According to ILAE, epilepsy is a brain disease, characterized by following conditions:

1. More than two unprovoked seizures occurring more than 24 hours apart.
2. One unprovoked (or reflex) seizure and a probability of further seizures similar to the general recurrence risk (at least 60%) after two unprovoked seizures, occurring over the next 10 years.
3. Diagnosis of an epilepsy syndrome [1].

The first line of treatment for epilepsy is the administration of antiseizure drugs (ASDs) [2]. The selection of antiseizure medications is based upon the clinical characteristics of the various seizure types, electroencephalogram results, epileptic syndrome, and medication stability [3]. Extended use of ASDs has been linked to a number of side effects, including endocrine disruption of the thyroid, adrenal, and reproductive systems, idiosyncratic effects, weight gain, and an increased risk of teratogenicity [4]. It is well known that Valproic acid (VPA) has no effect on cognition, gastrointestinal tolerance, less sedative influence, and broad-spectrum antiseizure effectiveness. This anti-seizure drug is widely used [5]. Valproic acid's sodium salt is called sodium valproate. This ASD, which is a member of the Branched Chain Aliphatic Carboxylic Acid class, is used to treat bipolar disorder, anxiety disorders, migraines, epilepsy, panic attacks, anorexia nervosa, and post-traumatic stress disorder.

Valproic acid is rarely administered intravenously and is typically taken orally. Good oral absorption occurs. Over 90% of it is attached to plasma proteins, and the kidneys eliminate it when the liver uses the glucuronide conjugation and oxidation route to fully metabolize it. The antiseizure effect lasts longer. Its plasma half -life is 10-15 hours [6]. Personalized VPA dosages should take into account the patient's age, weight, type of seizure, medications being taken concurrently, and plasma concentration. For paediatric patients, the first dosage of VPA is typically given in 2 or 3 doses, ranging from 10 to 15 mg/kg/day. Until seizure control is attained or side effects start to manifest, the dosage can be raised by 5 to 10 mg/kg every week. Paediatric patients typically receive a maintenance dose of VPA of 20 to 60 mg/kg/day [7].

Valproic acid appears to act by multiple mechanisms, which includes a phenytoin-like frequency-dependent prolongation of Na channel inactivation; weak attenuation of Ca mediated T current (ethosuximide like); increased release of GABA, the inhibitory transmitter, as a result of both preventing its breakdown (by GABA-transaminase) and most likely increasing its synthesis from glutamic acid; and blockade of excitatory NMDA glutamate receptors. Valproic acid has a low level of toxicity. Heartburn, diarrhea, vomiting, and anorexia are common but moderate symptoms. Tremor, ataxia, and drowsiness are side effects that are related to dosage. Alopecia, hair curling, weight gain, and increased bleeding tendency have all been seen. Serum transaminase levels are frequently observed to rise asymptomatically [8].

The production and degradation of proteins, as well as the metabolism of carbohydrates and fats in all tissues, are significantly impacted by thyroid hormones. Thyroid hormones are necessary for the central nervous system to develop. Even in children whose growth hormone (GH) levels are within normal ranges, thyroid hormone insufficiency can lead to growth and developmental abnormalities [9]. VPA may have some influence on thyroid hormones because it is a known inhibitor of hepatic enzymes. Displacement from protein binding sites, a decrease in T4 5′-deiodinase activity, and a drop in serum T4-binding globulin levels results from VPA. Studies have also demonstrated that VPA stimulates γ-aminobutyric acid (GABA), and that GABA may suppress somatostatin release, which prevents TSH secretion. Additionally, low zinc and selenium levels can result from VPA, which have an important role in thyroid hormones synthesis [10].

Subclinical hypothyroidism, which is characterized as a slight rise of TSH levels (5–25 mIU/l) in the presence of normal thyroid hormone concentrations, is caused by thyroid hormone abnormalities linked to antiseizure medicines. It is possible for subclinical hypothyroidism to develop into overt hypothyroidism [11].

