随访十年的脊髓小脑性共济失调3型一家系研究及伦理学分析

目的 探讨随访十年的脊髓小脑性共济失调3型(SCA3)一家系的临床特征、影像学特点和基因型及其所带来的医学伦理学问题。方法 描述一家系7例患者的临床表现,对部分患者行头颅核磁共振及基因检测,结合文献复习并分析该家系中患者的临床表现、遗传特征,且进行相关的伦理学分析。结果 一家系4代21名成员中共有7例发病,以步态不稳和言语不清为突出表现,头颅MRI示小脑萎缩,其中4例患者基因检测SCA3相关基因的CAG重复数分别为76、77、76、78次,1例症状前患者为77次。结论 SCA3为一组神经系统遗传性疾病,临床特征以小脑性共济失调和构音障碍为突出表现,具有高度异质性,CAG 重复序列数目的检测对于基因诊断和症状前诊断是一种十分有效的方法。临床要严格按照医学伦理规范进行严谨的遗传检测。长期随访促进家族成员进行基因筛查,有助于发现症状前患者及促进产前诊断和优生优育。     

脊髓小脑共济失调7型一个家系的临床和基因分析

目的总结脊髓小脑共济失调7型（SCA7）的临床表现，开展基因检测。方法对1个表现为视力下降、辨色力异常和行走不稳的家系完成家系调查及体格检查，部分成员行视网膜形态学及电生理检查；19名家系成员及12名健康对照者行SCA7突变基因PCR，测序仪直接检测三核苷酸胞嘧啶-腺嘌呤-鸟嘌呤（CAG）重复数目。结果6例成员存在小脑性共济失调、视力下降和辨色力异常，眼底示黄斑及视网膜周边色素异常，视网膜电图波形熄灭，震荡电位幅值和光闪视觉诱发电位振幅明显下降；正常等位基因CAG重复数目为8～25次，该6例异常等位基因CAG重复数目为50～97次，诊断为SCA7患者；1例无异常临床表现的成员CAG重复数目分别为18次和56次，后者超出正常范围，诊断为未到发病年龄的症状前患者。结论SCA7患者的临床表现具有异质性，CAG重复数目检测可以为基因诊断和症状前诊断提供依据。     

两遗传性脊髓小脑型共济失调7型家系的临床特征和基因突变研究

目的 探讨遗传性脊髓小脑型共济失调(SCA)7型(SCA7)的临床特征和基因突变.方法 采用聚合酶链反应(PCR)和琼脂糖凝胶电泳(AGE)等技术,检测临床诊断为SCA的5个家系26例患者和37例表型正常的家系成员的SCA7基因内CAG三核苷酸重复次数,对异常等位基因片段进行DNA测序,分析临床表现和基因突变的关系. 结果 2个SCA7家系患者的SCA7等位基因内CAG重复数目为44～50次;临床表现主要为共济失调、视力下降及视网膜色素变性.该家系内表型正常的家系成员SCA7等位基因CAG重复数目为10～30. 结论 CAG过度扩增为SCA7的致病原因,分子遗传学分析有助于SCA7的诊断.     

宁夏地区回、汉族脊髓小脑共济失调家系SCA3/MJD基因突变研究

目的通过对宁夏地区临床诊断为脊髓小脑共济失调的3个家系(2个汉族家系、1个回族家系)进行SCA3/MJD基因检测,探讨脊髓小脑共济失调的发病机制与临床特点,以为临床应用提供依据。方法对3家系受试者进行神经系统检查和系谱调查,部分行头部MRI和肌电图检查,以及SCA3/MJD基因胞嘧啶-腺嘌呤-鸟嘌呤(CAG)重复数目检测。结果3家系中共计8例脊髓小脑共济失调患者(汉族家系1中6例、汉族家系2中1例和回族家系中1例),符合常染色体显性遗传特点,以共济失调与构音障碍为主要表现,其次为眼外肌麻痹、眼球震颤、慢眼动、锥体束征等。其中汉族家系1和回族家系明确诊断为SCA3/MJD家系,两家系中7例患者(汉族家系1中6例、回族家系中1例)及2例临床表型正常亲属(两家系中各1例)检测出SCA3/MJD异常等位基因,其CAG重复数目为66～81次。汉族家系2中1例患者及汉族家系1中4例临床表型正常亲属SCA3/MJD基因CAG重复数目为20～33次。正常等位基因与异常等位基因CAG重复数目差异有统计学意义(t=5.309,P=0.000)。结论宁夏地区回、汉族脊髓小脑共济失调患者中存在SCA3/MJD基因型,基因检测分析有利于明确诊断脊髓小脑共济失调且能够检出症状前患者。     

