Nitrazepam in the Treatment of Epilepsy in Childhood

The anticonvulsant activity of nitrazepam (Mogadon) was studied in 31 children with various seizure patterns. Dosage ranged from 0.3 to 2.2 mg. per kg. body weight daily.Eleven of 15 children with minor motor seizures showed improvement and six obtained complete relief. Nine of 16 with miscellaneous seizures were improved, but only one was completely relieved and the other eight responded to a variable extent. In cases with more than one type of seizure, the myoclonic elements were those most often diminished, but sometimes this effect was only temporary. Side effects were transient and usually mild, consisting of drowsiness, ataxia, slurred speech and excessive secretion of mucus and saliva. However, three cases of aspiration pneumonia were encountered and may have been at least partly due to the side effects. No hematological or biochemical abnormalities were observed.The results indicate that nitrazepam is a relatively safe and effective drug in the treatment of minor motor seizures, particularly infantile spasms, and is even more useful than ACTH in this serious form of epilepsy. In older children its value is chiefly for myoclonic seizures, but the degree and duration of its effectiveness appear to be more limited.     

Antipentylenetetrazol action of clobazam in developing rats

Clobazam (0.5 to 7.5 mg/kg i.p.) was tested against motor seizures elicited by pentylenetetrazol in rats 7, 12, 18, 25 and 90 days old. Minimal, predominantly clonic seizures with preserved righting ability were reliably induced by pentylenetetrazol and suppressed by clobazam in rats aged 18 days or more. The incidence of minimal seizures after clobazam pretreatment was not increased in 7- and 12-day-old rat pups. Generalized tonic-clonic seizures were markedly suppressed by clobazam in all age groups. In 18-day-old and older animals clobazam doses suppressing generalized seizures were always lower than those necessary for exerting an effect on minimal seizures. The differences in clobazam action appearing at various levels of maturation are only quantitative.     

Role of the brain-stem reticular formation in tonic-clonic seizures: lesion and pharmacological studies

Bilateral lesions of the pontine tegmentum involving the superior cerebellar peduncles and the nucleus reticularis pontis oralis have been shown to attenuate the tonic components of maximal seizures induced by electroshock, sound stimulation (audiogenic), or pentylenetetrazol, although having no effect on clonus in three separate seizure models. The pontine tegmental lesion also abolishes the clonus of minimal audiogenic seizures that have a motor pattern different from that of other clonic models, and are believed to originate in the brain stem. The preponderant suppression of tonus by the pontine tegmental lesion as well as the inhibition of clonus in audiogenic seizures is strikingly similar to the effects of phenytoin in these same seizure models. The findings presented are consistent with the hypothesis that the pontine reticular formation (RF) plays a key role in the generation and/or expression of tonic convulsions. Additional findings are presented that suggest that serotonin may attenuate the tonic components of maximal electroshock seizures by an action on the brain stem. Thus, it seems likely that pontine tegmental lesions as well as antiepileptic drugs and neurotransmitters with preferential effects on tonic seizures act on a common neural substrate that appears to include the brain-stem RF.     

Action of two neuroactive steroids against motor seizures induced by pentetrazol in rats during ontogeny

The anticonvulsant action of two neuroactive steroids, 3alpha-hydroxy-5beta-pregnan-20-one (pregnanolone) and triethylammonium 3 alpha-hydroxy-20-oxo-5 alpha-pregnan-21-yl hydrogensuccinate (THDOC-conjugate), was tested against motor seizures induced by pentetrazol in immature rats. Five age groups (7, 12, 18 and 25 days old and adult rats) were pretreated with the steroids in doses from 2.5 to 40 mg/kg i.p. Twenty minutes later pentetrazol (100 mg/kg s.c.) was administered. Minimal seizures (clonic seizures of head and forelimb muscles with preserved righting ability) could be induced in the three older age groups. They were suppressed by pregnanolone in all these tested groups (this effect was best expressed in 18-day-old rats and decreased with age), whereas significant changes in THDOC-conjugate-pretreated animals appeared only in 18-day-old rats. Generalized tonic-clonic seizures were suppressed by both neuroactive steroids in all age groups, this effect being more marked with pregnanolone and again decreased with age. The 7- and 12-day-old rats exhibited higher sensitivity of the tonic phase so that generalized clonic seizures were observed. Duration of the effect was studied in 12- and 25-day-old animals; it was substantially shorter in the older rats than in 12-day-old animals. Both drugs exhibited an anticonvulsant action in developing rats but, unfortunately, their effect was only shortlasting.     

