Effects of Carbamazepine on Pituitary Responsiveness to Luteinizing Hormone-Releasing Hormone, Thyrotropin-Releasing Hormone, and Metoclopramide in Epileptic Patients

Pituitary responsiveness to luteinizing hormone-releasing hormone (LH-RH), thyrotropin-releasing hormone (TRH), and metoclopramide (MC) was studied in 40 epileptic patients (24 men and 16 women) receiving carbamazepine (CBZ) treatment and in 29 (20 men and 9 women) untreated epileptic patients. Mean basal concentration of serum LH was significantly lower in the CBZ-treated female patients than in untreated female patients. The response of LH to LH-RH was also blunted in CBZ-treated female patients. No differences were found in basal or stimulated LH levels between the two groups of male patients. Nevertheless, the mean basal concentration of serum prolactin (PRL) was lower and the response of PRL to TRH was higher in male patients treated with CBZ. No differences were found in serum levels of follicle-stimulating hormone (FSH) or in responses of FSH to LH-RH between the CBZ-treated and untreated patients. These results indicate that CBZ has effects on pituitary responsiveness.     

GABA levels in cerebrospinal fluid of patients with epilepsy

The lumbar cerebrospinal fluid (CSF) gamma-aminobutyric acid (GABA) levels were measured in 27 patients with epilepsy, another three epileptic patients with status epilepticus and three epileptic patients with chronic cerebellar ataxia. The mean lumbar CSF GABA levels of the 27 patients with epilepsy were not significantly different from those of normal controls. Six of these 27 patients who had daily partial complex and partial motor seizures showed significantly low CSF GABA levels as did the six other patients, three each with status epilepticus and chronic cerebellar ataxia. These findings suggest that some epileptic patients have impaired brain GABAergic neurons.     

Effects of common anti-epileptic drug monotherapy on serum levels of homocysteine, vitamin B12, folic acid and vitamin B6.

There is emerging evidence to support the unfavorable effects of some anti-epileptic drugs on the plasma homocysteine concentrations. Elevated homocysteine levels induced by anti-epileptic drug administration can theoretically increase not only the risk of vascular occlusive diseases, but also the risk of resistance to anti-epileptics and development of refractory epilepsy. To investigate the effect of common anti-epileptic drugs on the homocysteine metabolism, a total of 75 epileptic patients receiving phenytoin (n=16), carbamazepine (n=19), or valproic acid (n=22) and no anti-epileptic drug (n=18) were enrolled. Eleven age- and sex-matched healthy subjects served as the control group. Blood concentrations of homocysteine, folic acid, Vitamin B12 and pyridoxal 5'-phosphate (active circulating form of Vitamin B6) were measured. Compared to the control group, epileptic patients on anti-epileptic drug had higher blood levels of homocysteine. No difference in homocysteine concentrations was observed among epileptic patients in terms of the anti-epileptic drug used. Patients receiving phenytoin had significantly lower folic acid levels and those receiving carbamazepine had marginally lower pyridoxal 5'-phosphate levels in comparison with those using other anti-epileptic drugs. A negative correlation between homocysteine and folic acid concentrations was detected in epileptic patients on anti-epileptic drug. The duration of anti-epileptic drug use was correlated to the decrease of folic acid levels, but not with changes observed in homocysteine, Vitamin B12 and pyridoxal 5'-phosphate levels. No relationship between seizure frequency and homocysteine levels was observed in epileptic patients. Our results confirm that common anti-epileptic drugs has disadvantageous effects on homocysteine status. Because there was no significant change in homocysteine concentrations in epileptic patients who were not receiving an anti-epileptic drug, and no positive correlation between seizure frequency and homocysteine levels, we suggest that increase of homocysteine levels may be due to anti-epileptic drug use, rather than being epileptic in origin. Additionally, the underlying mechanism for homocysteine increase seems to be a decrease of cofactor molecules in patients using carbamazepine and phenytoin (pyridoxal 5'-phosphate and folic acid, respectively). However, changes observed are not related to the alteration in the levels of cofactors and remain unclear in the patients using valproic acid.     

