Abstract
Epileptic patients have to continue anti-epileptic drugs (AED) over a long period of time which can have deleterious effects on the endocrine system including the thyroid hormones with rare check. Risk factors for the development of thyroid dysfunction are still unclear. Therefore the aim of study was to evaluate thyroid functions in epileptic patients receiving anti-epileptic drugs (AED) as monotherapy and polytherapy and to determine potential risk of low thyroid function in epileptic patients receiving treatment. This cross-sectional study included 100 epilepsy patients more than 12 years of age. Serum levels of free thyroxin (FT4), free triiodothyronine (FT3), and thyroid stimulating hormone (TSH) were evaluated in all subjects in addition to serum AED levels. TSH levels were found to be significantly higher in the polytherapy subgroup (p < 0.05) in comparison to the monotherapy group. 44% of the patients in the VPA monotherapy group had raised TSH levels and 41.2% of the patients on CBZ had low FT4. A significant negative correlation was observed between CBZ and FT4 (p < 0.05). Female sex and old age were additional risk factors detected for deranged thyroid function. Female patients with epilepsy, an older age and AED polytherapy were found to be associated with a higher risk of thyroid dysfunction. Thus, Thyroid function in these patients should be monitored closely. In conclusion, we observed significant changes in thyroid hormone levels in patients receiving antiepileptic treatment in both monotherapy and polytherapy. Elevated CBZ levels were significantly associated with decreased FT4 levels.
Keywords: Antiepileptic drugs, Thyroid hormones, Epilepsy, Hypothyroidism, Monotherapy, Polytherapy
Introduction
Epilepsy is a common neurological disorder knowing no geographical, racial or social boundary. The disorder shows a prevalence of 5,500,000 in India [1]. The International League against Epilepsy (ILAE) and the International Bureau for Epilepsy (IBE) have come to consensus definitions for the terms epileptic seizure and epilepsy. An epileptic seizure is a transient occurrence of signs/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain. Epilepsy is a disorder of the brain characterized by an enduring predisposition to generate epileptic seizures and by the neurobiological, cognitive, psychological, and social consequences of this condition. Physiologically, epilepsy is defined as a disorder in which the balance between cerebral excitability and inhibition is tipped toward uncontrolled excitability [2]. Patients with epilepsy have to be on anti-epileptic drugs (AED) for a long period of time. This can have deleterious effects on the endocrine system in both paediatric and adult populations, affecting mainly the reproductive system, thyroid hormones and bone metabolism [3]. Observations from various studies indicate that epileptic discharges from the temporal lobe and AEDs may cause changes in hormone levels by affecting the hypothalamic-pituitary axis through nerve pathways which may affect the endocrine system [4]. Commonly used AED’s such as carbamezepine (CBZ), valproate (VPA), phenytoin (PHT), phenobarbitone (PHB) are known to affect the thyroid hormone functioning [5, 6]. These changes are accompanied by major alterations in metabolic, cardiovascular, central nervous, musculoskeletal, haematological, reproductive, dermatologic and gastrointestinal activity [7]. Thyroid hormones are important for maintaining the lipid and carbohydrate metabolism and cell growth and development of many tissues. Henceforth, disturbances of thyroid function may impede growth and development in children and also adversely affect the endocrine haemostasis in adults [8]. AED’s may alter the thyroid hormone homeostasis at the level of biosynthesis, release, transport, metabolism and excretion of thyroid hormones. Varied results have been observed in different studies regarding effects of AED therapy on thyroid functioning [6, 8, 9]. One study showed significant decrease in FT4 levels without changes in FT3 and TSH levels in subjects on treatment with CBZ, PHT, PHB and clonazepam (CLB). No change in hormone level was observed on taking VPA therapy [9]. However, earlier studies found elevated TSH levels in girls on VPA. [10] Another study showed no effects of levetiracetam on thyroid hormone functioning as compared to other conventional anti-epileptic drugs [11]. Thereafter, a number of studies were performed to evaluate the thyroid profiles in patients with epilepsy, but with inconsistent results. Many studies have highlighted the need of thyroid function testing in patients with epilepsy as long term AED therapy could alter the thyroid hormone balance and predispose to hypothyroidism. To the best of our knowledge there are limited studies in India are available which assessed the thyroid hormone function abnormality in patients on long term AED therapy. Therefore the prevalence of the disease in patients with epilepsy is still undefined. Thyroid hormone tests are rarely performed on patients with AED due to which the prevalence of AED-induced thyroid dysfunction and the long-term consequences remain uncertain. In view of this the aim of the present study was to evaluate the thyroid hormone levels in epileptic patients receiving AED monotherapy and polytherapy, so as to bridge the gap between clinical and biochemical evaluation of this disorder and to identify the risk factors for its development.
