The evaluation of thyroid functions, thyroid antibodies, and thyroid volumes in children with epilepsy during short-term administration of oxcarbazepine and valproate

PURPOSE: The aim of this study was to evaluate the effects of short-term oxcarbazepine (OXC) and valproate (VPA) monotherapy on thyroid functions in children. METHODS: Fifty-five newly diagnosed epileptic children with normal thyroid functions (confirmed with the thyrotropin releasing hormone stimulation test) participated in this study. VPA treatment was started in 30 patients and OXC in 25 patients. Serum thyroxine (T(4)), free thyroxine (fT(4)), triiodothyronine (T(3)), free triiodothyronine (fT(3)), reverse T3 (rT(3)), thyroid peroxidase antibodies (TPO-ab), and urine iodine levels were evaluated at baseline and at the third and sixth months of therapy. RESULTS: In the OXC group, serum T(4), fT(4), T(3), fT(3), and rT(3) levels were found to be decreased at the third and sixth months, the differences were significant compared to the baseline values except for fT(3) levels at the third month and fT(4) and rT(3) levels at the sixth month (p < 0.05). At the sixth month, serum T(4) level dropped below the normal reference value in 8 (32%), fT(4) in 5 (20%), T(3) in 4 (16%), and fT(3) in 3 (12%) patients. In the VPA group, mean T(4), fT(4), T(3), fT(3), and rT(3) levels at 3 and 6 months remained similar compared to the baseline values (p > 0.05). Mean serum thyroid stimulating hormone levels increased significantly at the sixth month compared to the baseline values in the VPA group (p < 0.05) while it remained unchanged in the OXC group (p > 0.05). There was no effect of either drug on urinary iodine excretion and serum TPO-ab levels remained in normal ranges throughout the study. CONCLUSIONS: In this prospective study, it is documented that children under short-term OXC or VPA therapy showed altered thyroid functions similar to the changes observed after long-term treatment. Although, the clinical significance of these results need to be evaluated with future studies, this observation of altered thyroid functions points out that thyroid functions may need to be monitored closely in children receiving antiepileptic treatment, even in the short-time interval.     

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.     

The effect of antiepileptic drugs on thyroid function in children

BackgroundLimited and conflicting data exist for the influence of antiepileptic drugs on thyroid function in children.ObjectiveThe aim of this study was to investigate the effects of phenobarbital, valproate, carbamazepine, oxcarbazepine, and levetiracetam monotherapy on thyroid function in daily clinical practice during a 12-month treatment period.MethodA total of 223 children (103 females and 120 males) with new onset and controlled epilepsy treated with valproate (n = 129), phenobarbital (n = 33), carbamazepine (n = 36), oxcarbazepine (n = 14), levetiracetam (n = 11) were enrolled in the study. Serum free thyroxine (fT4) and thyroid-stimulating hormone (TSH) levels were measured before and at first, sixth and twelfth months of therapy.ResultsAt baseline, average fT4 and TSH concentrations were not different between the drug groups. Valproate-treated patients had decreased fT4 and increased TSH levels at months 1, 6, and 12. Carbamazepine-treated patients had decreased fT4 levels at months 1, 6, and 12 and increased TSH levels at months 1, and 6. Phenobarbital-treated patients had decreased fT4 levels at months 1, and 6, and increased TSH levels at months 6 and 12. Oxcarbazepine-treated patients had decreased fT4 levels at month 1. Levetiracetam-treated patients showed no significant change of fT4 and TSH at any times. The frequency of subclinical hypothyroidism at month 12 was 28% in valproate, 21.4% in oxcarbazepine, 18.2% in phenobarbital, 13.9% in carbamazepine, and 0% in levetiracetam groups.ConclusionOur data suggest that all antiepileptic drugs studied except levetiracetam had varying degrees of deleterious effects on thyroid function.     

