Genetic polymorphism of drug refractory epilepsy.

Epilepsy is a common neurological disorder affecting over 50 million people worldwide with distinct symptoms, aetiology and prognosis. In India, it is estimated that there are 55,00,000 persons with epilepsy and prevalence rate of epilepsy is 5.59 per 1,000 population1. Current treatment regimens for epilepsy focus on seizure suppression or prorogation. Although epileptic seizures can be effectively controlled with anti-epileptic drugs (AEDs) in up to 70-80 per cent of patients, about one third of patients are drug-refractory despite optimal AED treatment2.

An important characteristic of drug resistant epilepsy is that many patients are resistant to several, if not all anti-epileptic drugs (AEDs). Based on several studies it was reported that patients who fail to respond to first-line or second-line AED therapy will develop drug resistance, even on using AEDs acting via diverse mechanisms3. Drug-resistant epilepsy affects individual health and the quality of life, with heavy burden on society. Studies have shown that drug refractory epilepsy imposes serious threats to patient's life which include neuropsychological illness, psychiatric and social impairment, reduced marriage rates and decreased life span4. Further, only a subgroup of refractory patients responds to surgery or other specialized treatments and make them seizure free but others will continue to have seizures2. Identifying the factors that contribute to drug resistance is, therefore, a major challenge, with a potentially significant impact on clinical practice.

The plausible factors for drug resistance could be environmental and seizure related causes. But, there are reports conferring running of epilepsy among families, indicating a possible genetic cause for the disease. Genetic causes have gained attention for both epilepsy as well as drug resistance. For various cases, the causes and response to treatment are closely related. This holds true for various sodium channel mutations implicated in disease and also acting as novel targets for various AEDs. Identification of predictive markers for drug resistance may revolutionize the existing treatment strategies. There are reports about the associations between many genetic variations and clinical drug resistance; however, none of these associations has been unequivocally replicated5. Two separate studies done in south and north Indian patients were also not able to find any evidence for association67. Therefore, further exhaustive studies about the influence of genetic variations on drug resistance may be valuable.

The two well known hypotheses for understanding the biological mechanism underlying multidrug resistance are the target and transporter hypotheses38. In target hypothesis, epilepsy-induced alterations in specific drug targets (reduction in sensitivity) such as sodium channels have also been a major cause for pharmacoresistant epilepsy9. Transporter hypothesis suggests that increased expression of efflux transporter p-glycoprotein (P-gp), encoded by ATP binding cassette (ABCB1) gene, leads to decreased bioavailability and limited brain access of antiepileptic drugs that may result in drug resistance. As we know, AEDs are lipophilic in nature and P-gp transporters have a wide variety of specificity for lipohilic molecules10 but still, most commonly used anticonvulsants namely carbamazepine and sodium valproate were not found to be a substrate to P-gp1112. Phenytoin was shown to be a weak substrate of P-gp and non-ABC transporter such as RLIP76 may also be involved in transporting this drug in blood brain barrier13. Thus, there may be alternative mechanisms behind the development of drug resistance to these specific drugs which needs to be explored11.

Recently, CYP2C19 a polymorphic drug metabolizing enzyme (DME) was shown to be associated with clobazam response14. The responder rate was significantly greater in CYP2C19 poor metabolizers and CYP2C19 heterozygous extensive metabolizer than in CYP2C19 homozygous extensive metabolizers. However, studies are sparse which demonstrate the association between multiple AEDs resistance and drug metabolizing enzymes. A study by Ufer et al15showed that heterozygous CYP2C9*3 were under-represented among non-responders to AEDs in Caucasians epileptic patients.

In this issue, Lakhan et al16 explored the possible association between CYP2C gene polymorphisms and resistances to AEDs in Indian epileptic patients. Authors have shown the distribution of variant genotypes of CYP2C9 and CYP2C19 in patients with drug resistance and responder to AEDs. They observed CYP2C9*3 variant allele frequency was under-represented in drug resistant patients compared to responder patients. They did not find any significant association between variants of CYP2C19 in drug resistance/responder. Hence, it was suggested that the carrier of CYP2C9*3 may contribute towards lower risk for developing multiple drug resistance in epileptic patients. In Indian population, the frequency of CYP2C9FNx013 was 8 per cent17. A recent study by Kesavan et al18 demonstrated the association of CYP2C9*3 in development of phenytoin-induced neurological toxicity in Indian population. However, the clinical significance of these studies should be carefully interpreted. Multicentric studies in large number of samples involving all major ethnic groups in India are needed to confirm these findings. If we find positive association with high degree of statistical significance, screening for CYP2C9*3 genotype may help the clinicians in predicting the responders and non-responders for AEDs as well as risk for developing phenytoin toxicity.

The database for variant alleles of genes encoding for drug metabolizing enzymes, transporters and channels (CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP3A4, EPHX1, UGT1A1, UGT2B7, MDR1, SCN1A, SCN1B, and SCN2A) are available for healthy volunteers171920 as well as for Indian epileptic patients21. This information may be useful for future studies of drug resistance in epilepsy. Not only the candidate gene studies but also whole exome sequencing (WES), transcriptional studies in surgery-resected brain tissue from patients with drug-resistant epilepsies, gene expression studies and multidisciplinary approaches, including neuropathology and imaging are important to understand their mechanisms.