Materials and Methods
Cross-Sectional Study
The present cross-sectional study was conducted in the Department of Biochemistry & Neurology at G.B Pant Institute of Postgraduate Medical Education & Research (GIPMER), Associated to Maulana Azad Medical College, New Delhi. Adult consented 100 epileptic patients more than 12 years of age, who were on AED treatment for at least 6 months, attending the Intractable Epilepsy Clinic, Neurology OPD or admitted to the Neurology ward of GIPMER, were included in the study. Diagnosis of epilepsy was in accordance to the ILAE and patients were classified accordingly.
Exclusion Criteria
It included Systemic or endocrine disorders, previous history of thyroid disorder, any co-morbid medical illness such as respiratory illness, cardiac illness or liver disorder which can alter thyroid levels.
Demographic Features
All patients with epilepsy were evaluated by taking a detailed history regarding duration of epilepsy, age of seizure onset, seizure type, frequency and control, family history of seizure, anti-epileptic drug therapy with regards to number of drugs prescribed, their dosage and compliance of therapy.
Sample Collection
A detailed general, systemic and neurological examination was performed and 6 mL of fasting blood sample was collected for estimation of blood sugar, anti-epileptic drug levels-phenytoin, carbamezepine, valproate, phenobarbitone and thyroid hormones FT3, FT4 and TSH under asceptic conditions.
Thyroid Hormones Estimation
Serum levels of thyroid hormones were estimated by electrochemiluminescence immunoassay on Cobas e411 (Roche Diagnostics, Risch-Kotkreuz, Switzerland). Normal serum levels of different hormones were defined as (1) FT3-2.4–4.2 pg/ml, (2) FT4-0.9–1.60 ng/dl, (3) TSH-0.4–4.0 mIU/ml. Low FT4 was defined as less than 0.9 ng/dL and high TSH as > 4.0 mIU/mL.
Statistical Analysis
Data was analysed using IBM SPSS advanced statistics version 20 (SPSS Inc., Chicago, IL). Numerical data was expressed as Mean ± SD. Comparison of two groups was done by Students t test. Qualitative data was expressed as frequency and percentage and analysed by Chi square test. P value of less than or equal to 0.05 was considered as statistically significant.
Results
The present study included 50 monotherapy patients (25 Male and 25 female) with a mean age of 22.6 ± 8.5 years and 50 polytherapy patients (32 male and 18 female) with a mean age of 23.1 ± 8.6 years. No significant difference in mean age was observed between the two groups. The male female ratio was higher in polytherapy group. 74% of the patients were unmarried in the polytherapy group whereas 64% in the monotherapy subgroup. There was no significant difference in the age of onset of seizure and mean duration of seizures in the monotherapy vs. polytherapy group (p = 0.240 and p = 0.321 respectively). On evaluating the frequency of seizures in both the sub-groups, the polytherapy group showed 48% of the patients to have increased frequency of seizures with one seizure every 6 months. We found less frequency of seizures in monotherapy group with 46% patients having one seizure per year or in two years. Generalised tonic clonic seizures were more common in the monotherapy group whereas partial seizures were more common in the polytherapy subgroup. After evaluation, 36% of the patients in the monotherapy group were on VPA therapy, 34% on CBZ, 10% on PHT and 20% on LEV. In the polytherapy group, 24% of the patients were treated with CBZ + CLB, 10% with CBZ + VPA, 16% with PHT + CLB, 10% with VPA + PHT, 12% with LEV + CLB, 10% with VPA + LEV and 18% with VPA + CLB. As shown in Table 1.