Long-term treatment of children with epilepsy with valproate or carbamazepine may cause subclinical hypothyroidism

PURPOSE: The aim of the study was to evaluate serum thyroid hormone balance in children receiving long-term therapy with carbamazepine (CBZ), valproate (VPA), and phenobarbital (PB). METHODS: We determined serum levels of triiodothyronine (T3), thyroxine (T4), free thyroxine (FT4), thyroxine-binding globulin (TBG), and thyroid-stimulating hormone (TSH) in 148 healthy children and 141 children with epilepsy who had been receiving CBZ (61 patients), VPA (51 patients), or PB (29 patients) for 12-161 months. In view of TSH values, three categories of subclinical hypothyroidism were considered: I, TSH greater than the control-group mean + 2 SD (4.37 mIU/L in our study) and <6 mIU/L; II, TSH between 6 and 12 mIU/L; and III, TSH >12 mIU/L. RESULTS: In all treated groups, mean T4 and FT4 levels were lower than in the control group, whereas the CBZ- and VPA-treated children additionally showed reduced mean T3 and TBG levels and increased mean TSH levels. In the group receiving CBZ, 8.2% had TSH values higher than the normal-range maximum, by comparison with only 3.6% of healthy children. The increase in TSH levels was particularly marked in VPA-treated children, accounting for 26% of patients with subclinical hypothyroidism. CONCLUSIONS: Our results, in contrast to previous reports, suggest that CBZ and particularly VPA may induce subclinical hypothyroidism. This suggests a need for careful monitoring of TSH levels in children receiving CBZ or VPA.     

Increased oxidative stress in epileptic children treated with valproic acid

PURPOSE: To determine influence of Valproic Acid (VPA) treatment on oxidative status in non-obese and overweight epileptic children. METHODS: A prospective study was conducted at the Departments of Pediatrics, University of Chieti and Bologna. Thirty-one epileptic children were studied before and after 1 year of therapy with VPA. Also 31 sex-, age- and BMI-matched healthy controls were evaluated. Insulin and glucose serum levels and plasma Vitamin E, Lag phase and Malondialdehyde (MDA) levels were determined. RESULTS: Before the beginning of VPA therapy, insulin and glucose serum values and plasma Vitamin E, Lag phase and MDA levels were normal in all subjects. At the end of follow-up, 11 (35.5%) epileptic patients developed obesity. In obese VPA treated patients, we found lower serum levels of antioxidant (Vitamin E, p<0.001) and higher levels of oxidant markers (MDA, p<0.001; Lag phase, p<0.001) compared to VPA-treated non-obese patients and controls. CONCLUSION: After 1 year of VPA therapy oxidative stress occurs only in overweight children. This increase in the levels of oxidant markers, probably caused by obesity, might contribute to the development of endothelial dysfunction and atherosclerosis later in life.     

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。     

Hypouricemia in severely disabled children: influence of valproic acid and bed-ridden state

Although hypouricemia does not directly elicit clinical symptoms, it is a sensitive indicator for detecting renal tubular involvement. To determine the influence of valproic acid (VPA) and a non-ambulatory state on the serum uric acid level in epileptic children, we performed a cross-sectional study of laboratory data including serum and urinary uric acid levels and renal tubular function levels in epileptic children. We studied 93 patients in our outpatient clinic. They were divided into four groups according to two factors; VPA administration and the ambulatory state: non-ambulatory patients taking VPA (24 cases), non-ambulatory patients not taking VPA (18 cases), ambulatory patients taking VPA (29 cases), and ambulatory patients not taking VPA (22 cases). The laboratory data including uric acid levels and renal tubular function in each group were analyzed statistically using analysis of variance. Both VPA (P<0.05) and a non-ambulatory state (P<0.01) significantly decreased the serum uric acid levels with its increased urinary excretion of uric acid. However, in ambulatory patients, the uric acid level was not decreased. Serum uric acid levels was significantly decreased in non-ambulatory, severely disabled children treated with VPA. It should be borne in mind that VPA-induced renal tubular dysfunction may be present in severely disabled children. However, further investigation is necessary to determine the factor in severely disabled children that causes hypouricemia     