GABA Levels in Cerebrospinal Fluid of Patients with Epilepsy

Abstract: The lumbar cerebrospinal fluid (CSF) γ-aminobutyric acid (GABA) levels were measured in 27 patients with epilepsy, another three epileptic patients with status epilepticus and three epileptic patients with chronic cerebellar ataxia. The mean lumbar CSF GABA levels of the 27 patients with epilepsy were not significantly different from those of normal controls. Six of these 27 patients who had daily partial complex and partial motor seizures showed significantly low CSF GABA levels as did the six other patients, three each with status epilepticus and chronic cerebellar ataxia. These findings suggest that some epileptic patients have impaired brain GABAergic neurons.     

癫痫患者智能状况与事件相关电位P300的研究

目的探讨癫痫患者智能状况、事件相关电位P300(ERP P300)的特点及ERP P300对癫痫患者智能状况的评定价值.方法对40例癫痫患者进行智商及ERP P300测定.结果40例癫痫患者中总智商FIQ≤89者14例,占35%;P300异常者16例,占40%.癫痫智能障碍组的VIQ、PIQ、FIQ、P300 PL分别与智能正常组及正常对照组比较,均具有显著性差异(P<0.01).且癫痫患者P300PL与VIQ、PIQ、FIQ呈负相关.结论癫痫患者易发生智能损害,且智能损害无选择性.智力量表和ERPP300二种检测方法对评判癫痫患者智能障碍具有良好的一致性,而ERP P300能更早期、更客观、快捷、准确地评价癫痫患者智能状况.     

托吡酯长期治疗对成年癫疒间患者血清甲状腺激素水平的影响

目的 探讨托吡酯(TPM)长期治疗对成年癫疒间患者血清甲状腺激素水平的影响.方法 用化学发光分析法测定成年癫疒间组患者(32例)TPM治疗前、后的血清甲状腺激素水平,并与健康对照组(40人)进行比较. 结果治疗前成年癫疒间组患者甲状腺激素水平与健康对照组比较无统计学意义(均P>0.05);TPM治疗后3个月、6个月、12个月及24个月的甲状腺激素水平与治疗前及健康对照组比较差异亦无统计学意义(均P>0.05).结论 TPM短期与长期治疗对成年癫疒间患者的甲状腺激素水平没有影响.     

癫痫患者与假性发作患者血清S100B蛋白、超敏C反应蛋白和神经元特异性烯醇化酶水平的改变及其意义

目的研究癫痫患者与假性发作患者血清S100B蛋白、超敏C反应蛋白(hs-CRP)和神经元特异性烯醇化酶(NSE)水平的改变及其意义。方法在癫痫(32例)及假性发作(30例)患者发作后第1 d、3 d、8 d、15 d时,分别采用酶联免疫吸附法(ELISA)、免疫比浊法和时间免疫荧光法检测其血清S100B蛋白、hs-CRP和NSE含量。并与正常对照者进行比较。结果癫痫组患者发作后第1 d、第3 d时血清S100B蛋白、hs-CRP和NSE含量均明显高于假性发作组和正常对照组(均P<0.01);发作后第8 d、第15 d时与正常对照组比较差异无统计学意义。假性发作组发作后各时间点的血清S100B蛋白、hs-CRP和NSE水平与正常对照组比较,差异均无统计学意义。结论癫痫患者发作后3 d内血清S100B蛋白、hs-CRP和NSE水平均明显升高,而假性发作患者无明显改变。血清S100B蛋白、hs-CRP和NSE水平可作为鉴别癫痫与假性发作的生物学指标。     

Valproate-associated reproductive and metabolic abnormalities: are epileptic women at greater risk than bipolar women?

OBJECTIVE: Evidence indicates that valproate (VPA) may have an adverse impact on reproductive endocrine and metabolic functions in women with epilepsy. This study explores whether the association of VPA with reproductive endocrine abnormalities is applicable to women with bipolar disorder (BD) or is unique to women with epilepsy. METHODS: Thirty female patients aged 18-40 years with a DSM-IV diagnosis of BD (15 on lithium monotherapy and 15 on VPA monotherapy or VPA in combination with lithium therapy) and 15 with idiopathic generalized epilepsy (IGE) on VPA monotherapy were evaluated for reproductive endocrine functioning and metabolic parameters. RESULTS: The menarche age, mean length of menstrual cycle and mean length of menses were not significantly different between groups. None of the bipolar patients on lithium, three (20%) of the bipolar patients on VPA and seven (47%) of the epileptic patients on VPA reported menstrual disturbances. Hirsutism scores of the epilepsy group were significantly higher than those bipolar women, regardless of treatment. Serum total testosterone levels were significantly higher in patients (both with BD and with IGE) treated with VPA than in those treated with lithium. Serum FSH levels were significantly lower and LH-to-FSH ratio was significantly higher in patients with epilepsy than in patients with BD, regardless of treatment. The weight parameters and lipid values investigated did not differ significantly between the groups. CONCLUSION: The study supports the conclusion that VPA may be associated with menstrual abnormalities and increased total testosterone levels in both bipolar and epileptic patients although women with BD did not show clinical features of hyperandrogenism (menstrual abnormalities, hirsutism and truncal obesity) as did frequently as women with epilepsy.     