Models of epileptic seizures in immature rats

Models of basic types of epileptic seizures are elaborated not only in adult but also in immature rodents. It is important because at least half of human epilepsies starts during infancy and childhood. This paper presents a review of chemically and electrically induced models of generalized convulsive and nonconvulsive (absence) seizures as well as models of partial simple (neocortical) and complex (limbic) seizures in immature rats. These models can also serve as a tool for study the development of central nervous system and motor abilities because the level of maturation is reflected in seizure semiology. Age-dependent models of epileptic seizures (absences and flexion seizures) are discussed. Models of seizures in immature animals should be used for testing of potential antiepileptic drugs.     

Subclinical epileptic seizures; impairment of motor performance and derivative difficulties

Modern clinical observations have greatly expanded the conception of the characteristics of the various kinds of epilepsy. By simultaneously recording electroencephalograms and the performance of simple motor tasks, it has been possible to demonstrate the effects of epileptic seizures not detectable by unaided observation and not noted by the patient. The effects of these subclinical seizures have been manifested variously-by a lengthening of the time between stimulus and reaction, by inaccuracies of response to stimuli, or by total cessation of performance. From this study it is suggested that subclinical seizures probably play a role in producing some of the psychiatric conditions associated with the convulsive disorders, as well as primary behavior disturbances and undifferentiated mental deficiency. It is also suggested that such subclinical seizures may possibly contribute to the characteristics of some cases of criminality and antisocial reactions and schizophrenic reactions.     

Effects of ionotropic glutamate receptor channel blockers on the development of audiogenic seizures in Krushinski-Molodkina rats

The action of noncompetitive blockers of glutamate receptors has been investigated on Krushinski-Molodkina rats genetically-prone to audiogenic seizures. The selective blockers of NMDA receptor channels, memantine and IEM-1921, and their dicationic homologues, IEM-1925 and IEM-1754, capable of blocking in varying degrees both NMDA and Ca-permeable AMPA receptor channels, were studied. The drugs were injected intramuscularly to rats with the different time intervals (30 min, 1, 2 or 3 hours) before sound signal. The effects of the drugs on latent period of initial locomotor activity provoked by audio stimulation (8 kHz sine-wave tone, 90 dB volume), the appearance of clonic convulsions of different intensities, and, finally, tonic convulsions with limb and tail extension were evaluated. Within 30 min after injection IEM-1921 at a dose of 5 mg/kg, 33% of rats manifested a complete absence of convulsive reactions to sound, and in 59% of rats audiogenic seizures occured only in the form of motor excitation without a generalized clonic-tonic convulsions. Memantine at a dose of 5 mg/kg did not cause a complete blockade of seizures, but after 1 h of injection in 50% of the rats and after 2 h in 70% of rats a weakening of the audiogenic seizures to the level of motor excitation only was observed. After 3 hrs after administration of blockers its anticonvulsive action weakened significantly (p < 0.01). Dicationic blockers that block both NMDA and AMPA/kainate receptors, IEM-1925 (in doses of 0.001-20.0 mg/kg) and IEM-1754 (0.025-50.0 mg/kg), did not affect audiogenic clonic-tonic convulsive reactions. The involvement of activation of NMDA and calcium permeable AMPA/kainate receptors in the pathogenesis of audiogenic seizures is discussed.     