Table 1.
Characteristics of Epileptic patients under study
| Characteristic | Monotherapy (N = 50) | Polytherapy (N = 50) |
|---|---|---|
| Age (years) | 22.6 ± 8.5 | 23.1 ± 8.6 |
| Male:Female | 1:1 | 2:1 |
| Marital status [N (%)] | ||
| Married | 18 (36%) | 13 (26%) |
| Unmarried | 32 (64%) | 37 (74%) |
| Age of onset of seizure (years) | 19.4 ± 6.8 | 18.9 ± 6.1 |
| Mean duration of seizure (years) | 4.02 ± 2.31 | 4.72 ± 3.5 |
| Frequency of seizure [N (%)] | ||
| < 1/6 months | 5 (10%) | 24 (48%) |
| 1/6 months – 1/1 year | 7 (14%) | 22 (44%) |
| 1/1 year – 1/2 years | 23 (46%) | 4 (8%) |
| Type of seizure [N (%)] | 13 (26%) | 32 (64%) |
| Partial seizures generalised tonic clonic seizures | 37 (74%) | 18 (36%) |
| AED Type: | N (%) | N (%) |
| VPA | 18 (36) | – |
| CBZ | 17 (34) | – |
| PHT | 5 (10) | – |
| LEV | 10 (20) | – |
| CBZ + CLB | – | 12 (24) |
| CBZ + VPA | – | 5 (10) |
| PHT + CLB | – | 8 (16) |
| VPA + PHT | – | 5 (10) |
| LEV + CLB | – | 6 (12) |
| VPA + LEV | – | 5 (10) |
| VPA + CLB | – | 9 (18) |
On evaluating thyroid hormone levels, they were found to be significantly higher in patients of monotherapy subgroup receiving VPA compared to other subgroups. TSH levels were found to be significantly higher in the polytherapy subgroup (p < 0.05) in comparison to the monotherapy group. FT4 and FT3 levels were also lower in the polytherapy group however results were not significant as shown in Table 2.
Table 2.
Thyroid hormone levels in monotherapy and polytherapy subjects
| Hormone | CBZ | VPA | PHT | LEV | Polytherapy |
|---|---|---|---|---|---|
| FT3 | 3.10 ± 1.3 | 3.05 ± 1.2 | 3.3 ± 0.3 | 3.14 ± 1.2 | 2.96 ± 1.2 |
| FT4 | 1.0 ± 0.4 | 1.02 ± 0.4 | 0.97 ± 0.10 | 1.12 ± 0.4 | 0.96 ± 0.20 |
| TSH | 2.77 ± 1.1 | 3.15 ± 1.7 | 3.01 ± 0.9 | 2.27 ± 1.6 | 3.31 ± 0.8* |
*p < 0.05
Table 3 shows maximum patients (44.4%) on VPA monotherapy to have elevated TSH levels > 4.0 followed by 29.4% in the CBZ group. 41.2% of the patients on CBZ monotherapy had decrease in levels of FT4 ≤ 0.90.
Table 3.
Number of subjects with deranged thyroid hormone levels in monotherapy and polytherapy subgroups
| Deranged hormone levels | CBZ | VPA | PHT | LEV | Polytherapy |
|---|---|---|---|---|---|
| FT4 ≤ 0.90 | 7 (41.2%) | 2 (11.1%) | 2 (20%) | 0 (0%) | 2 (4%) |
| TSH > 4.0 | 5 (29.4%) | 8 (44.4%) | 1 (20%) | 0 (0%) | 12 (24%) |
On correlating thyroid hormones with drug levels a significant negative correlation was observed in between CBZ and FT4 (p < 0.05). No significant correlation of thyroid hormones was observed with other AED drugs as seen in Table 4.
Table 4.
