Drug Resistance Proteins: A Potential Mechanism for Medically Refractory Epilepsy
Abstract & Commentary
Source: Sisodiya SM, et al. Brain. 2002;125:22-31.
Multiple drug resistance (MDR) has been recognized as an obstacle to cancer treatment for at least two decades. Tumor cells may demonstrate intrinsic or acquired resistance to diverse chemotherapeutic agents. This could be effected by various mechanisms, but one of the best studied involves cellular drug transporters. Sisodiya and colleagues explored the possibility that a similar mechanism may be involved in focal epilepsies that are resistant to anticonvulsant drug (ACD) treatment.
Sisodiya et al performed immunohistochemistry for 2 MDR proteins (multidrug-resistance gene 1 P-glycoprotein, MDR1, and multidrug resistance-associated protein 1, MRP1) on pathological specimens of dysembryoplastic neuroepithelial tumors (DNET, 8 cases), focal cortical dysplasia (FCD, 14 cases), and hippocampal sclerosis (HS, 8 cases). MDR1 can transport phenytoin, phenobarbital, and other planar lipophilic molecules. MRP1 transports epoxides and glucurides, such as metabolites of carbamazepine and lamotrigine. The tissue was acquired during resective surgery from patients with medically refractory epilepsy. Neurons and astrocytes do not normally express these MDRs. The lesional tissue was compared to histologically normal adjacent tissue. All DNET and FCD cases showed increased expression of both MDRs in reactive astrocytes. Five FCD patients had MRP1 expression in dysplastic neurons as well. Five HS specimens expressed both MDRs in astrocytes in the gliotic hippocampus. Interestingly, immunohistochemically detectable overexpression of MDRs did not extend into normal adjacent tissue.
Commentary
Epidemiologic studies demonstrate that 60-70% of patients with epilepsy can achieve seizure freedom on ACDs. Why do the remainder of patients have medically intractable epilepsy? Clearly, there is no single answer to this question. Seizure disorders are heterogeneous in their pathophysiology, as are the patients who suffer from them. Nevertheless, one must try.
There are at least 3 intriguing features of the theory that MDRs may be involved in refractory epilepsy. The first is that the hypothesis does not appeal to any of the conventional theories of epileptogenesis (ie, excess cortical excitation, reduced inhibition, or aberrant cortical-cortical or cortical-subcortical networks). Intraoperative microdialysis for ACDs performed immediately prior to resection might help to confirm that there are lower ACD levels in tissue subsequently shown to have increased MDR expression.
Second, potentially important diagnostic tools may become available to identify patients who are destined to develop intractable seizures. For example, Rao et al (Rao VV, et al. Proc Natl Acad Sci U S A. 1999;96: 3900-3905) have used noninvasive single-photon-emission computed tomography (SPECT) with a membrane permeant radiopharmaceutical whose transport is mediated by MDR1 and MRP1 to obtain images indirectly reflecting the contribution of these MDRs to the blood-CSF barrier. Further studies should address whether SPECT or a similar technique has sufficient resolution to detect changes in MDR-mediated transport that would predict intractable epilepsy.
Finally, MDR-reversing agents are currently undergoing clinical trials in cancer chemotherapy (Tan B, et al. Curr Opin Oncol. 2000;12:450-458). Might some of these agents be useful adjuncts to ACD treatment in patients now categorized as medically refractory? Neurology Alert recognizes that this commentary is more speculative than usual, but believes that this unconventional hypothesis may have important implications for a medically and psychosocially devastating disorder. —Andy Dean
Dr. Dean is Assistant Professor of Neurology and Neuroscience, Director of the Epilepsy Monitoring Unit, Department of Neurology, New York Presbyterian Hospital—Cornell Campus.
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