REVIEW URRENT C OPINION
Neuroimaging of drug resistance in epilepsy Matthias J. Koepp
Purpose of review Drug resistance is an important clinical problem: it is associated with higher rates of somatic and psychiatric comorbidities and cognitive/memory decline, with seizures being just the ‘tip of the iceberg’. This review summarizes recent developments in imaging research, focusing specifically on the functional consequence of chronic epilepsies and mechanisms of drug resistance, restricted to work published in 2013. Recent findings Functional imaging approaches reliably identify underlying specific networks in patients with different epileptic syndromes, show specific responses to certain antiepileptic drugs and differentiate between responder and nonresponder. Functional MRI (fMRI) and the intracarotid amobarbital test (IAT) are generally congruent, but fMRI may be more sensitive than IAT to right hemisphere language processing. In addition, memory fMRI supports the functional adequacy of ipsilateral structures rather than functional reserve of the contralateral hemisphere. There is further evidence from group analysis of fMRI data for a node within the ipsilateral piriform cortex to be important for seizure modulation in focal refractory epilepsies of different cortical origin. Molecular imaging with verapamil-PET identifies P-glycprotein overexpression as a mechanism contributing to drug resistance in individual patients. Summary Neuroimaging in epilepsy has progressed from correlations with demographic, semiologic, neuropsychological and other observational data primarily in patients undergoing presurgical investigations to imaging network connectivity changes in epilepsy syndromes, and testing specific mechanisms underlying drug-resistant epilepsy. Keywords connectivity, functional MRI, MRI, PET
INTRODUCTION
syndromes, and potentially to a better understanding of the anatomy of epileptic networks [3 ]. &&
Imaging research has focused primarily on patients undergoing presurgical evaluations, as postoperative seizure freedom is conceptualized as ‘gold standard’ for identifying the ‘epileptogenic zone’. Electrophysiological and imaging data suggest that changes beyond the temporal lobe may affect outcome negatively, supporting the concept of disordered distributed brain networks [1 ]. A network perspective helps also to understand not only ‘surgical failure’, but also the development and progression (epileptogenesis) of epilepsy: focal epilepsies show highly diffuse, often bilateral, structural and functional disturbances, which may contribute to the development and maintenance of chronic or drug-resistant epilepsy [2 ]. In addition to identifying pathogenic mechanisms in the development of chronic epilepsy, imaging studies of structural and functional connectivity may also lead to a better understanding of the cognitive and behavioral problems commonly associated with specific &&
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FROM ZONES TO NETWORKS Resting-state investigations suggest functional connectivity alterations in regions that comprise the ‘default mode’ network (DMN) [4]. During interictal epileptiform discharges (IEDs), DMN regions decrease their metabolic demand and undergo an electroencephalogram (EEG) change consisting of decreased gamma and increased lower frequencies. Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, National Hospital for Neurology & Neurosurgery, Queen Square, London, UK Correspondence to Matthias J. Koepp, Epilepsy Society, Chalfont Centre for Epilepsy, Gerrard’s Cross, Buckinghamshire SL9 0RJ, UK. Tel: +44 601344; e-mail: [email protected] Curr Opin Neurol 2014, 27:192–198 DOI:10.1097/WCO.0000000000000072 Volume 27 Number 2 April 2014
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Neuroimaging of drug resistance in epilepsy Koepp
KEY POINTS fMRI approaches can identify underlying networks in patients with specific epileptic syndromes. fMRI and IAT are generally congruent, but fMRI may be more sensitive than IAT to right hemisphere language processing. fMRI provides evidence for importance of functional adequacy of ipsilateral structures rather than functional reserve of the contralateral hemisphere, and for a node within the ipsilateral piriform cortex common to focal epilepsies of different cortical origin. Structural and functional neuroimaging techniques can differentiate between responder and nonresponder to surgical interventions and detects effects specific to particular AEDs. Molecular imaging with [11C]verapamil (VPM)-PET can differentiate between drug-responsive and drug-resistant patients, and identifies individual patients with increased Pgp activity in vivo.
