Trial of Amino-oxyacetic Acid,an Anticonvulsant

It has been shown experimentally that the drug amino-oxyacetic acid (AOA) can raise the level of gamma aminobutyric acid (GABA) in the brain. Since GABA is a powerful neuronal inhibitor it seemed worth while to assess the value of AOA as an anticonvulsant.This drug was given to 23 infants and children, all but one of whom were resistant to usual anticonvulsant medication. The types of seizure patterns were classed as major (including focal) and minor (akinetic, myoclonic and hypsarrhythmic) and the patients were followed for up to one year. Of eight children with major seizures, five were improved; of eight with minor seizures, three were improved; and of six with hypsarrhythmia, none were improved. One patient with phenylketonuria and minor seizures was improved.It is concluded that this approach to anticonvulsant therapy is worth pursuing and that the drug may also find some use in the treatment of phenylketonuria and of seizures due to vitamin B₆ dependency.     

Anticonvulsant effects of thymoquinone, the major constituent of Nigella sativa seeds, in mice.

The anticonvulsant effects of thymoquinone, the major constituent of Nigella sativa seeds, were investigated using pentylenetetrazole (PTZ)- and maximal electroshock (MES)-induced seizure models. We also studied the effect of thymoquinone on pentobarbital-induced hypnosis, locomotor activity, and motor coordination. In PTZ-induced seizure, the intraperitoneally injection of thymoquinone with doses of 40 and 80 mg/kg, prolonged the onset of seizures and reduced the duration of myoclonic seizures. The protective effect of thymoquinone against mortality was 71.4% and 100% in the mentioned doses, respectively. In MES model, thymoquinone failed to reduce the duration of seizure, whereas exhibited a complete protection against mortality. In PTZ model, flumazenil (10 mg/kg, i.p.), an antagonist of benzodiazepine (BZD) site in the GABAA-BZD receptor complex, inhibited the prolongation of seizure latency, but did not show any effect on the duration of myoclonic seizures. Also, pretreatment with naloxone (0.1 and 03 mg/kg, i.p.) inhibited the prolongation of myoclonic seizure latency and antagonized the reduction of myoclonic seizure duration induced by thymoquinone (40 and 80 mg/kg) in the PTZ model. Moreover, thymoquinone (40 and 80 mg/kg) did not have any hypnosis effect in the pentobarbital-induced hypnosis, but impaired the motor coordination and reduced the locomotor activity. These results indicate that thymoquinone may have anticonvulsant activity in the petit mal epilepsy probably through an opioid receptor-mediated increase in GABAergic tone.     

Vagus nerve stimulation in children with mitochondrial electron transport chain deficiencies

We retrospectively investigated outcome data for vagus nerve stimulation (VNS) in children less than 12 years of age with intractable seizures and mitochondrial disease. Five children with a mitochondrial disease, due to electron transport chain deficiency, were studied. Information was collected from clinic visits prior to, and subsequent to, VNS implantation. Data were collected by type and frequency of seizures, encephalogram and neuroimaging findings, and medication history. Four of the children had predominantly myoclonic seizures, while the other child had focal seizures with secondary generalization and myoclonic seizures. All five children did not have significant reduction in seizure frequency with VNS. VNS may not be an effective method to control myoclonic seizures in children with electron transport chain disorders.     

The effect of naloxone administration on pregnancy-associated seizures

Pregnant mice are more susceptible to flurothyl-induced seizures than are non-pregnant controls. The possibility that the well-known increase in beta-endorphin concentration which accompanies pregnancy was involved in this effect was examined by testing whether naloxone administration could block the increased seizure susceptibility. Pregnant female, control female and male C3H mice were treated with 5-50 mg/kg naloxone 5 min before flurothyl seizure testing. Naloxone markedly increased clonic seizure susceptibility in all three groups at a dose of 50 mg/kg, but had little effect at lower doses. In contrast, naloxone had differential effects on myoclonic seizures in pregnant and control female mice, being anticonvulsant in the controls, but proconvulsant in the pregnant mice. A role for endogenous opiates is unlikely in mediating clonic seizures in pregnant mice, but may be involved in myoclonic seizures.     