SUBCLINICAL EPILEPTIC SEIZURES—Impairment of Motor Performance and Derivative Difficulties

Modern clinical observations have greatly expanded the conception of the characteristics of the various kinds of epilepsy. By simultaneously recording electroencephalograms and the performance of simple motor tasks, it has been possible to demonstrate the effects of epileptic seizures not detectable by unaided observation and not noted by the patient. The effects of these subclinical seizures have been manifested variously—by a lengthening of the time between stimulus and reaction, by inaccuracies of response to stimuli, or by total cessation of performance.From this study it is suggested that subclinical seizures probably play a role in producing some of the psychiatric conditions associated with the convulsive disorders, as well as primary behavior disturbances and undifferentiated mental deficiency. It is also suggested that such subclinical seizures may possibly contribute to the characteristics of some cases of criminality and antisocial reactions and schizophrenic reactions.     

Analysis of inherited epilepsy using single locus mutations in mice.

The neurological expression of mutations at defined gene loci in isogenic mice provides a singular opportunity to investigate the developmental pathophysiology of inherited central nervous system (CNS) diseases. Analysis of the single locus mutants that are currently available shows that CNS diseases that include spontaneous seizures as symptoms can be inherited as simple recessive traits. Mutant gene dose is highly correlated with the spontaneous occurrence of seizures. Single gene defects at one of multiple chromosomal loci may give rise to similar epileptic patterns. One mutation, tottering (tg, chromosome 8, recessive) produces in young mice a focal motor seizure pattern with a somatotopic progression, and behavioral absence seizures accompanied by abnormal bursts of bilaterally synchronous, spike-wave discharges in the electrocorticogram. Spontaneous electrographic and clinical seizures of this general pattern bear close resemblance to common forms of human epilepsy. Defined alterations in restricted neuronal pathways of the mouse brain produced by single locus mutations can be used to infer general principles of inherited epileptogenesis, and may provide specific biological test systems for the development of more selective chemical antagonists of seizure activity.     

Ontogenetic development of convulsant action of Ro 5-3663 in the rat

Motor seizures were induced by Ro 5-3663 in 156 male albino rats aged 7,12,18,25, and 90 days. Both minimal and maximal seizures could be elicited in 18-day-old and older animals, whereas only maximal seizures were induced in the two youngest groups. ECoG changes were studied in other 21 young rats. First changes induced by Ro 5-3663 were formed by isolated sharp waves in 7- and 12-day-old rats and by episodes of rhythmic activity in older animals. An imperfect form of this rhythmic activity could be seen even in 12-day-old rats. Ictal ECoG activity exhibited an increase in frequency of individual graphoelements, in generalization and in synchronization of activity among different cortical regions with maturation. Correlation between motor and ECoG phenomena was poor in 7-day-old rats and ameliorated with age but it never reached perfection. The actions of Ro 5-3663 are identical with those induced by metrazol but they differ from those elicited by bicuculline or 3-mercaptopropionic acid.     

The development of kindled seizures is accelerated in the genetically epilepsy-prone rat

The kindling phenomenon was examined in genetically epilepsy-prone (GEPR) and non-epileptic control Sprague-Dawley rats. Kindling stimulations were administered three times a day until each rat had exhibited three Class 5 kindled motor seizures. The mean total number of kindling stimulations required for each experimental group to exhibit three motor seizures of each motor seizure class was determined. The results indicated that the early stage of kindling development was accelerated significantly in both the GEPR-3 and GEPR-9 rats, compared to non-epileptic control rats. Later stages of kindling development were accelerated in GEPR-9 but not GEPR-3 rats. Thus a differential acceleration of kindling development was exhibited by GEPR-3 and GEPR-9 rats. The results suggest the possibility that some brain region(s) involved in the early stages of kindling development may be hyperexcitable in both GEPR-3 and GEPR-9 rats. Other brain region(s) involved with the later stages of kindling development may be more excitable in GEPR-9 rats. These putative alterations may, in part, contribute to the seizure prone state of GEPR rats and the differential seizure responses of GEPR-3 and GEPR-9 rats.     

