthermore, the incidence and severity of the reperfusion arrhythmias were lower in WAR and normal Wistar rats injected with nifedipine. In WAR, these effects were mediated, at least in part, by a decrease in heart rate. Thus, our results indicate that nifedipine may be considered to be a potential adjuvant drug for epilepsy treatment, especially in those cases associated with cardiac rhythm abnormalities.     

Monozygotic twins with MELAS-like syndrome lacking ragged red fibers and lactacidaemia

Typical cases of MELAS present a combination of clinical and neuroradiological features, lactacidaemia, and ragged red fibers (RRFs) in striated muscle. We have observed a MELAS-like syndrome in monozygotic twins. They developed seizures typically in conjunction with physical exertion, sleep deprivation or febrile episodes. Stroke-like episodes occurred usually during seizures. In twin 2 the course was fatal at age 20 years. Neuroradiological findings were typical of MELAS. Plasma lactate was normal in both. CSF lactate was normal in twin 1 and normal/elevated in twin 2. RRFs were not seen in muscle biopsies of the twins. Complex I activity was reduced in muscle in twin 1. Brain tissue removed at epilepsy surgery in twin 2 showed the presence of mitochondrial angiopathy. The commonest mitochondrial DNA mutation in MELAS, at base pair 3243, was absent. Lactacidaemia and mitochondrial myopathy with RRFs constitute part of the diagnostic criteria of MELAS. However, the absence of these features does not exclude mitochondrial disorder with the serious manifestations of MELAS (seizures and stroke-like episodes) as seen in these twins.     

Epileptiform EEG activities of the centromedian thalamic nuclei in patients with intractable partial motor, complex partial, and generalized seizures

Centromedian thalamic nuclei (CM) epileptiform EEG activities were recorded in patients with intractable partial motor, complex partial, and generalized seizures through implanted recording-stimulating electrodes, used for seizure control. CM epileptiform activities showed either little or no correlation to focal surface cortical and amygdaloid activities in patients with partial motor and complex partial seizures: CM paroxysmal discharges were correlated to focal epileptiform ictal activities only during the contraversive movements of partial motor and complex partial seizures. In contrast, CM epileptiform activities were consistently correlated to widespread surface cortical activities and clinical symptoms of fully developed nonconvulsive and convulsive tonic-clonic generalized seizures; i.e., unilateral CM double spike-wave complex discharges significantly preceded (p less than 0.001) the contralateral CM and bilateral surface cortical discharges and symptoms of nonconvulsive generalized seizures. Unilateral CM fast-slow-fast paroxysmal discharges significantly preceded (p less than 0.005) those of the contralateral CM and bilateral surface cortical regions and symptoms of the convulsive tonic-clonic generalized seizures. Individual spike-wave complexes from the frontal region preceded (p less than 0.001 and p less than 0.005) those at CM and other cortical regions during the nonconvulsive and clonic generalized attacks. No correlations between CM and cortical epileptiform activities were found, however, in the case of abortive, subclinical thalamocortical EEG discharges.     

Benign infantile familial convulsions

Five infants, three girls and two boys, first had convulsions between the ages of 4 and 6 months. Although the aetiology of the attacks was unknown, all the infants had a family history of similar convulsions occurring at the same age and having a benign outcome. The attacks, which always occurred in a cluster, were promptly controlled, in four cases with phenobarbital and in one case with valproate. Seizures were partial with secondary generalization and were characterized by head and eye deviation (not always the same side in each attack) diffuse hypertonia and then bilateral limb jerks. The interictal EEG was normal. The ictal EEG showed diffuse discharge with onset in the central-occipital region. Laboratory, radiological and neurological findings were normal. A history in at least one paternal relative (the father in four cases) of similar seizures, occurring at the same age suggested a genetic predisposition. No seizures or EEG anomalies were observed during the follow up.     

Glutamate receptor subunits GluR1 and GluR2/3 distribution shows reorganization in the human epileptogenic hippocampus