Cerebrospinal fluid norepinephrine alterations during electrical stimulation of cerebellar, cerebral surfaces in epileptic patients.

Lumbar cerebrospinal fluid norepinephrine concentrations were determined by radioenzymatic assay in five epileptic patients receiving double-blind cerebellar stimulation and in three epileptic patients with subdural cerebral surface electrodes. Mean CSF norepinephrine levels were significantly elevated by chronic cerebellar stimulation and significantly depressed after intermittent cerebral cortical stimulation. Lumbar CSF cyclic adenosine monophosphate levels determined by radioimmunoassay were not significantly altered by either cerebellar or cerebral surface stimulation. Our study suggests that (1) electrical stimulation of the anterodorsal cerebellum in man evokes alterations in noradrenergic metabolism. Cerebellar stimulation-induced elevations in norepinephrine may inhibit cerebellar, cerebral, and spinal neuronal activity. In addition, (2) noradrenergic responses to brain surface stimulation may exhibit regional specificity, and (3) noradrenergic alterations evoked by cerebral surface stimulation may not mimic those induced in isolated brain preparations.     

Ovarian hormones, anticonvulsant drugs, and seizures during the menstrual cycle in women with epilepsy.

The excretion of three oestrogen fractions and progesterone metabolites in 64 female epileptic patients was determined during the menstrual cycle, and in 50 women of this sample serum phenytoin and phenobarbitone levels were measured. A significant decrease of both hormones in epileptic patients was found as compared to a control group. The variations in serum phenytoin levels were greater in females with so-called catamenial epilepsy with a marked fall of drug levels between days 27 and 28 corresponding with an increase of seizure frequency. The effect of progesterone deficit on seizure susceptibility before menstrual bleeding is discussed, and the need of serum anticonvulsant level determination during the premenstrual phase in epileptic women is suggested.     

Contribution of EEG to the diagnosis of epilepsy in Shanghai

The electroencephalographs (EEGs) of 9963 patients examined for some form of neurological disorder were studied. The male:female ratio was 129:1 and the age range of 11-40 years accounted for 67.12% of those studied. Of 3914 clinically confirmed epileptic patients, 68.37% had an abnormal EEG characterized by major general or focal discharges. 50.56% of 3814 suspected epileptic patients exhibited high levels of abnormal discharge and 452 non-epileptic patients also exhibited abnormalities. Such discharges also occurred in 671 patients suspected of other neurological disorders.     

Valproate-induced hyperammonemia

A patient with carbamyl phosphate synthetase deficiency had four episodes of hyperammonemia, up to 226 μM, associated with valproate (VPA) treatment. These were accompanied by vomiting, lethargy, and coma. A group of epileptic patients receiving VPA remained asymptomatic but had significantly higher mean plasma ammonium levels when compared to epileptic patients receiving other anticonvulsants: 33.6 ± 1.9 (SEM) versus 23.6 ± 1.5 μM. Thus, VPA caused symptomatic hyperammonemia in a patient with an impairment in urea synthesis and resulted in mildly elevated ammonium levels in epileptic patients. These data suggest that ammonium levels should be monitored in patients receiving VPA who exhibit signs of vomiting or lethargy.     

Serum and hair trace element levels in patients with epilepsy and healthy subjects: does the antiepileptic therapy affect the element concentrations of hair?

