The real mechanism of VPA-induced hyperammonemia remains unknown

Valproic acid (VPA) is a well-tolerated and effective agent for the treatment of epilepsy, bipolar disorder, and schizoaffective disorder. Several case reports have indicated that VPA may induce serious symptomatic hyperammonemia. Based on analysis of susceptible patients, several possible mechanisms and risk factors have been proposed to identify the patients at risk. Nevertheless, we report the case of a schizoaffective patient who developed severe hyperammonemia occurring after brief exposure to VPA, despite the absence of any known risk factors. Until now, early recognition of the signs and symptoms of hyperammonemia is crucial to managing this unusual adverse reaction.     

我国农村地区607例癫痫患者应用丙戊酸钠治疗效果评价

目的 观察基层医生使用国产丙戊酸钠(VPA)治疗癫痫的可行性、疗效及其不良反应.方法 癫痫患者来自湖北省天门市和广西田东县农村地区.由县、乡级医生按规定的入选标准筛选病例,并使用VPA治疗和随访.疗效评估以发作频率与治疗前的变化为标准,其中无发作、显效和有效三者之和为总有效率.结果 入组607例癫痫患者接受治疗随访,男性395例,女性212例,其中579例随访满12个月.患者中全面强直-阵挛性发作517例(85.2%),失神发作20例(3.3%),其余70例(11.5%)为部分性发作、单纯强直、阵挛、肌阵挛或失张力发作.服药满3个月、6个月、12个月时癫痫发作完全控制的患者分别有270例(45.5%)、249例(42.3%)和238例(41.1%),总有效率三个时段分别为65.2%、75.4%和85.5%.治疗随访期间共有58例出现困倦、嗜睡、疲乏、头晕等不良反应.治疗随访期间有19例(3.1%)先后脱组.结论 VPA是一种疗效较好、严重不良反应少、基层医生比较容易掌握的广谱抗癫痫药,同苯巴比妥一样适合在我国农村地区推广应用.

Abstract：

Objective To observe the efficacy and the side-effects of sodium valproate (VPA) in patients with epilepsy in rural China. Methods Epilepsy patients were selected from rural areas of Tianmen in Hubei province and Tiandong county in Guangxi province according to the inclusion and exclusion criteria.Efficacy evaluation standard depending on the change of seizure frequency compared with the situation prior to entering the treatment group. Among the treated patients, no seizures, seizure reduced ＞ 75%, seizure reduced 50%-75% sums for the total effective rate. Results All 607 patients with epilepsy were treated and followed up, the male were 395 (65. 1% ) female 212 (34. 9% ), and 579 patients were treated for 12 months. Patients with generalized tonic-clonic seizures were 517 (85.2%), absence seizures 20 (3. 3% )and the other types of seizures 70 (11.5% ) including simple partial seizures, tonic, clonic, myoclonic or atonic seizures etc. The completed control of seizures ( without any seizures) during the period after taking 3 months, 6 months, 12 months were 270 (45.5%), 249 (42. 3% ) and 238 (41.1%) respectively. The total effective rates in the three periods were 65.2% , 75.4% and 85.5% respectively. The 58 patients in the total group showed side-effects during the follow-up period, mainly including drowsiness, lethargy,fatigue, dizziness, headache and tremor. Nineteen patients (3. 1% ) quitted the treatment group.Conclusions The VPA is an effective antiepileptic drug and no more severe side-effects. It is the same as Phenobarbital and suitable to be used in rural areas of China.     