The AMPA-type glutamate receptor subunits GluR1 and GluR2/3 were localized by immunohistochemistry with subunit-specific antibodies in hippocampi removed surgically from patients with temporal lobe epilepsy for the control of seizures. The flip and flop splice variants of the subunits were localized by in situ hybridization histochemistry with specific oligoprobes. In patient hippocampi that were not the seizure focus, the GluR1 subunit proteins were diffusely expressed on the dendrites of neurons in all regions. In contrast, in these same hippocampi, the GluR2/3 subunit proteins were expressed strongly on the soma and proximal dendrites of principal neurons in all regions. The flip variant of these subunits was localized in the hilus and fields of Ammon's Horn (CA), while the flop variants were prominent on the dentate granule cells. In the epileptogenic hippocampus, while immunoreactivity was decreased in all fields that showed neuronal loss, there was an increased expression of GluR1 on the dendritic excrescences on the proximal dendrites of hilar neurons and CA3 pyramidal neurons, as well as expression of GluR2/3 in hilar neuron excrescences. Electron microscopic examination confirmed that the GluR1 immunoreactivity was only in dendritic processes, particularly dense at the postsynaptic membranes. Such expression of GluR1 may provide for an enhanced glutamatergic response by these neurons. GluR2/3 was also significantly increased on the dendrites of dentate granule cells in the epileptogenic hippocampus and may provide some protection against excitotoxic injury by reducing calcium flux into neurons.     

Conditionally immortalized cell lines, engineered to produce and release GABA, modulate the development of behavioral seizures

Transplantation of genetically engineered cells can provide sustained focal delivery of naturally occurring molecules, including neurotransmitters and growth factors. We have engineered immortalized mouse cortical neurons and glia to deliver GABA by driving GAD(65) expression. Engineered cell lines showed GAD(65) mRNA expression, enzymatic activity, and GABA release. In vitro, basal flux of GABA was approximately 20% of total cellular GABA. We transplanted these GABA-producing cells bilaterally into either the anterior or the posterior substantia nigra of 43 rats. The rats were subsequently kindled through an electrode placed in the entorhinal cortex. GABA-producing cells, but not beta-galactosidase-producing cells, affected kindling rates. The number of stimulations needed to reach the first stage-5 seizure and to achieve full kindling differed significantly between the anterior and posterior transplantation sites when GAD(65)-producing cells were transplanted but not when beta-galactosidase-producing cells were transplanted. Our data show that transplanted engineered cells can make and release GABA at physiologically meaningful concentrations.     

Localization of an Anatomic Substrate for the Anticonvulsant Activity Induced by D-Cycloserine

Summary: D-Cycloserine is a partial agonist of the strychnine-insensitive glycine site that inhibits the tonic hindlimb extension (THE) component of maximal electroshock seizures (MES). This study determined the effect of focal D-clycoserine microinfusion into nucleus re-ticularis pontis oralis (RPO) on the THE component of MES in rats. Bilateral microinfusion of D-cycloserine (50 nmol per side) into the RPO region 5.4 and 5.6 mm posterior to bregma inhibited THE in 80% of rats tested. Unilateral D-cycloserine (50 nmol) RPO microinfusions were ineffective. Likewise, RPO microinfusion of vehicle, L-cycloserine (50 nmol per side), or the strychnine-insensitive glycine site antagonist 7-chlorokynurenic acid (10 and 50 nmol per side) did not alter THE incidence. However, coinfusion of 7-chlorokynurenic acid (50 nmol per side) with D-cycloserine (50 nmol per side) completely antagonized the anticonvulsant activity induced by D-CYcloserine (8 of 8 rats with THE). These data indicate that the anticonvulsant activity of D-cycloserine is mediated by RPO. Because the anticonvulsant effect is stereospecific and is reversible by 7-chlorokynurenic acid, these results also indicate that D-cycloserine acts through the strychnine-insensitive glycine site to inhibit THE.     

Topiramate Monotherapy for Partial Onset Seizures

Summary: Purpose: Evaluation of topiramate (TPM) as monotherapy in patients with uncontrolled partial onset seizures.
Methods: A total of 48 patients were evaluated in a doubleblind, parallel-group trial. During a 56-day baseline period, patients had at least eight partial onset seizures while being treated with one or two standard antiepileptic drugs (AEDs). After 1–2 weeks of open-label treatment with TPM 100 mg/day, patients were randomly assigned, in equal proportions, to receive double-blind therapy with TPM 100 or 1,000 mg/day in a 5-week conversion and an 11-week monotherapy period. The study endpoint was completion of 112 study days (success) or fulfillment of one or more exit criteria: doubling of average 28- day or highest 2-day baseline seizure rate, a generalized tonic-clonic seizure (GTCS) if none had occurred at baseline, or significant prolongation of generalized seizure duration.
Results: Time until exit was longer (p = 0.002) and success frequency was higher (p = 0.005) with TPM 1,000 as compared with 100 mg/day. Seizure-rate reductions of 50, 75, or 100% were achieved by 46, 25, and 13% of the 1,000-mg/day group, respectively, as compared with 13, 8, and 0% of the 100-mg/day group, respectively. Most adverse events (AE) were mild or moderate in severity.
Conclusions: Monotherapy with TPM 1,000 mg/day for partial onset seizures with or without secondarily generalized seizures was effective, with a favorable safety profile.