Serum total amylase, pancreatic amylase and lipase activities in epileptic children treated with sodium valproate monotherapy

To investigate by a prospective, self-controlled method, whether early treatment with sodium valproate (VPA) monotherapy has some effect on serum total amylase and particularly on its pancreatic isoenzyme and lipase activities in epileptic children. Serum total amylase, pancreatic amylase and lipase activities have been evaluated in 23 epileptic children, before and at 6 and 12 months of VPA monotherapy. All children remained without clinical symptoms of pancreatitis during the period of study. Serum pancreatic amylase activities were significantly decreased at 6 and 12 months of treatment with VPA, whereas serum total amylase and lipase activities did not show any significant changes at 6 or 12 months of treatment. Non-pancreatic isoenzyme activities of amylase were significantly higher at 6 and 12 months of treatment. Three patients (13%) had slightly elevated serum total amylase levels at 6 and 12 months of treatment. There was no significant correlation of serum pancreatic amylase levels or non-pancreatic isoenzyme levels of amylase with serum VPA levels at 6 and 12 months of treatment. Non-pancreatic amylase activities, probably derived from salivary glands, may be increased in children treated with VPA monotherapy. Measurement of serum pancreatic amylase and/or serum lipase activities is indicated in patients with increased serum total amylase levels but without clinical symptoms of pancreatitis and, furthermore, in patients with symptoms suggesting dysfunction of pancreas, in order to avoid unnecessary discontinuing of VPA.     

Migraine and thyroid dysfunction: Co-occurrence,shared genes and biological mechanisms

Background and purpose

Migraine and thyroid dysfunction, particularly hypothyroidism, are common medical conditions and are known to have high heritability. Thyroid function measures, thyroid stimulating hormone (TSH) and free thyroxine (fT4), are also known to be genetically influenced. Although observational epidemiological studies report an increased co-occurrence of migraine and thyroid dysfunction, a clear and combined interpretation of the findings is currently lacking. A narrative review is provided of the epidemiological and genetic association evidence linking migraine, hypothyroidism, hyperthyroidism and thyroid hormones TSH and fT4.

Methods

An extensive literature search was conducted in the PubMed database for epidemiological, candidate gene and genome-wide association studies using the terms migraine, headache, thyroid hormones, TSH, fT4, thyroid function, hypothyroidism and hyperthyroidism.

Results

Epidemiological studies suggest a bidirectional relationship between migraine and thyroid dysfunction. However, the nature of the relationship remains unclear, with some studies suggesting migraine increases the risk for thyroid dysfunction whilst other studies suggest the reverse. Early candidate gene studies have provided nominal evidence for MTHFR and APOE, whilst more recently genome-wide association studies have provided robust evidence for THADA and ITPK1 being associated with both migraine and thyroid dysfunction.

Conclusions

These genetic associations improve our understanding of the genetic relationship between migraine and thyroid dysfunction, provide an opportunity to develop biomarkers to identify migraine patients most likely to benefit from thyroid hormone therapy, and indicate that further cross-trait genetic studies have excellent potential to provide biological insight into their relationship and inform clinical interventions.     

Effects of chronic mild stress (CMS) on thyroid hormone function in two rat strains

This work was carried out to assess the effects of chronic mild stress (CMS) on thyroid function. The CMS model produced an anhedonic effect (reduced preference to sucrose) in Sprague-Dawley and Wistar rats and this effect was reversed by imipramine (IMI) treatment. The effects of CMS on thyroid function were assessed by measuring tT4 (total Thyroxine), tT3 (total Triiodothyronine), TSH (Thyroid Stimulating Hormone) and fT4 (free Thyroxine) serum levels with appropriate immunoassays. CMS increased tT4 and tT3 serum levels in Sprague-Dawley and Wistar rats, but not TSH and fT4 serum levels. Imipramine (IMI) treatment normalized tT4 values. Albumin which binds a fraction of peripheral tT4 and tT3 was also significantly increased in response to CMS, possibly contributing to tT4 and tT3 elevations. The above findings suggest an impact of CMS on thyroid function, especially in tT4 values the changes being reversed with IMI treatment.     

