431Pharmacogenetics of Epilepsy
More than one-third of the patients experience adverse drug reactions (ADRs) with
AED treatment that are related to individual susceptibility, the specifi c AED used,
prescribing physician’s skills rather than toxic effects of multiple AEDs (Canevini
et al. 2010 ). Pharmacogenetic factors have been implicated in immune-mediated or
hypersensitivity reactions. Most of the ADRs are predictable and mild as well as
tolerable and can be alleviated by dose reduction or discontinuation. However,
unpredictable severe ADRs that are fatal in some cases have also been reported and
cause signifi cant mortality and long-term morbidity (Gaitatzis et al. 2013 ). ADRs
may be a cause for non-compliance or discontinuation of AED therapy.
Polymorphisms of genes for drug metabolizing enzymes such as CYP2C9 and
CYP2C19 can infl uence the effi cacy, pharmacokinetics and ADR patterns of AEDs.
Polymorphisms of gene encoding CYP2C9 are more likely to be found in patients
who required higher dosages of AEDs such as carbamazepine and phenytoin.
Variation in genes can affect tolerability, and safety of AEDs. Pharmacogenetic
studies, which show that Asian patients with a particular human leucocyte antigen
(HLA) allele, HLA-B15:02, are at a higher risk for Stevens-Johnson syndrome
when using carbamazepine, improve our knowledge of how genetic variations
affect the treatment of epilepsy (Löscher et al. 2009 ). Prospective screening for
HLA- B15:02 prior to carbamazepine therapy in patients from South East Asia is
widely accepted and could prevent or reduce the incidence of Stevens-Johnson syn-
drome as well as toxic epidermal necrolysis, which is another hypersensitivity reac-
tion. Pre-prescription screening may be useful for prevention of these serious ADRs,
but is not cost-effective.
Available evidence suggests that genetic variants from ABCC2 transporter may
be associated with an altered response to AEDs. Results of a meta-analysis the lit-
erature indirectly suggest possible role of the ABCC2 transporter 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.
No AED treatment guidelines based on pharmacogenetic data are yet available.
There is a need for, and an opportunity to, establish standards specifi c to the conduct
of future AED studies to improve the management of epilepsy.
Drug Resistance in Epilepsy
One of the problems with current therapy of epilepsy is development of drug resis-
tance. One third of patients with epilepsy develop resistance to drugs, which is
associated with an increased risk of death and debilitating psychosocial conse-
quences. Multiple seizures prior to diagnosis, correlated with epilepsy type as
well as intrinsic severity, are risk factors for development of drug resistance.
Personalized Management of Epilepsy