The possible effect of SCN1A and SCN2A genetic variants on carbamazepine response among Khyber Pakhtunkhwa epileptic patients, Pakistan.

PURPOSE: SCN1A (3184 A>G) and SCN2A (56G>A) gene encodes α subunit of the neuronal voltage-gated sodium channel, which is a target for carbamazepine (CBZ). Recent studies have demonstrated that polymorphism of SCN1A (3184 A>G) and SCN2A (56G>A) was associated with use of CBZ. However, it has not been determined whether the polymorphism affects CBZ or other antiepileptic drug responsiveness. The aim of the study was to establish whether the SCN1A (3184 A>G) and SCN2A (56G>A) polymorphisms of the SCN1A and SCN2A genes affect responsiveness to CBZ. METHODS: SCN1A (3184 A>G) and SCN2A (56G>A) gene polymorphisms were genotyped in 93 Khyber Pakhtunkhwa epileptic patients treated with CBZ. The association between CBZ responsiveness and the polymorphism was estimated by adjusting for clinical factors affecting the outcome of therapy. The number of seizure episodes was documented at baseline, and the therapy of each of the 93 patients was followed up. The plasma level of CBZ was determined using reverse-phase high-performance liquid chromatography. SCN1A and SCN2A genes were genotyped using RFLP. Data were analyzed using Graph Pad Prism 6. RESULTS: Mean age of the patients was 18.6±9.3 at the 3rd month and 18.7±9.5 at the 6th month. The baseline dose of CBZ was 468±19.8 mg/d and titrated at the rate of 48±1.4 and 4.0±0.2 mg/d. The difference in plasma level of CBZ was significant (P=0.004) between 3rd and 6th month among different genotypes of SCN1A gene in nonresponder and responder patients. At the 3rd month of the therapy, the poor responders were more likely (P=0.003 and P=0.01) to have variants (3184AG and 3184GG) of SCN1A gene. Similarly, poor responsders were more likely (P=0.0007 and P=0.001) to have variant genotypes (56GA, 56AA) of SCN2A gene at the 3rd month of the therapy. CONCLUSION: This study demonstrated a significant association between the SCN1A (3184 AG and GG) and SCN2A (56GA and AA) genotype with CBZ-nonresponsive epilepsy.

Carbamazepine Verses Valproic Acid as Monotherapy in Epileptic Patients.

OBJECTIVE: To evaluate the effectiveness of carbamazepine and valproic acid as monotherapy in epileptic patients of Pakhtun population. STUDY DESIGN: An experimental study. PLACE AND DURATION OF STUDY: The outpatient Neurology Department, Lady Reading Hospital, Peshawar, from August 2014 to April 2016. METHODOLOGY: Epileptic patients placed on carbamazepine and volproic acid were inducted. Carbamazepine and valproic acid plasma levels were determined using reverse phase high performance liquid chromatography. Plasma levels of vitamin B6 and homocysteine were determined at baseline before the switching to carbamazepine and valproic acid therapy, and on the sixth month of the therapy. Hemoglobin (Hb) level were also determined through blood analyser. Clinical response (number of seizures per week) was evaluated on third and sixth month of the therapy. RESULTS: There were 79 patients in carbamazepine group and 82 in the valproic acid group. Mean age of patients was 18.08 ±8.6 years in carbamazepine group and 17.5 ±7.04 years in the valproic acid group. Median dose of carbamazepine was 400 mg/day at baseline and at 6th month of therapy. Median dose of valproic acid was 500 mg/day and 750 mg/day of valproic acid at baseline and end study point. Difference in homocysteine, vitamin B6 and Hb levels were statistically significant (p<0.05) in carbamazepine cohort compared to valproic acid cohort. The frequency of seizures in the carbamazepine was 0.85 times more compared to valproic acid at the end study point. CONCLUSION: Hyperhomocysteinaemia and lower vitamin B6 and Hb levels was found in the carbamazepine cohort. The frequency of number of seizures/week was higher in the carbamazepine cohort compared to valproic acid cohort.

The Epidemiological Characteristics of Epilepsy in the Province of Khyber Pakhtunkhwa, Pakistan.

