甲基丙二酸血症诊治研究进展

甲基丙二酸血症是一种常见的有机酸血症,属于常染色体隐性遗传病,临床表现无特异性,以反复呕吐及嗜睡、惊厥等神经系统症状为主.诊断依靠串联质谱检测血中的酰基肉碱和气相色谱-质谱检测尿甲基丙二酸.对伴有同型半胱氨酸血症患儿,治疗以维生素B12、甜菜碱和左旋肉碱为主;对不伴有同型半胱氨酸血症患儿以限制天然蛋白质摄入,给予去除异亮氨酸、缬氨酸、甲硫氨酸和苏氨酸的特殊奶粉及左旋肉碱治疗为主.维生素B12治疗有效型预后较好,治疗无效型预后较差.     

新生儿甲基丙二酸血症及丙酸血症各2例

甲基丙二酸血症(methylmalonic academia,MMA)和丙酸血症(propionic acidemia,PA)是两种较少见的常染色体隐性遗传病。由于该类疾病较少见,缺乏特异性临床表现,且新生儿科医生对此病的认识不足,常难以在新生儿期明确诊断,以致延误治疗[1]。MMA及PA的临床表现均由于严重的代谢性酸中毒及异常代谢产物堆积的毒性作用所致[3],因此发病症状相似,偶有特殊表现的报道[4]。现报告吉林大学第一医院新生儿科2011—     

甲基丙二酸血症儿童尿液硫化氢的变化及意义

目的　探讨尿硫化氢（H2S）在甲基丙二酸血症（methylmalonic acidemia,MMA）患儿尿液中的变化及临床价值。方法　将2016年9月至2017年11月在北京大学第一医院就诊的20例MMA 患儿作为病例组（男13例,女7例）,同时将20例健康儿童作为对照组（男11例,女9例）,留取所有儿童新鲜尿液。采用自由基检测仪检测正常儿童与MMA 患儿尿液中的H2S浓度,对照病例组与对照组尿H2S浓度的差异,并对结果进行分析。结果　20例MMA患儿尿H2S浓度（64.9±52.0） μmmol/L高于对照组尿H2S 浓度（43.9±40.0） μmmol/L,差异具有统计学意义（Z＝-3.435,P＝0.001）;尿H2S浓度辅助判断MMA的ROC 曲线分析中曲线下面积（AUC）为0.818,以尿H2S浓度47.72 μmmol/L为界值,辅助判断MMA 的敏感度为95%,特异度为60%。结论　MMA 患儿尿液H2S含量高,尿H2S浓度检测有助于MMA的尽早诊断,或可作为新生儿筛查、MMA 患儿动态观察和疗效评估的参考指标。     

甲基丙二酸血症86例患儿的神经发育特征

目的分析甲基丙二酸血症患儿神经发育特征及可能影响因素。方法设计临床调查表,对2016年2月至2018年2月于河南中医药大学第一附属医院儿科就诊的86例甲基丙二酸血症患儿进行调查,采用Gesell发育量表进行神经发育评估。结果86例患儿中男45例,女41例;年龄2.4~62.5个月,中位数8.3个月。新生儿期筛查确诊的患儿33例,发病后临床诊断的患儿53例,患儿各能区多为轻到重度发育缺陷。其中,0~6月龄患儿28例,精细运动、大运动、适应性缺陷显著;>6~12月龄患儿24例,语言、适应性、个人-社交缺陷显著;>12~36月龄患儿23例,语言、适应性、大运动缺陷显著;>36~72月龄患儿11例,语言、个人-社交、适应性缺陷显著;新生儿筛查发现的患儿在精细运动、大运动、适应性、个人-社交和语言方面发育商均不同程度高于发病后临床诊断的患儿,差异均有统计学意义(均P<0.05)。结论虽经积极规范治疗,大多数发病后诊断的甲基丙二酸血症患儿仍存在神经发育障碍,各能区存在轻到重度发育缺陷。不同年龄段患儿神经发育能区损害稍有不同,6月龄以下的患儿精细运动、大运动、适应性发育缺陷显著,6月龄以上患儿语言、适应性、个人-社交缺陷显著。经新生儿筛查发现的患儿神经损害较轻。     