丙戊酸和托吡酯对癫(癎)患儿游离肉毒碱的影响

目的探讨丙戊酸(VPA)和托吡酯(TPM)对癫癎患儿游离肉毒碱的影响。方法35例癫癎患儿,年龄6～8岁,男20例,女15例,其中12例予VPA单药治疗,11例予TPM单药治疗,12例予VPA及TPM联合治疗6～8个月。15例健康儿童作为正常对照组。测定血浆游离肉毒碱的浓度。结果VPA组血浆游离肉毒碱的浓度明显低于对照组及TPM组,VPA-plus- TPM组与VPA组比较差异无显著性,TPM组与对照组比较差异无显著性。结论VPA可降低癫癎患儿血浆游离肉毒碱水平,而TPM对血浆游离肉毒碱无明显影响。     

Risk factors for developing epilepsy after craniotomy in children

Introduction We performed a retrospective analysis of children undergoing supratentorial craniotomy, attempting to identify possible risk factors for postoperative epilepsy and the need for prophylactic anticonvulsant therapy.Materials and methods We analysed 107 consecutive patients (55% males) who had supratentorial craniotomy for a variety of diagnoses (tumours, trauma, infection, vascular malformations and others) during 1995–1999. Mean age at operation was 89 months (range: 1–180 months). Patients who presented with epilepsy were excluded. Postoperative epilepsy was considered present if patients required systematic pharmacological treatment, at a minimum follow-up of 6 months. Linear regression was used to analyse the effect of sex, anticonvulsant prophylaxis, duration of operation, closure of dura, postoperative infection, the diagnosis, anatomical region of brain affected, operation type (craniotomy/craniectomy) and the need for brain resection.Results Prophylactic anticonvulsants were given to 52% of the patients; 97% had craniotomy; in five patients, the dura was left open; in 33%, some kind of brain tissue resection had been performed; two patients (1.8%) developed postoperative infection; one patient died. Only 13 patients (12%) developed postoperative epilepsy. The only two factors with statistical significance were female sex (p=0.045) and the absence of dural closure (p=0.001). All other factors were not significant (p>0.258).Conclusions Postoperative epilepsy after supratentorial craniotomy is uncommon in children, incidence being 12%. The administration of prophylactic anticonvulsants does not appear to influence the risk of epilepsy. Surprisingly, females have statistically higher risk. Lack of dural closure has higher risk of epilepsy, but this may reflect the type of pathology.The material of this paper was presented at the 18th Biannual Congress of the European Society for Pediatric Neurosurgery, Kiruna, 15 June 2002.     

丙戊酸单药治疗与癫痫患者血浆同型半胱氨酸水平间关系的Meta分析

目的分析癫痫患者血浆同型半胱氨酸水平变化与丙戊酸单药治疗间的关系。方法选择epileDsv、valproate、homocysteine和epilep。为检索词,计算机检索1990年1月-2013年8月美国国立医学图书馆、科学引文索引数据库、荷兰医学文摘等数据库,获得丙戊酸单药治疗与癫痫患者血浆同型半胱氨酸水平间关系的相关英文文献,均为丙戊酸单药治疗的癫痫患者与正常对照受试者血浆同型半胱氨酸水平比较的病例．对照临床研究。通过Newcastle—Ottawa量表独立进行文献质量评价和数据提取,Stata12．0统计软件行Meta分析。结果共纳入符合条件的英文文献8篇,包括266例行丙戊酸单药治疗的癫痼患者和489例正常对照受试者,所有纳入文献质量评分均〉6分。Meta分析显示,丙戊酸单药治疗组患者血浆同型半胱氨酸水平显著高于正常对照组[标准化均数差（SMD）：0．620,95％CI：0．320-0．920;P=0．000];经异质性检验存在显著异质性（I^2=65．600％,P=0．005）,根据不同地区和受试者年龄差异行进一步亚组分析,结果显示西亚组癫痫患者异质性风险（I^2=47．400％,P=0．107）较整体（I^2=65．600％,P=0．005）降低。采用敏感性分析评价Meta分析之稳定性,当任何一项研究被剔除后,相应的SMD值均不发生变化,表明分析结果稳定性良好。结论丙戊酸单药治疗可显著增加癫痫患者血浆同型半胱氨酸水平,后者是否受种族因素的影响尚待进一步研究。     

