难治性癫痫中谷氨酸脱羧酶抗体的测定

目的　研究难治性癫痫与血清谷氨酸脱羧酶抗体 (GAD-A)水平的关系 ,探讨难治性癫痫的发病机制。方法　应用酶联免疫吸附法 (EL ISA)测定了 3 0例难治性癫痫和 3 0例完全缓解的癫痫患者血清 GAD-A水平。结果　难治性癫痫患者和完全缓解癫痫患者血清 GAD-A水平无显著性差异 (P>0 .0 5) ,并且 ,各种类型癫痫患者其 GAD-A亦无明显差异 (P>0 .0 5)。结论　 GAD-A与难治性癫痫无明确的相关性 ,需要进一步扩大规模研究难治性癫痫中的谷氨酸脱羧酶抗体的变化     

Clinical significance of glutamic acid decarboxylase antibodies in patients with epilepsy

Purpose: Glutamic acid decarboxylase antibodies (GADAs) have been detected in patients with epilepsy, but the clinical determinants of epilepsy associated with GADA have not been defined. Methods: We analyzed GADA with a radioimmunoassay in sera of 253 well‐characterized patients with epilepsy and 200 control subjects. The positive samples were confirmed by immunohistochemistry and western blotting (WB). Sera were screened for other autoantibodies. Results: GADA were detected in 15 patients (5.9%) and in three control subjects (1.5%) (p = 0.026). Seven patients (2.8%) had high GADA titers [≥1,000 relative units (RUs)/ml], six of whom had temporal lobe epilepsy (TLE). All three GADA‐positive control subjects had low titers. Two of the five patients with high GADA titers and available cerebrospinal fluid (CSF) samples had intrathecal synthesis (IS) of GADA; one patient had CSF oligoclonal bands. The prevalence of increased levels of GADA tended to be higher in patients with TLE than in patients with extra‐TLE [odds ratio (OR) 1.32, 95% confidence interval (CI) 0.39–4.42; p = 0.657]. The patients with high GADA titers had significantly higher number of other autoantibodies compared to the patients with low GADA titers (p = 0.001) and the patients with normal GADA (p < 0.001). Discussion: High GADA titers were present in a subgroup of patients; close to 90% had TLE. The immunologic profile of these patients suggests that the most probable origin of their epilepsy is autoimmune. A positive IS of GADA may be a marker of an ongoing immune response that could identify those patients in whom a trial with immunosuppressive therapy might be warranted.     

不同抗癫痫药物对新诊断癫痫患者一年保留率的回顾性研究

目的 比较几种一线抗癫痫药物单一治疗对新诊断癫痫患者的保留率.方法 我们利用门诊随访的方式,对284名新诊断癫痫患者首次使用单一抗癫痫药物治疗进行回顾性研究,采用多样本率的卡方分割法,对单一抗癫痫药的一年保留率进行分析.结果 最常见的一线抗癫痫药为丙戊酸钠(70例,24.6%),拉莫三嗪(59例,20.7%),卡马西平(56例,19.7%),奥卡西平(48例,16.9%),托吡酯(35例,12.3%).一年保留率依次为拉莫三嗪(93.2%),奥卡西平(72.9%),托吡酯(65.7%),卡马西平(62.5%),丙戊酸钠(65.7%).拉莫三嗪的一年保留率,与奥卡西平相比较,无统计学差异(P=0.08),与卡马西平(P=0.00089)、丙戊酸钠(P=0.00027)和托吡酯(P=0.018)相比,具有统计学差异.其他药物之间无明显统计学差异(P=0.315).结论 拉莫三嗪治疗新诊断癫痫患者的一年保留率最高.深入研究新诊断癫痫患者的首次抗癫痫药物保留率,将对我国癫痫患者的临床治疗提供更详细、准确的指导.     

新型和传统抗癫痫药治疗新诊断癫痫患者的评价

目的评价新型和传统抗癫痫药(AEDs)单药治疗新诊断癫痫患者的疗效及安全性。方法前瞻性收集143例新诊断癫痫患者,分为卡马西平(CBZ)、丙戊酸钠(VPA)、托吡酯(TPM)和拉莫三嗪(LTG)治疗组,其中CBZ用于癫痫部分性发作,VPA用于癫痫全面性发作,而TPM和LTG用于各种类型癫痫发作,至少观察1年。采用生存分析Kaplan-Meier法比较治疗后癫痫初次发作时间、治疗失败时间,同时比较各组患者达"6月、1年无发作"比例和药物不良反应。结果 4组AEDs单药治疗后至癫痫初次发作时间、治疗失败时间的差异均无统计学意义(P0.05);CBZ、VPA、TPM和LTG组"6月无发作"率分别为80%、78%、87.9%、63.3%(均P0.05);"1年无发作"率分别为70%、66%、66.7%、50%(均P0.05)。TPM组不良反应率为63.3%,高于CBZ组(20%)、VPA组(24%)(均P0.01),而LTG组不良反应率为16.7%,与CBZ、VPA组相当(均P0.05)。结论从疗效和安全性综合考虑,新型AEDs治疗癫痫并不优于传统AEDs,其中TPM轻、中度不良反应还明显高于传统AEDs。     

