INTRODUCTION

 

Both seizures and antiepileptic drugs may induce disturbances in hormonal system¹. Treatment with antiepileptic drugs (AEDs) is associated with multiple short and long term effects. Effect on endocrine, in particular, alteration of thyroid function, is an example of these side effects. Many AEDs may alter thyroid hormone homeostasis at the level of biosynthesis, release, transport, metabolism and excretion of thyroid hormones^2,3. Subclinical hypothyroidism (SH) refers to a state in which patient may exhibit the symptoms of hypothyroidism. These patients also have a normal amount circulating triiodothyronine (T3) and thyroxin (T4). The only abnormality is an increased TSH on their blood work >4.50 micron IU/ml⁴. The majority of these patient can be expected to progress to obvious hypothyroidism especially if thyroid-stimulating hormone-(TSH) level is >5 micron IU/ml⁵. Some reports suggest that antiepileptic drugs, like carbamazepine, are well known to affect serum concentrations of thyroid hormones in a way similar to phenytoin to induce hypothyroidism⁶. Carbamazepine reduces levels of circulating T4, both total (TT4) and free

 

 (FT4), exerts variable effects on T3-again total (TT3) and FT3^7-9, due to their hepatic enzyme induction properties which lead  to increase clearance of thyroid hormones¹⁰.  Valproate did not seem to have the same effect on thyroid function as it was not a hepatic enzyme inducer¹¹.

The aim of this study was to evaluate the possible relation between the commonly used antiepileptic drugs and subclinical hypothyroidism.

 

PATIENTS AND METHODS

 

The present study was conducted on 130 epileptic patients recruited from the outpatient clinic of neurology and psychiatry department in El-Minia University Hospital and Insurance hospital and 50 healthy person served as a control group. The patients were classified according to the type and duration of therapy in the way shown in Table (1).

Inclusion criteria: patients presented with two or more unprovoked seizure above the age of 18 years of both sex.

Exclusion criteria: Patients presented with any neurological or psychiatric disorder other than epilepsy, thyroid disease, patients with positive antithyroidal antibodies, past history of radioiodine therapy or any surgical procedure of thyroid gland, pregnancy as well as liver or kidney disease.

Table 1. Classification of patients according to type and duration of therapy.

 

 

 

All the participants will be subjected to the following:

1.      Full history taking: Careful history including (family history, past history) taken from the patients or near relative, drug history including patient compliance, type, dose and duration of therapy, seizure characterization including age at onset, frequency and seizure type (only for patients).

2.      Clinical examination: General and neurological examination, assessment of  height, weight, and body mass  index (BMI)^12,13, assessment of subclinical hypothyroidism by using  Scoring  of symptoms and signs of  hypothyroidism (a valuable tool for estimation of tissue hypothyroidism at peripheral target organs)¹⁴.

3.      Laboratory investigations: Assessment of thyroid functions (TSH, total T3 and T4), assessment of lipid profile and digital electroencephalogram (only for patients).

 

Statistical Methodology

Data Obtained were fed into a computer software package (SPSS, version 13) through which, descriptive statistics were calculated. Descriptive statistics i.e. mean (M), standard deviation (SD), range; minimum and maximum reading and frequency were calculated. To test the 2- tailed significance of differences in means, student T-test for Independent samples for 2 groups and One-Way Analysis Of Variance (ANOVA) test for comparison between more than 2 groups were used.  A probability of (P) ≤ 0.05 is accepted as significant. Pearson Correlation Coefficient TEST “R” was calculated to measure the strength of association between quantitative data.

