Cutaneous Hypersensitivity Reaction After Phenytoin Therapy in a Neonate: A Case Report and Review of Literature Elucidating the Potential Pharmacological Plausibility and Preventive Strategies.

BACKGROUND: Drug-induced hypersensitivity reaction is a potentially life-threatening condition reported among patients of different age groups. Phenytoin is a prototypic drug prescribed for the treatment of a variety of seizure disorders. Allergic reaction to phenytoin therapy in a newborn is relatively a rare clinical manifestation that is not frequently reported. OBJECTIVE: The objective of this study is to report a suspected case of hypersensitivity reaction in a newborn possibly due to phenytoin and the strategies to prevent these immune-mediated reactions. CASE REPORT: An early term newborn on the 4th day of life developed erythematous rashes over the abdominal region following phenytoin treatment for recurrent generalized tonic-clonic seizures. Prenatal history was uneventful except for the mother had preeclampsia during the third trimester of pregnancy. The suspected phenytoin was replaced with phenobarbitone to control seizure episodes. Subsequently, the rashes disappeared. The baby had also suffered from skin discolouration after phototherapy. Radiological investigations and cerebrospinal fluid culture were performed to detect the etiology of seizures. CONCLUSION: Hypersensitivity reaction to phenytoin in newborns is a rare clinical entity but may lead to serious lethal complications. Thus, stringent clinical monitoring of patients on phenytoin therapy is mandatory, especially in the pediatric population.

Low-frequency electroacupuncture suppresses focal epilepsy and improves epilepsy-induced sleep disruptions.

BACKGROUND: The positive effects of acupuncture at Feng-Chi acupoints on treating epilepsy and insomnia have been well-documented in ancient Chinese literature. However, there is a lack of scientific evidence to elucidate the underlying mechanisms behind these effects. Our previous study demonstrated that high-frequency (100 Hz) electroacupuncture (EA) at Feng-Chi acupoints deteriorates both pilocarpine-induced focal epilepsy and sleep disruptions. This study investigated the effects of low-frequency (10 Hz) EA on epileptic activities and epilepsy-induced sleep disruptions. RESULTS: In rats, the Feng-Chi acupoint is located 3 mm away from the center of a line between the two ears. Rats received 30 min of 10 Hz EA stimuli per day before each day's dark period for three consecutive days. Our results indicated that administration of pilocarpine into the left CeA at the beginning of the dark period induced focal epilepsy and decreased both rapid eye movement (REM) sleep and non-REM (NREM) sleep during the consequent light period. Low-frequency (10 Hz) EA at Feng-Chi acupoints suppressed pilocarpine-induced epileptiform EEGs, and this effect was in turn blocked by naloxone (a broad-spectrum opioid receptor antagonist), but not by naloxonazine (a µ-receptor antagonist), naltrindole (a δ-receptor antagonist) and nor-binaltorphimine (a κ-receptor antagonist). Ten Hz EA enhanced NREM sleep during the dark period, and this enhancement was blocked by all of the opioid receptor antagonists. On the other hand, 10 Hz EA reversed pilocarpine-induced NREM suppression during the light period, and the EA's effect on the sleep disruption was only blocked by naloxonazine. CONCLUSIONS: These results indicate that low-frequency EA stimulation of Feng-Chi acupoints is beneficial in improving epilepsy and epilepsy-induced sleep disruptions, and that opioid receptors in the CeA mediate EA's therapeutic effects.

Evaluation of the role of chronic daily melatonin administration and pinealectomy on penicillin-induced focal epileptiform activity and spectral analysis of ECoG in rats: an in vivo electrophysiological study.