In this study, hair magnesium (Mg), zinc (Zn), copper (Cu), and manganese (Mn) levels, and serum Zn and Mg levels were measured by atomic absorption spectrophotometer in patients with epilepsy (n = 33) and healthy subjects (n = 21), and results obtained were statistically compared. The mean hair Cu, Mg, and Zn levels of epileptic patients were significantly lower than the levels of control subjects. There was no significant difference between epileptic patients and control subjects in respect to the mean Mn levels. Mean serum Mg levels in epileptic patients showed significant difference, but serum Zn levels were similar among both groups. When the effects of anticonvulsant therapy on Cu, Zn, Mn, and Mg in the hair, and Mg and Zn in the serum were analyzed in epileptics, there was no significant difference between the patients with or without therapy. Likewise, the mean trace element levels in epileptics showed no significant difference according to the type of antiepileptic drug and seizure, and gender. We suggest that the changed element status (Zn, Mg, and Cu) in hair may play an indicator role in the diagnosis of epileptic patients.     

The effects of carbamazepine, valproic acid and phenobarbital on the oxidative and antioxidative balance in epileptic children

BACKGROUND: Oxidative stress has been related in a wide variety of ways with nervous tissue. We studied the effect of antiepileptic monotherapy on serum level of total antioxidant capacity, lipid hydroperoxide, total peroxide, oxidative stress index, and individual serum antioxidants such as albumin, bilirubin and uric acid. PATIENTS AND METHODS: We studied 122 subjects including healthy controls, untreated epileptic patients and epileptic patients treated with valproic acid, carbamazepine or phenobarbital. Serum total antioxidant capacity was measured as an index of antioxidants, and total peroxide was measured as index of oxidative stress. The serum concentrations of uric acid, albumin, bilirubin and lipid hydroperoxide were monitored simultaneously. RESULTS: We found that serum total antioxidant capacity levels were significantly decreased in the untreated group compared with the controls. Serum total peroxide levels were markedly increased in the untreated and carbamazepine-treated groups compared to in the controls; and lipid hydroperoxide and oxidative stress index levels were significantly higher in the phenobarbital-treated group than in the controls. Uric acid concentrations were significantly lower in the valproic-acid-treated group than in the untreated group, and total bilirubin concentrations were higher in the untreated group than in the controls. CONCLUSION: Epileptic children exposed to oxidative stress and conventional antiepileptic drugs change the oxidative/antioxidative balance. The serum oxidant and antioxidant status of epileptic children with valproic acid monotherapy are better regulated compared with children with carbamazepine and phenobarbital monotherapy.     

Serum lipids, lipoproteins and apolipoproteins A and B in epileptic patients treated with valproic acid, carbamazepine or phenobarbital

Serum lipids, lipoproteins and apolipoproteins A and B were measured in 101 epileptic patients receiving chronic treatment with valproic acid, carbamazepine or phenobarbital and in 75 age- and sex-matched control subjects. In relation to controls, subjects treated with valproic acid showed significantly lower values of total and LDL-cholesterol levels; subjects treated with carbamazepine showed significantly higher values of HDL-cholesterol and apolipoprotein A concentrations and subjects treated with phenobarbital showed significantly higher values of total cholesterol, HDL-cholesterol, apolipoprotein A and apolipoprotein B levels. The total cholesterol/HDL-cholesterol ratio was significantly lower in patients receiving valproic acid or carbamazepine but not in the phenobarbital-treated group. Changes in serum lipids profile did not correlate with drug plasma concentrations nor the duration of the treatment.     

Sex Hormones and Pituitary Function in Male Epileptic Patients with Altered or Normal Sexuality

Summary Male epileptic patients frequently complain of sexual dysfunction, particularly impotence and loss of libido. Epilepsy itself, antiepileptic drugs (AEDs), and psychosocial factors are believed to contribute to impaired sexuality. We studied luteinizing hormone (LH) ulsatile secretion, gonadotropin, and prolactin (PRL) esponses to LH-releasing hormone (LHRH) and thyrotropin-releasing hormone (TRH) in 37 adult male epileptic patients receiving AED monotherapy who were seizure-free and had normal EEGs. Sexuality was assessed by psychological interview. Impotence was diagnosed in 8 patients (in 2 combined with loss of sexual desire). The occurrence of hyposexuality (-20%) was independent of epilepsy syndrome or AED. No change in total testosterone (T) level was observed. Free T (ft)and dihydrotestosterone (DHT) levels were lower and sex hormone binding globulin (SHBG) levels were higher in epileptic subjects than in healthy controls, but a statistically significant difference was not observed between hypo- and normosexual patients. In impotent epileptic patients, estradiol (E2) levels were significantly increased as compared with those of patients with preserved sexuality and of healthy controls. The unbalanced relation between androgen and E2 levels was emphasized by decreased fT/E2, fT/E2, and DHT/E2 ratios obtained in hyposexual epileptic patients. In this group, LHRH induced blunted LH peaks. No changes were noted in LH pulsatility features. These findings of higher E2 levels and of decreased LH response to LHRH administration in some epileptic patients with impaired sexuality, may suggest they have subclinical hypogonadotropic hypogonadism.     