Symptomatic epilepsy associated with intracranial calcifications in children with acute lymphoblastic leukemia (ALL)

Acute and long-term sequels of central nervous system (CNS) prophylaxis with irradiation and intrathecal chemotherapy in children suffering from acute lymphoblastic leukemia (ALL) include vasculopathies, leucoencephalopathies, intracranial calcifications, intellectual and neurological impairment. We report two children at the age 5 and 8 years who manifested partial motor or complex seizures and intracranial calcifications 2-4 years after the diagnosis of ALL had been established. The occurrence of these disorders was much earlier than reported in the literature. Both children received prophylactic CNS treatment with irradiation and intrathecal methotrexate (MTX). Their brain CT scans and EEG had been normal before the first epileptic seizure was registered. Children are now seizure free on carbamazepine, and a boy with complex partial and myoclonic seizures is also on valproate and vigabatrine. Symptomatic epilepsy associated with intracranial calcifications and persisting EEG changes might occur as side effects of ALL treatment.     

The temporal dimensions of anticonvulsant action of some newer benzodiazepines against metrazol induced seizures in mice and rats

In a time-distribution study, the anticonvulsant effects of four benzodiazepine compounds were compared with those of three standard antiepileptics against metrazol-induced seizures in mice and rats. Ethosuximide and trimethadione had the shortest duration of action in mice, but protected the rats up to 6 hr. Phenobarbitone, diazepam, flurazepam and nitrazepam protected the mice up to 12 hr, but the rats were effectively protected only up to 3-4 hr. Clonazepam, the most potent and effective agent, protected the mice from clonic-tonic seizures up to 18-20 hr and the rats up to 6-7 hr. Comparison of the PD50 from clonic seizure at the peak-effect hours revealed that the benzodiazepines were 16 to 96 times more potent than phenobarbitone on a molar basis, while phenobarbitone itself was 12 to 26 times more potent than ethosuximide and trimethadione. Tonic seizures and mortality were largely suppressed by all drugs until 18-20 hr in mice and 6-7 hr in rats. Seizure latency and mortality patterns varied from drug to drug but not in a dose-dependent manner.     

Epilepsy in the first 10 years of life: findings of the child health and education study.

OBJECTIVES--To identify children with afebrile seizures in a national cohort, classify the seizures, and document progress in the first 10 years of life. DESIGN--Population based birth cohort study. SETTING--The child health and education study, which includes 16,004 neonatal survivors (98.5% of infants born in the United Kingdom during one week of April 1970). SUBJECTS--14,676 children for whom relevant information was available. MAIN OUTCOME MEASURES--Responses to parental and general practitioner questionnaires and hospital records at 5 and 10 years after birth. RESULTS--84 children (42 boys, 42 girls) had had one or more afebrile seizure (incidence 5.7/1000). 63 children (31 boys, 32 girls) had epilepsy (incidence 4.3/1000). 49 of 55 children had a second seizure within a year of the first. The commonest seizure types were tonic-clonic (42) and complex partial (25). A greater proportion of children with complex partial seizures had recurrences. Children who had infantile spasms or a mixed seizure disorder had a poor outcome. All six children who died had symptomatic seizures in the first year, but seizures were not the direct cause of death. CONCLUSIONS--The results of this study are probably representative of seizure patterns in the general population. Outcome after seizures is determined more by the underlying disease than by the seizures themselves.     

Anticonvulsant effects of clonazepam on chemically induced convulsions

The anticonvulsant effects of two doses of clonazepam (CZP, Rivotril Roche, 0.1 and 1 mg/kg i.p.) were studied on model motor seizures induced by strychnine, bicuculline, 3-mercaptopropionic acid and metrazol in male laboratory rats (Wistar strain). In the first part the effects of different doses of the convulsants were investigated and for interaction with CZP doses were chosen after which more than 70% of the animals displayed generalized tonic-clonic convulsions (a grand mal seizure). Strychnine induced this type of seizure only: two doses (2 and 3 mg/kg s.c.) were used. CZP reduced the incidence of convulsions only after the larger dose, but plain solvent (propylene glycol, ethanol, water) was equally effective. The other substances first induced a seizure of minimal (mainly clonic) convulsions and only later a grand mal seizure. CZP was highly effective against bicuculline (3 mg/kg s.c.) and metrazol (100 mg/kg s.c.), but was less so against 3-mercaptopropionic acid. The effect on grand mal seizures was more pronounced in every case than on minimal seizures. The decisive role in the anticonvulsant effect of CZP is played by the mechanisms by which the convulsants induce epileptic manifestations. CZP is most effective against substances acting on the supramolecular complex GABA receptor (benzodiazepine receptor) chloride ionophore (bicuculline and probably metrazol).     

