Thyroid hormones in epileptic children receiving carbamazepine and valproic acid

Carbamazepine and valproic acid are effective antiepileptic drugs for treating many types of epilepsy. Although they are well tolerated, many effects on endocrine function have been reported. Changes in serum thyroid hormones levels in 37 children with epilepsy during carbamazepine and valproic acid therapy were analyzed, and the thyroid hormone concentration after thyrotropin-releasing hormone test was evaluated. Serum thyroxine and free thyroxine levels were significantly lower in patients treated with carbamazepine and carbamazepine plus valproic acid than in the control subjects; serum thyroxine and free thyroxine concentrations were unaffected by valproic acid monotherapy. Serum triiodothyronine and free triiodothyronine concentrations were similar in the three groups of patients studied. Thyroid-stimulating hormone serum levels were normal in all patients, and the thyrotropin responses to the thyrotropin-releasing hormone were similar to control group. Our data suggest that children treated with carbamazepine may have subclinical signs of hypothyroidism, and these changes are more evident if carbamazepine is given in association with valproic acid, while no alteration in thyroid hormones can be found with valproic acid monotherapy. Thyroid-stimulating hormone and thyrotropin-releasing hormone levels do not seem to be affected by these drugs, suggesting that hypothalamic function is not affected in these children.     

Effects of valproic acid and levetiracetam monotherapy on carotid intima-media and epicardial adipose tissue thickness in non-obese children with epilepsy

ObjectiveThe aim of the study was to investigate the risk of subclinical atherosclerosis independent from obesity and high blood lipid levels in pediatric patients with idiopathic epilepsy receiving valproic acid or levetiracetam monotherapy by evaluating carotid intima-media thickness (CIMT) and Epicardial adipose tissue thickness (EATT).MethodsA total of 75 patients (38 males, 37 females; mean age 127.2 ± 37.9 months) with epilepsy receiving either valproic acid or levetiracetam monotherapy for more than 12 months (Epilepsy Group) and 75 sex, age, body mass index (BMI) matched healthy children (40 males, 35 females; mean age 133.8 ± 38.7 months) (Control Group) were included in the study. The mean duration of therapy was 27.6 ± 10.5 months. Serum lipid levels (total cholesterol, triglycerides, low density lipoprotein, high density lipoprotein) and CIMT-EATT of the patients and controls were assessed. Also, epilepsy group were divided according to antiepileptic drugs (valproic acid group and levetiracetam group).ResultsThe CIMT was determined as 0.6 ± 0.08 mm in epilepsy group and 0.49 ± 0.15 mm in control group (p < 0.001). The EATT was measured as 5.96 ± 0.8 mm in epilepsy group and 3.7 ± 0.5 mm in control group (p < 0.001). Of epileptic patients, 45 were using valproic acid monotherapy and 30 were on levetiracetam monotherapy. There was no significant difference in terms of CIMT between valproic acid and levetiracetam groups (0.61 ± 0.09 mm vs. 0.57 ± 0.07 mm; p = 0.07). EATT measurements were significantly higher in valproic acid group compared to levetiracetam group (6.14 ± 0.8 mm vs. 5.7 ± 0.7 mm; p = 0.02). CIMT and EATT values were not associated with the dosage and duration of each antiepileptic drug.ConclusionNon-obese children with epilepsy receiving valproic acid or levetiracetam monotherapy might have an increased risk for developing subclinical atherosclerosis despite normal lipid levels. The effect of valproic acid was more evident especially on EATT.     

Subclinical hypothyroidism during valproic acid therapy in children and adolescents with epilepsy

The aim of this study was to evaluate the incidence of thyroid dysfunction during valproic acid (VPA) therapy in children and adolescents with epilepsy. The serum levels of thyroid-stimulating hormone (TSH), free thyroxine, and triiodothyronine were evaluated in 61 children with epilepsy who received VPA monotherapy for more than 6 months and in 144 controls. We analyzed the effect of age, seizure type, duration of VPA treatment, dose of VPA, and serum level of VPA on thyroid function. The incidence of subclinical hypothyroidism was significantly higher in patients with VPA therapy than in controls (52.4 vs. 16.7%; p < 0.001). In addition, of the 61 patients, 5 (8.1%) exhibited TSH levels that were >10 μIU/mL. However, none of the patients and controls showed overt hypothyroidism. Serum VPA level and daily dose of VPA were correlated with TSH level. Subclinical hypothyroidism developed frequently in children and adolescents during VPA therapy.     