新生儿甲基丙二酸血症28例

目的对新生儿期发病的甲基丙二酸血症(MMA)患儿的临床特征进行分析,提高早期识别、早期诊断该病的能力。方法对2008年6月-2011年8月河南省15家省市级医院新生儿童症监护病房确诊的28例MMA患儿临床资料进行回顾性分析。男17例,女11例;足月儿27例,早产儿1例。结果新生儿期MMA多于出生1周内起病,起病越早,病情越重,预后越差,遗传家族史有助于疾病诊断。首发症状主要表现为呼吸急促及呼吸困难(9/28例)、反应差和拒乳(6/28例)、嗜睡(4/28例)、抽搐(3/28例)等。实验室检查异常主要为严重代谢性酸中毒(12/28例)、血糖增高(10/28例)、高氨血症(7/28例)等。结论新生儿期起病的MMA其临床表现无特异性,病情进展快,病死率高,预后极差。应加强对新生儿期起病MMA的早期识别能力。     

甲基丙二酸血症患儿正中神经体感诱发电位变化的意义

目的观察28例甲基丙二酸血症（MMA）患儿正中神经体感诱发电位（MN-SEP）特点,探讨MN-SEP在MMA患儿中的临床应用价值。方法对1999年1月-2007年5月临床确诊的28例MMA患儿进行MN-SEP检查。其中男21例,女7例;年龄5个月-12岁5个月。其尿液有机酸测定采用气相色谱/质谱联用分析（GC-MS）,MN-SEP检查应用尼高力肌电型诱发电位测试仪对MMA患儿进行检测。结果28例患儿尿液中甲基丙二酸水平明显升高。23例于婴儿期起病和2例于幼儿期发病的患儿临床表现以神经系统损害为主;1例学龄前期起病和2例学龄晚期起病的患儿智力、运动倒退突出。患儿均伴头颅影像学改变,头颅CT或MR I主要表现为脑沟增宽、脑室扩大脑室旁低密度灶。28例MMA患儿中24例MN-SEP异常（85.7%）,主要为2例（7.1%）N9潜伏期延长,14例（50%）N9-N13峰间期延长,19例（67.9%）N13-N20峰间期延长,1例（3.6%）N20波形消失。结论MMA患儿的MN-SEP异常发生率高,MN-SEP检测有助于发现MMA患儿的神经系统感觉传导功能异常。     

甲基丙二酸血症患儿血浆microRNA表达变化的初步研究

目的 筛选甲基丙二酸血症（MMA）患儿血浆中表达差异的microRNA（miRNA）,并检测miR-9-1 在MMA 患儿血浆中的表达变化,初步探讨miR-9-1 作为MMA 潜在的生物标记物的意义。方法 收集17 例MMA 患儿血浆样本,其中MMA 合并高同型半胱氨酸血症12 例（MMA+HHcy 组）、不伴高同型半胱氨酸血症的MMA 5 例（MMA 组）;另收集10 例非MMA 的高同型半胱氨酸血症（HHcy 组）和10 例健康对照者的血浆样本。采用miRNA 微阵列基因芯片法筛选具表达差异的miRNA,选择具有表达差异的miR-9-1 行RTPCR法检测血浆中miR-9-1 的表达。选择经维生素B12 治疗的MMA 患儿检测治疗后血浆miR-9-1 表达的变化。结果 miRNA 微阵列基因芯片共筛选出26 个具有表达差异的miRNA,其中下调2 倍以上的miRNA 16 个（包括miR-9-1）,上调2 倍以上的10 个。MMA+HHcy 组、MMA 组及HHcy 组 miR-9-1 的表达量较健康对照组均显著下调（P结论 miR-9-1 在MMA 患儿血浆中显著下调,维生素B12 治疗后显著上调,可作为监控MMA 病情变化的指标。     

抗癫药物的安全性及癫患儿的生活质量

抗癫(癎)药物的安全性对儿童十分重要,主要是指药物的不良反应、药物之间的相互作用以及药物可能加剧癫(癎)发作.癫(癎)患儿的生活质量评估包括健康的各个方面,反映疾病本身及其治疗对躯体、心理以及社会的作用.评估包括普适性量表和疾病特异性量表,建议通过二者综合来评估癫(癎)患儿的生活质量.     