These findings, specific to DMN regions, indicate that epileptic activity may momentarily reduce the consciousness level and cognitive reserve [5]. There are important common features in the networks involved in IEDs. Flanagan et al. [6 ] confirmed previous observations from functional MRI (fMRI) and PET studies [7] of a node within the ipsilateral piriform cortex, as well as patterns involving distant cortical or subcortical areas common to patients with a heterogeneous range of epileptogenic foci. Resting-state studies are particularly sensitive to detect disruptions of brain organization, which are closely linked with impaired neuropsychological function [8]. In children with frontal lobe epilepsy [9], changes in intrinsic connectivity network (ICN) explained cognitive impairments caused by generalized spike-and-wave discharge (GSWD): GSWDrelated increase of intra-network connectivity was found only in the thalamus, and extensive decreases were found in the ICNs corresponding to higherorder cognitive processes including the DMN, dorsal attention network and central executive network. The perceptive and motor networks were less affected by GSWD [10]. Network changes are detected early in the disease process, suggesting that the neurodevelopmental impact of new-onset epilepsies alters largescale brain networks, resulting in greater vulnerability to network failure and cognitive impairment, or reflective of alteration even before the onset of epilepsy contributing to epileptogenesis and cognitive impairment. Children with new-onset epilepsy &
showed a suboptimal topological structural organization with enhanced network segregation and reduced global integration compared with controls [3 ]. A subgroup of children with epilepsy, namely those with lower IQ and poorer executive function, had a reduced balance between network segregation and integration. &&
FROM SEIZURES TO SYNDROMES EEG–fMRI has been applied mainly to localize generators of IEDs in focal and generalized epilepsies with varying success depending on time of seizure and frequency of IEDs [11], but is ideally suited to detect underlying networks in patients with specific epileptic syndromes [12]. A specific fingerprint of hemodynamic changes was detected in association with several syndromes: (1) In Lennox–Gastaut syndrome, characteristic paroxysmal fast activity was associated with diffuse network activity that includes association cortices as well as an unusual pattern of simultaneous activation of subcortical structures (brainstem, thalamus, basal ganglia) [13]. (2) In West syndrome, the neuronal network underlying hypsarrhythmia involved the brainstem, putamen and cortical regions, supporting the theory that hypsarrhythmia results from ascending brainstem pathways projecting widely to basal ganglia and cortex [14]. (3) In Dravet syndrome, IEDs were not associated with common activation patterns, despite a common genetic cause, suggestive of different neuronal networks underlying individual IEDs [15]. (4) In rolandic epilepsy, connectivity was decreased between the left sensorimotor area and right inferior frontal gyrus, which correlated with lower language scores, linking rolandic (sensorimotor) pathology to syndrome-specific language problems [16]. (5) In atypical benign partial epilepsy, fMRI signal changes across patients were similar to studies in rolandic epilepsy with focal changes in the spike field, as well as similar to patterns observed in patients with continuous spikes and waves during slow sleep with distant fMRI signal changes in cortical and subcortical structures. This similarity of findings supports the notion that idiopathic focal epilepsies of childhood form a spectrum of overlapping syndromes [17]. Structural imaging abnormalities, such as subtle variation in hippocampal morphology and asymptomatic hippocampal sclerosis, were observed in
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close relatives of patients with mesial temporal lobe epilepsy (mTLE) due to hippocampal sclerosis [18]. Findings in asymptomatic siblings provide evidence for a hereditary component for hippocampal sclerosis, and may provide imaging markers for future studies seeking susceptibility genes in specific syndromes. Investigating specific imaging phenotypes in epilepsy can therefore potentially help to understand how gene variations may lead to epilepsy or, vice versa, imaging phenotypes may help to identify common mechanism in complex inherited epilepsy syndromes.
