视神经脊髓炎谱系疾病缓解期修饰治疗的研究进展

<正>视神经脊髓炎谱系疾病(neuromyelitis optica spectrum disorders,NMOSD)是以视神经、脊髓和脑的中央结构炎性脱髓鞘为特征的中枢神经统免疫性疾病,本病目前已被公认为是一类独立的自身抗体(水通道蛋白4抗体)介导的自身免疫性疾病,其分为NMO-Ig G阳性组及NMO-Ig G阴性组~([1-5])。NMOSD在西方国家发病率约为1/10万~([6]),而在亚     

视神经脊髓炎研究发展史

19世纪中叶对视神经脊髓炎的认识是双侧同时发病的视神经炎和脊髓炎,而后续研究则发现两侧视神经炎呈先后发病,一般相隔数周、数月甚至数年。自2004年水通道蛋白4抗体被发现以来,"视神经脊髓炎"的概念遇到挑战并被修改。因此,2007年提出"视神经脊髓炎谱系疾病"的概念,并由此产生一系列不同命名,包括视神经脊髓型多发性硬化、视神经脊髓炎谱系疾病、视神经脊髓炎疾病谱系、视神经脊髓炎谱系、视神经脊髓炎扩展谱系等。笔者拟通过对不同时期"视神经脊髓炎"概念的回顾,对19~21世纪有关视神经脊髓炎研究的历史沿革进行全面复习,前瞻未来研究方向。     

视神经脊髓炎谱系疾病全身表现分析及其机制探讨

目的研究视神经脊髓炎谱系疾病合并中枢神经系统以外受累脏器或组织的免疫学改变。方法回顾分析56例视神经脊髓炎谱系疾病患者(视神经脊髓炎33例、非视神经脊髓炎23例)临床资料,逐一记录是否合并其他自身免疫性疾病,并行血清免疫学检测。结果视神经脊髓炎患者伴桥本甲状腺炎2例,以及系统性红斑狼疮和干燥综合征、哮喘、甲状腺功能亢进、风湿性关节炎和虹膜睫状体炎各1例。血清免疫学指标异常检出率较高者分别为甲状腺功能异常(10/17例)、抗核抗体阳性(14/28例)和补体C3阳性(8/19例),2例于分娩后发病。结论视神经脊髓炎谱系疾病患者可合并多种自身免疫性疾病,同时存在多种自身抗体,可能与视神经脊髓炎谱系疾病的发病有关。此外,妊娠期或分娩可能加重患者病情。     

视神经脊髓炎谱系疾病神经眼科表现

视神经脊髓炎谱系疾病包括经典视神经脊髓炎、视神经脊髓型多发性硬化、视神经脊髓炎限定型,以及伴系统性自身免疫性疾病或视神经脊髓炎特征性影像学表现的孤立性视神经炎或脊髓炎。其特征性神经眼科表现包括双侧同时或相继发生的视神经炎、视盘水肿和盘周渗出,视功能恢复差,对糖皮质激素有较好的反应性和依赖性。这些临床特征与水通道蛋白4抗体检测和头部MRI检查相结合,可为视神经脊髓炎谱系疾病与多发性硬化的早期鉴别诊断提供帮助。视神经脊髓炎谱系疾病可能出现某些特征性眼球运动异常,尚待进一步研究。     

视神经脊髓炎谱系疾病临床和影像学特点及自身抗体分析

目的初步总结视神经脊髓炎谱系疾病患者临床和影像学特点,回顾分析其血清和脑脊液自身抗体表达变化,为临床选择合理诊断方法提供参考。方法与结果共10例视神经脊髓炎谱系疾病患者,头部或脊髓MRI检查显示病灶分别位于脑干(3例)、颈髓(3例)、胸髓(6例)或颈胸髓(1例)。其中血清NMO-IgG阳性3/8例、抗核抗体阳性1/3例、甲状腺球蛋白和甲状腺过氧化物酶抗体阳性2/3例、甲状腺功能减退2例和甲状腺功能亢进1例、同型半胱氨酸升高2例。结论视神经脊髓炎谱系疾病好发于青壮年,女性多见,对高度怀疑视神经脊髓炎谱系疾病的患者应行血清和脑脊液自身抗体,以及头部和脊髓MRI检查,为明确诊断和合理治疗提供临床依据。缓解期对自身抗体阳性病例进行实验室指标复查,能够明确自身抗体与视神经脊髓炎谱系疾病之间的关系。     