This study aims to prospectively evaluate the changes in thyroid profile in children with epilepsy treated with valproic acid monotherapy.

This study is a prospective observational one, carried out at a Paediatric neurology clinic, Telangana, India. The study group consisted of 150 children. The study lasted for 1 year, from May 2023 to May 2024.

Inclusion criteria:

• Children aged 1 – 12 years old with epilepsy for whom valproic acid is recommended.
• Children who have just received an epilepsy diagnosis.
• Children who are on valproic acid medication at the moment.
• Children whose thyroid profiles are currently in place.

Exclusion criteria:

• Children who have pre-existing thyroid conditions and other medical conditions.
• Children with severe neurological conditions such as mental retardation, global development delay, and autism, as well as chronic diseases of the kidneys and liver.
• Children receiving valproic acid treatment in addition to other antiseizure medications.

Study procedure:

A questionnaire was used to gather information about the patient demographics details, past medical history, birth history, diagnosis, valproic acid usage, thyroid profile before initiation of VPA, at 3 months, and at 6 months. Parents or legal guardians gave their informed consent for the collection of all the data.

Serum levels of Thyroid Stimulating Hormone (TSH), Triiodothyronine (T3), and Thyroxine (T4) were assessed in epileptic patients who were scheduled to receive valproic acid therapy. In order to monitor their thyroid function before starting anti-epileptic treatment, as well as at three and six months, patients were asked to regularly attend the neurology clinic. A proforma that had been predesigned was then used to record the values.

Statistical analysis:

Data were input into a Microsoft Excel spreadsheet, and the Statistical Package for the Social Sciences (SPSS) was used for analysis. The values of the data were presented as mean ± standard deviation. Statistical significance was assessed using ANOVA and a p-value of <0.05 was used.

The study involved 150 children in total. Of these children, 88 were male and 62 were female, as depicted in [Table/Fig The mean age was 7.8 (±2.1) years. Among these participants, 17.3% were aged between 1-3 years, 21.3% were aged between 4-6 years, 28% were aged between 7-9 years, and 33.4% were aged between 10 - 12years; as shown in [Table/Fig Valproic acid was given the dose of 10 mg/kg/day to 42mg/kg/day, with the mean of 25.87mg/kg/day.

Table/Fig 1: Gender Wise Distribution

[Table/Fig 3] illustrates the assessment of serum levels of Thyroid stimulating hormone (TSH), Triiodothyronine (T3), and Thyroxine (T4) levels at the time of initiation of valproic acid therapy, at three months after VPA therapy, and at six months after VPA therapy. TSH levels were increased significantly from 2.11±1.54 µIU/mL at initiation of VPA to 3.78±1.84 µIU/mL at 3 months and to 4.45±1.96 µIU/mL at 6 months (p<0.001), T4 decreased significantly (p=0.021) and T3 decreased significantly (p=0.023) at 6 months after VPA therapy.

Table/Fig 2: Age Wise Distribution

At 3 months after the initiation of VPA monotherapy, 11 children had developed hypothyroidism, as described in [Table/Fig 4]. Out of the 11 children, 9 have developed subclinical hypothyroidism, with 7 females and 2 males; the other 2, both of whom are female, have developed overt hypothyroidism, for which VPA was stopped along with the initiation of thyroxine treatment.

Table/Fig 3: Serum levels of Thyroid stimulating hormone (TSH), Triiodothyronine (T3), and Thyroxine (T4) levels at the time of initiation of valproic acid therapy, at three months after VPA therapy, and at six months after VPA therapy.

Table/Fig 4: Abnormal thyroid profile at three months after VPA therapy, between 3 to 6 months of VPA therapy and at six months after VPA therapy.

At 6 months after the initiation of VPA therapy, 17 children had developed hypothyroidism. Of the 17 children, 15 (11 females and 4 males) have developed subclinical hypothyroidism, and 2 (also females) have developed overt hypothyroidism.