Altered Thyroid Hormones and Behavioural Change in a Sub‐Population of Rats Following Chronic Constriction Injury

Hypothyroidism is associated with a disturbance of behaviour and mood. There are also individuals, not classified as hypothyroid, with low to ‘low normal’ thyroid hormone levels and normal thyroid‐stimulating hormone (TSH) levels who have mood and behavioural changes. As the peripheral thyroid hormones decrease, TSH is expected to increase. However, there are a number of physiological mechanisms known to suppress TSH. In the present study, we report on thyroid hormone regulation in a rat model of neuropathic pain and altered social behaviour that is usually transient, but is persistent in a sub‐group of the population. Following ligation of the sciatic nerve, male Sprague‐Dawley rats were assessed for social dominance towards an intruder: 20% showed persistently decreased social dominance. Plasma levels of thyroid hormones, TSH and corticosterone were measured before and on days 2, 3, 4, 5 and 6 after injury in 21 rats. The mean plasma thyroxine (T4), free thyroxine (fT4) and triiodothyronine (T3) levels decreased significantly post‐injury in rats with persistently changed behaviour compared to rats with unchanged behaviour (P ≤ 0.002). There was no significant difference between groups for mean change in free triiodothyronine (fT3) or TSH. There was a correlation between decreased dominance behaviour and decrease in both T4 (r = 0.62, P = 0.009) and fT4 (r = 0.71, P = 0.001), but no correlation with TSH. In a sub‐population of rats, decreased thyroid hormones did not result in the expected increased levels of TSH to restore pre‐injury levels, nor did they show increased hypothalamic thyrotrophin‐releasing hormone mRNA expression, indicating altered hypothalamic‐pituitary‐thyroid axis regulation. Because T3 availability to the brain is dependent on both circulating T3 and T4, decreased peripheral thyroid hormones may result in changed neural function, as expressed in altered complex behaviours in this sub‐population of rats.     

Renal tubular function in patients receiving anticonvulsant therapy: a long-term study

PURPOSE: The goal of the study was to evaluate the tubular renal function in children and adolescents who are undergoing monotherapy with sodium valproate (VPA), carbamazepine (CBZ), and phenobarbital (PB). METHODS: The urinary excretion of N-acetyl-beta-glucosaminidase (NAG), beta-galactosidase (beta-Gal), alanine-amino-peptidase (AAP), and alpha1-microglobulin (alpha1M) was measured in 58 epileptic patients (29 girls and 29 boys), aged 12.6 +/- 3.9 years, who were subdivided into three groups according to their therapy. Fifty healthy sex-and age-matched children served as controls. The measurements were taken before the beginning of therapy and after 6 months, 1 year, and 2 years of therapy. RESULTS: Before the beginning of therapy, there were no significant differences in NAG, beta-Gal, AAP, and alpha1M values between the control group and the three groups of epileptic children. After 6 months of therapy, patients treated with VPA and CBZ showed a significant increase in the urinary excretion of NAG and beta-Gal compared with baseline data and control values. After 1 and 2 years, these patients showed a persistence of the changes found after 6 months of therapy. In patients treated with PB, we did not find any significant variation in NAG, beta-Gal, AAP, and alpha1M urinary excretion. CONCLUSIONS: Our study demonstrates that in patients treated with VPA and CBZ, an impairment of tubular function can be present, whereas PB does not cause any significant change.     