视神经脊髓炎的发病机制

视神经脊髓炎免疫球蛋白G(NMO-Ig G)作用于水通道蛋白-4(AQP4),使AQP4含量减少并产生抗AQP4抗体。透过受损的血脑屏障,使NMO-Ig G进入中枢神经系统内,抗AQP4抗体损害了AQP4和Na+-依赖兴奋性氨基酸转运体复合物,引起谷氨酸兴奋性毒性和血脑屏障破坏。抗AQP4抗体通过细胞免疫毒性和补体依赖性细胞毒性、化学因素(过敏毒素如C3a、C5a)引起星形细胞损害。所有机制综合性损害血脑屏障,增加抗体,各种细胞(淋巴细胞和粒细胞)侵入中枢神经系统,造成视神经脊髓炎。     

视神经脊髓炎谱系疾病免疫靶向药物治疗研究进展

视神经脊髓炎谱系疾病是一种抗体介导的获得性自身免疫性疾病。近年,多种免疫靶向药物被批准用于治疗视神经脊髓炎谱系疾病。因为疗效确切,靶向性特异性免疫治疗极大的改变了视神经脊髓炎谱系疾病患者的预后。本文将从靶点、疗效、不良反应等方面综述靶向性特异性免疫治疗进展。     

视神经脊髓炎谱系疾病患者妊娠相关问题的研究进展

视神经脊髓炎谱系疾病是一种中枢神经系统自身免疫性脱髓鞘性疾病,一般认为是体液免疫性疾病。血液循环中针对水通道蛋白4的自身抗体(AQP4-IgG)是其重要的生物标记物。妊娠期女性体内激素的变化对体液免疫产生较大影响,成为该病的好发人群。因此,对女性视神经脊髓炎谱系疾病患者妊娠期间及妊娠前后的一段时期应给予高度重视。本文就妊娠与视神经脊髓炎谱系疾病的相互影响与可能机制,以及女性视神经脊髓炎谱系疾病患者妊娠时机的选择和妊娠期间药物的选择作一综述。     

中国人视神经脊髓炎的临床特征和诊断分析

目的 观察中国人视神经脊髓炎的起病情况及临床特点,提高对该病的认识。方法 回顾性分析2012-01—2016-09河南省人民医院收治的56例视神经脊髓炎患者发病情况及临床表现、治疗结果,包括性别、年龄、诱因、疾病特征及实验室和影像学检查。结果 52例患者确诊为视神经脊髓炎,4例高度怀疑视神经脊髓炎;单次发病者24例,二次复发者14例,三次以上者18例;20例患者首发症状为眼部视神经炎,7例首发症状为四肢感觉或肌力异常,5例首发症状是呕吐或发热,剩余病例两者或三者同时出现。男女发病比例为11:45,年龄20~30岁者居多。具有眼部症状的患者中,双眼累及与单眼累及的比例为36:14;磁共振检查发现12例头颅异常改变,40例视神经异常改变,46例脊髓异常改变;实验室血清免疫指标异常者18例,NMO-Ig G阳性者16例;我院首诊患者中视觉诱发电位检查异常35例,磁共振检查阳性26例。结论 视神经脊髓炎多见于女性,高发年龄为20~30岁,最常见的首发症状是双眼视神经炎,同时伴有脊髓病理体征,随病程进展绝大部分可符合视神经脊髓炎的诊断,视觉诱发电位较眼眶MRI具有更高敏感性,NMO-Ig G阳性对其诊断及预后均有重要意义。     

对视神经脊髓炎谱系疾病国际诊断标准和中国指南的综合理解

正2015-07由国际视神经脊髓炎诊断小组(IPND)公布了《视神经脊髓炎谱系疾病诊断标准的国际共识》(简称"国际标准")~([1]),2016-05中国免疫学会神经免疫学分会等公布了《中国视神经脊髓炎谱系疾病诊断与治疗指南》(简称"中国指南")~([2])。尽管仍有一些免疫介导的中枢神经系统(CNS)炎性脱髓鞘疾病既不能满足国际标准和中国指南,也不能诊断为其他疾病,需要密切结合临     

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.     

Diagnostic Difficulties and Treatment Implications

Summary: Differentiation between types of epileptic seizures has been aided in recent years by the introduction of intensive neurodiagnostic techniques and the development of increasingly detailed classification systems. Paradoxically, these developments have not simplified the task of matching the appropriate antiepileptic drug to a particular seizure type. It is reasonable to assume that anticonvulsant drugs will have different effects on different types of seizures, but faulty, circular reasoning can enter the picture if one also assumes that responses of seizures to different drugs signify different seizure types. There are several examples of differential diagnoses that can fall prey to this problem, including the diagnosis between partial seizures with secondary generalization and generalized tonic-clonic seizures, and the diagnosis between complex partial seizures and absence seizures with automatisms, among others. Considerations of etiology in future classification systems can further complicate the problem: should one then choose an anticonvulsant drug on the basis of individual seizure type or on the basis of the type of epilepsy? Ramifications of this issue extend even to the drug approval process. Official sanction is not given for use of a drug for a seizure type not included in the original efficacy studies, even if later scientific evidence shows that seizure type to be related to a type that is included. New trials must be undertaken. These problems arise from how we choose to classify seizures.     

