432
Neuroinfl ammation also plays a key role of in the pathophysiology of resistant epi-
lepsy. Furthermore, transporter polymorphisms contributing to the intrinsic severity
of epilepsy are providing robust neurobiological evidence on an emerging theory of
drug resistance. Because resistance develops to multiple AEDs, the mechanism is
likely nonspecifi c involving drug-effl ux transporters such as ATP-binding cassette
sub-family B member 1 (ABCB1, also known as MDR1 and P-glycoprotein 170).
Lessons learnt from the ABCB1 studies can help guide future association genetics
studies for multidrug resistance in epilepsy (Tate and Sisodiya 2007 ). Use of AEDs
that are not ABCB1 substrates, inhibition of ABCB1 or the development of drugs
that can evade ABCB1 might improve the effi cacy of treatment in some patients
with drug-resistant epilepsy. Further studies in this direction might eventually
enable the drugs to be tailored to the patient’s profi le.
Examination of resected hippocampal tissue at surgery from patients with
therapy- resistant TLE shows that the mechanism of action of anticonvulsant carba-
mazepine, i.e. block of voltage-dependent Na + channels, is completely lost as com-
pared to tissue from patients who still respond to carbamazepine. These data suggest
that study of changes in ion channel pharmacology and their contribution to the loss
of anticonvulsant drug effi cacy in human epilepsy may provide an important impe-
tus for the development of novel anticonvulsants specifi cally targeted to modifi ed
ion channels in the epileptic brain. It is possible to use human tissue for the demon-
stration of drug resistance in an in vitro preparation, providing a unique tool in the
search for novel, more effi cient anticonvulsants. Altered expression of subtypes of
the GABA A receptor has also been observed in patients with drug-resistant temporal-
lobe epilepsy (Loup et al. 2009 ). This represents a TLE-specifi c dysfunction in
contrast to stable GABA A -receptor function in the cell membranes isolated from the
temporal lobe of TLE patients affl icted with neoplastic, traumatic, or ischemic tem-
poral lesions and can be antagonized by BDNF. These fi ndings may help to develop
new treatments for drug-resistant TLE.
Another mechanism underlying drug resistance in epilepsy may be the same as
in cancer: a cellular pump called P-glycoprotein, which protects cells from toxic
substances by actively exporting the offending compounds. In one case that became
resistant to phenytoin, low levels of phenytoin were demonstrated in association
with high levels of P-glycoprotein expression, the product of the MDR1 gene.
Currently, there are plenty of opportunities to develop personalized antiepileptic
medicines because of the wide variations in effectiveness and adverse effect profi le
of current AEDs.
The “target hypothesis” postulates that alteration in the cellular targets of AEDs
leads to a reduction in their sensitivity to treatment. Use-dependent blockade of the
fast Na current in dentate granule cells by carbamazepine is lost in hippocampi
resected from patients with carbamazepine-resistant temporal-lobe epilepsy, although
this fi nding does not extend to lamotrigine, which has a pharmacologic action similar
to that of carbamazepine. Polymorphisms of the SCN2A gene, which encodes the α 2
subunit of the neuronal Na channels, were found to be associated with resistance to
AEDs in general as well as to those that act on the sodium channels (Kwan et al.
2008 ). Whether these changes result in reduced sensitivity to antiepileptic drugs that
12 Personalized Management of Neurological Disorders