Autoantibodies to glutamic acid decarboxylase in patients with epilepsy are associated with low cortical GABA levels

Antibodies to glutamic acid decarboxylase (GAD), the major pathway for the synthesis of γ‐aminobutyric acid (GABA) in humans, are found at elevated levels in a subgroup of patients with chronic epilepsy. To test whether the antibodies were associated with changes in cortical GABA levels we used magnetic resonance spectroscopy. Four patients with epilepsy and high serum GAD antibody levels (107–6,200 units/ml) and 10 healthy controls were recruited. A 3T GABA‐optimized spectrum was obtained from a reproducible voxel in the cortex. Compared to the control group, the patient group had significantly lower GABA concentrations within the cortex. Demonstration of an association between high serum GAD antibodies and low cortical GABA levels in patients with epilepsy suggests that GAD antibodies are, at least, a marker of a specific disease process and support a role for immune‐mediated GABAergic dysfunction.     

Autoantibodies against voltage‐gated potassium channel and glutamic acid decarboxylase in psychosis: A systematic review,meta‐analysis,and case series

Antibodies to the voltage‐gated potassium channel (VGKC) complex and glutamic acid decarboxylase (GAD) have been reported in some cases of psychosis. We conducted the first systematic review and meta‐analysis to investigate their prevalence in people with psychosis and report a case series of VGKC‐complex antibodies in refractory psychosis. Only five studies presenting prevalence rates of VGKC seropositivity in psychosis were identified, in addition to our case series, with an overall prevalence of 1.5% (25/1720) compared to 0.7% in healthy controls (12/1753). Meta‐analysis established that the pooled prevalence of GAD65 autoantibodies was 5.8% (95% confidence interval [CI]: 2.0–15.6%; I² = 91%; nine studies) in psychotic disorders, with a prevalence of 4.6% (95%CI: 1.2–15.9%; nine studies; I² = 89%) and 6.2% (95%CI: 1.2–27.0%; two studies; I² = 69%) in schizophrenia and bipolar disorder, respectively. People with psychosis were more likely to have GAD65 antibodies than controls (odds ratio [OR], 2.24; 95%CI: 1.28–3.92%; P = 0.005; eight studies; I² = 0%). Among 21 participants with treatment‐resistant psychosis, none had VGKC antibodies. The prevalence of VGKC antibodies is low in psychosis. Our preliminary meta‐analysis suggests that GAD autoantibodies are more common in people with psychosis than in controls, although few studies accounted for the possibility of co‐existing type 1 diabetes mellitus and the clinical significance of reported GAD titers remains unclear. The paucity of studies reporting thresholds for defining GAD abnormality and rates of comorbid type 1 diabetes mellitus precludes interpretations regarding the influence of GAD antibodies on the development of psychotic disorders and may have led to an overestimate of the prevalence of GAD. Our case series fails to support the hypothesis that VGKC antibodies are linked to treatment resistance in psychosis, but the literature to date is remarkably sparse.     

Cramp‐fasciculation syndrome in patients with and without neural autoantibodies

Introduction: We investigated the clinical, electrophysiological and neural autoantibody characteristics in cramp‐fasciculation syndrome (CFS) patients. Methods: We reviewed Mayo Clinic records from 2000 to 2011 to identify clinically defined CFS patients who underwent neural autoantibody testing. Stored sera of patients who tested positive for antibodies to voltage‐gated potassium channel complex (VGKC complex) were analyzed further for leucine‐rich glioma‐inactivated 1 (LGI1) or contactin‐associated protein‐2 immunoglobulin G (CASPR2‐IgG) antibodies. Results: Thirty‐seven patients were identified. Twelve were seropositive for neural autoantibodies. Clinical manifestations were similar in seropositive and seronegative patients, although central and autonomic neuronal hyperexcitability symptoms were more common in seropositive cases. No patients had a malignancy. Repetitive tibial nerve stimulation at 10 Hz revealed longer afterdischarges in seropositive patients. Two of 7 patients with VGKC‐complex autoimmunity demonstrated LGI1 or CASPR2‐IgG antibodies. Only 2 of 12 seropositive patients required immunotherapy. Conclusions: VGKC‐complex autoimmunity occurs in a minority of CFS patients. Antibody positivity was associated with extramuscular manifestations, typically without malignancy. Target antigens within the VGKC complex remain unknown in most patients. Muscle Nerve 49 :351–356, 2014     