Amiloride but Not Memantine Reduces Neurodegeneration,Seizures and Myoclonic Jerks in Rats with Cardiac Arrest-Induced Global Cerebral Hypoxia and Reperfusion

It has been reported that both activation of N-methyl-D-aspartate receptors and acid-sensing ion channels during cerebral ischemic insult contributed to brain injury. But which of these two molecular targets plays a more pivotal role in hypoxia-induced brain injury during ischemia is not known. In this study, the neuroprotective effects of an acid-sensing cation channel blocker and an N-methyl-D-aspartate receptor blocker were evaluated in a rat model of cardiac arrest-induced cerebral hypoxia. We found that intracisternal injection of amiloride, an acid-sensing ion channel blocker, dose-dependently reduced cerebral hypoxia-induced neurodegeneration, seizures, and audiogenic myoclonic jerks. In contrast, intracisternal injection of memantine, a selective uncompetitive N-methyl-D-aspartate receptor blocker, had no significant effect on cerebral hypoxia-induced neurodegeneration, seizure and audiogenic myoclonic jerks. Intracisternal injection of zoniporide, a specific sodium-hydrogen exchanger inhibitor, before cardiac arrest-induced cerebral hypoxia, also did not reduce cerebral hypoxia-induced neurodegeneration, seizures and myoclonic jerks. These results suggest that acid-sensing ion channels play a more pivotal role than N-methyl-D-aspartate receptors in mediating cerebral hypoxia-induced brain injury during ischemic insult.     

Differential effects of perinatal hypoxia and anoxia on long term seizure susceptibility in the rat.

We have previously demonstrated that hypoxia is acutely epileptogenic in the immature rat but not in the adult. The window during which hypoxia induces seizures in the rat ranges from postnatal day (P) 5-17, with the most severe seizures occurring at P10-12. Perinatal hypoxia resulted in significantly more acute seizure activity than perinatal anoxia. The present study evaluates the long term effects of perinatal hypoxia versus anoxia. Animals were exposed to hypoxia (3%O2) or anoxia (0%O2) at P10 and challenged later in adulthood (P55-60) with administration of pentylenetetrazol (PTZ) (45 mg/kg subcutaneously). Compared to normal littermate controls, the animals which had been exposed to perinatal hypoxia had a significantly higher frequency of generalized convulsions (GC) and a significantly shorter latency to the first myoclonic jerk (MJ) after PTZ. In contrast, perinatal anoxia did not alter long term seizure susceptibility. These results are discussed in context of previous studies which have shown variable long term effects using different models of perinatal hypoxia and/or ischemia.     

The piriform cortex and the cortical nucleus of the amygdala in epileptogenesis--the role of the rostrocaudal gradient

The seizure susceptibility of amygdaloid complex in rat was investigated. In piriform cortex and cortical nucleus of amygdaloid complex the structural and electrophysiological rostro-caudal differences were found (using relative spectral densities EEG, seizure thresholds, electrical kindling rate). The fundamental dependence of severity of motor seizures from structural (nuclear or cortical) organization of stimulating area was shown. There were more of limbic stages while stimulating anterior and posterior cortical nuclei, and there were more generalized stages while stimulating piriform and periamygdaloid cortex. Using the model of electrical kindling anticonvulsant effects of Sacricin were demonstrated. Sacricin is one of the compounds of polycarbonic acid. Sacricin has fully coped the process of secondary generalization of epileptic seizures.     

De novo mutations in the sodium-channel gene SCN1A cause severe myoclonic epilepsy of infancy

Severe myoclonic epilepsy of infancy (SMEI) is a rare disorder that occurs in isolated patients. The disease is characterized by generalized tonic, clonic, and tonic-clonic seizures that are initially induced by fever and begin during the first year of life. Later, patients also manifest other seizure types, including absence, myoclonic, and simple and complex partial seizures. Psychomotor development stagnates around the second year of life. Missense mutations in the gene that codes for a neuronal voltage-gated sodium-channel alpha-subunit (SCN1A) were identified in families with generalized epilepsy with febrile seizures plus (GEFS+). GEFS+ is a mild type of epilepsy associated with febrile and afebrile seizures. Because both GEFS+ and SMEI involve fever-associated seizures, we screened seven unrelated patients with SMEI for mutations in SCN1A. We identified a mutation in each patient: four had frameshift mutations, one had a nonsense mutation, one had a splice-donor mutation, and one had a missense mutation. All mutations are de novo mutations and were not observed in 184 control chromosomes.     