 

RESULTS

 

The mean duration of illness was 6 months-25 years (5.70±6.52 years). We found statistically significant positive correlations between duration of treatment and cholesterol level and the scoring of symptoms and signs of hypothyroidism as shown in Table (2). Our results show that, there is a significant increase in TSH level and Scoring of symptoms and signs of hypothyroidism in epileptic patients on long term therapy compared to control group (Table 3). We classified the epileptic patients on long term therapy into 3 subgroups according to type of antiepileptic treatment. We found that, mean TSH level (±SD) was increased in patients receiving phenytoin compared to valproate and carbamazepine without significant difference. In comparing the mean Scoring of symptoms and signs of hypothyroidism (±SD), in the monotherapy group, it was increased in patients receiving valproate more than patients receiving carbamazepine and phenytoin and the difference was statistically significant as shown in Table (4). There was a statistically significant   increase in TSH levels and a statistically insignificant increase in mean ± SD of clinical score of symptoms and signs of hypothyroidism in epileptic patients receiving polytherapy than monotherapy as shown in Table (5). We found the number of epileptic patients with subclinical hypothyroidism had increased in polytherapy (4 patients out of 21) (19.04%) more than those receiving monotherapy (3 patients out of 59) (5.08%). There was a statistically significant positive correlation between TSH level and cholesterol level in epileptic patients on long term therapy as shown in Figure (1). In the group of patients receiving a monotherapy treatment and on long term therapy, we found 2 patients (10%) on valproate to have subclinical hypothyroidism, one patient (5%) on carbamazepine and no one on phenytoin had subclinical hypothyroidism (Table 8). In the recently diagnosed group, we found a statistically significant increase of the mean ± SD of TSH level and Scoring of symptoms and signs of hypothyroidism after taking antiepileptic drugs for six months (regardless of the type of antiepileptic drug) (Tables 6 and 7). We found 4 patients (20%) on valproate to have subclinical hypothyroidism, 3 patients (15%) on carbamazepine and one on phenytoin had subclinical hypothyroidism (14.3%) (Table 8).

Table 2. Correlation between duration of treatment, thyroid hormones and scoring of symptoms and signs of hypothyroidism.

 

Table 3. Long term antiepileptic therapy effect on thyroid hormones and scoring of symptoms and signs of hypothyroidism.

 

	Group of patient	Mean± SD	P-value
TSH level (Normal TSH level o.45-4.50 uIU/ML)	Control (n=50) Epileptic patient (n=80)	1.86±0.90 2.25±1.26	0.04*
Total T3 level (Normal T3 level 87-180 ng/dl)	Control (n=50) Epileptic patient(n=80)	134.6±23.8 124.7±40.67	0.07
Total T4 level (Normal T4 level 5.6- 13.7 ug/dl)	Control (n=50) Epileptic patient(n=80)	9.44±2.33 9.41±2.72	0.90
Scoring of symptoms and signs of hypothyroidism	Control (n=50) Epileptic patient(n=80)	1.34±1.14 2.41±1.35	0.000**

*significant at p<0.05 **significant at p<0.01

 

Table 4. Effect of long term use of different antiepileptic drugs on thyroid hormones.

*significant at p<0.05

 

Table 5. Comparison between the effect of long term monotherapy and polytherapy on thyroid hormones and Scoring of symptoms and signs of hypothyroidism.

*significant at p<0.05

 

Table 6. Comparison between thyroid hormone level in epileptic patients before treatment and 6 months after treatment.

		Mean±SD	P-value
TSH level (Normal TSH level o.45-4.50 uIU/ML)	Before treatment After 6 month of treatment	2.35 ±73 2.99±96	0.000*
Total T3 level (Normal T3 level 87-180 ng/dl)	Before treatment After 6 month of treatment	149.4±25.3 1465±134.4	0.5
Total T4 level (Normal T4 level 5.6- 13.7 ug/dl)	Before treatment After 6 month of treatment	9.2±1.7 9.1±2.90	0.07
Scoring of symptoms and signs of hypothyroidism	Before treatment After 6 month of treatment	1.8±1,18 2.6±1.17	0.000*

*significant at p<0.01

Table 7. Effect of antiepileptic drugs on TSH level 6 months after initiation of therapy.

 

*significant at p<0.05 **significant at p<0.01

 

Table 8. The frequency of subclinical hypothyroidism in patients receiving different antiepileptic drugs.

 

 

 

 

Figure 1. Correlation between TSH level and cholesterol level in patients on long term therapy.

 

 

DISCUSSION

 

We found a statistically significant increase in TSH level in epileptic patients on long term therapy than in control group. This result  is in partial agreement with Mikko et al.¹⁵  who studied thyroid status of epileptic patients receiving long term anticonvulsant and found that the mean concentration of T4 but not T3 of patients were significantly lower than those of control group, and  mean concentration of TSH of patients was slightly but  significantly higher in patients than  control group.