Thyroid dysfunction in children with autism spectrum disorder is associated with folate receptor α autoimmune disorder

Folate receptor α (FRα) autoantibodies (FRAAs) are prevalent in autism spectrum disorder (ASD). FRAAs disrupt folate transport across the blood‐brain barrier by binding to the FRα. Thyroid dysfunction is frequently found in children with ASD. We measured blocking and binding FRAAs and thyroid‐stimulating hormone (TSH), free thyroxine (T4) (FT4), total triiodothyronine (T3) (TT3), reverse T3 (rT3), thyroid‐releasing hormone (TRH) and other metabolites in 87 children with ASD, 84 of whom also underwent behaviour and cognition testing and in 42 of whom FRAAs, TSH and FT4 were measured at two time points. To better understand the significance of the FRα in relation to thyroid development, we examined FRα expression on prenatal and postnatal thyroid. TSH, TT3 and rT3 were above the normal range in 7%, 33% and 51% of the participants and TRH was below the normal range in 13% of the participants. FT4 was rarely outside the normal range. TSH concentration was positively and the FT4/TSH, TT3/TSH and rT3/TSH ratios were inversely related to blocking FRAA titres. On repeated measurements, changes in TSH and FT4/TSH ratio were found to correspond to changes in blocking FRAA titres. TSH and the FT4/TSH, TT3/TSH and rT3/TSH ratios were related to irritability on the Aberrant Behavior Checklist and several scales of the Social Responsiveness Scale (SRS), whereas TT3 was associated with SRS subscales and TRH was related to Vineland Adaptive Behavior Scale subscales. The thyroid showed significant FRα expression during the early prenatal period, although expression decreased significantly in later gestation and postnatal thyroid tissue. The results of the present study suggest that thyroid dysfunction in ASD may be related to blocking FRAA. The high expression of FRα in the early foetal thyroid suggests that foetal and neonatal exposure to maternal FRAAs could affect the development of the thyroid and may contribute to the pathology in ASD.     

Valproate reduces spontaneous generalized spikes and waves but not photoparoxysmal reactions in patients with idiopathic generalized epilepsies

Purpose: Patients with idiopathic generalized epilepsies (IGEs) often present with interictal spike‐wave discharges (SWDs) at rest (spontaneous SWDs), during hyperventilation, and in response to photic stimulation (photoparoxysmal response or PPR). Valproic acid (VPA) is a first‐line antiepileptic drug for therapy of patients with IGE. Herein we investigated the effect of VPA on all three types of SWDs in children and adolescents with IGE. Methods: Routine electroencephalography (EEG) during wakefulness, which was recorded before VPA monotherapy and up to four times during the first year of the VPA treatment, was analyzed retrospectively. For the analysis of the VPA effect on spontaneous SWDs and SWDs under hyperventilation, the number and duration of SWDs were counted. SWDs under intermittent photo stimulation (IPS) were classified according to the extent of propagation (grading). Response to VPA treatment (rest/hyperventilation) was defined as a disappearance of SWDs within the year after VPA introduction. Key Findings: Eighty‐four patients (37 male and 47 female, mean age 9.5 ± 4.1 years) exhibited spontaneous SWDs or SWDs under hyperventilation. From this sample, 34 patients exhibited the PPR (7 male and 27 female, mean age 10.1 ± 3.9 years). A significant reduction in the number and duration of spontaneous SWDs and SWDs under hyperventilation was observed in the first 6 weeks of treatment (p ≤ 0.001, corrected, 87.3% responders). This effect remained stable over the 1 year observation period. Concerning PPR, only 4 (12.9%) of 31 patients were classified as responders. The difference between groups of patients with spontaneous/induced SWDs and PPR according to the number of responders was significant (p < 0.001). Significance: This study provides evidence that the effect of VPA on SWDs differs dependent on the types of SWDs. In the majority of patients, spontaneous SWDs and SWDs induced by hyperventilation disappeared, whereas the PPR mostly remained under VPA treatment. These results point to different pathogenetic mechanisms underlying the spontaneous and the evoked generalized epileptic activity in the EEG.     