Clinical course of untreated tonic-clonic seizures in childhood: prospective,hospital based study.

OBJECTIVE: To assess decleration and acceleration in the disease process in the initial phase of epilepsy in children with new onset tonic-clonic seizures. STUDY DESIGN: Hospital based follow up study. SETTING: Two university hospitals, a general hospital, and a children''s hospital in the Netherlands. PATIENTS: 204 children aged 1 month to 16 years with idiopathic or remote symptomatic, newly diagnosed, tonic-clonic seizures, of whom 123 were enrolled at time of their first ever seizure; all children were followed until the start of drug treatment (78 children), the occurrence of the fourth untreated seizure (41 children), or the end of the follow up period of two years (85 untreated children). MAIN OUTCOME MEASURES: Analysis of disease pattern from first ever seizure. The pattern was categorised as decelerating if the child became free of seizures despite treatment being withheld. In cases with four seizures, the pattern was categorised as decelerating if successive intervals increased or as accelerating if intervals decreased. Patterns in the remaining children were classified as uncertain. RESULTS: A decelerating pattern was found in 83 of 85 children who became free of seizures without treatment. Three of the 41 children with four or more untreated seizures showed a decelerating pattern and eight an accelerating pattern. In 110 children the disease process could not be classified, mostly because drug treatment was started after the first, second, or third seizure. The proportion of children with a decelerating pattern (42%, 95% confidence interval 35% to 49%) may be a minimum estimate because of the large number of patients with an uncertain disease pattern. CONCLUSIONS: Though untreated epilepsy is commonly considered to be a progressive disorder with decreasing intervals between seizures, a large proportion of children with newly diagnosed, unprovoked tonic-clonic seizures have a decelerating disease process. The fear that tonic-clonic seizures commonly evolve into a progressive disease should not be used as an argument in favour of early drug treatment in children with epilepsy.     

Increased seizure susceptibility and cortical malformation in beta-catenin mutant mice

Beta-catenin has been implicated in epilepsy because of its altered post seizure expression and the role of Wnt2 signaling in autism. To determine beta-catenin's role in seizure susceptibility, we injected penetylenetetrazol intraperitoneally in beta-catenin cerebral cortex- and hippocampus-specific knockout mice. We then analyzed the latency, number, and duration of four phases of seizure behaviors: (I) non-seizure activity, (II) myoclonic jerks, (III) generalized clonic seizures, and (IV) tonic seizures. The latencies to both death and Phase IV were significantly reduced in mutant mice. Mutant mice also spent significantly more time in Phases III and IV and showed significantly less time in the non-convulsive state (Phase I). Nissl and gold chloride staining indicated that the knockout mice had underdeveloped cortices, lacked a corpus callosum, and were missing hippocampal structures. This suggests that dysfunction of beta-catenin-mediated signaling pathways in mice leads to cortical malformation and increased seizure susceptibility.     

Glycine potentiates the action of some anticonvulsant drugs in some seizure models

The anticonvulsant effect of either phenobarbital or dilantin was potentiated by exogenous glycine in DBA/2 audiogenic seizure mice and in 3-mercaptopropionic acid-induced seizures. In seizures caused by pentylenetetrazol, glycine potentiated the anticonvulsant effect of phenobarbital only slightly; in combination with dilantin, which was ineffective by itself, it did not have an effect. Valproic acid, in large doses, prevented 3-mercaptopropionic acid-induced seizures; glycine did not potentiate its effect. Glycine thus potentiates anticonvulsant effects, but only of some drugs and only in some of the seizure models. This suggests that the mechanism of the anticonvulsant effect of glycine is similar to that of some of the anticonvulsant drugs such as dilantin and different from others, and that this mechanism is not effective in all seizure models.     

The influence of cortical lesions on penicillin induced convulsive activity in the awake rat

