Reduced ACTH, while normal beta-endorphin CSF levels in early epileptic encephalopathies

Since ACTH and the opioids display opposite effects on experimentally-induced seizures, cerebrospinal fluid (CSF) levels of ACTH and beta-endorphin (beta-EP) were measured in 6 children (4-8 months) affected by infantile spasms with hypsarhythmia, an idiopathic early onset encephalopathy, and in 8 age-matched controls. beta-EP levels in the patients (76.3 +/- 14.7 fmol/ml, M +/- SD) did not differ from those in controls (109.8 +/- 42.7) while babies with epileptic encephalopathy showed reduced ACTH levels in the CSF (3.8 +/- 1.5) as compared to controls (9.0 +/- 3.7, p less than 0.01). This resulted in an increased beta-EP/ACTH ratio. Another patient previously treated with ACTH showed a normal CSF level of ACTH (9.0) with a normal beta-EP/ACTH ratio while in clinical and EEG remission. These results are consistent with the hypothesis that some infantile seizures unrelated to brain injuries could originate from an ACTH deficiency at central level and/or an imbalance of neuropeptidergic pathways.     

Proteomic Analysis of Adrenocorticotropic Hormone Treatment of an Infantile Spasm Model Induced by N-Methyl-d-Aspartic Acid and Prenatal Stress

Infantile spasms is an age-specific epileptic syndrome associated with poor developmental outcomes and poor response to nearly all traditional antiepileptic drugs except adrenocorticotropic hormone (ACTH). We investigated the protective mechanism of ACTH against brain damage. An infantile spasm rat model induced by N-methyl-d-aspartate (NMDA) in neonate rats was used. Pregnant rats were randomly divided into the stress-exposed and the non-stress exposed groups, and their offspring were randomly divided into ACTH-treated spasm model, untreated spasm model, and control groups. A proteomics-based approach was used to detect the proteome differences between ACTH-treated and untreated groups. Gel image analysis was followed by matrix-assisted laser desorption/ionization time-of-flight mass spectrometric protein identification and bioinformatics analysis. Prenatal stress exposure resulted in more severe seizures, and ACTH treatment reduced and delayed the onset of seizures. The most significantly up-regulated proteins included isoform 1 of tubulin β-5 chain, cofilin-1 (CFL1), synaptosomal-associated protein 25, malate dehydrogenase, N(G),N(G)-dimethylarginine dimethylaminohydrolase 1, annexin A3 (ANXA3), and rho GDP-dissociation inhibitor 1 (ARHGDIA). In contrast, tubulin α-1A chain was down-regulated. Three of the identified proteins, ARHGDIA, ANXA3, and CFL1, were validated using western blot analysis. ARHGDIA expression was assayed in the brain samples of five infantile spasm patients. These proteins are involved in the cytoskeleton, synapses, energy metabolism, vascular regulation, signal transduction, and acetylation. The mechanism underlying the effects of ACTH involves the molecular events affected by these proteins, and protein acetylation is the mechanism of action of the drug treatment.     

基于小波变换的婴儿痉挛症脑干听觉诱发电位复杂性分析

采用多尺度小波变换计算脑干听觉诱发电位近似熵的方法,对比婴儿痉挛症患儿与正常幼儿的近似熵值,按照脑干听觉诱发电位成份波对应的解剖位置,分段、分尺度计算并统计近似熵值,从神经信息传递角度探讨阻碍婴儿痉挛症患儿智能发育的原因。采集12例正常儿童和13例婴儿痉挛症患儿的脑干听觉诱发电位,将它们进行60尺度小波分解,分段、分尺度计算各尺度近似熵值。发现婴儿痉挛症组患儿脑干听觉诱发电位中代表脑干活动的3~7ms段的分尺度近似熵明显高于正常组(P<0.01),小尺度上表现尤为显著。结果表明婴儿痉挛症患儿脑干传导通路不畅通,其中的随机成份增多,阻碍信息在脑干的传递,进而影响患儿大脑皮层的发育。     

Disruption of the serine/threonine kinase 9 gene causes severe X-linked infantile spasms and mental retardation