癫痫病人脑电信号的奇异谱

癫痫是一种常见的神经系统疾患,其唯一客观证据为脑电图的癫痫样发放。在癫痫发作间期,仅有偶发的很难辨别的癫痫样放电,为了正确诊断癫痫病,往往需要医生长时间监测病人的脑电信号,在对脑电信号进行相空间重构,进而对其进行奇异系统分析,发现癫痫病人无论在癫痫发作前、发作中、发作后,其脑电信号的奇异谱曲线不存在噪声平台,明显区别于正常人。是否可以认为脑电信号的奇异谱正代表着大脑的一种基本状态,癫痫患者在未发作时,大脑的基本状态已经处于异常。无论如休,奇异系统分析方法使得可以利用很短的一段脑电数据诊断癫痫。无疑为癫痫病人的临床诊断提供了一条简单、有效的途径。     

Early prognosis of epilepsy.

In 94 previously untreated new referrals to a neurological clinic with tonic-clonic or partial seizures or both the failure rate for optimum single-drug treatment with phenytoin or carbamazepine after a median of 32 months was 17%. Failure of single-drug treatment was associated especially with the presence of additional neuropsychiatric handicaps but also with partial or mixed seizures, symptomatic epilepsy, and a higher number and frequency of tonic-clonic or partial seizures before treatment. Analysis of the recurrence of seizures suggested that the first year of treatment may be crucial in determining the long-term prognosis. These findings are in keeping with the concept that seizures may predispose to further seizures, and imply that early, effective treatment may be important to prevent evolution into chronic and more intractable epilepsy.     

Inherited progressive epilepsy of the dog with comparisons to Lafora's disease of man.

A familial progressive form of epilepsy in the beagle dog is clinically characterized by intermittent seizures, often of grand mal type. If not properly treated, the seizures may lead to status epilepticus. The seizures are often elicited by external stimuli, especially a change in noise or light in the surroundings. Histologically, intracytoplasmic inclusions, 2-10 mum in diameter, occur in glial and neuronal cells in the brain, especially the thalamus. The inclusions are strongly positive for carbohydrate stains, weakly metachromatic, and lipid negative. They are spherical with a dense core and an often radiating, less dense periphery. Histologic changes in other organs include basophilic myocardial degeneration, degeneration and variation in diameter size of skeletal muscle fibers, and deposition of periodic acid-Schiff positive material in the cytoplasm of reticuloendothelial cells of the liver, spleen, and lymph nodes. Based on clinical and morphologic manifestations, the beagle disorder resembles Lafora's disease of man. This disorder will provide a useful model for comparative studies with progressive myoclonic epilepsy (Lafora's disease) of man and for defining the pathomechanisms of other forms of epilepsy.     

A bidirectional kinesin motor in live Drosophila embryos

Spindle assembly and elongation involve poleward and away-from-the-pole forces produced by microtubule dynamics and spindle-associated motors. Here, we show that a bidirectional Drosophila Kinesin-14 motor that moves either to the microtubule plus or minus end in vitro unexpectedly causes only minor spindle defects in vivo. However, spindles of mutant embryos are longer than wild type, consistent with increased plus-end motor activity. Strikingly, suppressing spindle dynamics by depriving embryos of oxygen causes the bidirectional motor to show increased accumulation at distal or plus ends of astral microtubules relative to wild type, an effect not observed for a mutant motor defective in motility. Increased motor accumulation at microtubule plus ends may be due to increased slow plus-end movement of the bidirectional motor under hypoxia, caused by perturbation of microtubule dynamics or inactivation of the only other known Drosophila minus-end spindle motor, cytoplasmic dynein. Negative-stain electron microscopy images are consistent with highly cooperative motor binding to microtubules, and gliding assays show dependence on motor density for motility. Mutant effects of the bidirectional motor on spindle function may be suppressed under normal conditions by motor: motor interactions and minus-end movement induced by spindle dynamics. These forces may also bias wild-type motor movement toward microtubule minus ends in live cells. Our findings link motor : motor interactions to function in vivo by showing that motor density, together with cellular dynamics, may influence motor function in live cells.     

Effects of experimental cortical seizures on respiratory motor nerve activities in piglets.