Serum copper, zinc, selenium, glutathione peroxidase and superoxide dismutase levels in epileptic children before and after 1 year of sodium valproate and carbamazepine therapy

To assess whether epileptic children have abnormal values of serum copper (Cu), zinc (Zn), selenium (Se), glutathione peroxidase (GSH-PX) and superoxide dismutase (CuZn-SOD), and to evaluate the effect of long-term therapy with sodium valproate (VPA) and carbamazepine (CBZ) on these parameters, we studied 36 epileptic patients before the beginning of therapy and after 1 year of therapy with VPA or CBZ. Before the beginning of therapy, there were no differences in levels of all parameters studied between controls and epileptics. After 1 year of therapy, patients treated with VPA and CBZ continued to show normal values. In conclusion our study demonstrates that epilepsy per se and treatment with VPA and CBZ do not affect levels of Cu, Zn, Se, GSH-PX and CuZn-SOD concentrations.     

Thyroid function in patients with Alzheimer disease: implications on response to anticholinesterase treatment

Increasing evidence supports an extensive interrelationship between thyroid hormones and the cholinergic system, which is selectively and early affected in Alzheimer disease (AD). The aim of the present study was to explore thyroid function in patients with AD before and after acetylcholinesterase inhibition treatment to possibly identify variances in response. Thyroid function tests were evaluated in 28 AD patients and 24 age and sex-matched controls. Nineteen of the patients were reevaluated after (4 mo) treatment with donepezil. Serum thyrotropin (TSH), triiodothyronine (T3), thyroxine (T4), the free fractions (fT3, fT4) and thyroid autoantibodies were determined using standard methods. All subjects were clinically euthyroid. Patients presented with higher fT4 and anti-thyroperoxidase levels, as compared with the controls. Significant reduction in T4, fT3, fT4, and anti-thyroperoxidase levels were observed 4 months after treatment. Responders had higher T4 and fT4, than nonresponders, followed by significant reductions after treatment. The above, within the normal range alterations, may represent a direct effect on hormone release from the thyroid gland and/or increased conversion of T4 to T3 within the brain. Higher T4 and fT4 levels before treatment might predict a favorable response to donepezil treatment.     

Valproate (VPA) Metabolites in Various Clinical Conditions of Probable VPA-Associated Hepatotoxicity

Summary: Of a cohort of 470 epileptic patients in whom valproate (VPA) serum metabolites had been measured, 170 subjects without symptoms or signs of hepatic side effects were chosen as a reference group to establish the usual metabolic pattern. A wide interindividual variation of VPA metabolite concentrations was noted. Infants receiving VPA monotherapy and comedication with other antiepileptic drugs (AEDs) showed lower concentrations of the potential hepatotoxin 4-ene-VPA than did older children. In 11 patients with early symptoms and signs of possible fatal VPA-associated hepatotoxicity, the following spectrum of benign clinical conditions was observed: unusually severe side effect during initiation of VPA therapy (1 patient), high VPA dosage (2 patients), reversible impairment of coagulation with bleeding manifestations in association with a slight increase in transaminase levels (1 child), and reversible liver dysfunction associated with febrile illness (7 patients). Reversible or irreversible fulminant liver failure had occurred in 5 children. Three of the 4 children with a fatal outcome had massive lactic acidosis. In all patients with probable VPA-associated hepatotoxicity, some aspects of VPA metabolism differed distinctly from that of the reference group, but the interindividual profile of metabolites varied considerably, even in the subgroup of 4 children who died. Impairment of VPA β-oxidation and increase of metabolites of alternative metabolic pathways (ω- and ω1-hydroxylation, dehydrogenation reactions) were the most frequent findings. Increased values of 2-n-propyl-4-pentenoic acid metabolite of VPA (4-ene-VPA), could be detected only in 1 of the 5 patients with fulminant liver failure and in one other child with a slight hepatic dysfunction, indicating that this VPA metabolite is not the decisive hepatotoxin or indicator of hepatotoxicity. Because we cannot distinguish between benign and life-threatening hepatic adverse reactions on the basis of VPA metabolites, all identified changes are considered secondary to an as-yet-unknown primary metabolic event. The most toxic compound could be VPA itself, which may unmask an inborn or an acquired metabolic defect in the processing of fatty acids.     

