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: 15.36). 09/2012; 8(12). DOI: 10.1038/nrneurol.2012.181
Source: PubMed


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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    • "Mesial temporal lobe epilepsy (mTLE) due to hippocampal sclerosis (HS) is the most common and most frequently operated medically intractable epilepsy disorder [Janszky et al., 2005; Wiebe and Jette, 2012]. It is well documented that patients with mTLE have brain abnormalities beyond the hippocampus. "
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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.
    Full-text · Article · Dec 2014 · Human Brain Mapping
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    • "Although seizure freedom is 2.7—3 times higher (Tellez-Zenteno et al., 2010) in patient with substrate localization on MRI, 1/3—1/4 of patients will still 'fail' a surgical resection. In addition, approximately 40% of patients must continue their anti-epileptic medications (Wiebe and Jette, 2012a,b) even after surgery. In the present study, we evaluated the concordance of non-invasive investigations iSPECT and FDG-PET to study their combined utility in localizing and predicting the long-term outcomes following resective epilepsy surgery. "
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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.
    Full-text · Article · Sep 2014 · Epilepsy Research
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    • "While surgery remains the cornerstone for treatment of medically refractory epilepsy, it is important to note that some seemingly medically refractory patients may in fact go into seizure remission following introduction of a new antiepileptic drug, all the more relevant as the number of seizure medications available to clinicians increase (Luciano and Shorvon 2007). However, this observation is intriguingly contested by recent studies demonstrating that remission in a medically refractory patient after change to a new antiepileptic drug may actually be the result of the spontaneous and/or periodic remissions seen in the natural course of epilepsy (Wiebe and Jette 2012, Wang et al. 2013). Downloaded by [] at 22:57 21 August 2015 E "
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    ABSTRACT: Mesial temporal lobe epilepsy is a common subtype of temporal lobe epilepsy. Its most common cause is hippocampal sclerosis, which contributes to its distinct electroclinical phenotype that is seen commonly in the epilepsy monitoring unit setting. The common electrophysiological data show anterior temporal interictal sharp waves as well as rhythmic theta activity in the same localization. While the electrophysiological data can at times be misleading, its stereotyped and characteristic semiology can often allow for accurate diagnosis on its own. As patients with mesial temporal lobe epilepsy often fail medical therapy, surgical therapy can be considered. Early accurate diagnosis in these patients is essential for optimal care.
    Preview · Article · Sep 2014 · The Neurodiagnostic journal
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