雷公藤内酯醇对癫痫大鼠电压门控钾通道kv1.1表达的影响

目的 探讨雷公藤内酯醇(TL)对癫痫大鼠神经的保护作用及其机制.方法 60只SD大鼠分成对照组、模型组、雷公藤组,每组各20只.雷公藤组大鼠腹腔注射TL(每日15μg/kg),模型组大鼠腹腔注射等量生理盐水,注射7d后,雷公藤组与模型组通过颈内皮下注射海人酸(KA)致痫,对照组则颈内皮下注射等量的生理盐水.用免疫组化和Western blot方法检测大鼠海马CA3区瞬时外向钾离子通道kv1.1蛋白表达.结果 模型组大鼠海马CA3区kv1.1蛋白表达水平低于对照组(P＜0.05);雷公藤组海马CA3区kv1.1蛋白表达高于模型组(P＜0.05);雷公藤组与对照组大鼠kv1.1蛋白表达水平无明显差异(P＞0.05).结论 TL对KA致痫大鼠神经元有保护作用,其作用的发挥可能与TL可增加海马CA3区神经元kv1.1的表达有关.     

Voltage-gated potassium channel (K(v) 1) autoantibodies in patients with chagasic gut dysmotility and distribution of K(v) 1 channels in human enteric neuromusculature (autoantibodies in GI dysmotility)

Background Autoantibodies directed against specific neuronal antigens are found in a significant number of patients with gastrointestinal neuromuscular diseases (GINMDs) secondary to neoplasia. This study examined the presence of antineuronal antibodies in idiopathic GINMD and GINMD secondary to South American Trypanosomiasis. The GI distribution of voltage‐gated potassium channels (VGKCs) was also investigated. Methods Seventy‐three patients were included in the study with diagnoses of primary achalasia, enteric dysmotility, chronic intestinal pseudo‐obstruction, esophageal or colonic dysmotility secondary to Chagas’ disease. Sera were screened for specific antibodies to glutamic acid decarboxylase, voltage‐gated calcium channels (VGCCs; P/Q subtype), nicotinic acetylcholine receptors (nAChRs; α3 subtype), and voltage‐gated potassium channels (VGKCs, K_V1 subtype) using validated immunoprecipitation assays. The distribution of six VGKC subunits (K_V1.1–1.6), including those known to be antigenic targets of anti‐VGKC antibodies was immunohistochemically investigated in all main human GI tract regions. Key Results Three patients (14%) with chagasic GI dysmotility were found to have positive anti‐VGKC antibody titers. No antibodies were detected in patients with idiopathic GINMD. The VGKCs were found in enteric neurons at every level of the gut in unique yet overlapping distributions. The VGKC expression in GI smooth muscle was found to be limited to the esophagus. Conclusions & Inferences A small proportion of patients with GI dysfunction secondary to Chagas’ disease have antibodies against VGKCs. The presence of these channels in the human enteric nervous system may have pathological relevance to the growing number of GINMDs with which anti‐VGKC antibodies have been associated.     

Clinical significance of cation channel antibodies in motor neuron disease

Introduction: Antibodies against cation channels, including voltage‐gated potassium channel (VGKC) complex, voltage‐gated calcium channel (VGCC), and ganglionic acetylcholine receptor (gAChR), are detected in subgroups of autoimmune disorders, and rarely occur in motor neuron disease (MND). Methods: This investigation was a case–control study of 28 MND patients positive for cation channel antibodies in comparison with 56 age/gender/onset/diagnostic‐category‐matched MND patients without such antibodies. Results: One or more cation channel antibodies were detected in 6.9% of MND patients, mostly at low titers. The rate of MND progression determined by the revised ALS Functional Rating Scale–revised (ALSFRS‐R) and Kaplan–Meier survival analysis was statistically indistinguishable between the antibody‐positive and control groups. Incidence rates of cancer and coexisting autoimmune disorders were similar between both groups, based on non‐comprehensive screening. Conclusion: Cation channel antibodies in MND patients do not appear to affect disease progression. Routine testing for paraneoplastic antibodies is probably of limited usefulness in most MND patients. Muscle Nerve 54 : 228–231, 2016     

Persistent frequent subclinical seizures and memory impairment after clinical remission in smoldering limbic encephalitis

Aim. To delineate a possible correlation between clinical course and EEG abnormalities in non‐infectious “smoldering” limbic encephalitis. Methods. Long‐term clinical data, including video‐EEG monitoring records, were analysed in two patients. Results. The two patients were positive for anti‐voltage‐gated potassium channel complex antibody and unspecified antineuronal antibody, respectively. The latter patient had small cell lung carcinoma. Both patients had memory impairment and clinical seizures. EEG showed frequent subclinical seizure patterns in the bilateral temporal regions. Subclinical seizure patterns and memory impairment persisted over one to two years after clinical seizure remission. Therapy (prednisolone and chemoradiation in the two patients, respectively) resulted in decreased occurrence of subclinical seizure patterns and memory improvement. Conclusions. EEG seizure patterns may persist years after clinical seizure remission in “smoldering” limbic encephalitis and lead to memory impairment.     

