Effects of anticonvulsant drugs on thyroid hormones in epileptic children.

Serum total and free thyroid hormones, reverse T3 (rT3), thyroxin binding globulin (TBG) and thyroid stimulating hormone (TSH) concentrations were measured in 35 epileptic patients receiving anticonvulsants (phenobarbitone, phenytoin). There was a significant reduction found in total thyroxine (TT4), free thyroxine (FT4), total triiodothyronine (TT3), free triiodothyronine (FT3) and rT3 in the group treated with, phenytoin. The thyroid hormone levels were within normal limits in the group receiving phenobarbitone.     

Serum alkaline phosphatase isoenzymes in epileptic children receiving anticonvulsant drugs

In 40 epileptic children on long-term anticonvulsant treatment, serum alkaline phosphatase (AP) isoenzymes were separated semiquantitatively using a combination of L-phenylalanine inhibition and heat inactivation. Though mean total serum AP activity was significantly increased compared to age matched controls, only 4 individual values exceeded the upper limit (mean + 2SD) of the reference sample. In epileptics the mean activity of the heat-sensitive non L-phenylalanine sensitive AP fraction (non-LPSAP) was significantly increased (P<0.01) and the mean Q-value (i.e. percentage ratio of heat-stable non-LPSAP/non-LPSAP) was significantly decreased (P<0.05), thus indicating an enhancement of the bone isoenzyme during anticonvulsant treatment. In 4 patients the isoenzyme pattern was abnormal although total serum AP activity was normal and in 3 of them the deviation indicated enhanced bone isoenzyme. The data provide evidence that in anticonvulsant treated children the bone isoenzyme, rather than hepatobiliary isoenzyme fraction, may be increased even when total serum AP activity is normal. Thus, semiquantitative separation of serum AP isoenzymes may be a helpful guide as to whether or not an epileptic child should be given vitamin D.Supported in part by Deutsche Forschungsgemeinschaft (Ba 246/11)The data form part of the thesis of H. Günther, Medical School of Lübeck     

卡马西平对癫痫患儿甲状腺激素水平影响的临床观察

目的探讨卡马西平(CBZ)对癫痫患儿甲状腺激素水平的影响.方法对27例初诊为癫痫患儿行CBZ单药治疗前、平均治疗3个月后及25例长期行CBZ单药治疗平均1年7个月后的癫痫患儿,用放射免疫法分别测定血清甲状腺素(T4)、游离T4(FT4)、三碘甲腺原氨酸(T3)、游离T3(FT3)及促甲状腺激素(TSH)的水平,并以32例健康儿童作为对照.结果CBZ平均治疗3月后T4、FT4分别为(113.1±40.6)nmol/L和(16.6±3.6)pmol/L,均明显低于治疗前的(138.2±35.6)nmol/L(P<0.01)和(20.5±4.5)pmol/L(P<0.01).长期服用CBZ平均1年7个月的患儿与健康对照组相比,T4、FT4水平同样降低,分别为(108.9±44.6)nmol/L(P<0.05)和(15.5±3.7)pmol/L(P<0.001).结论甲状腺激素水平的改变与CBZ的肝酶诱导作用有关,提示CBZ治疗期间监测患儿甲状腺功能的必要性.     

Serum thyroid hormones and pituitary response to thyrotropin-releasing hormone in epileptic children receiving anti-epileptic medication

Thyroid hormones and pituitary function were assessed in 49 children with epilepsy who were receiving either a single medication of carbamazepine, phenobarbital and valproate or a combination of carbamazepine with phenobarbital or valproate. All therapeutic regimens except valproate monotherapy were associated with low levels of circulating thyroxine, free tri-iodothyronine and free thyroxine. Carbamazepine with valproate was associated with the lowest serum concentration of thyroid hormones. It seems probable that accelerated hormone metabolism is responsible for these hormonal changes. However, all drug regimens also had effects on the function of the hypothalamic pituitary axis. Because of these findings, thyroid hormones should be checked frequently during anti-epileptic drug treatment, although clinical hypothyroidism was not seen in our patients.     