Risk factors for fatigue in patients with epilepsy

Fatigue is highly prevalent in patients with epilepsy and has a major impact on quality of life, but little data is available on its effects and management in epilepsy. To identify the incidence and risk factors of fatigue in patients with epilepsy, 105 epilepsy patients (45 women and 60 men) were enrolled in our study. Demographic and clinical data were collected and psychological variables including fatigue, sleep quality, excess daytime sleepiness, anxiety, and depression were measured by Fatigue Severity Scale, Pittsburgh Sleep Quality Index, Epworth Sleepiness Scale, and Hospital Anxiety and Depression Scale, respectively. Of 105 patients, 29.5% exhibited fatigue (FSS score ⩾4). We found no correlation between the occurrence of fatigue and any of our demographic or clinical variables. Fatigue is correlated with low sleep quality, anxiety, and depression, but not with excess daytime sleepiness. Thus, we concluded that fatigue is highly prevalent in patients with epilepsy, and that low sleep quality, anxiety, and depression are significantly correlated with fatigue in epileptics, while excess daytime sleepiness not.     

Risk factors of childhood epilepsy in Kerala

Background:

We aimed to identify the risk factors for epilepsy in children.

Materials and Methods:

This case–control retrospective study was carried out in the pediatric neurology outpatient service of the Trivandrum Medical College. All children (1–12 years) with epilepsy satisfying the selection criteria were included, after obtaining consent from parents. Those with single seizures or febrile seizures were excluded. Controls were children without epilepsy attending the same hospital. Parents were interviewed and clinical data were obtained from medical records. Statistical analysis included chi-square test, odds ratio (OR), and logistic regression.

Results:

There were 82 cases and 160 controls whose mean age was 6.9 + 3.6 and 5.2 + 3.1, years respectively. On univariate analysis, family history of epilepsy, prolonged labor, cyanosis at birth, delayed cry after birth, admission to newborn intensive care unit, presence of congenital malformations, neurocutaneous markers, incessant cry in the first week, delayed developmental milestones, meningitis, encephalitis, and head trauma were found to be significant. On logistic regression, family history of epilepsy (OR 4.7), newborn distress (OR 8.6), delayed developmental milestones (OR 12.6), and head trauma (OR 5.8) were found to be significant predictors. Infants who had history of newborn distress are likely to manifest epilepsy before 1 year if they are eventually going to have epilepsy (OR 3.4).

Conclusion:

Modifiable factors such as newborn distress and significant head trauma are significant risk factors for childhood epilepsy. Newborn distress is a risk factor for early-onset (<1 year age) epilepsy.     

Effects of valproic acid on sleep in children with epilepsy

Purpose:   Parents frequently report increased sleep duration in their children during treatment with valproic acid (VPA). We assessed sleep duration and sleep behavior before and after tapering VPA in children treated for more than 6 months.
Methods:   Sleep variables were assessed by questionnaire, diary, and actigraphy (for 7 consecutive days and nights) before and 8–12 weeks after termination of VPA.
Results:   Forty-six children (age range 1.7–17.4 years) completed the study. The questionnaire data showed no significant difference in bed and wake time, duration of sleep, and time to fall asleep before and after ending VPA treatment, although some qualitative measures on daytime sleepiness improved after tapering VPA. The actigraphy data revealed that the average sleep amount without VPA was reduced in 33 children (9 of them >30 min) and longer in 13 children (1 of them >30 min). The mean Assumed Sleep Time per Day decreased by 15.2 min or 9.5 min when the physiologic decrease of sleep duration within 0.3 years was considered. Also mean Actual Sleep Time per Day was significantly reduced after VPA termination (−15.2min; after correction −10.7 min). The reduction was only significant in children older than age 6 years.
Discussion:   Termination of VPA after long-term treatment leads to a significant reduction of sleep duration in children older than 6 years of age. The change was small in the majority, but considerable in a subgroup of children.     