X-linked West syndrome, also called "X-linked infantile spasms" (ISSX), is characterized by early-onset generalized seizures, hypsarrhythmia, and mental retardation. Recently, we have shown that the majority of the X-linked families with infantile spasms carry mutations in the aristaless-related homeobox gene (ARX), which maps to the Xp21.3-p22.1 interval, and that the clinical picture in these patients can vary from mild mental retardation to severe ISSX with additional neurological abnormalities. Here, we report a study of two severely affected female patients with apparently de novo balanced X;autosome translocations, both disrupting the serine-threonine kinase 9 (STK9) gene, which maps distal to ARX in the Xp22.3 region. We show that STK9 is subject to X-inactivation in normal female somatic cells and is functionally absent in the two patients, because of preferential inactivation of the normal X. Disruption of the same gene in two unrelated patients who have identical phenotypes (consisting of early-onset severe infantile spasms, profound global developmental arrest, hypsarrhythmia, and severe mental retardation) strongly suggests that lack of functional STK9 protein causes severe ISSX and that STK9 is a second X-chromosomal locus for this disorder.     

Common ABCB1 polymorphisms associated with susceptibility to infantile spasms in the Chinese Han population

Infantile spasms are a severe epileptic encephalopathy with a variety of etiologies that occur in infancy and early childhood. Subjects with infantile spasms are at a higher risk for evolving into intractable epileptic spasms, tending to be refractory to conventional antiepileptic drugs. Genetic polymorphisms of the P-glycoprotein-encoding gene ABCB1 are suspected to be associated with pharmacoresistance phenotypes in epilepsy patients. Conflicting findings have been reported in different populations; few studies have explored whether this apparent association is affected by other host factors, such as specific epilepsy syndrome. We performed a case-control study to determine whether the risk of infantile spasms is influenced by common ABCB1 polymorphisms in a Han Chinese children's population consisting of 91 patients and 368 healthy individuals. DNA was isolated from whole blood, and three genetic polymorphisms (C1236T, G2677T/A, and C3435T) were assayed by PCR-RFLP. There were significant differences in the distributions of 3435TT [P = 0.001; odds ratio = 2.47; 95% confidence interval (CI) = 1.44-4.27] and 3435CT [P < 0.001; odds ratio = 0.28; 95% CI = 0.15-0.54] genotypes between infantile spasm cases and controls. No significant differences were observed in allelic and haplotypic frequencies of ABCB1 polymorphisms between the two groups. This study demonstrated that variations in the C3435T gene play an important role in the pathogenesis of infantile spasms in the Han Chinese population; 3435TT is associated with increased risk of having this epilepsy syndrome.     

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.     

Preclinical Screening for Treatments for Infantile Spasms in the Multiple Hit Rat Model of Infantile Spasms: An Update

Infantile spasms are the typical seizures of West syndrome, an infantile epileptic encephalopathy with poor outcomes. There is an increasing need to identify more effective and better tolerated treatments for infantile spasms. We have optimized the rat model of infantile spasms due to structural etiology, the multiple-hit rat model, for therapy discovery. Here, we test three compounds administered after spasms induction in the multiple hit model for efficacy and tolerability. Specifically, postnatal day 3 (PN3) male Sprague-Dawley rats were induced by right intracerebral injections of doxorubicin and lipopolysaccharide. On PN5 p-chlorophenylalanine was given intraperitoneally (i.p.). Daily monitoring of weights and developmental milestones was done and rats were intermittently video monitored. A blinded, randomized, vehicle-controlled study design was followed. The caspase 1 inhibitor VX-765 (50–200 mg/kg i.p.) and the GABA_B receptor inhibitor CGP35348 (12.5–100 mg/kg i.p.) each was administered in different cohorts as single intraperitoneal injections on PN4, using a dose- and time-response design with intermittent monitoring till PN5. 17β-estradiol (40 ng/g/day subcutaneously) was given daily between PN3-10 and intermittent monitoring was done till PN12. None of the treatments demonstrated acute or delayed effects on spasms, yet all were well tolerated. We discuss the implications for therapy discovery and challenges of replication trials.     

