429Choice of the Right Antiepileptic Drug
The primary criterion for the selection of antiepileptic drugs (AEDs) is the patient’s
seizure type. This practice derives largely from drug studies that assess AED effec-
tiveness for specifi c seizure types rather than the defi ned causes of seizures. Despite
restriction to partial seizures, the response to an investigational AED is quite vari-
able. The reasons for this include: (i) patient-to-patient variation in the metabolism
of the AED; (ii) variations in the ability of AED to bind to the target; (iii) variations
in the amount of AED target produced by different individuals; and (iv) different
pathophysiological events accounting for the same seizure phenotype.
There are several old AEDs and several new drugs have been introduced in the
past few years. However, no single AED is clearly superior to others. Causes of
variability of effects of AEDs include genetic differences, pathogenesis and severity
of epilepsy, age, nutritional status, renal and liver function, concomitant illnesses,
and drug interactions. Available evidence suggests that genetic variants from
ABCC2 transporter may be associated with an altered response to AEDs. Results of
a meta- analysis the literature indirectly suggest possible role of the ABCC2 trans-
porter at the blood brain barrier in altered drug response in patients with epilepsy
(Grover and Kukreti 2013 ). The authors suggest further studies in different ethnic
groups to investigate the effects of the ABCC2 haplotypic variants and perform
stratifi ed analysis on the basis of different phenotypic covariates.
Physicians try to match a drug to the patient by trial and error. The fi nal choice
may take several months and depends on the effi cacy and tolerability of adverse
effects. However, the problems still remain of adverse side effects and failure to
control seizures in more than 30 % of patients, i.e. drug-resistant epilepsy.
Pharmacogenomics of Epilepsy
One of the approaches to optimize AED therapy is pharmacogenomic testing to
detect polymorphisms that may affect effi cacy, tolerability, and safety of AEDs
include variations in the genes encoding drug-metabolizing enzymes such as cyto-
chrome P450, or drug transporters such as MDR1 and MRP2 (Yoshida et al. 2011 ).
SNP studies have shown that polymorphisms of the gene for malic enzyme 2, a
mitochondrial enzyme that converts malate to pyruvate and is involved in neuronal
synthesis of GABA, predisposes to idiopathic generalized epilepsy. It is also becom-
ing increasingly clear that SNPs play an integral role in variability in both pharma-
cokinetics and pharmacodynamics of AEDs. Gene expression patterns of children
on valproic acid monotherapy differ according to whether they have continuing sei-
zures or remain free from seizures. This information can be used for personalizing
AED therapy. The publication of the human genome and increasing sophisticated
and powerful genetic tools offer new methods for screening drugs and predicting
serious idiosyncratic side effects. Variations of genes that encode drug targets
Personalized Management of Epilepsy