Risk factors for hyperammonemia associated with valproic acid therapy in adult epilepsy patients

Hyperammonemia is one of the side effects of treatment with valproic acid (VPA), but the risk factors and mechanisms involved remain obscure. This study analyzed the risk factors for hyperammonemia associated with VPA therapy in adult epilepsy patients. A retrospective analysis of 2724 Japanese patients (1217 males and 1507 females aged from 16 to 76years) treated with VPA between January 2006 and December 2010 were analyzed. The ammonia level increased markedly in a VPA dose-dependent manner, and was significantly elevated in patients who also used hepatic enzyme inducers such as phenytoin (PHT), phenobarbital (PB), carbamazepine (CBZ), and combinations of these drugs. When a blood ammonia level exceeding 200μg/dl was defined as hyperammonemia, the risk factors for hyperammonemia according to multiple regression analysis were a VPA dose >20mg/kg/day (odds ratio (OR): 4.1; 95% confidence interval (CI): 1.6-10.8) and concomitant use of PHT (OR: 11.0; 95% CI: 3.1-38.7), concomitant PB (OR: 4.3; 95% CI: 1.0-17.9), concomitant CBZ (OR: 2.8; 95% CI: 0.6-11.9), and concomitant topiramate (OR: 2.8; 95% CI: 1.2-6.5). Regimens containing multiple inducers were associated with an increased risk of hyperammonemia. Identification of risk factors for hyperammonemia associated with VPA therapy can help to minimize side effects during its clinical use.     

Risk factors of cognitive impairment in pediatric epilepsy patients with focal cortical dysplasia

Objective

The purpose of this study was to identify the risk factors of cognitive impairment in pediatric epilepsy patients with focal cortical dysplasia (FCD).

Neuropsychological results in pediatric patients with epilepsy surgery in the parietal cortex

This study evaluated pre- and postoperatively cognitive functions in 15 pediatric patients with surgically treated parietal lobe epilepsy (PLE). Seizure outcome was very satisfying with 87% seizure-free patients 1 year after surgery, and 82% in the long-term follow-up. Preoperative intelligence was in the subaverage range. Impairments in specific cognitive functions (memory, attention, executive functions) were evident preoperatively for 39-66% of patients. Behavioral disorders were rare. No side differences (left versus right PLE) were indicated pre- or postoperatively. Postoperative improvements were found in behavior and attention; other cognitive functions were unchanged. All in all, this preliminary study indicated a satisfactory neuropsychological outcome in pediatric patients with PLE.     

丙戊酸钠对癫(癎)患儿血淀粉酶和脂肪酶的影响

目的研究丙戊酸钠对癫癎患儿血淀粉酶和脂肪酶的影响。方法观察22例癫癎患儿,男12例,女10例,年龄1·5～11岁,均丙戊酸钠单药治疗,治疗前及治疗6月后测定血淀粉酶和脂肪酶浓度。结果血淀粉酶浓度治疗前为(61·14±12·96)IU/L,治疗后为(69·09±9·22)IU/L,二者相比较,t=2·24,P=0·036。血脂肪酶浓度治疗前为(62·50±11·88)IU/L,治疗后为(71·14±14·59)IU/L,二者相比较t=2·46,P=0·023。结论丙戊酸钠可升高癫癎患儿血淀粉酶和脂肪酶浓度。     

癫痫患者生活质量影响因素分析

目的 调查和分析影响癫痫患者生活质量的相关因素,为采取相应措施提高癫痫患者的生活质量提供理论依据.方法 选择自2007年7月至2008年12月在广州医学院第二附属医院癫痫中心就诊的门诊及住院癫痫患者65例,采用癫痫患者生活质量表-31(中文版)对患者进行问卷调查,以患者的年龄、性别、文化程度、发作类型、病程、认知功能、用药依从性、发作担忧作为自变量,以生活质量表-31(中文版)中相关评分作为应变量,多元线性回归分析应变量和自变量之间的线性关系.结果 文化程度、病程可以影响癫痫患者的记忆力(标准化回归系数分别为0.380、0.264);年龄可以影响患者的社会活动(标准化回归系数为-0.303);性别影响患者的发作(标准化回归系数为0.332).结论 影响癫痫患者生活质量的因素是年龄、性别、病程、文化程度等,且病程与文化程度影响最大.     