Previous studies have shown that Khyber Pakhtunkhwa, Pakistan has a high incidence of epilepsy and a high proportion of low socioeconomic background and high treatment gap. Considering the changes over the past 20 years little is known about the current epidemiological characteristics of epilepsy in Khyber Pakhtunkhwa, Pakistan. The current study was focused to find the impact of various contributing factors on the clinical response to anti-epileptic drugs in the KP population, Pakistan. A total of 315 participants aged 19.1 ± 8.6 years were examined. Mean age of the patients was 18 ± 8.1 year. Epilepsy was high in male patients (64.39%) and urban areas (60.1%). Mostly, 88.6% of patients were belonging to low socioeconomic status background. 42.4% patients have positive family history for epilepsy and 42.8% patients had consanguineous marriages. Middle SES class patients (OR, 2.22 [CI, 0.54-9.1]) were slightly associated with controlled response to CBZ and VPA therapy. Absence seizure (OR, 1.16 [CI, 0.59-2.3]), and Complex partial seizure (OR, 1.29 [CI, 0.58-6.3]) showed good response to CBZ therapy while, Myoclonic seizure (OR, 2.23 [CI, 0.05-8.8]) was responsive to VPA therapy. However, non-compliance (R 2 0.82, P < 0.0001) and nature of seizures (R 2 0.83, P < 0.0001) were associated with the high risk for poor response to both CBZ and VPA therapy. Epilepsy was high in male patients and in urban areas. Most patients were belonging to low socioeconomic status. Non-compliance, low socioeconomic and nature of seizures strongly predict poor clinical response of anti-epileptic drugs therapy.

Epilepsy control with carbamazepine monotherapy from a genetic perspective.

BACKGROUND: Ethnicity variation is one of the main factors that may affect drug response in clinical practice. As MTHFR gene affects different transcriptome and proteome which affect the clinical response of drugs. Purpose of the current study was to observe possible variations in plasma levels of carbamazepine monotherapy and seizures' control in Pakhtun population of Khyber Pakhtunkhwa (KP) in the context of MTHFR (C677T and A1298C) gene polymorphisms. METHODS: Blood was collected from the epileptic patients treated with carbamazepine monotherapy for the first time following respective oral doses on its steady state concentration after 3 h of morning dose at 3rd and 6th month of the therapy. Plasma carbamazepine levels were determined using reverse phase high performance liquid chromatography after method validation. MTHFR (C677T, AA298C) gene was genotyped. Patients were followed on 3rd and 6th month of the therapy for monitoring of response to carbamazepine therapy. RESULTS: Following for 3rd and 6th month of duration of carbamazepine therapy, poor seizure controlled patients were more likely noticed in heterozygous variants (677CT and 1298 AC) of MTHFR gene (P < 0.05). There was no significant (P > 0.05) difference in the dose and plasma level of carbamazepine among different genotypes of MTHFR (C677T and A1298C) gene. Similarly, the difference in dose and plasma level of carbamazepine was not significant (P > 0.05) in the responder and non-responder people with epilepsy. CONCLUSION: Our study suggests that heterozygous variants of MTHFR (C677T and A1298C) gene are associated with poor seizure control in Pakhtun population of KP despite the fact that plasma level of carbamazepine were found within the therapeutic range.

Vitamin B6 and homocysteine levels in carbamazepine treated epilepsy of Khyber Pakhtunkhwa.

OBJECTIVES: The study focused on the plasma levels of vitamin B6 and homocysteine in different genotypes of MTHFR (C677T, A1298C) and GABRG2 (C588T, C315T) genes in carbamazepine resistant epilepsy in the population of Khyber Pakhtunkhwa. METHODOLOGY: Patients who were possible candidates for carbamazepine therapy were followed for six months for their seizure control. Plasma levels of vitamin B6 and homocysteine were determined using immunoassay based techniques at baseline and after six months. MTHFR (C677T, A1298C) and GABRG2 (C588T, C315T) genes were genotyped using restriction fragment length polymorphisms. Seizure control during therapy was recorded on a standardized proforma. RESULTS: Low vitamin B6 levels and hyperhomocysteinemia were found in 61.7% of resistant patients (n=34). Resistant patients had the following frequencies of variant genotypes (677CT=38.1% and 677TT=24.4%; 1298AC=42.2% and 1298CC=26.1%; 588CT= 47.6% and 315TT= 33.3%) of MTHFR (C677T and A1298C) and GABRG2 (C588T and C315T) genes. A significant decline in vitamin B6 (P<0.0001) and hyperhomocysteinemia were found in variant genotypes of MTHFR (C677T, A1298C) and GABRG2 (C588T, C315T) genes. CONCLUSION: Following six months of carbamazepine of therapy in heterozygous variant genotypes of MTHFR (677CT and 1298AC) and GABRG2 (588CT and 315CT) genes, we observed a significant fall in vitamin B6 levels and hyperhomocysteinemia.