甲基丙二酸血症1例

患儿,男,8个月,因竖头不稳就诊。系第1胎,第1产,足月,顺产,无窒息史,新生儿期安静,混合喂养,吸奶无力,喂养困难,哭声弱,父母非近亲婚配,母孕期体健。查体:体温37.3℃,脉搏128次/min,呼吸30次/min;无特殊面容,嗜睡状,面色苍白,全身无皮疹,浅表淋巴结无肿大,头围39 cm,囟门1 cm×     

儿童额叶癫癎的临床及脑电图特征

目的总结儿童额叶癫痫（FLE）的临床和脑电图（EEG）特征及预后,加强对于FLE的认识。方法收集本科2000～2006年治疗40例FLE患儿,进行临床资料回顾性分析。病例均行24hEEG和影像学检查。内容包括FLE病例的家族史、发作类型、先兆、伴随症状,EEG和影像学表现及治疗效果。比较各发作类型、EEG表现和药物疗效差异。结果癫痫发作表现为阵挛24例,强直4例,精神行为3例,侧转、失张力、呕吐各2例,视觉、感觉异常、头痛各1例。头颅影像学检查发现异常9例。有明确脑损伤史,病毒性脑炎病史各1例。均有发作期额叶样放电或者慢波表现。随访1～6年,其中用药后发作消失35例,3例发作减少,2例无效。一线抗癫痫药物效果比较无统计学差异。结论FLE发作表现为频繁、短暂和夜间多发。认识特征性的发作表现,可为FLE诊断提供线索,动态EEG检查对于FLE是必须检查手段;抗癫痫药物首选使用卡马西平。     

Evaluation and management of bone health in children with epilepsy on long-term antiepileptic drugs: United Kingdom survey of paediatric neurologists

Background and objective

Current evidence indicates long-term use of antiepileptic drugs (AEDs) is associated with impaired childhood bone health. The objective of this study was to ascertain the current clinical practice of paediatric neurologists managing children with epilepsy on long-term (>2 years) AED therapy, particularly against the UK Medicines and Healthcare products Regulatory Agency (MHRA) current recommendation of vitamin D supplementation in patients on long-term AEDs at-risk of impaired bone health.

Methods

An internet-based survey of UK paediatric neurologists who routinely see children with epilepsy (n = 95) covered clinicians’ epilepsy case-load and reflection on their current clinical practice with estimation of the frequency with which they considered various bone health issues. Responses were graded as ‘frequent’(≥50%), ‘sometimes’(25%–50%) and ‘infrequent’(<25%).

Results

Overall response rate was 72/95 (76%). 3% frequently recommend prophylactic calcium and vitamin D supplementation, 6% frequently perform bone screening investigations, 7% frequently give bone health advice and 10% frequently enquire about skeletal risk factors. Clinical practices were not associated with epilepsy caseload (p-values 0.44–1).84% infrequently performed bone health screening investigations. 54% of respondents indicated that, if performed, 100% would undertake bone profile, 64% 25(OH) Vitamin D, 18% PTH, 49% dual energy X-ray absorptiometry (DEXA) scan and 13% bone X-ray.

Conclusions

The majority of paediatric neurologists do not routinely consider bone health related issues in children on long-term AEDs. Greater emphasis should be placed on vitamin D supplementation in these children.     