Valproate-induced metabolic changes in patients with epilepsy: Assessment with 1H-MRS

Purpose:   Valproate (VPA) interferes with mitochondrial metabolism causing hyperammonemia, thereby shifting the balance reaction of glutamine (Gln)/glutamate (Glu) toward Gln. In this study we wanted to determine whether metabolic changes could be reproduced in VPA-treated patients with epilepsy and whether the results differed from those known in chronic hepatic encephalopathy (CHE).
Methods:   Seven patients with epilepsy pretreated with VPA and seven healthy volunteers were investigated on a 3T-scanner. We performed proton magnetic resonance spectroscopy (¹H-MRS) using a short echo time point-resolved spectroscopy (PRESS) in the parietal and occipital lobe, respectively. Spectral analysis was performed by LCModel, allowing a separation of Glu and Gln at 3T. Absolute values of myo -Inositol (mI), choline (Cho), creatine (Cr), N -acetyl-aspartate (NAA), glutamine (Gln), glutamate (Glu), and the sum of Gln and Glu (Glx) were calculated.
Results:   In the parietal lobe, mI was significantly decreased in the patients' group compared to the healthy volunteers. After separation of the signals of Gln and Glu, a significant increase of Gln was observed in the parietal lobe in the patients' group. No significant differences in the occipital spectra could be observed between the groups.
Discussion:   In VPA-treated patients the alteration of the Glu/Gln ratio differs from that in patients with CHE, where Glx is markedly increased because of an increase in Gln. The expected shift from the biochemical balance reaction of Gln/Glu induced by VPA could be reproduced for the parietal lobe. Significantly reduced mI in the parietal lobe of VPA-treated patients most likely reflects an osmolytic compensation for high Gln.     

Parent- and patient-validated content for pediatric epilepsy quality-of-life assessment

PURPOSE: The purpose of this study was to assess the parent-and patient-validated content of quality-of-life measurement for use in children with epilepsy. METHODS: We asked the parents of 80 consecutive children and adolescents with epilepsy to list in order of importance their concerns about living with or caring for their children with epilepsy. Patients were 3 months to 18 years of age (mean, 10 years) and identified at the outpatient clinic or during hospital stay. To minimize investigator bias, parents and children listed their concerns in a private setting without staff involvement. RESULTS: Twenty-six distinct domains were generated by the parents and children. Concerns listed by more than 20 of parents included medication adverse effects (58), cognitive effects of epilepsy (46), prospects for the future (41), safety (35), independence (31), and brain damage caused by seizures (30). Concerns ranked by parents as most important included safety (18), brain damage from seizures (12), enigma of epilepsy (12), cognitive effects of epilepsy (11), and prospects for the future (10). Concerns listed by more than 20 of children included social problems (35), cognitive effects of epilepsy (29), driving (29), sports (27), medication adverse effects (25), and schooling (21). Concerns ranked by children as most important included issues related to medication adverse effects (13), cognitive effects of epilepsy (10), hatred of epilepsy (8), social embarrassment (6), fear of seizures (6), injury (6), and dislike of hospital visits (6). CONCLUSION: The effect of epilepsy on health-related quality of life in pediatric patients is defined by a limited number of domains. A 20-item inventory was chosen from the 26 domains generated by the parents and children. Our study provides insight into parents' and children's perception of seizures and the impact of epilepsy on everyday life.     