On comparing epileptic patients and control group as regard scoring of symptoms and signs of hypothyroidism, there was a highly statistically significant increase in Scoring of symptoms and signs of hypothyroidism in epileptic patients on long term therapy than control group (p<0.000). This result is in agreement with previous studies of Verrotti et al.⁸, who found that epileptic patients on carbamazepine and valproate treatment had subclinical signs of hypothyroidism.  Our study shows that there was a positive correlation between duration of treatment and TSH, Cholesterol, triglyceride levels, and the Scoring of symptoms and signs of hypothyroidism. This result is in agreement with Mikati et al.⁵, who found one of the predictors of subclinical hypothyroidism is the duration of treatment between 6 and 24 months. Analysis of the result shows that epileptic patients receiving polytherapy had an increase in the mean level of TSH hormone, Scoring of symptoms and signs of hypothyroidism than epileptic patients receiving  monotherapy, this result is in agreement with Chakova  et al.¹⁶, who found an increase  in the thyroid hormones (including TSH) concentration  in epileptic  patients receiving antiepileptic drugs and these changes were significantly more common in patients undergoing anticonvulsant polytherapy. We also found that epileptic patients during treatment with valproate, carbamazepine, and phenytoin had an increase in the level of TSH. Also this result is in accordance with Mikko et al.¹⁵ and  Simko et al.¹⁰, who found that carbamazepine, phenytoin  increased  TSH level. This result is in partial agreement  with  previous studies done by Verroti  et al.⁸, who found that carbamazepine increase TSH level,  but valproate has variable effect on TSH level.

Analysis of the result shows that  epileptic patients on long term therapy  had a risk of hypercholesterolemia.  This result is in agreement with Mikko et al.¹⁵, who studied thyroid status of patients receiving long term anticonvulsant therapy assessed by peripheral parameters and  found that the mean serum TSH  concentration was slightly increased with increase the clinical score of subclinical hypothyroidism and that was associated with hypercholesterolemia. Studies in children undergoing long-term valproate therapy have shown a significantly higher level of TSH compared to controls.¹⁷ Higher levels of TSH, with normal T3 and T4, were  also seen in girls undergoing  valproate monotherapy⁹. Contradictory to this, some reports suggest that though antiepileptic drugs like carbamazepine and phenytoin have been found to induce hypothyroidism, due to their hepatic enzyme induction properties which lead to increased clearance of thyroid  hormones, valproate did not seem to have the same effect on thyroid function as it was not a hepatic enzyme inducer¹⁸. In case of long term therapy, we found 2 patients (10%) on valproate to have subclinical hypothyroidism, one patient (5%) on carbamazepine and no one on phenytoin had subclinical hypothyroidism. This was in disagreement with previous studies^8,9,10 which found carbamazepine to have the higher frequency of secondary subclinical hypothyroidism. Regarding the recently diagnosed epileptic group in this study the  risk of subclinical hypothyroidism increased in  patients recently diagnosed as epileptic after taking antiepileptic drugs as regard TSH level and Scoring of symptoms and signs of hypothyroidism. We found 4 patients (20%) on valproate to have subclinical hypothyroidism, 3 patients (15%) on carbamazepine and  one on phenytoin   (14.3%) had subclinical hypothyroidism. This result is in agreement with  previous studies performed by Simko et al.¹⁰, Castro Gago et al.¹⁸,  Isojarvi et al.¹⁹, who found that epileptic patients after receiving antiepileptic drugs may precipitated subclinical hypothyroidism. On the other hand , this result is in disagreement with  previous study by Isojarvi et al.⁷, who studied thyroid function in men taking antiepileptic drugs (carbamazepine and valproate ) and found a decrease in T4 level, but  there is no alteration in TSH and T3 levels). In conclusion,  it might be worthy to measure serum TSH, lipid profile regularly, especially those on polytherapy, regardless of the type of antiepileptic drugs to avoid development of overt hypothyroidism and hypercholesterolemia.

 

[Disclosure: Authors report no conflict of interest]

 

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