Duplication of the sodium channel gene cluster on 2q24 in children with early onset epilepsy

Purpose: Sodium channel gene aberrations are associated with a wide range of seizure disorders, particularly Dravet syndrome. They usually consist of missense or truncating gene mutations or deletions. Duplications involving multiple genes encoding for different sodium channels are not widely known. This article summarizes the clinical, radiologic, and genetic features of patients with 2q24 duplication involving the sodium channel gene cluster. Methods: A systematic review of the literature and report of two cases. Key Findings: Nine individuals with 2q24 duplication involving the sodium channel gene cluster are described (seven female, two male). All presented with severe seizures refractory to anticonvulsant drugs. Seizure onset was in the neonatal period in eight patients with SCN1A‐involvement, in infancy in one patient with SCN2A and SCN3A, but no SCN1A involvement. Seizure activity decreased and eventually stopped at 5–20 months of age. Seizures recurred at the age of 3 years in the patient with SCN2A and SCN3A, but no SCN1A involvement. Eight patients had a poor neurodevelopmental outcome despite seizure freedom. Significance: This article describes a distinct seizure disorder associated with a duplication of the sodium gene cluster on 2q24 described in otherwise healthy neonates and infants with severe, anticonvulsant refractory seizures and poor developmental outcome despite seizure freedom occurring at the age of 5–20 months.     

A novel KCNQ3 mutation in familial epilepsy with focal seizures and intellectual disability

Mutations in the KCNQ2 gene encoding for voltage‐gated potassium channel subunits have been found in patients affected with early onset epilepsies with wide phenotypic heterogeneity, ranging from benign familial neonatal seizures (BFNS) to epileptic encephalopathy with cognitive impairment, drug resistance, and characteristic electroencephalography (EEG) and neuroradiologic features. By contrast, only few KCNQ3 mutations have been rarely described, mostly in patients with typical BFNS. We report clinical, genetic, and functional data from a family in which early onset epilepsy and neurocognitive deficits segregated with a novel mutation in KCNQ3 (c.989G>T; p.R330L). Electrophysiological studies in mammalian cells revealed that incorporation of KCNQ3 R330L mutant subunits impaired channel function, suggesting a pathogenetic role for such mutation. The degree of functional impairment of channels incorporating KCNQ3 R330L subunits was larger than that of channels carrying another KCNQ3 mutation affecting the same codon but leading to a different amino acid substitution (p.R330C), previously identified in two families with typical BFNS. These data suggest that mutations in KCNQ3, similarly to KCNQ2, can be found in patients with more severe phenotypes including intellectual disability, and that the degree of the functional impairment caused by mutations at position 330 in KCNQ3 may contribute to clinical disease severity.     

Prevalence and predictors of subclinical seizures during scalp video-EEG monitoring in patients with epilepsy

Objective: This study first aimed to establish the prevalence and predictors of subclinical seizures in patients with epilepsy undergoing video electroencephalographic monitoring, then to evaluate the relationship of sleep/wake and circadian pattern with subclinical seizures. Methods: We retrospectively reviewed the charts of 742 consecutive patients admitted to our epilepsy center between July 2012 and October 2014. Demographic, electro-clinical data and neuroimage were collected. Results: A total of 148 subclinical seizures were detected in 39 patients (5.3%) during video electroencephalographic monitoring. The mean duration of subclinical seizures was 47.18 s (range, 5–311). Pharmacoresistant epilepsy, abnormal MRI and the presence of interictal epileptiform discharges were independently associated with subclinical seizures in multivariate logistic regression analysis. Subclinical seizures helped localizing the presumed epileptogenic zone in 24 (61.5%) patients, and suggested multifocal epilepsy in five (12.8%). In addition, subclinical seizures occurred more frequently in sleep and night than wakefulness and daytime, respectively, and they were more likely seen between 21:00–03:00 h, and less likely seen between 09:00–12:00 h. Thirty patients (76.9%) had their first subclinical seizures within the first 24 h of monitoring while only 7.7% of patients had their first subclinical seizures detected within 20 min. Conclusion: Subclinical seizures are not uncommon in patients with epilepsy, particularly in those with pharmacoresistant epilepsy, abnormal MRI or interictal epileptiform discharges. Subclinical seizures occur in specific circadian patterns and in specific sleep/wake distributions. A 20-min VEEG monitoring might not be long enough to allow for their detection.