Molecular Genetics of Drug-resistance in Epilepsies.

Nearly one-third of newly diagnosed patients with epilepsy remain unresponsive to antiepileptic drugs (AEDs), etiopathogenesis of which is poorly understood. The genes encoding the proteins that regulate the pharmacokinetics such as P-glycoprotein [ABCBI], major vault protein [MVP gene] and drug metabolizing enzymes [ABCB1, ABCG2, MVP, CYP2C9, CYP2C19, CYP3A4, CYP3A5, EPHX1, UGT1A1, UGT2B7], and pharmacodynamics such as sodium channels [SCN1A, SCN2A] and GABA receptors [GABRA1, GABRA6, GABRB2, GABRG2] of AEDs are under intense investigation to unravel the mysteries of AED-resistance. However, till today, a consistent and reliable result that could help the clinician either to predict drugresistance or to overcome it has not been forthcoming. The discrepant results may be related to variations in the definition of drug-resistance, heterogeneous patient populations, ethnic variations in the frequency distribution of single nucleotide polymorphisms (SNPs) and the selection of SNPs. Understanding of these limitations of existing studies, hopefully, will help in designing better studies.

Corpora amylacea deposition in the hippocampus of patients with mesial temporal lobe epilepsy: A new role for an old gene.

BACKGROUND: Mesial temporal lobe epilepsy (MTLE) is the most common medically refractory epilepsy syndrome in adults, and hippocampal sclerosis (HS) is the most frequently encountered lesion in patients with MTLE. Premature accumulation of corpora amylacea (CoA), which plays an important role in the sequestration of toxic cellular metabolites, is found in the hippocampus of 50–60% of the patients who undergo surgery for medically refractory MTLE-HS. However, the etiopathogenesis and clinical importance of this phenomenon are still uncertain. The ABCB1 gene product P-glycoprotein (P-gp) plays a prominent role as an antiapoptotic factor in addition to its efflux transporter function. ABCB1 polymorphism has been found to be associated with downregulation of P-gp expression. We hypothesized that a similar polymorphism will be found in patients with CoA deposition, as the polymorphism predisposes the hippocampal neuronal and glial cells to seizure-induced excitotoxic damage and CoA formation ensues as a buffer response. MATERIALS AND METHODS: We compared five single nucleotide polymorphisms in the ABCB1 gene Ex06+139C/T (rs1202168), Ex 12 C1236T (rs1128503), Ex 17-76T/A (rs1922242), Ex 21 G2677T/A (rs2032582), Ex26 C3435T (rs1045642) among 46 MTLE-HS patients of south Indian ancestry with and without CoA accumulation. RESULTS: We found that subjects carrying the Ex-76T/A polymorphism (TA genotype) had a five-times higher risk of developing CoA accumulation than subjects without this genotype (Odds ratio 5.0, 95% confidence intervals 1.34-18.55; P = 0.016). CONCLUSION: We speculate that rs1922242 polymorphism results in the downregulation of P-gp function, which predisposes the hippocampal cells to seizure-induced apoptosis, and CoA gets accumulated as a buffer response.

Drug resistance in epilepsy and the ABCB1 gene: The clinical perspective.

Multidrug resistance is one of the most serious problems in the treatment of epilepsy that is likely to have a complex genetic and acquired basis. Various experimental data support the hypothesis that over-expression of antiepileptic drug (AED) transporters may play a pivotal role in drug resistance. Hyyt 6however, key questions concerning their functionality remain unanswered. The idea that P-glycoprotein, encoded by the ABCB1 gene, might mediate at least part of the drug resistance was met with both enthusiasm and skepticism. As in oncology, initial optimism has been clouded subsequently by conflicting results. The first study reporting a positive association between genetic variation in the P-glycoprotein and multidrug-resistant epilepsy was published in 2003. Since then, several other genetic association studies have attempted to verify this result. However, taken overall, the role of P-glycoprotein in drug resistance in epilepsy still remains uncertain. We intend to critically review the inherent problems associated with epilepsy pharmacogenetic studies in general and with ABCB1 polymorphisms studies in particular. The lessons learnt from the ABCB1 studies can help us to guide future association genetics studies to investigate AED resistance, and thereby taking us closer to the cherished dream of personalized AED therapy.

Epilepsy surgery in India.

This review traces the evolution of epilepsy surgery in India from the beginning to the present state. During the last one and half decades, surgical treatment of epilepsies has made resurgence in this country and at present a few centers have very active and sustained epilepsy surgery programs. Within a 14-year period, the R. Madhavan Nayar Center for Comprehensive Epilepsy Care, Trivandrum, has undertaken over 1000 epilepsy surgeries. However, in the whole country, annually, not more than 200 epilepsy surgeries are currently being performed. This number is a miniscule when compared to the number of potential surgical candidates among the vast population of India. The enormous surgical treatment gap can only be minimized by developing many more epilepsy surgery centers in different parts of our country.

Electro-clinical characteristics and postoperative outcome of medically refractory tumoral temporal lobe epilepsy.

BACKGROUND: Very few studies have specifically addressed surgical treatment and outcome of patients with tumor-related temporal lobe epilepsy (TLE). AIM: To define the postoperative seizure outcome and the factors that influenced the outcome of patients with tumor-related TLE. MATERIALS AND METHODS: We selected patients whose surgical pathology revealed a temporal lobe neoplasm and who had completed > 1 year of postoperative follow-up. We reviewed the clinical, EEG, radiological and pathological data, and the seizure outcome of these patients and assessed the factors that influenced the outcome. RESULTS: Out of the 409 patients who underwent surgery for refractory TLE during the 8-year study period, there were 34 (8.3%) patients with temporal lobe neoplasms. The median age at surgery was 20 years and the median duration of epilepsy prior to surgery was 9.0 years. MRI revealed tumor in the mesial location in 21 (61.8%) patients. Interictal and ictal epileptiform EEG abnormalities were localized to the side of th lesion in the majority. Mesial temporal lobe structures were included in the resection, if they were involved by the tumor; otherwise, lesionectomy alone was performed. During a median follow-up of 4 years, 27 (79%) patients were completely seizure-free. The only factor that predicted long-term seizure-free outcome was being seizure-free during the first two postoperative years. CONCLUSIONS: Our results emphasize the fact that in patients with tumoral TLE, when the seizures are medically refractory, surgery offers potential for cure of epilepsy in the majority.