In the present study, we aimed to investigate the effects of pinealectomy and chronic melatonin administration on focal epileptiform activity induced by penicillin in the rat cortex and to determine the relation between melatonin levels and electrocorticogram (ECoG) power spectrum. For this purpose, male Sprague-Dawley rats were divided into six groups: control, sham operated, ethanol, melatonin, pinealectomy and pinealectomy + melatonin group. Melatonin-treated rats was intraperitoneally injected with a daily single dose of 10 mg/kg melatonin for 14 days, but the last dose was given 30 min after local application of penicillin as a convulsant agent. Focal epileptiform activity was produced by intracortical administration of penicillin (200 units/1 µl). While chronic melatonin application did not affect either the onset latency or the spike frequency of epileptiform activity, pinealectomy significantly reduced latency to onset of initial epileptiform discharges and increased cortical epileptiform activity. However, acute melatonin administration decreased the epileptiform activity. The results also indicated that exogenously applied melatonin did not change the spectral analysis of ECoG, but pinealectomy led to a reduction in the power of the fast bands (gamma) power in ECoG. We conclude that endogenous melatonin signaling seem to have a tonic inhibitory action on neuronal excitability and epileptiform activity, and also a certain concentration of melatonin required for normal cortical excitability.

The effect of electrical stimulation and lesioning of the anterior thalamic nucleus on kainic acid-induced focal cortical seizure status in rats.

PURPOSE: The present study aimed to clarify the effect of electrical stimulation and lesioning of the anterior nucleus of the thalamus (ANT) on kainic acid (KA)-induced focal cortical seizures in a rat model. To address the mechanism underlying these anticonvulsant actions, cerebral glucose metabolism after ANT electrical stimulation and lesioning was also examined. METHODS: Wistar rats were divided into five major groups: control (n = 9), unilateral (n = 9), and bilateral (n = 9) ANT electrical stimulation, and unilateral (n = 9) and bilateral (n = 9) ANT lesioning. After KA injection, average clinical-seizure frequencies in each group were measured. Electrical stimulation of ANT was introduced after induction of seizure status epilepticus. Stimulation was on for 30 min and off for 30 min per 60-min cycle. Local cerebral glucose utilization (LCGU) was also measured by using [(14)C] 2-deoxyglucose autoradiography in three groups of rats: control (n = 7), bilateral ANT stimulation (n = 7), and bilateral ANT lesioning (n = 7). RESULTS: Unilateral ANT electrical stimulation and lesioning significantly reduced clinical seizure frequency, compared with control animals. Strikingly, no animals treated with bilateral ANT procedures demonstrated any clinical seizure. LCGU was markedly increased in the sensorimotor cortex, striatum, thalamus, mammillary body, and midbrain tegmentum of control group rats after KA injection, but no increase in LCGU was noted in rats treated with bilateral ANT lesioning or stimulation. CONCLUSIONS: The electrical stimulation and lesioning of ANT suppressed focal cortical clinical seizures induced by KA injection. Additionally, an analysis of cerebral metabolic changes indicated that these procedures might suppress the function as amplifier and synchronizer of seizure activity.

[A case of intractable epilepsy showing frequent gelastic seizures by administration of clobazam].

A 13-year-old boy patient had severe mental retardation and spastic quadriplegia due to fetal distress and hypoxic-ischemic brain damage in the perinatal period. He suffered from West syndrome at the age of 7 months, and subsequently was diagnosed as having symptomatic localization-related epilepsy. His intractable epileptic seizures were not controlled by combination of various antiepileptic drugs. After prescribing nitrazepam and zonisamide for more than 1 year, we added clobazam (CLB), which has been marketed in Japan since 2000, to this combination therapy. After the introduction of CLB, tonic seizures disappeared. However, gelastic seizures laughing with a stiff face and a wry mouth appeared frequently before falling asleep, and sleep disturbance worsened subsequently. It has not been reported previously that gelastic seizures are a side effect of CLB, although irritability and sleep disturbance have been described.

Generalized seizures induced by an epileptic focus in the mesencephalic reticular formation: impact on the understanding of the generalizing mechanism.

The mode of seizure propagation was studied using a generalized seizure model induced by microinjection of kainic acid (KA) into a unilateral mesencephalic reticular formation (MRF) in cats and rats. Stereotactic surgery was performed under pentobarbital anesthesia; an injection cannula was placed into a unilateral MRF, and bipolar electrodes were implanted into the MRF and the thalamus. Microinjection of KA induced generalized seizures. Focal electrical seizures were elicited in the injected site of the MRF starting 30 min after the injection. The initial clinical change during each seizure was behavioral arrest. These seizures immediately developed to generalized seizures, which were characterized by generalized tonic convulsions with short-term clonic convulsions. On EEG, each generalized seizure started at the same time in all the sites of the brain recorded. Autoradiographic study using a rat model demonstrated high glucose utilization in the MRF, bilateral thalamus, forebrain and bilateral cerebral cortices. The results demonstrated an active participation of MRF in the mechanism of generalized seizures.