脊髓小脑性共济失调12型一家系的临床特征和基因突变分析

目的研究1个遗传性共济失调12型(spinocerebellar ataxia type 12 SCA12)家系的临床特征与基因突变特点。方法应用聚合酶链反应、毛细管电泳等方法对1个临床诊断为遗传性共济失调的家系进行SCA基因检测。结果确定该家系为遗传性共济失调SCA12型家系。共确诊7例现证患者,患者异常CAG的重复次数为51⁵5次。结论上肢震颤,逐渐出现共济失调、延髓麻痹,病理征阳性为SCA12型相对独特的临床表现。先证者异常片段CAG重复为55次,第3代患者Ⅲ2 CAG重复次数54次,发病年龄提前,可能存在遗传早现现象。SCAs核苷酸突变扩展的数目与年龄呈负相关,与症状严重程度呈正相关的特点可能也存在于SCA12型中。     

脊髓小脑性共济失调一家系的基因诊断

目的 对1个常染色体显性遗传的脊髓小脑性共济失调(SCA)家系进行基因诊断.方法 采用PCR技术,对一汉族SCA家系(包括3例患者及3位无症状成员)及50名正常对照者的SCA1 ～3基因进行检测,通过琼脂糖凝胶电泳和产物直接测序法计数等位基因内CAG三核苷酸重复次数.结果 该家系中所有成员SCA1、SCA2基因CAG三核苷酸重复次数在正常范围;3例患者SCA3 CAG重复次数分别为67、68和66次,1位无症状成员为71次.结论 该家系为SCA3,基因检测诊断出1例症状前患者.     

遗传性脊髓小脑共济失调3型2家系临床特征分析

目的分析遗传性脊髓小脑共济失调3型(spinocerebellar ataxia type 3,SCA3)患者的临床资料,以提高临床医师对该病的认识,减少误诊。方法收集遗传性脊髓小脑共济失调3型2家系患者的临床特征、影像学检查及基因检测结果,对其进行总结,并进行相关文献复习。结果 2个家系中共发现14例SCA3患者,1例症状前患者。现存的6例患者均成年发病,其中1例以双下肢痉挛性疼痛起病,其他5例以行走不稳起病,均表现出不同程度的共济失调症状,4例伴言语含糊,3例伴吞咽困难,3例伴头晕,2例伴眼震。3例患者行头颅MRI检查,2例患者表现出了不同程度的脑干、小脑萎缩。2家族中共6人经过基因检测,其中包括4例患者,1例症状前患者,及1例正常受检者。4例患者的致病基因ATXN3基因三核苷酸(CAG)重复数目均大于50,1例症状前患者,其致病基因重复数分别为25和64。结论依据患者成年缓慢起病、家族遗传、共济失调的典型临床表现,结合影像学不同程度的脑干、小脑萎缩,可临床诊断遗传性脊髓小脑共济失调(spinocerebellar ataxias,SCA),经基因检测,CAG重复数目大于50,可确诊为SCA3;对于单纯表现为肌肉痉挛性疼痛,或虽有共济失调症状但影像学不支持者,当其有阳性家族史,也应考虑SCA3的诊断。     