癫癎患儿托吡酯治疗前后甲状腺激素水平的检测及分析

目的探讨托吡酯(TPM)对癫癎患儿甲状腺激素水平的影响.方法对51例癫癎间患儿用托吡酯进行单药治疗,在治疗前及治疗6个月后用放射免疫法分别测定其血清甲状腺素(T4)、游离T4(FT4)、三碘甲状腺原氨酸(T3)、游离T3(FT3)、3,3,5三碘甲状腺原氨酸(rT3)及促甲状腺素(TSH)的水平,并进行前后比较.结果在托吡酯治疗前T4、FT4、T3、FT3、rT3、TSH分别为(124.085±23.348)nmol/L、(17.489±3.965)pmol/L、(1.663±0.297)nmol/L、(5.825±1.82)pmol/L、(1.124±0.216)nmol/L、(4.599±1.317)μIU/mL.用托吡酯治疗后T4、FT4、T3、FT3、rT3、TSH分别为(123.201±25.155)nmol/L、(18.502±3.543)pmol/L、(1.598±0.356)nmol/L、(6.444±1.865)pmol/L、(1.315±0.195)nmol/L、(4.474±1.331)μIU/mL,T4、FT4、FT3、TSH治疗前后比较无显著性差异(P>0.05).T3治疗后较治疗前显著降低(P<0.05,t=3.125),而rT3治疗后较治疗前升高(P<0.05).结论托吡酯治疗时有降低癫癎患儿血清中T3的作用,提示在使用托吡酯治疗时应定期监测甲状腺功能.     

The effect of primidone treatment of thyroid hormones in epileptic children and adolescents (author's transl)]

In primidon-treated patients there are significantly decreased serum concentrations of total and free thyroxin, protein bound iodine and base line serum TSH values. In primidon-treated children T3-resin test values, concentration of thyroxin-binding protein and total cholesterol are identical to those of the control group. Degree of diminution in serum concentration of protein bound iodine, total and free thyroxin and base line TSH was independant of the primidon dose per day. Probably the demonstrated alteration in the thyroid function tests studied, is mainly caused by phenobarbital, the major metabolite of primidon and not directly by unmetabolized primidon. It is suggested that the high protein-binding capacity of phenobarbital results in a competitive displacement of protein bound thyroxin comparable to that of DPH. Phenobarbital is know to be a stimulator of the drug metabolizing enzyme system in the liver. This effect may be the cause of an increased turnover of T4 which results in a decreased serum concentration of total and free T4 at last. It seems possible that there is a balance in serum concentration of thyroid hormones on a lower level. Normal euthyroid state may be presumed, if T4-secretion raises, but there is no clue for an increased pituarity response. In contrast to the normal group in primidon-treated children the base line serum TSH values are decreased. It is supposed that another effect of primidon is responsible for this fact. There may be an influence of primidon treatment on hypothalamic pituarity axis. Our findings do not indicate clearly a hypothyroid state in primidon-treated patients; further investigations should give an answer to the guestion, if side effects as tiredness, decreased impetus and constipation are not partly caused by alterations in thyroid hormone system.     

常用抗癫癎药物对小儿机体诱变作用

目的　通过检测外周血淋巴细胞姊妹染色体交换 (SCE)频率及血清叶酸 (FA)水平 ,研究抗癫药物 (AEDs)对机体的诱变作用及其对FA代谢的影响 ,寻求抗诱变作用的途径。方法　选择癫患儿 90例 ,依据应用AEDs不同分组 ,检测各组用药前后SCE频率及FA水平 ,以及补充FA后两指标变化。结果　服用卡马西平 (CBZ)和丙戊酸钠 (VPA)的癫患儿 ,服药后较服药前血清FA明显降低 ,SCE频率显著升高 ,而补充服用FA后两指标有明显改善。结论　CBZ、VPA对小儿机体具有诱变作用 ,但硝基安定无明显诱变作用。FA能够减轻AEDs对机体的诱变作用。     

Prevalence and treatment of vitamin D deficiency in children on anticonvulsant drugs