合并癫痫的幕上低级别胶质瘤病人癫痫预后的影响因素分析

目的探讨合并癫痫的幕上低级别胶质瘤病人癫痫预后的影响因素。方法回顾性分析2015年6月至2019年1月手术治疗的80例合并癫痫的幕上低级别胶质瘤的临床资料。术后1年,采用Engel分级评估癫痫预后,Ⅰ级为预后良好,Ⅱ~Ⅳ级为预后不良。用多因素logistic回归分析检验影响癫痫预后的影响因素;受试者工作特征(ROC)曲线分析术前癫痫发作频率预测癫痫预后的价值。结果80例中,术后癫痫预后良好59例,预后不良21例。多因素logistic回归分析结果显示,异柠檬酸脱氢酶(IDH)1突变和术前癫痫发作频率高是胶质瘤病人术后癫痫的独立危险因素(P<0.05),全切肿瘤和术后化疗是保护性因素(P<0.05)。术前癫痫发作频率预测癫痫预后的ROC曲线下面积为0.805(95%置信区间0.685~0.914;P<0.05);当术前癫痫发作频率≥2次/月时,预测术后癫痫预后不良的灵敏度和特异度分别为92.86%和46.85%。结论IDH1突变和术前癫痫发作频率高是合并癫痫的幕上低级别胶质瘤病人癫痫预后不良的危险因素,而肿瘤全切除和术后化疗明显改善癫痫预后。     

成年癫痫患者的自杀风险及相关危险因素研究

目的：研究成人癫痫患者自杀风险及相关危险因素。方法采用简明国际神经精神访谈（MINI）自杀风险模块和抑郁障碍模块对211例我院门诊的成年癫痫患者进行心理评估,并详细记录患者的年龄、性别、就业状况、婚姻、教育年限、发病年龄、病程、发作类型、发作频率、头颅M RI结果以及使用抗癫痫药种数,比较上述因素与自杀风险的关系。结果本组病例中有自杀风险的患者占21.3％（45/211）,伴抑郁障碍的患者占17.1％（36/211）;而伴抑郁障碍患者的自杀风险高达75.0％（27/36）,非抑郁障碍患者的自杀风险达10.3％（18/175）,差异有统计学意义（χ2＝74.525,P＜0.01）。结论伴抑郁障碍的癫痫患者自杀风险更高。     

丙戊酸治疗成人癫(癎)致血浆肉毒碱下降

目的观察丙戊酸(valproic acid,VPA)治疗成人癫患者后患者血浆游离肉毒碱改变规律,并探讨导致其改变的相关因素。方法VPA治疗组为41例成人癫患者,其中接受VPA单药治疗者33例,联合其他抗癫药物治疗者8例,30例非VPA治疗的成人癫患者作为癫对照组,包括其他抗癫药物治疗的患者14例,和未进行药物治疗的患者16例。33名同龄健康者作为正常对照,用酶循环法测定血浆游离肉毒碱浓度,3组间进行比较。结果VPA治疗组血浆游离肉毒碱浓度(31.43±11.75μmol/L)明显低于正常对照组(43.25±12.57μmol/L)和非VPA治疗的癫对照组(40.71±12.83μmol/L,P均<0.05)。血浆游离肉毒碱浓度与VPA剂量、VPA疗程、其他抗癫药物、年龄、性别、血ALT、AST无相关性。结论VPA治疗成人癫可能导致血浆游离肉毒碱水平下降,其下降程度和VPA无剂量和疗程依赖性,也不受患者的生理状态以及其他抗癫药物的影响。     

Valproate induced hyperammonemic encephalopathy successfully treated with levocarnitine

Valproate-induced hyperammonemic encephalopathy is an unusual but serious adverse effect that is usually characterized by the acute onset of impaired consciousness, focal neurological symptoms and increased seizure frequency. It has been reported to occur at therapeutic valproate levels. We report a patient who developed valproate-induced hyperammonemic encephalopathy after a short treatment with valproate and was successfully treated with levocarnitine. We discuss this patient and review the literature regarding the use of levocarnitine in similar patients.