Lacosamide in children with refractory status epilepticus. A multicenter Italian experience

ObjectiveStatus epilepticus (SE) is considered a life-threatening medical emergency. First-line treatment with antiepileptic drugs (AEDs) consists of intravenous benzodiazepines followed by phenytoin. SE is considered refractory (RSE) when unresponsive to standard doses of the first two AEDs. Scarce evidence is available to support specific guidelines for the management of RSE in either adults or children. This study aimed to assess the efficacy and tolerability of intravenous (iv) lacosamide (LCM) in children affected by RSE.MethodChildren with RSE who were treated with ivLCM were included in the study. Efficacy was defined as the cessation of seizures after administration of ivLCM, with no need for any further antiepileptic drug. All patients had been unsuccessfully treated following standard protocols before ivLCM was administered.ResultsEleven children entered the study (mean age: 9.4 years). Etiology was symptomatic in 7 patients (63%). RSE was convulsive (focal or generalized) in 6 patients and nonconvulsive in 5. The mean initial bolus dose of LCM was 8.6 mg/kg. The drug, which was used as a fourth or later option, was effective in stopping RSE in 45% of patients, with seizures terminating within 12 h in three children. No serious adverse events attributable to LCM were reported.ConclusionsLCM might be an effective and well-tolerated AED in children with RSE.     

Efficacy and safety of rufinamide in children under four years of age with drug-resistant epilepsies

BackgroundStudies on the efficacy and tolerability of rufinamide in infants and young children are scarce. Here we report on an open, retrospective, and pragmatic study about safety and efficacy of rufinamide in children aged less than four years, in terms of seizures types and epilepsy syndromes.MethodsForty children (mean age 39.5 months; range 22–48) were enrolled in the study. The mean follow-up period was 12.2 months (range 5–21). Rufinamide was initiated at a mean age of 26.7 months (range 12–42). Final rufinamide mean dosage was 31.5 mg/kg/day if associated with valproic acid and 44.2 mg/kg/day if not.ResultsThe highest seizure reduction rate was observed in the epileptic spasms (46%) and drop attacks (42%) groups. Seizure reduction was also observed in tonic seizures (35%) and in the focal seizure (30%) groups. In terms of epilepsy syndrome, rufinamide was effective in Lennox–Gastaut syndrome. Results were very poor for those affected by Dravet's syndrome. Globally, responder rate was 27.5%, including two (5%) patients seizure-free. Adverse reactions occurred in 37.5% of children and were mainly represented by vomiting, drowsiness, irritability, and anorexia. Discontinuation rate due to treatment-emergent adverse events was 15%.ConclusionThe present study concludes that rufinamide may be a safe and effective drug for a broad range of seizures and epilepsy syndromes in infants and young children and represents a valid therapeutic option in this population.     

Continuation rates of levetiracetam in children from the EULEVp cohort study

BackgroundSince indication extension to children data regarding the effectiveness of levetiracetam in paediatric patients remains limited.AimsInvestigate the real-life effectiveness of levetiracetam in paediatric patients.MethodsEpileptic children (<16 years) who had initiated levetiracetam between the 1 October 2006 and the 31 March 2007 were included and followed for 1 year by hospital or non-hospital neurologists practising in France.ResultsAmong the 156 identified children, 147 were analysed: 51.7% were female, and mean (SD) age was 9.2 years (4.2). Most patients had either partial symptomatic (30.6%) or partial cryptogenic (26.5%) epilepsy, 92.5% experienced seizures during the 6 months preceding levetiracetam initiation, and 19.2% were on levetiracetam alone at initiation. One-year levetiracetam continuation rate was estimated to be 72.0% (95%CI [63.8; 78.6]). Of the 104 children continuing levetiracetam treatment at end of study, 31.7% were seizure-free during the last six months of follow-up, and 23.1% on levetiracetam alone. Discontinuation of levetiracetam (n = 41) was mainly for insufficient efficacy (58.5% of those concerned).ConclusionsIn real-life clinical practice important treatment retention and non-negligible reduction of seizure frequency may be expected.     