Cognitive Dysfunction Associated with Antiepileptic Drug Therapy

Summary: Epilepsy is frequently associated with cognitive dysfunction. However, the reasons for this correlation are unclear. Possible influential factors include patient age; duration, frequency, etiology, and type of seizures; hereditary factors; psychosocial issues; and antiepileptic drug (AED) therapy. Whereas many of these factors are beyond the physician's control, AED therapy is one element that can be addressed in treatment decisions by recognizing the potential cognitive effects of particular AEDs. For example, phenobarbital impairs memory and concentration; phenytoin affects attention, problem solving ability, and performance of visuomotor tasks. In contrast, carbamazepine may affect concentration, while valproate would appear to have minimal effects on cognition. Moreover, cognitive effects of AEDs are amplified with coadministration of multiple anticonvulsants (polytherapy). A review of studies on the cognitive effects of monotherapy with AEDs, as opposed to those of polytherapy, provides evidence that drug-related cognitive dysfunction can be reversed if patients are switched to a simpler therapeutic regimen. Future research should be directed toward developing reliable measures for assessing and monitoring cognition, and understanding the particular cognitive side effects of each AED. Physicians also need to revise their opinions about which side effects are "tolerable" for epileptic patients.     

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.     

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.     

Carbamazepine Efficacy in Adults With Partial and Generalized Tonic-Clonic Seizures

Summary: Carbamazepine and phenytoin are drugs of choice in initial monotherapy for adult partial and secondarily generalized tonic-clonic seizures. These designations reflect the results of the Veterans Administration Epilepsy Cooperative Study Group of 1985. An earlier comparative study of carbamazepine and phenytoin by Ramsay and associates found both drugs equally effective in controlling new-onset seizures. Among the advantages of carbamazepine is that it causes relatively few cognitive and dysmorphic side effects. Its disadvantages are its unavailability in parenteral formulation and its metabolic autoinduction. The latter must be compensated for by planned dosage increases to maintain therapeutic plasma steady-state levels during the first 2 or 3 months of treatment. Carbamazepine is judged a drug of choice in the treatment of these secondarily generalized tonic-clonic seizures, and the drug of choice in children, adolescents, and women susceptible to the dysmorphic side effects associated with other anticonvulsant agents.     

Etiologic and Preventive Aspects of Epilepsy in the Child–Bridging the Gap Between Laboratory and Clinic

Summary: Four broad categories of basic phenomena are pertinent to developing ways to prevent epilepsy. These include mechanisms of epileptogenesis, ictal initiation and temporary entrainment by the seizure discharge of normally functioning brain, seizure propagation, and control mechanisms that function both to restrain the cascade of epileptic events culminating in a seizure and to arrest the epileptic event and restore the interictal state. In newborns and children, hypoxia-ischemia is a major factor leading to epileptogenesis, and several schemes are proposed to classify, quantify, and prevent hypoxic-ischemic encephalopathy. Control mechanisms must be better understood in order to develop prophylactic recommendations for epilepsy, and an experimental model of "kindling antagonism" may increase our understanding of these. Programs of prevention of seizures in children will evolve only if basic researchers and clinicians work productively together to develop an adequate understanding of factors important in epileptogenesis and antiepileptogenic control mechanisms.     

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.     

Predisposing and Causative Factors in Childhood Epilepsy

Summary: We review information from large studies of defined populations, examining the role of known factors and especially of prenatal and perinatal factors in contributing to nonfebrile seizure disorders of early childhood. We depend especially, but not exclusively, on the recently completed analyses from the Collaborative Perinatal Project of the National Institute of Neurological and Communicative Disorders and Stroke, the NCPP. About 4% of children in the NCPP who had at least one non-febrile nonsymptomatic seizure by the age of 7 years had a previous seizure during acute neurologic illness, such as meningitis or during the acute illness after trauma. Many such seizures should potentially be preventable. Of children with seizures, 10% had had a neonatal seizure and 13% had had a febrile seizure. Among the hundreds of prenatal and perinatal factors explored as predictors of childhood seizure disorders, the principal predictors identified were congenital malformations of the fetus, cerebral and noncerebral; family history of certain neurologic disorders; and neonatal seizures. In agreement with the British National Child Development Study, labor and delivery factors in the NCPP appeared to contribute very little to childhood seizure disorders. Maldevelopment, rather than damage at birth to an initially intact nervous system, appeared to be the more common mechanism. Most seizure disorders of early childhood remained unexplained by the large set of prenatal and perinatal characteristics examined.