Correlation of thyroid hormones with drug levels
| Hormone | CBZ | VPA | PHT | LEV |
|---|---|---|---|---|
| FT3 | r = 0.265; p > 0.05 | r = −0.351; p > 0.05 | r = 0.738; p > 0.05 | r = 0.111; p > 0.05 |
| FT4 | r = −0.492; p < 0.05 | r = 0.201; p > 0.05 | r = 0.756; p > 0.05 | r = 0.210; p > 0.05 |
| TSH | r = 0.039; p > 0.05 | r = 0.206; p > 0.05 | r = 0.138; p > 0.05 | r = 0.193; p > 0.05 |
Table 5 shows comparison of different patient variables in the monotherapy group. A significant increase in TSH levels was observed in the female epileptic patients in comparison to the male (p < 0.05). No significant difference was observed in between FT3 and FT4 in both groups. FT3 levels were found to be significantly decreased in patients > 20 years in comparison to younger patients (p < 0.05) and TSH levels were also found to be significantly higher in patients > 20 years in comparison to younger patients (p < 0.05). FT4 levels were also low but the result was not statistically significant. No significant difference in thyroid hormones was observed in between the patients who had partial seizures vs. GTCS.
Table 5.
Evaluation of thyroid hormones with different patient variables on monotherapy
| Variable | FT3 | FT4 | TSH |
|---|---|---|---|
| Male (N = 25) | 2.9 ± 1.3 | 0.92 ± 0.4 | 2.97 ± 1.5 |
| Female (N = 25) | 2.65 ± 1.5 | 0.93 ± 0.5 | 3.88 ± 1.6* |
| ≤ 20 years (N = 24) | 3.49 ± 0.9 | 1.14 ± 0.3 | 2.9 ± 1.5 |
| > 20 years (N = 26) | 2.84 ± 1.2* | 1.03 ± 0.4 | 3.8 ± 1.2* |
| Partial seizure (N = 24) | 3.23 ± 1.2 | 0.99 ± 0.4 | 2.37 ± 1.3 |
| GTC seizure(N = 24) | 3.12 ± 1.1 | 1.11 ± 0.3 | 3.71 ± 2.9 |
*p < 0.05, **p < 0.001
Discussion
In the present study we evaluated the thyroid status (FT3, FT4 and TSH) in patients on monotherapy and polytherapy. Long term administration of AED is associated with many effects however the findings have not be fully substantiated yet. Several mechanisms related to AED induced thyroid dysfunction have been suggested including competitive binding of thyroid hormones to thyroglobulin, increased peripheral conversion of T4 to active T3 and alterations of the hypothalamic pituitary axis [10, 11]. The adverse impact of AED on the hepatic P-450 enzyme system may be due to accelerated clearance of thyroid hormone [12]. Some studies have indicated that epileptic patients remain clinically euthyroid despite alterations in the thyroid function [13]. In the present study when comparing thyroid hormones amongst the monotherapy subject’s higher levels were observed in those on valproate therapy. On comparing the monotherapy and polytherapy group significantly higher TSH levels were observed in those on polytherapy. This was in accordance with findings of Shih et al. who found a strong association with number of AED and development of low FT4 [14]. In our study we found 44% of the patients who were on valproate to have to have elevated TSH levels, however low FT4 levels were observed in predominantly those on CBZ therapy. On correlating thyroid hormones with drug levels a significant negative correlation was observed between CBZ and FT4 level (p < 0.05). Reports on effect of VPA therapy on thyroid function are inconsistent. Some findings report VPA therapy to increase thyroid hormones whereas other studies show lowered or no effects. Valproic acid could increase serum TSH by affecting the complex central neuroendocrine control of TSH release leading to elevation in serum FT4. Serum FT4 levels were also found to be increased in 11.1% of our patients on valproate. Valproic acid also inhibits histone deacetylase and could therefore modify transcription of many genes [15]. Valproic acid (VPA) is also highly bound to plasma proteins allowing T4 to easily detach from its site. TT4 levels were found to be significantly increased in patients on VPA. However no change in levels of FT4, TT3, FT3 and TSH were detected [16]. In patients on CBZ, a significant decrease in FT4 and TT4 was found with no changes in FT3, TT3 and TSH level. Similar findings were also found in patients on PHT therapy. The highest decrease in T4 level was observed in patients using CBZ, VPA and PHT respectively. A decrease in mean TT4 and FT4 level were observed in patients treated with CBZ and VPA in comparison to control. 