Association between temporal lobe P-glycoprotein expression and seizure recurrence after surgery for pharmacoresistant temporal lobe epilepsy
Introduction
Despite appropriate drug treatment, 20–40% of patients with epilepsy continue to have seizures and are considered to have refractory or pharmacoresistant epilepsy (Kwan and Brodie, 2000, Schmidt and Löscher, 2005). Temporal lobe epilepsy (TLE) is the most common type of pharmacoresistant epilepsy (Semah et al., 1998), for which surgery in the form of anterior temporal lobectomy is a recommended treatment option in selected candidates (Engel et al., 2003). The most common pathological substrate identified in pharmacoresistant TLE is hippocampal sclerosis, the presence of which carries a higher probability of seizure-freedom after surgery (Radhakrishnan et al., 1998, Tonini et al., 2004, McIntosh et al., 2004, Spencer et al., 2005). However, despite careful selection, pharmacoresistant seizures recur in approximately one third of patients postsurgery, and no reliable clinical predictive factor has been identified (Hardy et al., 2003, Uijl et al., 2008). Identification of biological markers for seizure recurrence after surgery would be of great clinical value and may shed insights into the neurobiological basis underpinning pharmacoresistant epilepsy.
We hypothesized that P-glycoprotein expression in the epileptogenic temporal lobe might be one such marker. P-glycoprotein, encoded by the ABCB1 or MDR1 gene, is the “prototype” multidrug transporter belonging to the superfamily of ATP-binding cassette (ABC) proteins which are transmembrane proteins that extrude substrates from the cell against the concentration gradient. These proteins have been extensively studied in oncology because of their putative role in multidrug resistance to cancer chemotherapy (Gottesman et al., 2002). In the normal brain, P-glycoprotein is expressed at a basal physiologic level in capillary endothelial cells where it “pumps” a broad range of xenobiotics from intracellular space back to the capillary lumen, thereby maintaining the integrity of the blood–brain barrier and reducing the cerebral accumulation of substrate drugs. In a range of epileptogenic brain pathologies, including those associated with refractory TLE, upregulation of P-glycoprotein and other ABC multidrug transporters in capillaries, as well as novel or aberrant expression in glial and neuronal cells in some cases, have been reproducibly demonstrated (Tishler et al., 1995, Dombrowski et al., 2001, Sisodiya et al., 2002, Aronica et al., 2003, Aronica et al., 2004, Kubota et al., 2006, Ak et al., 2007). Such observations have lent support to the hypothesis that upregulation of P-glycoprotein (and other multidrug transporters) may play a mechanistic role in drug resistance in epilepsy (Kwan and Brodie, 2005, Löscher and Potschka, 2005). Given the common upregulation of P-glycoprotein in pathologies of refractory epilepsy we hypothesized that its expression might also correlate with surgical outcome. In this pilot study we compared P-glycoprotein expression levels and patterns by immunohistochemistry in the resected temporal lobe between patients with and without recurrent seizures after undergoing surgery for pharmacoresistant TLE. The study group was pathologically homogeneous, all having histopathologically proven hippocampal sclerosis, thereby minimizing potential confounding pathological factors in assessing the primary hypothesis.
Section snippets
Study patients and evaluation before surgery
Consecutive patients with pharmacoresistant TLE, with histopathology confirming hippocampal sclerosis, who underwent epilepsy surgery at the Royal Melbourne Hospital, Melbourne, Australia, between June 1993 and December 2005 were included in this study. All patients underwent a standard anterior temporal lobectomy by the same surgeon (A.H.K.) following a protocol-driven presurgical evaluation. The study was approved by the The Melbourne Health Human Research Ethics Committee.
The procedures for
Results
Sixty-nine (45 female) patients with histopathologically proven hippocampal sclerosis were included. Post-operative follow-up was a mean duration of 5.2 years (standard deviation 2.2 years). Forty-seven (68%) patients were seizure-free after surgery and 22 had recurrent seizures, all occuring while continuing to take antiepileptic drug therapy. Focal cortical dysplasia was found on histopathological examination of the resected temporal lobe in addition to hippocampal sclerosis in two patients,
Discussion
Approximately one third of the patients with hippocampal sclerosis-related medically refractory TLE in our series suffered recurrent pharmacoresistant seizures after surgery, which is similar to other reports. Confirming our previous analysis on a smaller sample (Kilpatrick et al., 1999), various preoperative clinical variables were not predictive of postsurgical seizure outcome (Table 1). The cohort provided a homogenous population who were otherwise identical in terms of the type and severity
Conflict of interest
None of the authors has any conflict of interest to disclose.
Acknowledgments
This work was supported by a grant from the Research Grants Council of the Hong Kong Special Administrative Region, China (Project no. CUHK4466/06M).
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