Bone metabolism was studied in a group of adolescent epileptic children given anticonvulsant drugs and compared with a matched group of nonepileptic children living in the same institutional environment. Biochemical evidence of vitamin D deficiency was more common in treated children than in controls, and 3 out of 60 children taking anticonvulsants had radiological evidence of rickets. The signs of vitamin D deficiency could not be corrected by giving 5 μg (200 IU) cholecalciferol daily for 12 weeks, but disappeared after treatment with 75 μg (3000 IU) cholecalciferol weekly for a further 12 weeks. Thus, in a residential home in southeast England the increased nutritional requirement for vitamin D caused by the administration of anticonvulsants to adolescent epileptic children was of the order of 10 μg cholecalciferol per day. It is likely that all epileptic subjects on anticonvulsants have increased needs for vitamin D and we advise regular supplementation of their diets.It is also shown that serum concentrations of γ-glutamyl transpeptidase, 5′nucleotidase, and leucine aminopeptidase are raised in children taking anticonvulsants. It seems likely that this is caused by drug induction of membrane-bound enzymes in the liver.     

Parathyroid function and serum calcitonin in children receiving anticonvulsant drugs

Serum calcitonin (CT) levels and other aspects of calcium metabolism were investigated in 40 epileptic children receiving long-term treatment with phenytoin and/or other anticonvulsant drugs, and in 38 age-matched controls. In the patients CT levels were significantly lower. Immunoreactive parathyroid hormone (iPTH) was significantly elevated exceeding the upper limit of controls in 11 patients. We also observed a highly significant correlation between iPTH and urinary cyclic AMP (cAMP) excretion but a lack of such a correlation with the renal handling of phosphate; this indicates to us a dissociation between cAMP production and phosphaturia. A significant correlation between iPTH levels and urinary hydroxyproline excretion points to a normal action of PTH on bone in the patients. The low CT levels are not due to hypocalcemia and may be directly attributed to the effects of anticonvulsant drugs. As the primary effect of CT is a direct inhibition of PTH induced calcium loss from bone, the drug-related low CT levels in association with secondary hyperparathyroidism possibly is an additional factor in anticonvulsant bone disease.Dedicated to Prof. Dr. H.-R. Wiedemann on the occasion of his 65th birthday     

Urinary N-acetyl-beta-D-glucosaminidase in epileptic children treated with antiepileptic drugs

AIM—To investigate the effect of prolonged use of antiepileptic drugs on renal function in children.
METHODS—Prospective study of 72 children (aged 3-18 years) with epilepsy, on either monotherapy (n = 44) or combined therapy (n = 28). The length of treatment varied from 1 to 13 years. Drugs used were valproic acid, carbamazepine, ethosuximide, clonazepam, clobazepam, and vigabatrin.
RESULTS—In 65 patients plasma concentrations of the drugs were in the therapeutic range. In the remaining seven, plasma concentrations were slightly high. In 33 patients urinary N-acetyl-β-D-glucosaminidase (NAG) activity was raised. The incidence of pathological NAG indices was significantly higher in the combined therapy group than in the monotherapy group. There were also significant differences in the NAG indices of patients depending on the duration of therapy.
CONCLUSIONS—Results suggest that chronic use of some antiepileptic drugs—in spite of normal blood concentrations—may alter tubular function, and the dysfunction may result in clinical symptoms. Therefore, we recommend screening of tubular function in these patients.

     

Urinary N-acetyl-beta-D-glucosaminidase in epileptic children treated with antiepileptic drugs.

AIM: To investigate the effect of prolonged use of antiepileptic drugs on renal function in children. METHODS: Prospective study of 72 children (aged 3-18 years) with epilepsy, on either monotherapy (n = 44) or combined therapy (n = 28). The length of treatment varied from 1 to 13 years. Drugs used were valproic acid, carbamazepine, ethosuximide, clonazepam, clobazepam, and vigabatrin. RESULTS: In 65 patients plasma concentrations of the drugs were in the therapeutic range. In the remaining seven, plasma concentrations were slightly high. In 33 patients urinary N-acetyl-beta-D-glucosaminidase (NAG) activity was raised. The incidence of pathological NAG indices was significantly higher in the combined therapy group than in the monotherapy group. There were also significant differences in the NAG indices of patients depending on the duration of therapy. CONCLUSIONS: Results suggest that chronic use of some antiepileptic drugs-in spite of normal blood concentrations-may alter tubular function, and the dysfunction may result in clinical symptoms. Therefore, we recommend screening of tubular function in these patients.     