FROM LATERALIZATION OF COGNITIVE FUNCTIONS TO IDENTIFICATION OF NETWORKS In addition to identifying robust and specific patterns of functional and structural connectivity underlying the development and progression of specific syndromes, imaging can help to understand how disease-related mechanisms or therapeutic interventions, such as resective surgery or antiepileptic drugs (AEDs), may lead to specific cognitive, in particular language and memory, impairments. Thus, imaging may serve as a useful prediction tool, or surrogate marker, of treatment or rehabilitation efficacy and as marker of treatment resistance. Functional MRI is sensitive to the variation in language network patterns, but large populations are needed to rigorously assess atypical patterns, exemplified by the following two studies: &&
(1) Berl et al. [19 ] studied 220 children with focal epilepsy and 118 healthy volunteers who performed an auditory description decision task and found six patterns of atypical language: a symmetrically bilateral, two unilaterally crossed, and three right dominant patterns. Beyond the established association of left-handedness, early seizure onset, and vascular pathology with atypical language, cluster analysis identified an association of handedness with right frontal/left temporal lateralization, early seizure onset with left frontal/right temporal lateralization, and left hemisphere focus with a unilateral right pattern. (2) Janecek et al. [20] studied 229 patients prospectively with both a standardized intracarotid amobarbital test (IAT) and a semantic decision fMRI language protocol. Discordant results were observed in 14% of patients. Discordance was highest among those categorized by either test as having bilateral language. In a multivariate model, the only factor that predicted 194
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discordance was the degree of atypical language dominance on fMRI. In a meta-analysis of 22 studies totaling 504 patients [21], fMRI language lateralization was found to be generally concordant with IAT. fMRI and IAT agreed in 94% for typical, but in only 51% for atypical language lateralization. The degree of rightward shift of language dominance on fMRI strongly correlated with IAT/fMRI discordance, suggesting that fMRI may be more sensitive than IAT to right hemisphere language processing, although the clinical significance of this increased sensitivity is unknown. Surprisingly, many patients fail to show rightward shift of language despite epileptogenic lesions in close proximity to eloquent cortex. Neuroanatomical asymmetries were linked to human language dominance with the size of the right, contra-lesional planum temporale region reflecting a ’reserve capacity’ for interhemispheric language reorganization in the presence of a seizure focus and lesions within left perisylvian regions [22]. Little is known of the extra-temporal networks involved in reorganization of memory. Activations within anterior cingulate and insula correlated with better verbal and visual subsequent memory in patients with left and right hippocampal sclerosis, respectively, representing effective extra-temporal recruitment [23]. Stretton et al. [24 ] reported disrupted segregation of task-positive and task-negative functional connectivity networks supporting working memory in mTLE, associated with working memory dysfunction. In patients with small lesions centered on the left anterior temporal lobe before surgery, dynamic causal modeling revealed selective network adjustments highlighting the role of feedback connections in enabling the integration of the semantic information: backward connectivity from anterior to posterior temporal lobe was decreased in the ipsilesional hemisphere, whereas it was enhanced in the contralesional hemisphere [25]. &
FROM CORRELATION WITH FUNCTION TO PREDICTION OF FUNCTIONAL OUTCOME Despite the widespread use of fMRI, evidence of its usefulness in predicting postoperative language performance is scant: (1) Functional MRI predicted postsurgical naming outcome with relatively better accuracy compared to the IAT [26] in those 10 of 229 patients with discordant language lateralization results who underwent left anterior temporal Volume 27 Number 2 April 2014
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Neuroimaging of drug resistance in epilepsy Koepp