No effect of long-term valproate therapy on thyroid and parathyroid functions in children

In this study, we studied serum calcium, phosphorus, alkaline phosphatase, thyroid hormones (total thyroxine, free thyroxine, thyroid-stimulating hormone), parathyroid hormone, and osteocalcine levels in children with epilepsy who had been receiving long-term valproate (VPA) therapy in order to determine whether there was any effect of VPA therapy on these hormones. The study included 31 patients with epilepsy receiving VPA and 22 healthy age-matched controls. The age ranged from 15 months to 16 years and 18 months to 17 years in the study and control group, respectively. The duration of VPA use was between 12 months and 5 years (1.93 +/- 1.90 years). When comparing the results, we did not find any significant difference in any of the parameters, including serum calcium, phosphorus, alkaline phosphatase, osteocalcine, and thyroid and parathyroid hormone levels, between the study and control group. We suggest that VPA can safely be used with regard to thyroid and parathyroid dysfunction in childhood epilepsy.     

Computerized Analysis of EEG Background Activity in Epileptic Patients

Background activity was studied in 128 idiopathic epilepsy patients and 30 normal controls using EEG topography and t-statistic significance probability mapping (t-SPM). In epileptic patients, EEG background activity showed a marked increase in delta, theta, alpha 1, and beta 1, and a decrease in alpha 2 activity as compared with controls. Untreated epileptic patients had a significant increase in delta, theta, and alpha 1 as compared with controls. For epileptic patients treated with antiepileptic drugs (AEDs), the most marked slowing was observed in the polytherapy group, followed by the monotherapy group and then the untreated group. Among seizure types, patients with partial seizures (PS) tended to exhibit more slowing than patients with only generalized tonic-clonic seizures (GTC). Moreover, PS had a right-left asymmetry in alpha 2 and beta 1 activities. In a comparison of AEDs, patients receiving carbamazepine (CBZ) and phenobarbital (PB) showed no significant difference as compared with the untreated group. In contrast, patients receiving valproate (VPA) showed a decrease in slow and fast activities. EEG changes associated with each AED were different in GTC and PS. Patients receiving VPA for GTC showed a decrease in theta and beta 1 activities, but those with PS showed a decrease only in delta activity.     

Treatment of Intractable Childhood Epilepsy with High-Dose Valproate

Forty-six children with refractory epilepsy (12 with symptomatic generalized epilepsy, 14 with symptomatic partial epilepsy, and 20 with undetermined epilepsy) were treated by high-dose (serum level above 100 micrograms/ml) valproate (VPA) therapy. Monotherapy was used with 34 patients and two drugs with 12. Serum VPA concentrations ranged from 105.1 to 198.4 micrograms/ml. Assessment of initial response to treatment, after the serum level had reached the appropriate level, showed seizures to be completely controlled in 15 (32.6%) of 46 patients and improved in 12 (26.1%) (50% or more). Follow-up of more than 6 months after the time of initial response showed control of seizures in 14 (30.4%) and improvement in 11 (23.9%). The initial effect on EEG was the disappearance of epileptic discharges in 3 (6.5%) of 46 patients and marked improvement in 15 (32.6%). Follow-up revealed the disappearance of epileptic discharges in 7 (15.2%) and marked improvement in 9 patients (19.6%). High-dose VPA therapy was especially effective for West syndrome and for epilepsy with continuous spike-waves during slow-wave sleep. Control of atypical absences and myoclonic seizures was relatively good. Hypofibrinogenemia and thrombocytopenia were sometimes encountered but these side effects were reversible with reduction of dosage.