After the 6 months of VPA therapy, a total of 24 patients (16%) have developed Subclinical Hypothyroidism, and 4 patients (2.67%) have developed Overt Hypothyroidism.

These results suggest that the changes in levels of TSH, T4, and T3 over the periods at initiation of VPA therapy, at 3 months of VPA therapy and at 6 months VPA therapy were statistically significant. i.e. after 6 months of VPA therapy TSH - p value is less than 0.001, T3 - p value is 0.0023 and T4 - p value is 0.021.

Valproic acid is the most commonly used antiseizure medication. Valproic acid is regarded as a broad-spectrum ASD, and particularly useful for both focal-onset and generalized-onset seizures, as well as different epilepsy syndromes. In addition, valproic acid is helpful in treating other comorbid conditions like bipolar disorder and migraines.

The present study revealed higher predominance of participants were males (58.7%), which was similar to the study conducted by Dwajani S et al., and Sumesh D et al. [4,12]

Serum TSH, T4, and T3 concentrations at baseline, at 3 months and at 6 months of valproic acid treatment were measured. Serum TSH levels were elevated, T4 levels were declined from initiation to 3 months and 6 months of VPA therapy, which corroborate with the findings from studies by Malwade S et al., Doneray H et al, Dr. Prasanta R et al., and Ravi L A et al. [13,14,15,16]

The underlying mechanism of VPA effect on thyroid levels is not known but the possibility includes the increase in the levels of GABA by stimulating the activity of the GABA synthetic enzyme (glutamic acid decarboxylase) and inhibiting GABA degradative enzyme (GABA transaminase and succinic semialdehyde dehydrogenase). GABA inhibits somatostatin. Inhibition of somatostatin releases the inhibition over TSH and thus increases the secretion of TSH. [17]

At 3 months after the initiation of VPA monotherapy, 9 children have developed subclinical hypothyroidism and 2 have developed overt hypothyroidism. At 6 months after the initiation of VPA therapy, 15 children have developed subclinical hypothyroidism and 2 have developed overt hypothyroidism.

According to American Thyroid Association (ATA), Subclinical hypothyroidism is a mild form of hypothyroidism where the only abnormal hormone level is an increased TSH accompanied by normal thyroxine (T4) and triiodothyronine (T3); and Overt hypothyroidism is, clear hypothyroidism, characterized by an increased TSH and a decreased T4 level. Typically, thyroid hormone medication is used to treat all patients with overt hypothyroidism. When a patient develops overt hypothyroidism, subclinical hypothyroidism can result in clinical symptoms like growth failure and cognitive impairment. Several studies have shown that treatment of subclinical hypothyroidism can reduce the risk of overt hypothyroidism. [18]

In our study, majority of children had Subclinical hypothyroidism (16%) than Overt hypothyroidism (2.67%). Similar findings were reported by Kim SH et al., Alhyan P et al., Malwade S et al., and Josephine JS et al., in which subclinical hypothyroidism is prevalent among children with epilepsy on VPA therapy. [3,5,13,19]

Limitations:

Our study was limited in that we were unable to establish a control group. The small sample size and short duration of study was another limitation.

Our research indicates that valproic acid monotherapy may result in early and long-lasting changes in thyroid function, indicating the necessity of careful and early monitoring of the concentration of thyroid hormones in serum in children with epilepsy receiving VPA