脊髓小脑性共济失调6型的分子遗传学诊断及临床特点

目的 研究脊髓小脑性共济失调6型(SCA6)的基因诊断方法及临床特点。方法 对临床诊断为脊髓小脑性共济失调(SCA)的36个家系43例患者及38例散发患者，应用聚合酶链反应对SCA6基因含有CAG三核苷酸重复片段进行扩增，并对异常等位基因片段进行DNA测序，计算CAG重复次数；对2例SCA6患者临床资料进行分析。结果 正常人的SCA6等位基因CAG重复数目为10～13。本组检出家族性患者1例，散发患者1例，其异常等位基因内CAG重复数目分别为25、24。患者临床基本特征为缓慢进展的小脑性共济失调、眼震、构音障碍。结论 致病基因内CAG三核苷酸重复异常扩增是SCA6的确诊依据。SCA6的临床表现与其他SCA亚型无明显差别。     

遗传性脊髓小脑型共济失调7型一家系的临床及基因突变分析

目的研究中国人遗传性脊髓小脑型共济失调7型(SCA7)的基因突变和临床特征。方法应用聚合酶链反应(PCR)、聚丙烯酰胺凝胶电泳(PAGE)等技术对一个表现为共济失调、视力下降、视网膜变性的家系(6位成员,包括2个患者)的SCA7基因内CAG三核苷酸重复序列进行检测,并对异常等位基因片段进行DNA直接测序,分析基因型和表型之间的关系。结果检测出该家系内2个患者的SCA7等位基因CAG重复数目为71,而该家系内其他表型正常的SCA7等位基因CAG重复数目为7～9。结论CAG过度扩增为SCA7的致病原因,分子遗传学分析有助于SCA7的诊断以及症状前患者的预测。     

遗传性脊髓小脑型共济失调7型遗传学诊断及临床特征

目的研究中国人遗传性脊髓小脑型共济失调(SCA)7型(SCA7)的基冈突变和临床特征。方法应用聚合酶链反应(PCR)、聚丙烯酰胺凝胶电泳(PAGE)等技术对临床表现为SCA的92个家系112例患者和16例散发SCA患者的SCA7基因内CAG三核苷酸重复序列进行检测,对异常等位基因片段进行DNA测序,分析基因型和表型之间的关系,并与表型正常的家系成员和健康人对照。结果在1个SCA7家系的6位成员中检测出2例患者的SCA7等化基因内CAG重复数目为71;临床表现主要为共济失调、视力下降、黄蓝色盲及视网膜色素变性。该家系内表型正常的4位成员SCA7等位基因CAG重复数目为7～9,另126例临床表现为SCA的患者、71名表型正常的家系成员及60名健康对照者SCA7等位基因内CAG三核甘三酸重复数为6—21。结论CAG过度扩增为SCA7的致病原因,分子遗传学分析有助于SCA7的诊断;视网膜色素变性为SCA7的重要特征。     

Epilepsy and anomalies of neuronal migration: MRI and clinical aspects

Neuronal migration disorders are the result of disturbed brain development. In such disorders, neurons are abnormally located. In diagnosing these conditions, magnetic resonance imaging is superior to any other imaging technique. This enables us to improve our knowledge of the clinical correlates of neuronal migration. With reference to migrational disorder, a retrospective study of all 303 patients with epileptic seizures referred for magnetic resonance imaging during a 3-year period was performed, 13 patients (aged 12-41, mean age 27) were identified. They represent 4.3% of the entire study group. Of the patients with known epilepsy, 6.7% and of the mentally retarded, 13.7% had migrational disorders. Four patients had schizencephaly as the dominant finding, one was classified as hemimegalencephaly, 2 had isolated heterotopias, and 6 had localized pachy- and/or poly-microgyria. The clinical pictures are complex. Ectopias of grey matter are recognised foci of epilepsy, but from an epileptological and a clinical viewpoint little attention has been given to these disorders. The present study shows that malmigration is not rare in epilepsy patients, especially not in the mentally retarded.     