1. Experiments were performed to investigate the effects of cortical lesions on convulsive behaviour. Rats were lesioned in the left motor or sensory cortex by aspirating cortical tissue 2 to 3 months prior to the elicitation of convulsions. Convulsions were induced in the awake rats by the GABA antagonist Na-penicillin (Na-PCN) which was applied into the superficial layer of the foreleg field of their right motor cortex. Convulsive activity was recorded by means of the EEG. 2. The time courses of convulsive cortical activity were similar in the animals without or with a cortical lesion. Generalized seizures belonged to the tonic-clonic type in both intact and lesioned rats. 3. The early period of convulsive activity was described by the time to the onset (latency) of the first convulsive potential, jerk and seizure, and by the mean repetition rate of jerks during the first ten minutes, and the duration of the first generalized seizure. None of these parameters was significantly affected by a cortical lesion. 4. The median duration of the convulsive activity in intact animals was 162 min. In rats with a lesion in the sensory cortex it raised to more than 540 min while a lesion of the motor cortex increased the median duration to more than 273 min. The differences between intact and lesioned rats were significant (p less than 0.01 and p = 0.05, respectively). 5. The median time to the onset of the last generalized seizure in intact rats corresponded to 92 min with respect to the time of Na-PCN application. In rats with a lesion of the sensory cortex the last seizure was generated 433 min and in animals with a lesion of the motor cortex 167 min after Na-PCN treatment of the motor cortex of one side. This increase of latency of the last seizure was significant for the rats with a lesioned sensory area (p less than 0.02) or motor area (p = 0.05) compared to that of the intact rats. Additionally, the number of generalized seizures was significantly (p less than 0.01) increased by both groups of rats with a lesion of the motor or sensory cortex. 6. It is suggested that a substantial lesion of the cortex decreases predominantly the intrinsic cortical inhibition thus destabilizing brain function. This destabilizing effect becomes pronounced under the condition of superimposed suppression of the GABAergic cortical component. It is concluded that the intrinsic cortical inhibitory mechanism which in the intact brain acts against hyperexcitation and prevents the development of neuronal synchronization, i.e. the formation of seizures, becomes less effective in performing this task once an abnormal brain activation has developed.     

Kindling of the limbic structures with a shortened interstimulus interval

We investigated the possibility to produce hippocampal or amygdala kindling syndrome in rabbits which had been electrically stimulated at a fixed interval between stimuli at 5 min. Animals were prepared with chronically implanted electrodes (neocortex, hippocampus, amygdala, nucleus caudatus). The initial stimuli produced only localized effect, but repeated applications of the stimuli progressively increased the seizure activity resulting in generalized kindled convulsions after 2-4 h period. At the first stage generalized seizures were followed by long lasting refractory period, but at the end of the procedure almost all stimuli evoke major motor seizures and recurrent widely spread electrographic epileptic changes. The most noteworthy findings emerging from this study is the inhibition of postictal seizure inhibition period. This effect was independent of whether stimulated the electrode was positioned in the hippocampus or amygdala, but the hippocampal formation occupied the central position for the once and propagation of the seizure activity in all cases. When established this syndrome persisted without any attenuation for some weeks. It was concluded that this model of rapid development of kindling syndrome is useful for investigation of the nature of epilepsy and postictal seizure inhibition.     

The Characterization of Childhood Occipital Epilepsy of Gastaut: A Study of Seven Patients

Characterization of the electroclinical features and evolution of childhood occipital epilepsy of Gastaut (COE-G). Seven children were retrospectively identified as having COE-G and were followed-up clinically using EEGs. Visual manifestations were the most common ictal event. Eye-associated ictal deviation was associated with ipsilateral turning of the head and migraine-like symptoms were frequent. Hemiconvulsions occurred in two children, and only one child had secondary generalized tonic–clonic seizures. In all patients, seizures occurred while awake, while two patients also had seizures while sleeping. EEG showed five patients with occipital spike-wave discharges when their eyes were closed which disappeared once their eyes were opened. Two cases continued having frequent seizures despite antiepileptic drug treatment. These patients also displayed learning difficulties and behavioral impairments after seizure onset. COE-G is a distinctive epileptic syndrome; however, the long-term prognosis for patients with the condition is unclear.     

托吡酯与苯巴比妥对小儿癫痫患儿发作次数及痫样放电的影响对比

目的:研究托吡酯(topiramate,TPM)与苯巴比妥(phenobarbital,PB)对小儿癫痫(Epilepsy)患儿发作次数及痫样放电的影响。方法:将我院2010年8月至2013年8月入院接受诊治的200例癫痫患儿作为观察对象,随机分成两组。观察组采用TPM治疗,对照组采用PB治疗。对比两组患儿治疗前以及治疗后3个月癫痫发作次数、疗效以及不良反应情况。结果:观察组部分性发作减少次数、全身性发作减少次数及总发作减少次数,均显著高于对照组;观察组治愈率、愈显率、总有效率,均显著高于对照组;观察组不良反应情况显著少于对照组;差异均具有统计学意义(均P0.05)。结论:与PB相比,TPM治疗小儿癫痫疗效更佳,且不良反应更少,值得临床推荐。