Cerebrospinal Fluid γ-Aminobutyric Acid Levels in Children with Different Types of Epilepsy: Effect of Anticonvulsant Treatment

The mean gamma-aminobutyric acid (GABA) level in lumbar CSF of 31 children with epilepsy was not significantly different from that of 41 age-matched controls. However, when the epileptic children were subdivided into untreated patients and patients treated with antiepileptic drugs, the medication-free subgroup had a significantly lower mean CSF GABA level than nonepileptic children. Patients controlled by anticonvulsant therapy had significantly higher CSF GABA levels than untreated epileptic patients. A more detailed analysis of the children taking antiepileptic medication indicated that the only drug that significantly increased GABA in CSF was valproic acid. Analysis of CSF data with respect to the seizure type of the patients showed that, compared with controls, significantly reduced average GABA levels were present in children with infantile spasms (mostly untreated) and unmedicated generalized tonic-clonic seizures, whereas treated children with generalized tonic-clonic seizures and patients with partial epilepsy (mostly treated) did not significantly differ from controls. The data provide further evidence that impairment of the central GABA system may be involved in human epilepsy.     

Duration of valproic acid monotherapy correlates with subclinical thyroid dysfunction in children with epilepsy

Aim. To identify potential risk factors for the development of subclinical hypothyroidism following long‐term valproic acid monotherapy in children with epilepsy. Methods. Serum levels of thyroid‐stimulating hormone, free thyroxine, free triiodothyronine, thyreoglobulin antibodies, and thyroid peroxidase antibodies were determined in 41 patients and in 41 sex‐ and age‐matched healthy children. Results. Mean valproic acid treatment duration was 2.80±1.96 years. The valproic acid group had higher serum thyroid‐stimulating hormone (p<0.001) and free triiodothyronine (p<0.05) levels compared to the control group. Serum thyroid‐stimulating hormone and free triiodothyronine were above the upper limit for healthy controls in 34% and 32% of patients, respectively, and no clinical features of thyroid dysfunction were observed. Duration of valproic acid monotherapy for less than four years was a risk factor for elevated thyroid‐stimulating hormone levels. Conclusion. One third of children with normal range serum valproic acid levels may have elevated serum thyroid‐stimulating hormone and free triiodothyronine levels, especially in the first four years of treatment.     

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.     

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.     

抑郁症患者治疗前后性激素水平的变化及与临床特征的关系

目的　探讨抑郁症患者治疗前后性激素水平的变化及其与临床特征的关系。方法　用酶联免疫吸附法测定 30例抑郁症患者治疗前、后血清雌二醇、孕酮、睾酮水平 ,并与 30名正常对照比较 ,同时作相关分析。结果　男性和女性抑郁症患者血清雌二醇水平均显著低于正常对照 (t=- 4 2 4 5 ,P <0 0 1;t =- 4 342 ,P <0 0 1) ,雌二醇水平与HAMD分和HAMA分呈负相关 (r =- 0 5 0 4 ,P <0 0 1;r =- 0 389,P <0 0 5 )。男性患者的睾酮水平显著低于正常对照 (t=- 2 319,P <0 0 5 ) ,而女性患者的睾酮水平与正常对照无显著差异 (t=0 5 6 9,P >0 0 5 )。抑郁症患者的孕酮水平无显著变化 (P >0 0 5 )。帕罗西汀治疗后 ,雌二醇水平显著升高 (t =- 4 335 ,P <0 0 1;t =- 4 0 14 ,P <0 0 1) ,但仍低于正常对照 (t=- 2 4 99,P <0 0 5 ;t=- 2 4 4 6 ,P <0 0 5 ) ,男性患者的睾酮水平恢复正常 ,孕酮水平及女性患者的睾酮水平治疗前后无显著变化 (P >0 0 5 )。治疗有效者比疗效不佳者的雌二醇水平显著增高 (t=4 12 7,P <0 0 1)。结论　抑郁症患者存在性激素水平改变 ,治疗后性激素水平仍未完全恢复正常 ,患者病前雌二醇水平与HAMD和HAMA分呈负相关 ,与抗抑郁疗效呈正相关。     