Unexpected, unexplained death in epileptic patients.

Thirty-seven cases of unexpected, unexplained death in epileptic patients were recorded by the Allegheny County Coroner's Office during the years 1969 through 1973. In no case was there anatomic or chemical evidence at autopsy sufficient to explain death. All patients had a duration of epilepsy greater than a year. All but two had less than one seizure per month. Blood levels of anticonvulsants at autopsy revealed only three patients with therapeutic levels of the drugs. Almost 50 percent of the cases studied had no demonstrable anticonvulsant. It is suggested that inadequate levels of anticonvulsant drugs are a significant factor associated with unexpected, unexplained death in epileptic patients.     

抗癫痫药物对癫痫患者甲状腺激素水平影响的研究

目的 研究癫痫患者甲状腺激素水平和抗癫痫药物对其影响以及与疗效之间的关系。方法 测定已确诊的45例未服用过抗癫痫药物的癫痫患者血清甲状腺激素水平并与30例健康对照组进行比较。再经卡马西平、苯妥英钠、丙戊酸钠三种抗癫痫药物分组单药治疗3个月、6个月、年后观察甲状腺激素水平的变化及与疗效之间的关系。结果 未服用抗癫痫药物的新诊断癫痫患者游离甲状腺素（FT4）水平显著低于健康对照组,经苯妥英钠、卡马西平分别治疗3个月、6个月、1年后T4、FT4、FT3显著低于治疗前水平,TSH无显著性变化。经丙戊酸钠治疗后的不同时间段各甲状腺激素水平与治疗前比较无显著性差异（P＞0．05）。甲状腺激素水平的变化与化疗效之间似无相关性。结论 癫痫的反复发作虽未经抗癫痫药物治疗已存在FT4水平的降低。苯妥英钠、卡马西平可明显造成癫痫患者的亚临床甲状腺功能降低（T4、FT4、FT3下降）,丙戊酸钠对患者甲状腺激素水平无显著影响。甲状腺激素水平的变化与疗效之间无相关性。     

Epidemiological observations on plasma levels of diphenylhydantoin in 130 patients on prolonged treatment (author's tranls)]

Plasma levels of diphenylhydantoin have been measured in 130 epileptic patients undergoing long-term anticonvulsant therapy. Only in a small percentage of the patients (15,38%) plasma levels were found to lie within the therapeutic range. Most patients (75,38%) exhibited subtherapeutic values, while in a few cases (9,24%) the upper limit of therapeutic range was exceeded. Although plasma concentrations significantly correlate with the administered dose, predictability of plasma levels in the individual patients given fixed dosage schedules is strongly limited by large interindividual variability. Sex, age and simultaneous administration of other drugs seem not to affect significantly DPH plasma levels. Our observations carried out in a meaningful sample of epileptic patients suggest that at present the practice of monitoring diphenylhydantoin plasma levels is still an essential tool for the management of epilepsy when a safe and effective therapeutic regimen is required.     

Human epileptic brain Na, K ATPase activity and phenytoin concentrations.

An abnormal flux of monovalent cations may be related to the epileptogenic process in man. One possible mechanism for deranged electrolyte metabolism in epileptic brain is an abnormality in sodium, potassium-dependent adenosine triphosphatase (Na, K ATPase). We found the activity of Na, K ATPase to be significantly less in epileptic human corfex than in nonepileptic cortex. Histological changes have been simultaneously evaluated in epileptic brain. A second membrane-bound enzyme, acetylcholinesterase (AChE), was also assayed as a marker for neuronal membranes and found not to correlate with the epileptogenicity of human brain. In addition, the concentrations of the anticonvulsant compound phenytoin have been determined in the serum and cerebral cortex of epileptic and nonepileptic patients. The ratio of phenytoin in cortex to serum concentration is significantly lower in epileptic patients than in nonepileptic controls.