Relationship between seizure-induced transcription of the DNA damage-inducible gene GADD45, DNA fragmentation, and neuronal death in focally evoked limbic epilepsy.

We investigated the temporal and spatial profile of mRNA transcription for the growth arrest and DNA damage-inducible gene GADD45, DNA fragmentation, and neuronal death in rat brain following focally evoked limbic seizures. GADD45 mRNA was detected by in situ hybridization, whereas fragmented DNA was detected using in situ nick end-labeling by the large (Klenow) fragment of DNA polymerase I. Kainic acid (0.1 microg) was injected into the right amygdala of rats to induce seizures for 45 min, after which diazepam (30 mg/kg) was administered. GADD45 mRNA, DNA fragmentation, and cell death were quantified bilaterally within six limbic brain regions 0-96 h following seizure cessation. All animals underwent seizures of equivalent severity and duration as determined electrographically. In situ hybridization detected bilateral up-regulation of GADD45 mRNA throughout the CA1, CA3, and dentate gyrus of the hippocampus, the piriform and retrosplenial cortices, and the thalamus within 1 h of seizure termination. GADD45 mRNA levels remained elevated for up to 6 h, declining to baseline within all structures by 16 h. Klenow-positive cells were only found within the CA3 pyramidal layer of the ipsilateral hippocampus and appeared 16-72 h following seizure cessation. Morphologic cell death was also restricted to the CA3 subfield. These data demonstrate that focally evoked limbic seizures trigger early bihemispheric GADD45 mRNA transcription within connected limbic structures, whereas subsequent DNA fragmentation and cell death are restricted to selectively vulnerable brain regions.

Epileptic discharge of cortical, subcortical and spinal neurons in penicillin induced experimental epilepsy.

The sensitivity and electrophysiological patterns of paroxysmal activity induced in different brain structures by topical application of penicillin-G were evaluated in the rat. Recordings were carried out in five groups of animals, in telencephalon, diencephalon, mesencephalon, rombencephalon and spinal cords. The following analysis were carried out: frequency distribution histograms, latency and time course duration of paroxysmal activity, duration and amplitude of epileptic bursts. The results obtained showed that the nervous structures tested with penicillin-G had a different epileptogenic sensitivity and response pattern which significantly changed along the cerebral cortex-spinal cord axis. The highest epileptic sensitivity was observed in somatosensory cortex (SI) at 500-600 microns depth; in the other cortical layers, a significant lenghtening in latency was observed. Among the other structures, the spinal cord seemed to be the most sensitive target to the epileptogenic action of penicillin-G, whereas in the remaining structures, sensitivity significantly decreased in rostro-caudal direction. As far as the features of the paroxysmal activity are concerned, significant differences among tested structures were observed. In particular, within the SI cortex, the main differences were represented by the gradual increase in burst frequency and voltage from the surface to the IVth layer and by their subsequent decrease in deeper layers (V-VI). In the diencephalon, the paroxysmal activity was similar to that observed in more superficial and deeper cortical layers even though epileptic bursts showed a lower amplitude. Mesencephalon and rombencephalon displayed a paroxysmal activity with a distinctive feature, characterized by long lasting bursts of low amplitude, although bulbar outbursts showed a shorter duration than the mesencephalic ones. In the spinal cord, the epileptiform activity displayed a different paroxysmal pattern, characterized by the longest duration and the highest amplitude. The different sensitivities of the investigated brain structures to penicillin-G and the characteristics of the induced paroxysmal activity have been extensively discussed.

The effect of lesionectomy and the perilesional GABAergic neuronal changes in alumina cream-induced focal motor epilepsy in cats.