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目的探讨合并癫疒间的脑性瘫痪患儿的临床特点及癫疒间治疗效果。方法总结1999年10月至2004年5月在西安交通大学第二医院住院的合并癫疒间的脑性瘫痪患儿的癫疒间发生率、临床类型、头颅计算机体层成像(CT)和(或)磁共振成像(MRI)、脑电图等方面的特点以及抗癫疒间治疗效果。结果139例脑性瘫痪患儿中有32例合并癫疒间,占23.0%(32/139);常见的癫疒间类型为强直阵挛发作12例(37.5%)和部分性发作6例(18.8%);25例(78.1%)癫疒间首发于1岁前;合并癫疒间脑性瘫痪儿童的头颅影像异常及脑电图异常分别占30例(93.8%)和27例(84.4%);常见的头颅影像异常为脑发育不良11例(36.7%)、脑积水6例(20.0%),余为脑萎缩、缺氧缺血性脑病样改变等13例(43.3%);脑电图异常中局灶性和弥漫性所占比例分别为48.2%(13/27)和51.8%(14/27);癫疒间多发生于痉挛性脑性瘫痪中(68.8%);81.3%(26/32)的癫疒间需要2种及2种以上的抗癫疒间药物治疗。结论脑性瘫痪患儿中癫疒间的发生率较高,其头颅影像学和脑电图分别以脑发育不良和弥漫性背景活动异常伴疒样波发放为主;脑性瘫痪儿童的癫疒大多为难治性,需要联合用药治疗。     

癫(癎)的免疫学研究进展

癫(癎)为临床常见综合征,近年来,关于癫(癎)的免疫学发病机制已逐渐被人们所认识,包括体液免疫和细胞免疫两个方面.体液免疫异常主要包括细胞因子、自身抗体及免疫球蛋白等的变化,细胞免疫异常则表现为淋巴细胞亚群、淋巴细胞增殖带及NK细胞等的变化.除外周血的异常,癫(癎)患者的脑脊液检查也可发现各项免疫指标的变化.抗癫癎药物...     

Efficacy of antiepileptic drugs in the era of pharmacogenomics: A focus on childhood

BackgroundIn recent years advances in the field of pharmacogenomics have expanded the concept for more individualized treatments. Our aim is to provide literature data about the relationship between genetic polymorphisms and efficacy of antiepileptic drugs in children.MethodsPubmed was used as the main medical database source. Only original research papers were considered. No year-of-publication restriction was placed. Quality of evidence was assessed according to American Academy of Neurology guidelines.ResultsA total of 12 cross-sectional and case–control studies fulfilled our selection criteria. ABCB1 gene was associated with drug responsiveness in 2 out of 6 studies and ABCC2 gene in 1 out of 1 studies. SCN1A gene was also associated with seizure control in 4 out of 5 studies. Cytochrome P450 genes were found to significantly affect drug responsiveness in 2 out of 4 studies, while polymorphisms of uridinediphosphateglucuronosyltransferaseUGT2B7 gene predisposed to drug-resistance in 1 out of 2 studies.ConclusionVariability in genes coding for sodium channels, drug transporters and cytochrome P450 enzymes can have a significant impact on response to antiepileptic drugs. Larger prospective studies with better stratification of samples are needed to shed light on these associations.     

Determinants of low bone mineral density in children with epilepsy

Introduction

Children with epilepsy on long-term antiepileptic drugs (AEDs) are at risk of low bone mineral density (BMD). The aims of our study were to evaluate the prevalence and determinants of low BMD among Malaysian children with epilepsy.

A new generation of anticonvulsants for the treatment of epilepsy in children

Over the past 12 years, a number of new anticonvulsant drugs have been introduced for the treatment of childhood epilepsy. The present article reviews these new agents and provides the considerations one should use in selecting an antiepileptic drug for use in children. While in some cases the newer antiepileptic drugs have a more favourable pharmacokinetic and toxicity profile than the older drugs, there appears to be no objective evidence that any currently available antiepileptic drug is superior in terms of therapeutic efficacy.