lobectomy, studied preoperatively by Janecek et al. [20]. (2) Decreased left lateralization preoperatively was predictive of better naming performance at 6 and 12 months after surgery in a subgroup of 17 left TLE patients who underwent surgery, out of 72 patients studied preoperatively [27]. The relative lack or of predictive studies for postoperative language functions might be due to technical constraints. In a systematic comparison of fMRI for covert (silent) and overt (spoken) versions of a language task, the overt task was advantageous for presurgical fMRI assessments of language; it produced higher-quality scans, was more sensitive for identifying activation in core language regions on an individual basis, and provided an online measure of performance crucial for improving the yield of preoperative fMRI [28 ]. In contrast to the paucity of studies predicting postoperative language functions, fMRI has advanced and expanded our understanding of material-specific memory deficits and hemispheric lateralization in mTLE [29], and is now being applied to pre and postoperative mapping of memory functions. Bonelli et al. [30,31 ] found evidence for effective preoperative reorganization of verbal memory function to the ipsilateral posterior medial temporal lobe due to the underlying disease, suggesting that it is the capacity of the posterior remnant of the ipsilateral hippocampus rather than the functional reserve of the contralateral hippocampus that is important for maintaining verbal memory function after anterior temporal lobe resection. Despite the negative effects of epilepsy, memory functioning was better supported by the affected hemisphere than the hemisphere contralateral to the seizure focus. In postoperative studies, early (3 month) postoperative reorganization to ipsilateral posterior or contralateral medial temporal lobe structures did not underpin better performance [32]. &
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PREDICTION OF DRUG RESPONSE Functional imaging is primarily used to predict cognitive sequelae of surgery for refractory TLE. The stage is now set to extend these methodologies to predict response to drug therapies. Similar neuropsychological responses and disruption of taskrelated DMN deactivations were observed in patients and healthy controls after both chronic administration and a single dose of the AED topiramate (TPM), which indicates a specific effect of TPM in DMN areas that may be essential components of the language network. This suggests
a mechanism by which TPM impairs cognitive processing during language function and highlights the sensitivity of fMRI to detect the effects of AEDs on cognitive brain networks [33]. Szaflarski et al. [34 ] compared patients with sodium valproate (VPA)-refractory and VPA-responsive idiopathic generalized epilepsy, suggesting that VPA-resistant and VPA-responsive patients may have different GSWD generators, and that these differences in GSWD generators may be the reason for different responses to VPA. Connectivity negatively correlated with duration of epilepsy, and reduced connectivity was more pronounced in treatment-resistant epilepsy. The use of VPA was also found to be associated with reduced parietal lobe thickness, total brain volume, and white matter volume, which might be related to the effects this drug has on neurodevelopment [35]. &
FROM IMAGING DRUG-RESISTANT PATIENTS TO STUDYING MECHANISMS OF DRUG RESISTANCE Elucidating basic mechanisms of drug response and development of drug resistance is the strength of preclinical and clinical molecular imaging. Substantial progress has been made in support of the transporter hypothesis, which maintains that broad resistance to AEDs might relate to overactivity of nonspecific transporter mechanisms at the blood– brain barrier (BBB) that reduce the local concentration of AEDs within the brain tissue below a therapeutic level. The recently developed P-glycoprotein (P-gp) PET radiotracer, [11C]N-desmethylloperamide ([11C]dLop), was assessed for measuring P-gp function in the rat brain and showed significantly increased uptake of [11C]dLop after P-gp inhibition, suggesting that [11C]dLop is a P-gp substrate [36]. Several P-gp inhibitor-based PET tracers ([11C]laniquidar [37], [11C]elacridar and [11C]tariquidar [38]) were characterized either as P-gp and/or BCRP substrates with biodistribution studies in animal models of naı¨ve, transporter knock-out and epileptic rodents [39]. Using the established PET radiotracer [11C]verapamil (VPM) as a model P-gp substrate and the PET receptor ligand [11C]flumazenil, partial inhibition of P-gp function the BBB by administration of half-maximum inhibitor dose allowed detection of regional differences in P-gp functionality at the rat BBB [40]. Findings in animal models were successfully translated to the human condition, with [11C]VPM-PET studies in healthy controls showing that tariquidar-induced P-gp modulation at the human BBB appeared to be transient and its