Serum concentrations of immunoglobulins in patients with epilepsy treated with carbamazepine

The concentrations of IgA, IgG and IgM were determined in sera of 16 patients, all of whom had partial epilepsy and had received CBZ as the only drug since the beginning of therapy. Fifty-three healthy subjects served as controls. Serum concentrations of IgA and IgG were significantly higher in patients than in controls (IgA: P = 0.05; IgG: P = 0.01). The concentration of IgM was not significantly different from that of the controls (P = 0.1). The IgG serum levels in the controls were lower with increasing age. Furthermore, IgG serum levels were higher with increasing CBZ concentrations.     

Biochemical evidence for osteomalacia with carbamazepine therapy

Many anticonvulsants are known to cause osteomalacia, however, carbamazepine has not previously been studied in this regard. We studied 31 patients on carbamazepine (mean dose 758 mg ± s.d. 468 mg per day), as a single drug for epilepsy for a duration of 20.5 ± 10 months. Three patients (10 %) had hypocalcaemia, and serum calcium was significantly lower ( P < 0.01)), and serum alkaline phosphatase significantly higher ( P < 0.05) than matched control subjects. Serum phosphorus was significantly inversely correlated and serum alkaline phosphatase was positively correlated with both dose and duration, but not blood levels of carbamazepine. These findings are consistent with mild biochemical changes of osteomalacia. None of the patients were symptomatic.
Serum bilirubin (mean 2.6 ± 1.4 μmol/l) was very significantly lower ( P < 0.01) than in controls. Both the calcium and bilirubin disturbances are probably due to carbamazepine causing hepatic microsomal enzyme induction.     

Levels of serum interleukin (IL)-6, IL-1beta, tumour necrosis factor-alpha and leptin and their correlation in depression

OBJECTIVE: To investigate the relationship between leptin and cytokines in depressed patients. METHODS: Thirty-three unmedicated patients (24 female, nine male) with depressive disorder and 23 healthy controls (16 female, seven male) were assessed for serum levels of interleukin (IL)-6, IL-1beta, tumour necrosis factor-alpha (TNF-alpha) and leptin. RESULTS: Levels of IL-6 and TNF-alpha in depressed patients were higher than in normal controls. There were significantly lower leptin levels in depressed patients than in normal controls. There were also significant differences in the leptin levels, being higher in female than in male patients, and in female than in male controls. CONCLUSIONS: IL-6 and TNF-alpha cytokines and leptin are important in the psychoimmunology of depressed patients. There were gender differences in leptin levels in depression.     

Hair zinc and copper concentration in patients with epilepsy

The concentration of zinc and copper in the hair of 55 patients with epilepsy was determined. The hair copper levels in patients with epilepsy were significantly lower than those in the normal control group (P less than 0.001). The hair zinc levels in female patients were significantly lower than those in the normal control group (P less than 0.05). In the following patients: (1) with generalized seizure, (2) with the disease course 0-5 years, (3) EEG showed heavy or middle abnormality, (4) had epileptic attacks within one year before the sample was taken, the zinc levels were also significantly lower compared with controls (P less than 0.05). Antiepileptic drugs had more effect on hair zinc than on copper. The increase in the hair zinc and copper and zinc: copper ratio seems to show the efficiency of drugs.     