听觉诱发脑电小波分量的混沌研究——婴儿痉挛症认知功能障碍的机制探讨

通过对婴幼儿期难治性癫痫———婴儿痉挛症(infantile spasms, IS)听觉诱发脑电细貌混沌特性的研究,探讨与IS相伴的认知功能障碍的发生机制。研究方法是分别记录IS组及正常对照组对象的听觉诱发脑电,经Mexihat连续小波变换后,分别计算信号各尺度小波分量的相关维数。结果表明IS组与正常对照组的各小波分量相关维数的差别主要表现在小波的第3尺度分量上(频带范围是32~64 Hz,主要为γ频带范围),在这个尺度上正常组相关维数明显低于IS组(P<0.05)。相关维数的降低意味着大脑活动自由度的减少,表明大脑的各单元耦合加强。因为正常组脑干内信息传递通道完好,使得大脑各个单元之间的信息耦合较强; IS组则由于脑干功能的异常,存在神经信息传递障碍,进而影响到脑干及其与大脑各个局部之间的信息耦合。小波第3尺度处于较高频率范围(γ频带范围),而在大脑皮层上的基频信号与听觉调频信号经加工后所产生的神经信号正在这一频率范围,且这一信号与大脑高级认知功能密切相关。因此,IS患者γ频带细貌信号的相关维数高于正常值,能够解释IS认知功能发生障碍的原因。     

Chronic ACTH treatment: influence on 5-HT2 receptors and behavioral supersensitivity induced by 5,7-dihydroxytryptamine lesions

The capacity of the serotonin (5-HT) precursor 5-HIP to induce the ACTH-responsive myoclonic-convulsive disorder infantile spasms in patients with Down's syndrome has been cited as evidence for altered serotonergic neurotransmission in infantile spasms. Since there is no animal model of infantile spasms, the suitability of behavioral supersensitivity (myoclonus) evoked by 5-HTP in rats with 5,7-dihydroxytryptamine (DHT) lesions as a model was tested by determining the effect of chronic treatment with ACTH (40 IU/kg) on 5-HTP-evoked myoclonus. In rats treated with DHT as adults, ACTH administration did not alter the "serotonergic behaviors," such as myoclonus, induced by 30 mg/kg 5-hydroxytryptophan (5-HTP), but induced a small significant increase in Bmax of neocortical 5-HT2 sites of the DHT group, with no change in rats without lesions. In rats treated with DHT as neonates, there was also no significant difference in behaviors evoked by several doses of 5-HTP. These data suggest that ACTH minimally modifies the effects on 5-HT receptors of DHT lesions, but the intracisternal DHT model is not a suitable model for infantile spasms because chronic ACTH was not antimyoclonic.     

The effect of ACTH therapy on serum dehydroepiandrosterone, androstenedione, testosterone and 5 alpha-dihydrotestosterone in infants

Serum concentrations of dehydroepiandrosterone (DHEA), androstenedione, testosterone, 5 alpha-dihydrotestosterone and cortisol were measured in 10 infants (age 5-22 months) before, during and after 6-weeks of ACTH therapy for infantile spasms. During therapy, their mean DHEA concentrations increased 2.3-fold, androstenedione 12.3-fold, testosterone 2.7-fold, 5 alpha-dihydrotesterone 2.5-fold and cortisol 2.9-fold compared to pre-therapy values. Serum dehydroepiandrosterone sulphate (DHEA-S) concentrations were also increased during ACTH therapy above the normal prepubertal range. Three days after the cessation of ACTH treatment, all androgens had returned to the pre-therapy level. We conclude: At least in pharmacologic doses ACTH alone stimulates adrenal androgen secretion in infants, excluding the necessity of a separate adrenal androgen stimulating hormone.     

