Epilepsy is the disorder of the brain characterised by a predisposition to develop seizures. Epilepsy is an important public health problem and the second most common neurological problem next to headache¹ It is defined as two or more episodes of unprovoked seizures by International League Against Epilepsy².The term seizure, a latin word (meaning - to take possession of) is a sudden unexpected event due to abnormal neuronal activity in the brain. It is manifested as episodes ranging from events indistinguishable by the observer to obvious convulsive activity. It can be provoked (due to underlying structural or metabolic causes) or unprovoked. In worldwide and in India its prevalence is about 50 million and 10 million persons respectively according to WORLD HEALTH ORGANISATION². The frequency rates for children vary from 2.0 to 22.2 per 1000 and nearly 50% of all epileptics suffer from their childhood^3,4.Antiepileptic medication remains the main line of treatment for a patient with epilepsy. Patients diagnosed with epilepsy are started on antiepileptic therapy irrespective of the cause. It is the mainstay of treatment for all patients in controlling the further episodes of the seizures.Antiepileptic medications can cause acute and chronic adverse effects with greater impact on quality of life⁵. Duration of treatment with these drugs are usually for chronic period of time and this imposes the patient on risk for fractures, bone loss due to abnormalities in the bone mineral metabolism^6,7. Evidence suggest association between AED’s and bone mineral abnormalities⁶. Long-term use of drugs like phenytoin, phenobarbitone, carbamazepine, and sodium valproate can lead to bone loss and fractures due to impaired vitamin D metabolism⁸ and decreased calcium absorption. These drugs, by inducing cytochrome P450 enzymes⁹, reduce active vitamin D levels¹⁰, impacting bone health.Bone remodeling is regulated by minerals, hormones, and factors like nutrition and physical activity, with medications such as antiepileptic drugs (AEDs) and decreased estrogen increasing fracture risk^11-13. Vitamin D, essential for calcium and phosphorus balance, is often deficient in patients, leading to subclinical bone loss and higher fracture risk¹⁴

AIM

^{The aim is to evaluate serum calcium and 25-hydroxyvitamin D3 levels in pediatric patients (ages 1–14) before and after 6 months of antiepileptic drug therapy.}

This study was conducted in the Department of Pediatrics at S. P. Medical College and PBM Hospital, Bikaner, with institutional ethical committee approval. The study period spanned one year, from January 2023 to December 2023. To assess the impact of antiepileptic drugs on serum calcium and 25-hydroxyvitamin D3 levels, a sample size of 100 newly diagnosed epilepsy patients, aged 1 to 14 years, was determined based on an 80% study power and a 5% alpha error. Given the prevalence of epilepsy in this age group is 6.00% according to a reference article, the study aimed to recruit approximately 91 cases.

Prevalence of epilepsy in peiadiatric age was 6.00% as per reference article.11

Alpha 5%

Beta 20%

Power of study -80%

N =4 pq/l2

The study design was a prospective observational cross-sectional study. Data collection involved selecting 100 patients of both sexes, fulfilling specific criteria. Inclusion criteria encompassed newly diagnosed cases of epilepsy within the age range of 1 to 14 years who were willing to participate. Exclusion criteria included patients who refused consent, those with diseases known to cause decreased calcium and vitamin D3 levels or dietary deficiencies, individuals on medications other than antiepileptic drugs that could cause hypocalcemia, and patients already receiving antiepileptic drug therapy

Table 1: Distribution of study population according to their Age

Table 1 shows distribution of study population according to their Age. Maximum 35% were in 1-4 year age group followed by 4-7 year (28%) whereas minimum 19% were in 10-14 year group followed by 7-10 years age group (18%).

Table 2: Distribution of study population according to their socio-economic status

Table 2shows distribution of study population according to their socio-economic status. Maximum 72% had lower socioeconomic followed by 27% middle and only 1% had upper socioeconomic status.

TABLE NO 3: ANTIEPILEPTIC PROFILE OF PATIENTS

 Maximum 74% had monotherapy followed by 23% had dual and only 3% had triple therapy.In monotherapy maximum 42% had sodium valproate followed by 22% levetriacetam whereas minimum 10% had phenytoin.In dual therapy maximum 15% levetriacetam + sodium valproate followed by 8% had sodium valproate + phenytoin.In triple therapy 3% had levetriacetam + sodium valproate + phenytoin.