Relationship between serum leptin and thyroid hormones in children

BACKGROUND: Because leptin decreases food intake and increases energy expenditure, the possible influence of thyroid status on the leptin system has been investigated mainly in adults and animals. However, the data available at present are very confusing. The aim of the present study was to assess the possible interaction of thyroid hormones with the leptin system. METHODS: Serum free thyroxine (FT4), a biologically active thyroid hormone, and thyroid stimulating hormone (TSH), a sensitive and reliable index of thyroid status, were examined in 51 children (19 males, 32 females) with mass screening-detected congenital hypothyroidism on continuous L-thyroxine (L-T4) substitution therapy. The subjects were divided into younger (n = 35, aged 1 month-5 years) and older (n = 16, 6 years-11 years) children groups. Serum levels of leptin and thyroid hormones were measured in the subjects. Body mass index (BMI) was estimated by the formula bodyweight (kg)/height x height (m2), which is known as the Kaup index in younger children and BMI in older children and adults. RESULTS: In the younger children group, serum leptin levels showed no correlation with serum TSH, FT4 or T4. In the older children group, serum leptin concentrations significantly correlated with T4 (r = 0.510, P < 0.05) and BMI (n = 16, r = 0.647, P < 0.01), but not with TSH or FT4. CONCLUSION: The role of thyroid hormones in modulating leptin synthesis and secretion seems to have little, if any, clinical or biological relevance.     

Calcium metabolism and vitamin D metabolite levels in children receiving anticonvulsant drugs

Calcium metabolism and plasma concentrations of vitamin D metabolites were investigated in 27 children on long-term anticonvulsant therapy. Serum calcium was in the low normal range, phosphorus was normal, parathyroid hormone concentrations and alkaline phosphatase were elevated. Plasma 25-hydroxyvitamin D (25-OH D) and 24,25-dihydroxyvitamin D (24,25-(OH)₂D) were decreased, but 1,25-dihydroxyvitamin D (1,25-(OH)₂D) was normal when compared with a synchronous control group. The serum concentrations of all anticonvulsant drugs given were measured. The decreases in 25-OH D and 24,25-(OH)₂D did not depend on the blood level of a single drug, or any combination of drugs given, or on the duration of therapy. The 25-OH D levels were negatively correlated with the number of different drugs used, which may reflect the severity of the neurologic disorder, and therefore with non-specific factors such as exposure to sunlight, nutrition, or physical activity.Our data do not support the hypothesis that anticonvulsant drugs act on vitamin D metabolism.Dedicated to Prof. Dr. G.-A. von Harnack on occasion of his 65th birthday     

The psychological development of children of epileptic parents. II. The differential impact of intrauterine exposure to anticonvulsant drugs and further influential factors

After obtaining evidence that tetratogenic effects were operant in a sample of children born to epileptic mothers, we analyzed the effects of type of medication and further influential factors. Children with prenatal exposure to polytherapy had significantly lower scores than controls for a large number of psychological tests. In addition to polytherapy, there were even stronger effects of socioeconomic status and sex was found to be less influential than polytherapy. Among further epilepsy variables, only seizure frequency of the mother during pregnancy had a modest impact on the child's developmental outcome, whereas a score of obstetric abnormality was less effective in predicting developmental outcome, as measured and defined by various standardized psychological tests.     

A teratological evaluation of anticonvulsant drugs

Reviewing the important teratological data on anticonvulsants, the Hungarian experiences are reported. In the Hungarian Congenital Malformation Register use of the anticonvulsants diazepam and phenobarbiturates during pregnancy was determined in infants delivered with cleft lip with or without cleft palate, posterior cleft palate and, as a control, anencephaly and spina bifida. The teratogenic effect of diphenyl-hydantoin was confirmed, while that of diazepam and phenobarbital was not supported.