1. Fisher, Robert S., et al. "ILAE Official Report: A Practical Clinical Definition of Epilepsy." Epilepsia, vol. 55, no. 4, 2014, pp. 475-82. doi:10.1111/epi.12550.
2. Hanaya, Rieko, and Kiyoshi Arita. "The New Antiepileptic Drugs: Their Neuropharmacology and Clinical Indications." Neurologia Medico-Chirurgica, vol. 56, no. 5, 2016, pp. 205-20. doi:10.2176/nmc.ra.2015-0344.
3. Kim, Hee, et al. "Antiepileptic Drug Selection According to Seizure Type in Adult Patients with Epilepsy." Journal of Clinical Neurology, vol. 16, no. 4, 2020, pp. 547-55. doi:10.3988/jcn.2020.16.4.547.
4. Dwajani, Shubhangi, et al. "Effect of Sodium Valproate and Levetiracetam on Thyroid Hormones in Pediatric Patients with Epilepsy." Advances in Pharmacology & Clinical Trials, vol. 5, no. 3, 2020. doi:10.23880/apct-16000182.
5. Alhyan, Parveen, et al. "Effect of Valproate Monotherapy on Thyroid Function Tests and Magnesium Levels in Children with Epilepsy." Cureus, vol. 15, no. 5, 2023, e39712. doi:10.7759/cureus.39712.
6. Parveen, K. P., and R. R. Pradeep. "Effect of Sodium Valproate Monotherapy on the Thyroid and Liver Function Tests of Pediatric Epileptic Patients." Paripex-Indian Journal of Research, vol. 5, no. 8, 2016, pp. 259-64.
7. Rahman, M., Awosika, A. O., and H. Nguyen. "Valproic Acid." StatPearls, StatPearls Publishing, 2024.
8. Tripathi, K. D. Essentials of Medical Pharmacology. 7th ed., Jaypee Brothers Medical, 2018.
9. Cansu, A. "Antiepileptic Drugs and Hormones in Children." Epilepsy Research, vol. 89, no. 1, 2010, pp. 89-95. doi:10.1016/j.eplepsyres.2009.09.008.
10. Zhang, Yuxian, et al. "Effects of Antiepileptic Drug on Thyroid Hormones in Patients with Epilepsy: A Meta-Analysis." Seizure, vol. 35, 2016, pp. 72-79. doi:10.1016/j.seizure.2016.01.010.
11. Yılmaz, Ümit, et al. "The Effect of Antiepileptic Drugs on Thyroid Function in Children." Seizure, vol. 23, no. 1, 2014, pp. 29-35. doi:10.1016/j.seizure.2013.09.006.
12. Sumesh, D., et al. "Evaluation of Thyroid Hormones, Prolactin & Insulin in Children on Prolonged Valproate Monotherapy for Epilepsy." Scholars Academic Journal of Biosciences, vol. 4, no. 12, 2016, pp. 1087-92.
13. Malwade, S. D., et al. "Effect of Valproic Acid Monotherapy on Thyroid Function on Short-Term Follow-Up in Children with Newly Diagnosed Epilepsy." Indian Journal of Child Health, vol. 5, no. 4, 2018, pp. 231-34.
14. Doneray, H., et al. "Serum Thyroid Hormone Profile and Trace Elements in Children Receiving Valproic Acid Therapy: A Longitudinal and Controlled Study." Journal of Trace Elements in Medicine and Biology, vol. 26, no. 4, 2012, pp. 243-47. doi:10.1016/j.jtemb.2012.03.001.
15. Prasanta, R., and K. Mani. "A Prospective Study on Thyroid Function in Children with Epilepsy Treated with Sodium Valproate Monotherapy." IOSR Journal of Dental and Medical Sciences, vol. 17, no. 8, 2018, pp. 6-11.
16. Ravi, L. A., et al. "Thyroid Profile in Children on Sodium Valproate Monotherapy." Paripex-Indian Journal of Research, vol. 7, no. 9, 2018, pp. 47-48.
17. Ranga, S., et al. "Detection of Subclinical Hypothyroidism in Children with Epilepsy on Valproate Monotherapy in the Age Group of 3-12 Years." MedPulse-International Medical Journal, vol. 2, no. 12, 2015, pp. 840-43.
18. "Clinical Thyroidology for Patients." A Publication of the American Thyroid Association, vol. 5, no. 6, 2012, pp. 6-7.
19. Sibarani, J., Deliana, M., and J. Saing. "Valproate Use and Thyroid Dysfunction in Children with Idiopathic Epilepsy." Paediatrica Indonesiana, vol. 58, no. 4, 2018, pp. 192-97.