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: Medically intractable temporal lobe epilepsy (TLE) remains a serious health problem. Across treatment centers, up to 40% of patients with TLE will continue to experience persistent postoperative seizures at 2-year follow-up. It is unknown why such a large number of patients continue to experience seizures despite being suitable candidates for resective surgery. Preoperative quantitative MRI techniques may provide useful information on why some patients continue to experience disabling seizures, and may have the potential to develop prognostic markers of surgical outcome. In this article, we provide an overview of how quantitative MRI morphometric and diffusion tensor imaging (DTI) data have improved the understanding of brain structural alterations in patients with refractory TLE. We subsequently review the studies that have applied quantitative structural imaging techniques to identify the neuroanatomical factors that are most strongly related to a poor postoperative prognosis. In summary, quantitative imaging studies strongly suggest that TLE is a disorder affecting a network of neurobiological systems, characterized by multiple and inter-related limbic and extra-limbic network abnormalities. The relationship between brain alterations and postoperative outcome are less consistent, but there is emerging evidence suggesting that seizures are less likely to remit with surgery when presurgical abnormalities are observed in the connectivity supporting brain regions serving as network nodes located outside the resected temporal lobe. Future work, possibly harnessing the potential from multimodal imaging approaches, may further elucidate the etiology of persistent postoperative seizures in patients with refractory TLE. Furthermore, quantitative imaging techniques may be explored to provide individualized measures of postoperative seizure freedom outcome.
    04/2015; 5(2):204-24. DOI:10.3978/j.issn.2223-4292.2015.01.01
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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.
    Human Brain Mapping 12/2014; DOI:10.1002/hbm.22722 · 6.92 Impact Factor
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    ABSTRACT: Objective There are competing explanations for persistent postoperative seizures after temporal lobe surgery. One is that 1 or more particular subtypes of mesial temporal lobe epilepsy (mTLE) exist that are particularly resistant to surgery. We sought to identify a common brain structural and connectivity alteration in patients with persistent postoperative seizures using preoperative quantitative magnetic resonance imaging and diffusion tensor imaging (DTI).Methods We performed a series of studies in 87 patients with mTLE (47 subsequently rendered seizure free, 40 who continued to experience postoperative seizures) and 80 healthy controls. We investigated the relationship between imaging variables and postoperative seizure outcome. All patients had unilateral temporal lobe seizure onset, had ipsilateral hippocampal sclerosis as the only brain lesion, and underwent amygdalohippocampectomy.ResultsQuantitative imaging factors found not to be significantly associated with persistent seizures were volumes of ipsilateral and contralateral mesial temporal lobe structures, generalized brain atrophy, and extent of resection. There were nonsignificant trends for larger amygdala and entorhinal resections to be associated with improved outcome. However, patients with persistent seizures had significant atrophy of bilateral dorsomedial and pulvinar thalamic regions, and significant alterations of DTI-derived thalamotemporal probabilistic paths bilaterally relative to those patients rendered seizure free and controls, even when corrected for extent of mesial temporal lobe resection.InterpretationPatients with bihemispheric alterations of thalamotemporal structural networks may represent a subtype of mTLE that is resistant to temporal lobe surgery. Increasingly sensitive multimodal imaging techniques should endeavor to transform these group-based findings to individualize prediction of patient outcomes. Ann Neurol 2015;77:760–774
    Annals of Neurology 01/2015; 77(5). DOI:10.1002/ana.24376 · 11.91 Impact Factor