The effect of lesionectomy depends on the reversibility of the epileptogenic changes in the perilesional cortex. We studied how the perilesional GABAergic neuronal changes are related to the effect of lesionectomy in the alumina cream-induced focal epilepsy model in cats. Sequential changes of GABAergic neurons and spike activities were measured after the micro-injections of alumina cream (AC). Alumina granulomas were excised 15 days and 40 days after the injections. At day 20 following the AC injection, GABAergic neurons were decreased 25 to 40% compared with those in the contralateral intact cortex. At day 40, a significant increase of spike activities occurred. GABA positive cells were decreased more than 50% compared with those in the contralateral cortex. At day 80, significant cell loss in perilesional cortex was demonstrated. The effect of lesionectomy was greater in the early excised group than in the late excised group. Decrease of GABAergic neuron was more severe in the late excised group compared to the early excised group. Our results indicate that more than 50% reduction of perilesional GABA neurons may be a critical point in epileptogenesis in this model. Lesionectomy alone prior to a 50% reduction in perilesional GABAergic neurons may be sufficient for seizure control. With these data it is still unclear whether these findings contribute to the choice between lesionectomy alone and lesionectomy with resection of the perilesional cortex. Further study is needed to understand the difference between the AC epilepsy model and human chronic epilepsy.

Coupling of cortical and thalamic metabolism in experimentally induced visual and somatosensory focal epilepsy.

Focal epileptic activity induces widespread metabolic disturbances beyond the area of the electroencephalographically detectable focus. In order to find out whether the metabolic coupling between the epileptic focus and other brain regions depends on the localization of the focus, two groups of rats with epileptic foci at different sites were investigated. In the first group acute epileptic activity was induced by application of penicillin to the secondary visual cortex (Oc2), and in the second group to the primary somatosensory cortex (Par1). Metabolism was analyzed using the [14C]deoxyglucose autoradiographic method. In both groups of animals, hypermetabolism in the area of the focus and in specific functionally coupled thalamic nuclei was observed. Focal epileptic activity in the secondary visual cortex induced significant hypometabolism in remote ipsilateral cortical areas. In rats with epileptic foci in the primary somatosensory cortex hypometabolism in extrafocal ipsilateral cortical areas was less prominent. These findings provide further support for the integral involvement of the thalamus in modulating metabolism in remote cortical brain regions during focal epileptic activity. The extent of metabolic alterations may depend on the site of the epileptic focus and the connectivity of the recruited thalamic nuclei.

[A morphometric study on hippocampus of epileptic rats induced by coriaria lactone].

This experiment was carried out with these rats were injected with 3.8 microliters (19 micrograms) convulsive dosage of coriaria lactone (CL) in the left cerebral motor cortex of the forelimb to induce acute focal epilepsy, while the other 5 rats as controls (no seizure) received normal saline solution of the same volume and at the same location. The brains were taken after seizuring for 60 min. The volume (water displacement method) and weight of the brain were measured. The brain was cut coronally and the structures of hippocampus were compared morphologically with those of the pair-matched control. The area of hippocampal formation was measured with paraffin section by test grid under 40x. The mean size (Feret's diameter) of pyramidal neurons in CA1 region was measured with semithin section by ocular micrometer under 1000x. The areal fraction of several organelles of the CA1 pyramidal cells was measured with EM negative film by magnifier. Under conditions of the consistent reference space, especially the size of CA1 pyramidal cells, the areal fraction of rough endoplasmic reticulum, lysosome and mitochondria increased significantly (P < 0.05) in epileptic rats. It indicated that their volume increased. The results show that certain ultrastructural changes have taken place after seizuring for 60 min.

[Changes in the activity of an epileptogenic focus in the rat hippocampus under the influence of bemitil]. / Izmenenie aktivnosti épileptogennogo ochaga v gippokampe krys pod vliianiem bemitila.

Experiments performed on male rats with chronically implanted electrochemotrodes showed bemitil (12.5 and 25.0 mg/kg, intra-abdominally, 24 h prior to the locus creation) suppresses he pathological activity of (100 ED) epileptogenic locus induced by he sodium salt of penicillin in the hippocampus of the animals. Probable mechanisms of antiepileptic action of bemitil are considered.

The intracortical neuronal connectivity subserving focal epileptiform activity in rat neocortex.