TABLE 4: Serum Calcium and vitamin D

 Mean serum calcium was 9.5 ± 0.44 mg/dl, at admission whereas 8.9 ± 0.56 mg/dl at 6 months. For the first group, the mean is 53.85 with a standard deviation of 10.5, while for the second group, the mean is slightly lower at 52.65, accompanied by a higher standard deviation of 12.56

Table 5: serum calcium according to therapy

In the study, patients on monotherapy had a mean serum calcium level of 8.92 mg/dL with 45 having normal and 29 having low levels. Dual therapy patients had a mean of 8.68 mg/dL, with a higher proportion having low serum calcium (16) compared to normal (7), while triple therapy patients had the lowest mean of 7.38 mg/dL, all having low serum calcium levels.

Table 6: serum vit D according to therapy

Monotherapy had the highest mean vitamin D level at 53.65 ng/mL with 70 normal and 4 low levels, while dual therapy had a mean of 51.44 ng/mL with 20 normal and 2 low levels, and triple therapy had the lowest mean at 45.2 ng/mL with 1 normal and 2 low levels.

Table 7: THE DRUG with serum calcium and vitamin D after 6 months

Phenytoin had the highest mean vitamin D level at 55.50 ng/mL with a standard deviation of 9.5, while the combination of Phenytoin, Levetiracetam, and Sodium Valproate had the lowest mean at 45.2 ng/mL with a standard deviation of 15.5. 

In our study Maximum 35% were in 1–4-year age group followed by 4-7 year (28%) whereas minimum 18% were in 7–10-year group followed by 10-14 years age group (19%). Similarly, Napakjira Likasitthananon et al. (2021)¹⁵ found the age ranged from 1.04 - 19.96 years.

In our study, on admission no case had hypocalcaemia whereas after 6 month of therapy 48 (48%) cases developed hypocalcaemia. Similarly, Niluh Suwasanti et al. (2019)¹⁶ found that at admission, there were 10.5% low calcium levels whereas 25% low calcium levels 6 months after therapy. Also Shweta Singla et al¹⁷ found 8% decrease in serum calcium levels.

In our study, mean serum calcium was 9.5 ± 0.44 mg/dl, at admission whereas 8.9 ± 0.56 mg/dl at 6 months (p<0.0001). Similarly, Chaudhuri IR et al. (2017)¹⁸ found mean serum calcium was significantly lower (8.3±1.5) in epileptic cases. Compared to other studies, the mean calcium is low in our study which may be due to low dietary calcium intake, poor supplementation due to poor socioeconomic status, high phytate content in north Indian diet which inhibits calcium absorption^19,20

In our study, at admission no case had vit D deficiency whereas after 6 month of therapy 8 (8%) cases developed vit D deficiency. Similarly Napakjira Likasitthananon et al. (2021)¹⁵ found the prevalence of vitamin D deficiency in epileptic cases was 23.2%. Similar increase in vit D deficiency was seen by Niluh Suwasanti et al. (2019)¹⁶ found that at admission, there were 57.9% low vitamin D and 70% had low vitamin D after 6 months. Also Chaudhuri IR et al. (2017)¹⁸ observed 45% cases whereas 24 % controls had 25-hydroxyvitamin D deficiency.

In our study, Mean Vit D was 53.85 ± 10.5 ng/mL, at admission whereas 53.65 ± 10.89 ng/mL at 6 months and the difference between Vit D levels after 6 months of therapy was statistically insignificant (p>0.05). Similarly Napakjira Likasitthananon et al. (2021)¹⁵ found that the mean serum 25(OH) D level was 26.56 ± 9.67 ng/ml.

In our study, Maximum all (100%) cases of triple therapy develops hypocalcaemia followed by dual therapy (69.56%) whereas minimum 39.19% of monotherapy developed hypocalcaemia. The difference between these groups in serum calcium levels after 6 months of therapy was statistically significant (p<0.007). The findings are similar to the studies conducted by RICHEN ROWE et al,²¹ GHAFGHAZI et al²² and the observations are that compared to monotherapy, patients on triple therapy are found to have significantly lower calcium.