Classification of methods in transcranial Electrical Stimulation (tES) and evolving strategy from historical approaches to contemporary innovations

Transcranial Electrical Stimulation (tES) encompasses all methods of non-invasive current application to the brain used in research and clinical practice. We present the first comprehensive and technical review, explaining the evolution of tES in both terminology and dosage over the past 100 years of research to present day. Current transcranial Pulsed Current Stimulation (tPCS) approaches such as Cranial Electrotherapy Stimulation (CES) descended from Electrosleep (ES) through Cranial Electro-stimulation Therapy (CET), Transcerebral Electrotherapy (TCET), and NeuroElectric Therapy (NET) while others like Transcutaneous Cranial Electrical Stimulation (TCES) descended from Electroanesthesia (EA) through Limoge, and Interferential Stimulation. Prior to a contemporary resurgence in interest, variations of transcranial Direct Current Stimulation were explored intermittently, including Polarizing current, Galvanic Vestibular Stimulation (GVS), and Transcranial Micropolarization. The development of these approaches alongside Electroconvulsive Therapy (ECT) and pharmacological developments are considered. Both the roots and unique features of contemporary approaches such as transcranial Alternating Current Stimulation (tACS) and transcranial Random Noise Stimulation (tRNS) are discussed. Trends and incremental developments in electrode montage and waveform spanning decades are presented leading to the present day. Commercial devices, seminal conferences, and regulatory decisions are noted. We conclude with six rules on how increasing medical and technological sophistication may now be leveraged for broader success and adoption of tES.     

Hepatic Considerations in the Use of Antiepileptic Drugs

Summary: Virtually all of the major antiepileptic drugs (AEDs) can cause hepatotoxicity, although fatal hepatic reactions are rare. The mechanisms, incidences, and risk profiles for such reactions differ from drug to drug. With carbamazepine and phenytoin, hepatotoxicity may be due to drug hypersensitivity. Although the profiles of patients at risk have not been well-defined for these two antiepileptic drugs, it would appear from reports in the literature that older adolescents and adults are at higher risk than children of developing serious or fatal hepatotoxicity. Once hepatotoxicity develops, mortality rates are 10–38% with phenytoin and 25% for carbamazepine. The risk profile for valproate fatal hepatotoxicity has been more clearly defined. Those at primary risk of fatal hepatic dysfunction are children under the age of 2 years who are receiving multiple anticonvulsants and also have significant medical problems in addition to severe epilepsy. The risk is considerably lower for patients over the age of 2 years on valproate monotherapy. In contrast to the risk profile with other AEDs, adults receiving valproate as monotherapy have the lowest risk of hepatotoxicity. Fatal hepatic dysfunction coincident with valproate may be the result of aberrant drug metabolism. Concomitant use of AEDs that induce microsomal P450 enzymes (e.g., phenytoin and phenobarbital) may enhance the production of a toxic metabolite, and hence the greater risk of hepatotoxicity with polypharmacy.     

Vascular Malformations and Epilepsy: Clinical Considerations and Basic Mechanisms

Summary: Vascular malformations (VMs) are associated with epilepsy. The natural history of the various VMs, clinical presentation, and tendency to provoke epilepsy determine treatment strategies. Investigations have probed the mechanisms of epileptogenesis associated with these lesions. Electrophysiologic changes are associated with epileptogenic cortex adjacent to VMs. Putative pathophysiologic mechanisms of epileptogenesis include neuronal cell loss, glial proliferation and abnormal glial physiology, altered neurotransmitter levels, free radical formation, and aberrant second messenger physiology.     

Neonatal Seizures: Problems in Diagnosis and Classification

Summary: The clinical identification of neonatal seizures is critical for the recognition of brain dysfunction; however, diagnosis is often difficult because of the poorly organized and varied nature of these behaviors. Current classification systems are limited in their ability to communicate motor, autonomic, and electroencephalo-graphic features of seizures precisely and to provide a basis for uniform effective diagnosis, therapy, and determination of prognosis. Recent investigations of neonates, utilizing bedside electroencephalographic/polygraphic/ video monitoring techniques, have provided the basis for improved diagnosis and classification of seizures in the newborn. These studies have demonstrated that not all clinical phenomena currently considered to be seizures require electrocortical epileptiform activity for their initiation or elaboration. In addition, the specific clinical character of the phenomena considered to be seizures, the clinical state of the infant, and the character of the EEG indicate the probable pathophysiological mechanisms involved and suggest probable etiologies, prognosis, and therapy. Similarities between animal models that demonstrate reflex physiology and neonates with motor automatisms and tonic posturing suggest that these clinical behaviors may not be epileptic in origin but, rather, primitive movements of progression and posture mediated by brainstem mechanisms. Although not all clinical behaviors currently considered to be neonatal seizures may have similar pathophysiological mechanisms, they are clinically significant because they all indicate brain dysfunction.     