癫痫患者血清中抗脑组织抗体的检测

补体结合试验对１１３例癫痫患者及６０例对照血清中抗脑组织抗体（ａｎｔｉ－ｅｎｃｅｐｈａｌｉｃａｎｔｉｂｏｄｙ，ＡＥＡｂ）进行检测，结果：１．癫痫患者ＡＥＡｂ阳性率为４２．２８％，明显高于对照组阳性率８．３３％（Ｐ＜０．０１）。２．原发性癫痫与继发性癫痫之间ＡＥＡｂ阳性率未见差异；ＡＥＡｂ阳性率与年龄、性别、是否用抗痫药亦无明显关系（Ｐ＞０．０５）。３．ＡＥＡｂ阳性率与癫痫病程长短有关（Ｐ＜０．０５）；与脑电图是否异常、用药效果、发作类型有关（Ｐ＜０．０１）     

Relationship of sexual dysfunction to epilepsy laterality and reproductive hormone levels in women

Sexual dysfunction has been reported to be common among women with epilepsy. Controlled studies, quantitative data, and investigations of potentially contributory factors, however, have been few. The purpose of this investigation was to determine if (1) sexual dysfunction is unusually common among women with partial seizures of temporal lobe origin (TLE), and (2) sexual dysfunction varies in relation to the laterality of EEG epileptiform discharges, antiepileptic drug use, and serum gonadal steroid levels. This controlled prospective investigation used a quantitative sexual rating scale and reproductive hormone measures to compare sexual dysfunction in women with left and right unilateral temporolimbic epilepsy and controls. Sexual dysfunction scores were significantly higher in women with TLE, and sexual dysfunction affected substantially more women with epilepsy than controls. Women with right-sided foci were affected more than women with left-sided foci. There was a significant inverse correlation between sexual dysfunction and bioactive testosterone levels in women with epilepsy as well as in controls. Serum estradiol was lower in women with TLE but did not correlate significantly with overall sexual dysfunction. The findings suggest that sexual dysfunction is significantly more common in women with right-sided epileptiform discharges than in controls and is inversely correlated with bioactive testosterone levels. The value of hormonal replacement or supplementation remains to be explored.     

托吡酯与卡马西平对成年癫痫患者甲状腺激素的影响

目的探讨托吡酯（TPM）及卡马西平（CBZ）对成年癫痫患者甲状腺激素水平的影响。方法选择新确诊的100例成年癫痫患者（50例服用TPM、50例服用CBZ）为试验组,用化学发光法测定用药前甲状腺激素水平并与40例成年健康对照进行比较；再经TPM、CBZ单药治疗3、6个月及1年后检测血中甲状腺激素水平,并与治疗前比较。结果未经治疗的癫痫患者甲状腺激素水平与正常对照组比较无显著性差异（P＞0．05）；与治疗前相比,CBZ治疗3个月、6个月及1年后的游离T4（FT4）、三碘甲状腺原氨酸（TT3）及CBZ治疗6个月及1年后的甲状腺素（TT4）显著降低（P＜0．05）,而CBZ治疗3个月的TT4与服用CBZ后各时点的游离T3（FT3）、促甲状腺素（TSH）无显著性变化（P＞0．05）；经TPM治疗后的不同时段的甲状腺激素水平与治疗前比较均无显著性差异（P＞0．05）。结论CBZ治疗可造成成年癫痫患者甲状腺激素水平的降低。癫痫本身及TPM治疗并不引起成年患者甲状腺激素水平的改变,表明TPM治疗对成年癫痫患者的甲状腺功能更安全。     

Effect of Phenytoin on Semen

Summary: Male patients receiving antiepileptic drugs (AEDs) have often complained of hyposexuality. Few studies have been done on semen analysis, which is relevant for assessment of potential and possible reproductive outcome in such cases. We evaluated the effect of epilepsy itself and/or phenytoin (PHT) on the male reproductive system. Fifty-five patients with epilepsy (42 with PHT and 13 untreated) and 28 healthy normal controls were studied by semen analysis. Serum samples from 21 of the 55 patients were also analyzed for testosterone, luteinizing hormone (LH), and follicle-stimulating hormone. Results showed lower volume of seminal fluid, spermatozoa concentration, and total sperm count in untreated and PHT-treated patients as compared with controls, although no difference was evident between the patient groups. Morphologically abnormal sperm were more increased in untreated patients than in PHT treated and control subjects. Hormonal analysis showed lower levels of testosterone in 9 patients. LH levels were increased in one third of the patients. Our results suggests an effect of seizures on the male reproductive system, and PHT may have a slight additive (if any) influence.     