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magnitude directly proportionate to serum drug exposure [41]. In patients with TLE, the brain uptake of [11C]VPM in drug-sensitive patients was higher than in drug-resistant patients. This increase in brain uptake was restricted to the temporal lobes both on the ipsilateral and contralateral sides, which suggests more efficient P-gp function in drugrefractory patients resulting in lower drug concentrations in the brain [42 ]. [11C]VPM uptake increases were attenuated following P-gp blockade in the drug-resistant patients compared to healthy volunteers, suggestive of overexpression of P-gp function, with the ipsilateral epileptogenic hippocampus being most significantly affected. This change in VPM uptake after P-gp inhibition with tariquidar in the hippocampus correlated inversely with P-gp-immunopositive labeling. &&
PREDICTION OF POSTOPERATIVE SEIZURE OUTCOME The main clinical indication for imaging remains the identification of a potential surgical target in drug-resistant focal epilepsies, and with this, the prediction of postoperative outcome. Reasons for failure of epilepsy surgery are multifactorial. Complete resection of the abnormality detected by preoperative MRI is generally considered the most important predictor of a favorable postoperative outcome, and additional outcome predictors are hard to identify [43]. Evidence for disease progression in the mesiotemporal lobe is mainly derived from global volumetry of the hippocampus, but extent of hippocampal atrophy is not a good predictor of postoperative outcome. Longitudinal and cross-sectional surface-shape analysis of mesiotemporal structures showed consistent patterns of progressive atrophy in hippocampal CA1, amygdala, and entorhinal cortex. Progression of hippocampal atrophy was faster in patients with a seizure frequency of at least 6 per month. High rates of contralateral entorhinal cortex atrophy predicted postsurgical seizure relapse [44 ]. A similar pattern of network re-organization was detected using presurgical brain connectome calculated through probabilistic connectivity from MRI– diffusion tensor imaging [45]. Patients exhibited a decrease in connectivity involving ipsilateral thalamocortical regions, with a pathologic increase in ipsilateral medial temporal lobe, insular, and frontal connectivity. Among patients, those not seizure-free exhibited a higher connectivity between structures in the ipsilateral medial and lateral temporal lobe, the ipsilateral medial temporal and parietal lobe, and the contralateral temporal pole and parietal lobe. &&
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PET tracer for important neurotransmitter systems was assessed primarily in drug-resistant epilepsies, with a view not only to identifying a surgical target and understanding mechanisms of seizure generation in chronic epilepsies, but also in parallel to identify molecular substrates and networks resulting in psychiatric comorbidities: (1) [18F]-flumazenil-PET showed high specificity (94%) and moderate sensitivity (68%) for the localization of the epileptogenic zone, with a more restricted abnormality than [18F]-FDG PET, but falsely localized in 3 of 31 patients (10%) [46]. (2) a-[11C]-methyl-L-tryptophan (AMT) hotspots correlated with the duration of seizure intractability in tuberous sclerosis: the longer the duration of seizure intractability, the greater the number of AMT hotspots, regardless of tuberours sclerosis complex mutation [47 ]. (3) Using the same tracer, AMT, a case report of a patient with new-onset refractory status epilepticus illustrated the value of PET imaging with AMT changes overlapping with the epileptogenic cortex mapped by chronic intracranial electroencephalographic monitoring [48]. Resection of the epileptic focus resulted in long-term seizure freedom, and the nonresected portion of the PET-documented abnormality normalized. Histopathology showed reactive gliosis and inflammatory markers in the AMT-PET-positive cortex, reflecting increased tryptophan transport and metabolism via the inflammatory and immunosuppressive kynurenine pathway. (4) 5-hydroxytryptamine transporter (HTT) activity was lower in the insula and fusiform gyrus on the epileptogenic side, more so in depressed patients with TLE than in nondepressed patients with TLE. In the insular cortex, there was a correlation between 5-HTT asymmetry and 5-HT1A asymmetry for patients with TLE, but not for healthy controls, suggesting greater loss of 5-HT1A receptors to compensate for reduced transport, such that higher synaptic serotonin levels will be maintained at the sites that have fewer 5-HT1A receptors [49]. &