Valproate Monotherapy in the Management of Generalized and Partial Seizures

Summary: For decades, therapeutic tradition has promoted the concept of polypharmacy in the management of epilepsy. In recent years, however, studies have shown that, for most patients, monotherapy can provide comparable or better seizure control than administration of multiple anticonvulsants, while diminishing the potential for adverse reactions, drug interactions, and poor compliance. Valproate is an important monotherapeutic agent that is highly effective in the control of idiopathic primary and secondarily generalized epilepsies, and partial seizures that do not generalize. Comparative studies have found that valproate is at least as effective as phenytoin and carbamazepine in the treatment of generalized and partial seizures. Given the similar efficacy, other factors such as pharmacokinetics and side effects may therefore determine anticonvulsant selection for monotherapy.     

Un nouveau cadre conceptuel de travail pour la psychiatrie

In an attempt to place psychiatric thinking and the training of future psychiatrists more centrally into the context of modern biology, the author outlines the beginnings of a new intellectual framework for psychiatry that derives from current biological thinking about the relationship of mind to brain. The purpose of this framework is twofold. First, it is designed to emphasize that the professional requirements for future psychiatrists will demand a greater knowledge of the structure and functioning of the brain than is currently available in most training programs. Second, it is designed to illustrate that the unique domain which psychiatry occupies within academic medicine, the analysis of the interaction between social and biological determinants of behavior, can best be studied by also having a full understanding of the biological components of behavior.     

Carbamazepine Efficacy and Utilization in Children

Summary: Carbamazepine is effective for preventing partial and generalized tonic-clonic seizures in children. Although absence epilepsies are more common in children than adults, an estimated 80% of children with epilepsy have seizure types or epilepsies that are potentially responsive to carbamazepine. The differential diagnosis of ictal staring is an especially important issue in children because absence and atypical absence seizures are more prevalent in children than adults. Age-related pharmacokinetic differences and drug interactions are major considerations in children. On average, children have higher clearance rates of carbamazepine, shorter half-lives, and higher ratios of carbamazepine-10, 11-epoxide to carbamazepine than adults. In addition, children with severe epilepsy are more likely to require multiple-drug therapy, which can lead to complex drug interactions. When carbamazepine is administered along with valproate, drug protein binding interactions can cause intermittent side effects.     

Special Pharmacokinetic Considerations in Children

Summary: Pediatric patients have greater degrees of pharmacokinetic variability and unpredictability than adults. This variability results from the effects of pharmacogenetics, age and growth, prior and current comedication, and disease. Newborns with seizures have the least predictable dosage requirements, and their needs change as drug-eliminating mechanisms mature in the neonatal period. Infants have the highest relative capacities to eliminate antiepileptics of any age group and require the largest relative doses. In addition to age-related trends, children demonstrate the same drug-specific, pharmacokinetic phenomena that adults do, including nonlinear phenytoin elimination, nonlinear valproate binding, and autoinduction of carbamazepine. Intercurrent illness and drug interactions further modify the age-related pharmacokinetic patterns in children and make dosage requirements even more unpredictable. Recent studies have shown that febrile illness can affect drug elimination, sometimes decreasing drug levels by 50% or more. Intermittent treatment with benzodiazepines administered either orally or rectally can be an important adjunct and help minimize this type of problem for children with marginally controlled epilepsy. Intermittent benzodiazepines are also helpful for children who have febrile seizures and who need only occasional antiepileptic protection.