26% patients on VPA also developed subclinical hypothyroidism [17]. In another study, mean FT4 and T3 levels were significantly lower in patients using CBZ compared to control whereas mean FT3 and T4 were significantly higher in patients on VPA as compared to control [18]. In the above studies, different results were found in the FT3 and FT4 levels in patients receiving VPA and CBZ monotherapy. Many studies have reported that CBZ therapy could affect thyroid hormone balance in epilepsy patients, by decreasing the FT4 level and not altering the FT3 or TSH levels [4, 7, 17]. Similar findings were found in our study where 41.2% patients had low FT4 levels and TSH was low in only 29.4% of the patients on CBZ. The effect of CBZ on thyroid hormones may be related to that CBZ blocks TRH-mediated stimulation of TSH release. CBZ reduces the FT4 and FT3 levels by increasing the hormone binding protein level as well as by its enzyme inducing effect [13]. In our study we found a significant negative correlation between CBZ and FT4. Similar findings were found in another study conducted by Dana-Heari et al. [13]. Additionally, in a small number of patients on monotherapy with LEV we found no change in thyroid hormone levels. It was observed that LEV did not affect FT4, FT3 and TSH levels in epilepsy patients [19]. On comparing between monotherapy and polytherapy groups, we found TSH levels to be significantly increased in patients on polytherapy. Similar results were observed who reported that AEDs altered thyroid function, especially in patients treated with polytherapy [20]. It was observed FT4 levels to be significantly lower in patients treated with AED polytherapy [14]. No significant change was reported in thyroid hormone levels in monotherapy and polytherapy subgroups. Varying results amongst different studies may be due to the fact that thyroid hormone levels vary with many factors [21]. We identified few more clinical risk factors for the development of a low thyroid hormone level in our patients, including female sex and old age. Older females are at a greater risk of developing hypothyroidism [22, 23]. In addition the risk is magnified when exposed to AED polytherapy [24]. Based on our findings presented here and different results related to thyroid hormone changes in other studies suggest that there may be many different factors affecting thyroid hormone levels. Old age, female sex and polytherapy increase the risk of thyroid abnormalities. Regular monitoring of thyroid hormone levels is important in patients receiving epilepsy treatment, especially in high doses. The small sample size was the limitation in our study; therefore, further prospective studies are required to be mediated on a larger scale of adult epileptic patients to substantiate our results.
Conclusion
In conclusion significant changes in thyroid hormone levels in patients receiving antiepileptic treatment in monotherapy subgroup and polytherapy subgroups was observed. Elevated CBZ levels were found to be significantly associated with decreased FT4 levels. Based on our findings presented here, it suggests that there might be different factors like old age, female sex and polytherapy which can affect the thyroid hormone levels and increases the risk of thyroid abnormalities. Thus, it is important to monitor thyroid hormone levels closely in patients receiving epilepsy treatment with special emphasis on patients receiving high doses of anti-epileptic drugs (AED).
Author’s Contribution
DPK—Design of the study. SS—Methodology. MR—Reviewed the manuscript. PV—Design of the manuscript.
Funding
The authors declared that this study received no financial support.
Availability of Data and Materials
All data availability in the Department of Biochemistry, G.B Pant Institute of Postgraduate Medical Education & Research, Associated to Maulana Azad Medical College, New Delhi, India.
Code Availability
Computer of Dr. Pradeep Kumar Dabla, Professor.
Compliance with Ethical Standards
Conflict of interest
All of the authors declare that they have no competing interests.
Ethical Approval
As per local ethics committee.
Consent to Participate
All patients were consent form before sampling.
Footnotes
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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Associated Data
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Data Availability Statement
All data availability in the Department of Biochemistry, G.B Pant Institute of Postgraduate Medical Education & Research, Associated to Maulana Azad Medical College, New Delhi, India.
Computer of Dr. Pradeep Kumar Dabla, Professor.