Although magnetic resonance spectroscopy (MRS) has had success in earlier studies in refractory TLE, there has only been one recent study evaluating the use of high-resolution 7T MRS imaging in 25 surgically treated patients studied over a 3.5-year period: outcome was better if the resected tissue was metabolically abnormal, consistent with the seizure-onset zone being characterized by metabolic dysfunction [50]. Volume 27 Number 2 April 2014
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Neuroimaging of drug resistance in epilepsy Koepp
Neurophysiological imaging modalities, such as magnetoencephalography (MEG)/magnetic source imaging (MSI), have clinical value in predicting seizure-free outcome, especially in nonlesional TLE or extra-temporal lobe epilepsies. Jung et al. [51 ] evaluated whether the spatial congruence between the spiking volume determined by MEG and the localization of the seizure-onset zone determined by stereo-electroencephalography (SEEG) could predict outcome of surgical treatment. Patients with focal MEG results and volumetric imaging of epileptic spikes had good outcome, if the implantation strategy incorporated volumetric imaging of epileptic spikes results. In contrast, patients with nonfocal MEG results were less likely to have a localized seizure-onset zone and SEEG is not advised unless clear localizing information is provided by other presurgical investigation methods. Similarly, a more complete removal of MEG source cluster area was associated with better clinical outcome in patients with small focal cortical dysplasias [52]. In contrast, number and density of clustered spike dipole sources within the surgical resection volume were not associated with postoperative seizure-free outcome in 22 children. MSI successfully localized the perilesional epileptogenic zone in cases with localized MRI lesions, but not in cases with nonlesional MRI [53]. &
CONCLUSION Our understanding of the mechanisms underlying drug resistance benefits from investigating global disturbances of structural and functional connectivity of the entire brain and specific molecular mechanisms. Combined measurements of aberrant functional and structural connections offer the potential of outcome predictors that can improve the selection of more suitable treatment options, and provide more adequate patient counseling about prognosis individually. Elucidation of epileptic networks in specific syndromes and fundamental mechanisms underlying the development of pharmacoresistance and behavioral comorbidities in individual patients will support the development of novel therapies and treatment strategies. Acknowledgements The author received funding from Wellcome Trust (project grant 083148), Medical Research Council, EU-FP7 framework program (201380), Department of Health’s NIHR UCLH Biomedical Research Centre funding scheme, Deutsche Forschungsgemeinschaft, FundacionCaja Madrid.
Conflicts of interest There are no conflicts of interest.
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38. Bauer M, Karch R, Zeitlinger M, et al. Interaction of 11C-tariquidar and 11C-elacridar with P-glycoprotein and breast cancer resistance protein at the human blood-brain barrier. J Nucl Med 2013; 54:1181–1187. 39. Ro¨mermann K, Wanek T, Bankstahl M, et al. (R)-[(11)C]verapamil is selectively transported by murine and human P-glycoprotein at the blood-brain barrier, and not by MRP1 and BCRP. Nucl Med Biol 2013; 40:873–878. 40. Syva¨nen S, Labots M, Tagawa Y, et al. Altered GABAA receptor density and unaltered blood-brain barrier transport in a kainate model of epilepsy: an in vivo study using 11C-flumazenil and PET. J Nucl Med 2012; 53:1974–1983. 41. Bauer M, Zeitlinger M, Karch R, et al. Pgp-mediated interaction between (R)[11C]verapamil and tariquidar at the human blood-brain barrier: a comparison with rat data. Clin Pharmacol Ther 2012; 91:227–233. 