INTRODUCTION

Epilepsy, which is defined as a chronic condition characterized by recurrent (2 or more) seizures with an interval of more than 24 hours unprovoked by any immediate identifiable cause, it is a major health problem worldwide¹. Epilepsy is one of the most common neurological disorders of childhood affecting more than 6% of all children and has a major impact on a child’s development either due to epilepsy themselves or the medications that are used to treat epilepsy.

Treatment with antiepileptic agents has a lot of complications such as affecting the function of endocrine gland (e.g. thyroid) and bone marrow healthiness².

Many antiepileptic drugs can change the plasma levels of T3 & T4 such as Phenobarbital, phenytoin, carbamazepine and sodium valproate, these drugs are powerful inducers of liver microsomal enzymes which can result in changing the metabolism of thyroid hormones².

In various studies, different results have been achieved regarding the effects of antiepileptic medications on thyroid function tests^3-5. Thus, considering the high incidence of seizure in the first years of life and the high usage of antiepileptic agents and also the fact that thyroid gland dysfunction in neonates and children can lead to growth and developmental retardation.

The current study was carried out to evaluate thyroid function tests in male children who use antiepileptic drugs in an attempt to identify the drug with the least complication.   

MATERIAL AND METHODS

This analytical study was carried out in a cohort fashion without an external group on 42 male children with epilepsy; they had not received any antiepileptic medications prior to the study. Each child diagnosed clinically as having epilepsy (2 or more unprovoked seizures) and by EEG which was included in the study. Patients with disturbed thyroid function tests before study were excluded.

Inclusion criteria included new cases of epilepsy, no history of using antiepileptic medications or any other drugs that may affect thyroid function and with no history of endocrine, cardiovascular, metabolic or other chronic diseases.

All children subjected for thyroid function tests including TSH, T3, FT3, T4 and FT4. The normal range of T3, T4 & TSH plasma levels were 1.19-1.7 ng/ml, 5.5-12.5 Mg/dL and 0.4-4.0 uIU/ml respectively

All patients under treatment with antiepileptic agent including carbamazepine 20 mg/kg, phenobarbital 5 mg/kg and sodium valproate 25 mg/kg. Choosing the drug as regard to the seizure type. Three and six months after treatment with antiepileptic, thyroid function tests were re-evaluated.

Statistical Analysis

Data was analyzed with repeated measurement statistical test (Freedman model) using SPSS #13 software in order to compare the test results. A statistical lower limit of 0.05 was considered for significance in Friedman test. Significant results were processed with ANOVA test with a significance level of 0.017. Comparisons were made between plasma levels of hormones at baseline and after 3 and 6 months and also between plasma levels of hormones after 3 months and after 6 months (Tables 1).

RESULTS

Fifteen patients received carbamazepine therapy, 15 patients were treated with sodium valproate drug and 12 patients with Phenobarbital drug. The mean age of the patients was 7.62 years (minimum 4 and maximum 13 years old). The decrease in the plasma level of FT3 was only significant in the sodium valproate group, T4 plasma level decreased significantly in all 3 groups of carbamazepine, sodium valproate and Phenobarbital 3 and 6 months after treatment while FT4 plasma level decrease significantly only in the carbamazepine group 6 months after treatment. The results of ANOVA test showed that the increase in the plasma level of TSH was only significant in the sodium valproate group. Only subjects in the Phenobarbital group showed a significant decrease in T3 plasma level 3 and 6 months after the onset of treatment.

Table 1. Laboratory data in epileptic children treated with Carbamazepine, Sodium Valproate and Phenobarbital.

SD: standard deviation     P-value > 0.05 is significant

DISCUSSION

Various differences in thyroid function tests were seen in patients who received antiepileptic medications. Other studies have reached similar conclusion as Vainionpaa et al. (2004) compared plasma levels of thyroid hormone between 41 children treated with carbamazepine and 14 children treated with sodium valproate, with 54 healthy volunteers as the control group in Finland children treated with carbamazepine showed a significant decrease in plasma level of T3 and T4 but children treated with sodium valproate showed an increase in TSH level but the plasma levels of T3 & T4 were normal⁶.

Hegedus et al. (1989) compared 28 patients who were treated with carbamazepine and volunteers in the control group in Spain mean plasma level of T3 and T4 decreased in patients⁷. In these studies as well as the current study, significant decrease in T4 plasma level was seen in children treated with carbamazepine but no significant change in T3 plasma level was seen in them. Cansu et al. (2006) evaluated 55 children with epilepsy who were treated with sodium valproate and carbamazepine in Turkey. He suggested that in patients on carbamazepine treatment, plasma levels of FT4, T4, FT3and T3 decreased significantly (P<0.05). Also, in children receiving sodium valproate, plasma levels of FT4, T4, FT3 and T3 were within normal range and the same as baseline but TSH plasma level increased significantly 6 months after treatment (P<0.05)⁵.

In the current study, only patients treated with sodium valproate experienced a significant increase in the plasma level of TSH. However patients who were treated with carbamazepine showed an increase in the plasma level of FT3 and decrease in the plasma levels of T4 and FT4. Hirfanoglu et al., (2007) evaluated thyroid function between 12 children treated with carbamazepine and 31 children treated with sodium valproate in Turkey. T4 mean plasma level in patients treated with carbamazepine was significantly lower than the group treated with sodium valproate (P<0.016). TSH showed no significant difference in either group⁹. Tanaka et al. evaluated 287 children who received antiepileptic drugs (26 children treated with carbamazepine 63 children treaded with phenobarbital, 66 children treated with sodium valproate and 132 children treaded with several medications). A decrease in the mean plasma level of T4 and T3 was recorded in patients treated with carbamazepine and Phenobarbital but not in patients treated with sodium valproate¹⁰. Similar to the above-mentioned studies, in the our study, a decrease in T3 plasma level was seen in patients treated with phenobarbital as well as a significant decrease in plasma level of 14 in patients treated with carbamazepine and phenobarbital. Antiepileptic drugs has a central effects on the nervous system, some studies have examined the theory that antiepileptic drugs can decrease plasma level of hormones, because of their central effects on hypothalamo-pituitary-thyroid axis. Other limited studies^5-12 showed a decrease in the plasma levels of hormones due to the central disturbance induced by such medications, the majority of them^13-14 did not suggest any problems in the hypothalamo-pituitary-thyroid axis. Another hypothesis is that carbamazepine increases the metabolism of thyroid hormones through enhancing the cytochrome P450 enzymatic system in the liver⁶. From the above results, there are a variety of changes in the thyroid function tests in patients that receive antiepileptic drugs and most of them are related to sodium valproate, phenobarbital and carbamazepine. In our study patients who were treated with sodium valproate a significant increase in TSH level and a decrease in T4 and FT3 were obvious and in patients treated with carbamazepine, a significant decrease in T4 and FT4 were seen, and on the other hand patients treated with phenobarbital T3 and T4 significantly decreased.

Conclusion & Recommendation

The current study, phenobarbital had the least effect on thyroid hormones considering the effect of other medications (carbamazepine and sodium valproate) on thyroid function test, it is necessary to check, test and evaluate the plasma levels of thyroid hormones in children under antiepileptic drugs periodically after the beginning of antiepileptic drugs therapy.

[Disclosure: Authors report no conflict of interest]

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