Intelligence and physical features of children of women with epilepsy

The teratogenicity of maternal epilepsy has been attributed to several factors, including the antiepileptic drugs taken to prevent seizures during pregnancy, the occurrence of seizures during pregnancy, and the factors in the mother that caused her to have epilepsy. We have addressed the hypothesis that the children of women who have a history of epilepsy (seizure history), but who took no antiepileptic drugs (AED) and had no tonic-clonic seizures in pregnancy, have an increased risk of malformations and diminished intelligence. The frequency of cognitive dysfunction was determined in 57 seizure history and 57 matched control children aged 6-l6 years. The masked evaluation of the children included a physical and neurologic examination and testing with the Wechsler Intelligence Scale for Children-Revised (WISC-R) and a systematic physical examination for the features of the fetal AED syndrome. The evaluation of both parents of each child included a test of reasoning (Ravens Progressive Matrix) and a physical examination. There were no differences between the two groups of children in either IQ scores or physical features; none of the seizure history children was judged to have the "anticonvulsant face" or digit hypoplasia. This study had 80% power to rule out a difference of seven or more IQ points between the two groups, based on a two-sided test at a 5% level of significance. Our confidence in concluding that there was no difference between seizure history and control infants was strengthened by the fact that no statistically significant differences were observed with respect to multiple outcomes, including eight related measures of intelligence. Thirty (53%) of the seizure history mothers resumed taking AED after the birth of the child we evaluated. Additional studies are needed to address the teratogenicity of the antiepileptic drugs as monotherapy.     

Anomalies in thyroid function in children with trisomy 21

Thyroid function of 60 children with Down (DS) aged 3 months to 16 years was studied by evaluation of serum concentration of ultra-sensitive thyroid stimulating hormone (TSH), free T4 and T3 (FT4, FT3), total T4 and T3 (T4 and T3) and reverse T3 (rT3). Each DS child was matched to a control of the same age. The concentration of TSH was increased in DS children while the concentration of rT3 of the DS children was significantly decreased compared to the controls as was the ratio rT3/TSH. These results showed that thyroid function of DS children is abnormal.     

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.     

Influence of ACTH on serum hormone content and its anticonvulsant action towards infantile spasms

Ten patients with infantile spasms were treated with ACTH, which resulted in a suppression of thyroxine through an increase of the serum cortisol level and suppression of pituitary TSH secretion. The thyroxine level in the excellent-response group was suppressed more than that in the other groups. There was a statistically significant difference (t-test, p < 0.01) in the suppression of T₄ between the excellent-response group and the others. Although the high cortisol level was essential for the clinical effectiveness of ACTH therapy and the suppression of the thyroid hormones, the therapeutic correlation with the elevated cortisol level might be weak as compared to that with the suppression of T₄. These findings suggest the possibility that the efficacy of ACTH therapy in infantile spasms may depend in part on the suppression of the thyroid hormone.     

Complicated relationship between autism with regression and epilepsy

We retrospectively evaluated a set of 205 children with autism and compared it to the partial sub-set of 71 (34.6%) children with a history of regression. From 71 children with regression, signs of epileptic processes were present in 43 (60.6%), 28 (65.12%) suffered clinical epileptic seizures, and 15 (34.9%) just had an epileptiform abnormality on the EEG. In our analysis, autistic regression is substantially more associated with epileptic process symptoms than in children with autism and no history of regression. More than 90% of children with a history of regression also show IQ < 70 and reduced functionality. Functionality and IQ further worsens with the occurrence of epileptic seizures (98% of children with regression and epilepsy have IQ < 70). We proved that low IQ and reduced functionality significantly correlate rather with epileptic seizures than just sub-clinical epileptiform abnormality on EEG. Clinical epileptic seizures associated with regression significantly influence the age of regression and its clinical type. The age of regression is higher compared to children with regression without epileptic seizures (in median: 35 months of age in patients with seizures while only 24 months in other patients). Patients with seizures revealed regression after 24th months of age in 68% of cases, while patients without seizures only in 27%. However, coincidence with epilepsy also increased the occurrence of regression before the 18th month of age (23% of patients), while only 4% of patients without epilepsy revealed regression before the 18th month. Epileptic seizures are significantly associated especially with behaviour regression rather than speech regression or regression in both behaviour and speech. Also epileptic seizures diagnosed before correct diagnosis of autism were significantly associated with delayed regression (both behavioural and speech regression).     