The mean serum calcium was maximum 8.92 ± 0.31 mg/dl in monotherapy followed by dual therapy (8.68 ± 0.41 mg/dl) whereas minimum 7.38 ± 0.32 mg/dl in triple therapy (p<0.05). Similarly RICHENS ROWE et al,²¹ found that the mean calcium of monotherapy, dual therapy and triple therapy was 9.48 (SD+_ 0.12)mg/dl, 9.29 (SD+_0.04)mg/dl and 9.02 (SD+_0.07)mg/dl respectively.

In our study, maximum 33.33% of all cases of triple therapy develops Vit D deficiency followed by dual therapy (13.04%) whereas minimum 5.41% of monotherapy developed Vit D deficiency. The mean Vit D was maximum 53.65 ± 11.56 ng/mL followed by dual therapy 51.44 ± 14.5 ng/mL whereas 45.2 ± 15.5 ng/mL in triple therapy. The difference between these groups in Vit D level after 6 months of therapy was statistically insignificant (p>0.05). Similarly Hussam Mohammed Alhaidari et al. (2022)¹⁷ found that Vitamin D deficiency is more prevalent among patients on polytherapy than in other Patients with epilepsy. Also Na Dong et al. (2022)¹⁵ observed that Anti epileptic therapy, alone or in combination, did not consistently reduce baseline serum VitD levels in children with epilepsy.

In our study, monotherapy maximum mean serum calcium level was 8.94 ± 0.15 mg/dl in phenytoin whereas minimum 8.86 ± 0.32 mg/dl was seen in sodium valproate. In dual therapy maximum mean serum calcium level was 8.68 ± 0.45 mg/dl in levetriacetam + sodium valproate users whereas minimum 8.55 ± 0.81 mg/dl in phenytoin + sodium valproate users was seen. Overall minimum serum calcium 7.38 ± 0.32 mg/dl was seen in triple therapy. In a study conducted y GHAFGHAZI et al²² among dual therapy lower calcium levels were found in patients on phenytoin and phenobarbitone and in triple therapy for patients on PHT, PB and CBZ because sodium valproate was not included in their study.

In opur study, on monotherapy maximum mean Vit D was 55.50 ± 9.5 ng/mL in levetriacetam whereas minimum 49.56 ± 10.50 ng/mL was seen in sodium valproate. On dual therapy maximum mean Vit D level was 52.56 ± 12.5 ng/mL in  phenytoin + sodium valproate users whereas minimum 50.65 ± 10.5 ng/mL in levetriacetam + sodium valproate users. Overall minimum Vit D level 45.2 ± 15.5 ng/mL was seen in triple therapy. The hypocalcaemia and vit D deficiency developed was not significantly associated with a single drug but associated with the number of drugs. Similarly Na Dong et al. (2022)¹⁵ found that the childhood epilepsy before initiation of and during treatment decreased the serum 25-OH-VitD concentrations, suggesting a clear association between epileptic disease and the risk of VitD deficiency. Also Chaudhuri IR et al. (2017)¹⁸ observed amongst antiepileptic drugs, sodium valproate were significantly associated with 25-hydroxyvitamin D deficiency. After adjustment using multiple logistic regression, antiepileptic drugs showed independent association with 25-hydroxyvitamin D deficiency.

Our study shows that as the number of drugs increased, mean calcium and vit D levels were decreased. So the physicians treating the patients who are on antiepileptic therapy for chronic duration should give awareness to their patients regarding the possible effects of these drugs on bone mineral metabolism, increased fracture risk and counsel them to avoid intake of factors like alcohol, smoking, steroids and other drugs which can increase the bone loss. The periodical monitoring of the levels of bone health markers like calcium, phosphorus, vitamin D and alkaline phosphatase in a interval of at least 6 months must be done. The supplementation with calcium and vitamin D3 if low levels are detected or if they have multiple risk factors should be started. The parents must be advised to give child adequate sunlight exposure, consume diet rich in calcium, vitamin D like diary products, fortified cereals and be started on calcium supplementation around 1000 to 1500 mg/d

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