Airway obstruction at the level of the larynx causes respiratory insufficiency during experimental seizures in spontaneously breathing, anesthetized piglets (T. E. Terndrup and W. E. Fordyce, Pediatr. Res., 38: 61-66, 1995). To investigate further the neural mechanisms of this obstruction, the activities of the phrenic nerve (PH) and the recurrent laryngeal motor branches to the thyroarytenoid (TA) and posterior cricoarytenoid (PCA) muscles were analyzed in 11 anesthetized, vagotomized, paralyzed, and ventilated piglets. After a control recording period, seizures were induced by subcortical penicillin G injections. Compared with baseline conditions, nerve activities became irregular during seizures. Extraneous TA bursts during PH activation were evident in all piglets during seizures. During ictal phases of seizures, the peak integrated activities of the PH and the expiratory component of the PCA, but not TA or inspiratory PCA activities, were significantly decreased compared with interictal phases. During seizures, a significant delay in the onset of the inspiratory component of PCA activation with respect to the onset of the PH was observed. This study helps to explain respiratory impairment during cortical seizures by providing evidence of impaired timing of activation of laryngeal dilator mechanisms and coordination with those activating the diaphragm. Cyclical PH inhibition during high-intensity cortical discharges may provide a secondary mechanism producing respiratory insufficiency during seizures.     

Pronounced increases in brain levels of calcitonin gene-related peptide after kainic acid induced seizures

Changes in immunoreactivity of calcitonin gene-related peptide (CGRP) were investigated in the brains of rats subsequently to seizures induced by intraperitoneal injection of kainic acid (10 mg/kg, i.p.). Increased levels of the neuropeptide were observed in the frontal cortex (increase of 1300% of control value), striatum (900%), dorsal hippocampus (400%) and amygdala/pyriform cortex (135%) three days after injection of the neurotoxin. Intravenous infusion of mannitol (1.5 g/kg, under thiopental anesthesia) which prevents seizures and post-seizure brain damage suppressed the changes in CGRP-like immunoreactivity. Injection of pentylenetetrazol causing generalized motor seizures resulted in no change of CGRP-immunoreactivity after three days. The pronounced but reversible increases of brain CGRP levels suggest a strong but short-lasting activation of the peptide system. The failure of pentylenetetrazol to produce a similar effect and the protective action of mannitol suggest that sustained seizures and/or post-seizure brain damage may be required to produce the rise in peptide levels.     

Nicotinic receptors in circuit excitability and epilepsy

Neuronal nicotinic acetylcholine receptors belong to the family of excitatory ligand-gated channels and result from the assembly of five subunits. Functional heteromeric nictonic receptors are present in the hippocampus and neocortex, thalamus, mesolimbic dopamine system and brainstem motor nuclei, where they may play a role, respectively, in memory, sensory processing, addiction and motor control. Some forms of autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) have been found to be associated with mutations in the genes coding for the alpha 4 or beta2 subunits of the nicotinic receptor. Mutant receptors display an increased acetylcholine sensitivity with respect to normal receptors. Since the thalamus and the cortex are strongly innervated by cholinergic neurons projecting from the brainstem and basal forebrain, an unbalance between excitation and inhibition, brought about by the presence of mutant receptors, could generate seizures by facilitating and synchronizing spontaneous oscillations in thalamo-cortical circuits.     

Prise en charge des complications de la maladie d’Alzheimer: mise au point

Complications in Alzheimer’s disease such as functional decline, weight loss, gait and balance disturbances and behavioral and psychological symptoms in dementia (BPSD) have a negative impact on quality of life. It is therefore important to identify these complications at an early stage. BPSD are major features of Alzheimer’s disease and related disorders. They represent half of admissions to special care units with, in order of frequency, agitation and agressivity. The non pharmacological approach must be implemented first and linked to a pharmacological approach. Weight loss is of complex physiopathology. It can be monitored by observation of the weight curve and use of the Mini Nutritional Assessment (MNA). Weight loss may be responsible for an increased risk of institutionalization and mortality. Gait and balance disturbances are also a prevalent complication of the illness and lead to an increased risk of falls and injuries. Neurological complications take the form of seizures and motor symptoms. Amongst these complications the burden of the caregiver must also be assessed. These complications and their consequences must be identified and, wherever possible, prevented with a specific care plan.