In the anaesthetized rat, regions of the somatosensory cortex have been subpially isolated, leaving intact the cortical blood supply and the connectivity via the white matter. Application of penicillin or strychnine into layer IV of intact cortex resulted in enhancement of amplitude and prolongation of evoked potentials together with the appearance of spontaneous epileptiform discharges. Within a partially isolated region of cortex, spontaneous and evoked potentials occurred as in normal cortex, but application of convulsant drug resulted in no changes in evoked potentials and in no spontaneous spiking. With incisions for which the surface profile measured 0.9 x 0.9 mm, full-depth isolation resulted in interruption of the propensity for epilepsy, whereas half-depth incisions left epileptic manifestations unimpaired. With the surface profile measuring 0.5 x 0.5 mm, half-depth isolation was sufficient to prevent epileptic activity. Results from isolated regions of various geometries and sizes indicated that the ability of cortical neurones to generate epileptic activity depends on the amount of connectivity with surrounding cortex. The propensity of cortex to become epileptic is thus a mass action effect and the 'epileptic neuronal aggregate' is operationally different from anatomically based modular organizations such as thalamo-cortical or cortico-cortical columns. In the small barrel field of the somatosensory cortex, partial isolations that prevented the appearance of spontaneous epileptiform spiking contained many barrels, indicating that a single thalamo-cortical module contains insufficient inherent lateral connectivity to support epileptiform activity. Theoretical considerations indicated that the excitability of a neurone depends both on its monosynaptic connections with other neurones and on the connectivity of these latter with neurones further afield. The interruption of epileptiform activity by partial isolation could be mimicked by a computer model in which connectivity was mediated via short synaptic paths. The model exhibited self-sustaining synchronized neural activity that could be prevented by interruption solely of polysynaptic paths.

[14C]2-deoxyglucose autoradiographic technique provides a metabolic signature of cobalt-induced focal epileptogenesis.

Brain glucose consumption in rats with unilateral visual cortex implants of epileptogenic cobalt rods was assessed by the 2-deoxyglucose (2-DG) method. Nine days postoperatively, "dark patches" of higher 2-DG uptake, bordered by tissue showing lesser uptake, were observed around the implant site. The dark patches were located just beyond the damaged perifocal zone, in normal-appearing Nissl-stained cortex designated by the electrocorticographic (ECoG) work of other investigators as the focus of epileptic activity. As was also predictable from earlier research, the cortical patches were prominent on day 9 and absent by day 35. Regions of high metabolic activity in thalamus, presumably the result of axonal transport of cobalt ions, were also strikingly evident in the projection nuclei connecting with the cortical implant sites. The abnormal thalamic activity is likely the metabolic counterpart of "secondary foci," a characteristic feature of the cobalt model. The longevity of these thalamic dark patches, which developed between days 2 and 9 and did not disappear until between days 90 and approximately 365, may account for the persistent sensitivity to seizure-inducing drugs that occurs secondary to cobalt implants. The absence of dark patches after control nonseizure-inducing but toxic copper implants argued against the possibility that the dark patches reflected some nonepileptogenic effect of the cobalt. As well, under pentobarbital anesthesia, the patches behaved in a manner suggesting that their 2-DG uptake reflected neural and not glial cell activity. Dark patches are a distinctive autoradiograph signature of tissue made epileptic by cobalt.

[The antiepileptic effects of the combined action of the new 1,4-dihydropyridine derivative glutapyrone with sodium valproate and phenobarbital]. / Antiépilepticheskie éffekty sochetannogo vozdeistviia novogo proizvodnogo 1,4-digidropirina glutapirona s val'proatom natriia i fenobarbitalom.

Antiepileptic effects of a novel amino acid-containing 1,4-dihydropyridine glutapyrone and sodium valproate during combined therapy on generalized pentylenetetrazol- and focal 4-aminopyridine-induced epileptic activity in rat brain cortex were studied, as were combined effects of glutapyrone and phenobarbital on maximal electroshock in mice. The results of these investigations suggest that combined treatment by glutapyrone and sodium valproate or phenobarbital is reasonable and helps potentiate the effect of each drug, thus significantly reducing their doses, and minimize the risk of side effects of the drugs id used in higher doses in case of long treatment.