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.     

Relationship between bronchial hyperresponsiveness and impaired lung function after infantile asthma

Wheezing during infancy has been linked to early loss of pulmonary function. We prospectively investigated the relation between bronchial hyperresponsiveness (BHR) and progressive impairment of pulmonary function in a cohort of asthmatic infants followed until age 9 years. We studied 129 infants who had had at least three episodes of wheezing. Physical examinations, baseline lung function tests and methacholine challenge tests were scheduled at ages 16 months and 5, 7 and 9 years. Eighty-three children completed follow-up. Twenty-four (29%) infants had wheezing that persisted at 9 years of age. Clinical outcome at age 9 years was significantly predicted by symptoms at 5 years of age and by parental atopy. Specific airway resistance (sRaw) was altered in persistent wheezers as early as 5 years of age, and did not change thereafter. Ninety-five per cent of the children still responded to methacholine at the end of follow-up. The degree of BHR at 9 years was significantly related to current clinical status, baseline lung function, and parental atopy. BHR at 16 months and 5 years of age did not predict persistent wheezing between 5 and 9 years of age, or the final degree of BHR, but it did predict altered lung function. Wheezing that persists from infancy to 9 years of age is associated with BHR and to impaired lung function. BHR itself is predictive of impaired lung function in children, strongly pointing to early airway remodeling in infantile asthma.     

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.     

Ontogeny of absence-like and tonic seizures in the spontaneously epileptic rat

The ontogeny of epileptic seizures in spontaneously epileptic rats (SER; zi/zi, tm/tm) was studied by examining behaviour and electroencephalogram (EEG) simultaneously. Weight gain and survival time were also studied. Compared with the control Kyo:Wistar rats, SER showed a much smaller increase in body weight. All male and female SER died before 20 and 18 weeks of age, respectively. Body tremor was observed at 2 weeks of age but disappeared after 11 weeks. Staggering gait appeared after 7 weeks of age, and intensified with age. Absence-like seizures characterized by paroxysmal appearance of 5-7 Hz spike-wave-like complexes were observed in the cortical or hippocampal EEG after 5 weeks of age, and tonic seizures with low voltage fast waves were observed after 6 weeks of age. All SER exhibited both absence-like and tonic seizures with high frequencies from 12 weeks of age. Differences with other spontaneous rat models of epilepsy and application methods for estimating seizure-inhibitory effects of anti-epileptic drugs are discussed.     

13例SCN2A 基因突变相关儿童神经系统疾病表型分析

摘要 目的：总结并分析SCN2A基因突变引起的儿童神经系统疾病相关表型谱特点。方法：采用回顾性研究,收集2018年6月至2021年6月在上海交通大学医学院附属上海儿童医学中心神经内科诊治的患儿,并经二代基因测序检测,纳入SCN2A基因突变者,研究并总结患儿神经系统临床表型特点。结果：共纳入13例SCN2A突变患儿,包括新生突变9例和遗传性突变4例。其中11例患儿伴有癫痫发作,发作年龄为1日龄~1岁11月龄,4例在新生儿期起病 （36%）,1~3 月龄起病2例（18%）,4~12月龄起病2例（18%）,1岁后起病3例（27%）;发作类型中强直阵挛发作、痉挛发作、局灶性发作均各有4例（36%）,阵挛发作1例（9%）。另有2例无癫痫发作的患儿,1例表现为全面性发育迟缓,另一例表现为发育迟缓合并孤独症谱系疾病。11例癫痫患儿中,丛集性发作患儿10例。遗传性突变4例患儿中2例智力、运动发育正常;9例新生突变的患儿中8例伴有运动、智力发育落后,1例发育正常。11例癫痫患儿表型中良性家族性新生儿癫痫1例,新生儿惊厥2例,婴儿痉挛症2例,不能分类的早发性癫痫性脑病3例,儿童期起病的癫痫性脑病2例,热厥附加症1例。结论：SCN2A基因突变引起的儿童神经系统疾病以癫痫表现居多、癫痫表型谱广,少数表现为不伴癫痫发作的发育迟缓和孤独症谱系疾病。