Pharmacoresistance and the role of surgery in difficult to treat epilepsy.

Departments of Clinical Neurosciences and Community Health Sciences and the Hotchkiss Brain Institute, University of Calgary, Division of Neurology, Foothills Medical Centre, 1403 29th Street NW, Calgary, AB T2N 2T9, Canada.
Nature Reviews Neurology (Impact Factor: 14.1). 09/2012; DOI: 10.1038/nrneurol.2012.181
Source: PubMed

ABSTRACT Pharmacoresistance occurs in up to 30% of patients with epilepsy, and is most commonly associated with epilepsy of structural or metabolic origin, abnormal findings on brain imaging or examination, and failure to respond to the first two antiepileptic drugs. However, in patients presumed to have difficult to treat epilepsy, factors that might result in apparent treatment resistance (misdiagnosis of epilepsy, incorrect drug and/or dose, and lifestyle issues) must first be excluded and the diagnosis re-examined. Epilepsy is commonly misdiagnosed, especially in patients with syncope and psychogenic events. The initial steps in confirming the diagnoses of both epilepsy and pharmacoresistance are to obtain a detailed, reliable history and to conduct a careful review of all prior trials of antiepileptic drug therapy. Once the diagnoses of epilepsy and pharmacoresistance are confirmed, the seizure type, epilepsy syndrome, and expected course of the disorder dictate its medical and surgical management. Epilepsy surgery should be considered promptly in these patients, since few interventions are as effective as brain surgery in this setting, particularly in patients with focal pharmacoresistant epilepsy. This Review discusses the concept of pharmacoresistance and describes the approach to management of the patient with difficult to treat epilepsy, focusing on the important role of epilepsy surgery.

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    ABSTRACT: Refractory mesial temporal lobe epilepsy (mTLE) is a debilitating condition potentially amenable to resective surgery. However, between 40 and 50% patients continue to experience postoperative seizures. The development of imaging prognostic markers of postoperative seizure outcome is a crucial objective for epilepsy research. In the present study, we performed analyses of preoperative cortical thickness and subcortical surface shape on MRI in 115 of patients with mTLE and radiologically defined hippocampal sclerosis being considered for surgery, and 80 healthy controls. Patients with excellent (International League Against Epilepsy outcome (ILAE) I) and suboptimal (ILAE II-VI) postoperative outcomes had a comparable distribution of preoperative atrophy across the cortex, basal ganglia, and amygdala. Conventional volumetry of whole hippocampal and extrahippocampal subcortical structures, and of global gray and white matter, could not differentiate between patient outcome groups. However, surface shape analysis revealed localized atrophy of the thalamus bilaterally and of the posterior/lateral hippocampus contralateral to intended resection in patients with persistent postoperative seizures relative to those rendered seizure free. Data uncorrected for multiple comparisons also revealed focal atrophy of the ipsilateral hippocampus posterior to the margins of resection in patients with persistent seizures. This data indicates that persistent postoperative seizures after temporal lobe surgery are related to localized preoperative shape alterations of the thalamus bilaterally and the hippocampus contralateral to intended resection. Imaging techniques that have the potential to unlock prognostic markers of postoperative outcome in individual patients should focus assessment on a bihemispheric thalamohippocampal network in prospective patients with refractory mTLE being considered for temporal lobe surgery. Hum Brain Mapp, 2014. © 2014 The Authors Human Brain Mapping Published by Wiley Periodicals, Inc. © 2015 The Authors Human Brain Mapping Published by Wiley Periodicals, Inc.
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    ABSTRACT: Objective F-18 Fluorodeoxyglucose positron emission tomography (FDG-PET) and ictally subtracted single photon emission tomography (iSPECT) are important for localizing the epileptogenic focus. The following study analyzes the role of inter-concordance between FDG-PET and iSPECT in predicting long-term outcomes after epilepsy surgery. Methods We prospectively evaluated (January 2003-January 2008) patients undergoing surgery for temporal or extratemporal drug refractory epilepsy (DRE) who had at least a 5 years follow up. Patients with MRI and video EEG (vEEG) concordance for the seizure focus underwent iSPECT and FDG-PET. Concordance of the iSPECT and FDG-PET with each other and with the substrate (defined by MRI and vEEG) for temporal and extra-temporal epilepsies was evaluated and correlated with outcomes. Results One hundred twenty-three patients (74 males) were included in the study (mean age at time of surgery: 18.9 ± 10.41 years). The mean age of onset of seizures was 9.87 ± 8.37 years. The most common semiology was complex partial (45%). When both FDG-PET and iSPECT were concordant with each other, this translated into a (Class I Engel at 5 years) outcome of 62% for extra-temporal epilepsies (provided they were also concordant with the lesion, as defined by MRI and vEEG). This percentage was significant (p < 0.01) compared with all other situations (both FDG-PET/iSPECT not concordant to MRI/vEEG, only PET or iSPECT concordant with MRI/vEEG). This correlation was not found for the temporal epilepsies, where the MRI and vEEG were the most important prognostic parameters. In both temporal and extratemporal epilepsies the concordance of the iSPECT/FDG-PET with the MRI/vEEG correlated with a better 5-year outcome (Temporal: 70% vs 25%; Extra-temporal: 62% vs 33%; p < 0.05). Significance: Concordance between non-invasive investigation iSPECT and FDG-PET is an important predictive factor for surgical outcomes in extra-temporal epilepsy.
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    ABSTRACT: Eslicarbazepine is the major active metabolite of eslicarbazepine acetate, a once-daily antiepileptic drug approved in Europe as adjunctive therapy for refractory partial-onset seizures in adults. This study was aimed to determine the effects of eslicarbazepine on persistent Na(+) currents (INaP) and the role of β subunits in modulating these effects. To study the role of β subunits of the Na(+) channel we used a mouse line genetically lacking either the β1 or β2 subunit, encoded by the SCN1B or SCN2B gene, respectively. Whole cell patch-clamp recordings were performed on CA1 neurons in hippocampal slices under control conditions and application of 300μM eslicarbazepine. We examined INaP in acutely isolated CA1 neurons and repetitive firing in hippocampal slices of mice lacking β subunits and corresponding wild-type littermates. We found that eslicarbazepine caused a significant reduction of maximal INaP conductance and an efficient reduction of the firing rate in wild-type mice. We have shown previously a paradoxical increase of conductance of INaP caused by carbamazepine in mice lacking β1 subunits in the subthreshold range, leading to a failure in affecting neuronal firing (Uebachs et al., 2010). In contrast, eslicarbazepine did not cause this paradoxical effect on INaP in SCN1B null mice. Consequently, the effects of eslicarbazepine on repetitive firing were maintained in these animals. These results indicate that eslicarbazepine exerts effects on INaP similar to those known for carbamazepine. However, in animals lacking the β1 Na(+) channel subunit these effects are maintained. Therefore, eslicarbazepine potentially overcomes a previously described putative mechanism of resistance to established Na(+) channel acting antiepileptic drugs.
    Epilepsy research 12/2013; 108(2). DOI:10.1016/j.eplepsyres.2013.11.022 · 2.19 Impact Factor