[The effect of the new amino acid-containing 1,4-dihydropyridine glutapyrone on penicillin-induced focal epileptic activity and convulsions induced by bicuculline and thiosemicarbazide]. / Vliianie novogo aminokislosoderzhashchego 1,4-digidropiridina glutapirona na fokal'nuiu penitsillinindutsirovannuiu épilepticheskuiu aktivnost' i sudorogi, vyzvannye bikukullinom i tiosemikarbazidom.

The experiments on focal penicillin-induced epileptic activity in the brain cortex (Wistar rats) and bicuculline- and thiosemicarbazide-induced seizures (Icr:Icl mice) showed that the glutapyrone possessed a significant antiepileptic activity. As previously shown, that glutapyrone has an influence on 45Ca2+ uptake by rat cortical synaptosomes (evoked by K+ depolarization) as compared with nifedipine and nimodipine, and it was effective in pentylenetetrazol-induced seizures in rats and mice. The mechanism of action of convulsants is associated with the disturbance of different links of GABAergic inhibition. It is suggested that the antiepileptic effects of glutapyrone are realized at least in part by the participation of GABAergic system.

[The antiepileptic effects of sodium valproate and the calcium antagonist riodipine when used jointly in a model of focal penicillin-induced epileptic activity]. / Antiépilepticheskie éffekty val'proata natriia i antagonista kal'tsiia riodipina pri ikh sochetannom primenenii na modeli fokal'noi penitsillin-indutsirovannoi épileticheskoi aktivnosti.

In experiments on 52 freely moving Wistar male rats, 200-220 g in weight, on the model of focal penicillin-induced epileptic activity (EpA) in brain cortex the efficacy of combined application of drugs influencing different mechanisms of epileptogenesis: sodium valproate enhancing GABA-ergic processes, and the calcium antagonist ryodipine (1,4-dihydropyridine) have been studied. It was shown that valproate and ryodipine when used in combination at relatively small doses (150 and 0.8 mg/kg l.p., respectively) produced a more marked antiepileptic effect than each of these drugs given alone. These and previously reported results of studies on the model of generalized pentylenetetrazol-induced EpA, suggest that complex pathogenic therapy (CPT) as a combination of the antiepileptic drugs acting on the corresponding basic pathogenic mechanisms of respective form of epilepsy is reasonable to be used. CPT allows to obtain a better curative effect with a lower dose of each drug used and to reduce the risk of side effects of the drugs applied at large doses in case of monotherapy.

Ectopic axonal firing in an epileptic cortical focus is not triggered by thalamocortical volleys during the interictal stage.

The triggering of ectopic action potentials (APs) at axon terminals in a chronic epileptic cobalt focus was investigated in thalamocortical (TC) neurons of rats under urethane anesthesia. TC cells which were in register with an active epileptic aggregate discharged bursts of 2-11 APs. According to the rules of the collision test, we ascertained that bursts contained APs of ectopic and/or somatic origin. During a transient blockage of TC orthodromic discharges produced by raising the extracellular concentration of Mg2+, ectopic bursts which were in close time relationship with the focal interictal electrocorticographic spikes persisted. These results demonstrate (i) the antidromic nature of identified ectopic APs and (ii) that, during the interictal stage, such axonal APs were not a consequence of TC discharges. The possible mechanisms for the triggering of ectopic axonal APs in the chronic cobalt focus are discussed.

[An electrophysiological analysis of the action of an antioxidant of the 3-hydroxypyridine class on the cerebral epileptic activity in rats with a cobalt-induced focus]. / Elektrofiziologicheskii analiz deistviia antioksidanta iz klassa 3-oksipiridina na épilepticheskuiu aktivnost' mozga krys s kobal'tovym ochagom.

In experiments on albino male rats with chronically implanted electrodes and an epileptogenic focus in the cortical sensomotor region it was shown that a derivative of 3-hydroxy-pyridine (2-ethyl-6-methyl-3-hydroxypyridine) possesses the pronounced antiepileptic effect. The effect of the agent is related to the functional state of the epileptic system whose resistance to pharmacotherapy depends on the power of the determinant focus.