Bone in idiopathic and symptomatic epilepsy

OBJECTIVE: Bone mineral density (BMD) is reduced in epilepsy and may underlie the observed increased fracture rate. Non-ambulatory patients have reduced BMD, although, it is not clear if normally weight bearing ambulatory patients are similarly vulnerable. DESIGN: Cross-sectional study examining age- and gender-specific z-score total bone mineral density (z-BMD) in 116 normally ambulatory children with epilepsy between ages 6 and 18 years (79 idiopathic epilepsy and 37 symptomatic epilepsy) were compared to 36 healthy controls. RESULTS: Both idiopathic and symptomatic epilepsies were associated with lower z-BMD (0.38+/-1 and 0.17+/-1, respectively) compared to controls (0.52+/-0.76). For both groups patients with generalized seizures had lower z-BMD than those with partial seizures. Symptomatic generalized epilepsy was associated with the lowest z-BMD (-0.15+/-1.1) compared to controls (p < 0.05). Increasing duration of symptomatic epilepsy, but not idiopathic epilepsy, was associated with lower z-BMD (correlation coefficient = 0.1; p < 0.01). CONCLUSIONS: Both idiopathic and symptomatic epilepsy are associated with reduced BMD. Those with symptomatic epilepsy, particularly symptomatic generalized epilepsy, had the greatest reduction in BMD despite normal weight bearing and ambulation. These data suggests that BMD is reduced in epilepsy beyond what can be explained by lack of ambulation and may underlie the vulnerability to fractures.     

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.     

血清尿酸与进行性核上性麻痹的相关性研究

目的探讨血清尿酸与进行性核上性麻痹(PSP)的相关性。方法收集71例PSP患者,选取70例健康人群为对照组。采用两独立样本t检验比较PSP组与健康对照组血清尿酸的差异,比较不同性别、PSP各亚型之间以及各亚型与对照组之间血清尿酸差异,采用Spearman分析PSP血清尿酸与Hoehn-Yahr分期、统一帕金森病(PD)评定量表第Ⅲ部分(UPDRSⅢ)评分及病程的相关性。结果 PSP组UPDRSⅢ评分、PSPRS评分明显高于健康对照组(P0.05)。而PSP组尿酸则明显低于健康对照组(P0.05)。按不同性别比较时,男性PSP组尿酸明显低于女性(P0.01),亦低于男性健康对照组(P0.01)。PSP各亚型尿酸均明显低于健康对照组(P0.05),差异均有统计学意义。Spearman相关分析,HY分期、UPDRSⅢ评分与尿酸呈明显负相关,而病程与尿酸呈显著负相关(P0.01)。结论血清尿酸减低可能与PSP患病相关,尤其是男性患者,血清尿酸越低,PSP患病越严重;尿酸作为抗氧化剂,对PSP患者可能具有一定的保护作用。     

Biochemical and behavioural phenotyping of a mouse model for GAMT deficiency

Deficiency of guanidinoacetate N-methyltransferase (GAMT) is the first described creatine (CT) deficiency syndrome in man, biochemically characterized by accumulation of guanidinoacetic acid (GAA) and depletion of CT. Patients exhibit severe developmental and muscular problems. We created a mouse model for GAMT deficiency, which exerts biochemical changes comparable with those found in human GAMT-deficient subjects. CT and creatinine (CTN) levels are significantly decreased and GAA is increased in knockout (KO) mice. In patients, other guanidino compounds (GCs) appear to be altered as well, which may also contribute to the symptomatology. Extensive evaluation of GCs levels in the GAMT mouse model was therefore considered appropriate. Concentrations of 13 GCs in plasma, 24-h urine, brain and muscle of GAMT mice were measured. We also report on the detailed behavioural characterization of this model for GAMT deficiency. Besides an increase of GAA and a decrease of CT and CTN in plasma, 24-h urine, brain and muscle of KO mice, we observed a significant increase of other GCs in brain and muscle that was sometimes reflected in plasma and/or urine. KO mice displayed mild cognitive impairment. In general, it could be concluded that the GAMT mouse model is very useful for biochemical research of GAMT deficiency, but shows only a mild cognitive deficit.