42. Feldmann M, Asselin MC, Liu J, et al. P-glycoprotein expression and function && in patients with temporal lobe epilepsy: a case-control study. Lancet Neurol 2013; 12:777–785. First in-vivo human evidence of an association between overactivity of P-glycoprotein at the blood–brain barrier and drug resistance in TLE. 43. Harroud A, Bouthillier A, Weil AG, Nguyen DK. Temporal lobe epilepsy surgery failures: a review. Epilepsy Res Treat 2012; 2012:201651. 44. Bernhardt BC, Kim H, Bernasconi N. Patterns of subregional mesiotemporal && disease progression in temporal lobe epilepsy. Neurology 2013; 81:1840– 1847. This excellent study evaluated the relation between disease progression and surgical outcome, and highlights the importance of early surgery. Serial scanning may provide markers of surgical outcome. 45. Bonilha L, Helpern JA, Sainju R, et al. Presurgical connectome and postsurgical seizure control in temporal lobe epilepsy. Neurology 2013; 81: 1704–1710. 46. Vivash L, Gregoire MC, Lau EW, et al. 18F-flumazenil: a g-aminobutyric acid A-specific PET radiotracer for the localization of drug-resistant temporal lobe epilepsy. J Nucl Med 2013; 54:1270–1277. 47. Chugani HT, Luat AF, Kumar A, et al. a-[11C]-Methyl-L-tryptophan: PET in & 191 patients with tuberous sclerosis complex. Neurology 2013; 81:674– 680. Comprehensive assessment of the role of AMT-PET in patients with tuberous sclerosis complex. 48. Juha´sz C, Buth A, Chugani DC, et al. Successful surgical treatment of an inflammatory lesion associated with new-onset refractory status epilepticus. Neurosurg Focus 2013; 34:E5. 49. Martinez A, Finegersh A, Cannon DM, et al. The 5-HT1A receptor and 5-HT transporter in temporal lobe epilepsy. Neurology 2013; 80:1465–1471. 50. Pan JW, Duckrow RB, Gerrard J, et al. 7T MR spectroscopic imaging in the localization of surgical epilepsy. Epilepsia 2013; 54:1668–1678. 51. Jung J, Bouet R, Delpuech C, et al. The value of magnetoencephalography for & seizure-onset zone localization in magnetic resonance imaging-negative partial epilepsy. Brain 2013; 136 (Pt 10):3176–3186. This study assesses the predictive value of MEG in comparison with stereo EEG for postoperative outcome in the clinically challenging group of patients with noncontributive MRI. 52. Wilenius J, Medvedovsky M, Gaily E, et al. Interictal MEG reveals focal cortical dysplasias: special focus on patients with no visible MRI lesions. Epilepsy Res 2013; 105:337–348. 53. Kim H, Kankirawatana P, Killen J, et al. Magnetic source imaging (MSI) in children with neocortical epilepsy: surgical outcome association with 3D postresection analysis. Epilepsy Res 2013; 106:164–172.
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Neuroimaging of drug resistance in epilepsy Matthias J. Koepp
Purpose of review Drug resistance is an important clinical problem: it is associated with higher rates of somatic and psychiatric comorbidities and cognitive/memory decline, with seizures being just the ‘tip of the iceberg’. This review summarizes recent developments in imaging research, focusing specifically on the functional consequence of chronic epilepsies and mechanisms of drug resistance, restricted to work published in 2013. Recent findings Functional imaging approaches reliably identify underlying specific networks in patients with different epileptic syndromes, show specific responses to certain antiepileptic drugs and differentiate between responder and nonresponder. Functional MRI (fMRI) and the intracarotid amobarbital test (IAT) are generally congruent, but fMRI may be more sensitive than IAT to right hemisphere language processing. In addition, memory fMRI supports the functional adequacy of ipsilateral structures rather than functional reserve of the contralateral hemisphere. There is further evidence from group analysis of fMRI data for a node within the ipsilateral piriform cortex to be important for seizure modulation in focal refractory epilepsies of different cortical origin. Molecular imaging with verapamil-PET identifies P-glycprotein overexpression as a mechanism contributing to drug resistance in individual patients. Summary Neuroimaging in epilepsy has progressed from correlations with demographic, semiologic, neuropsychological and other observational data primarily in patients undergoing presurgical investigations to imaging network connectivity changes in epilepsy syndromes, and testing specific mechanisms underlying drug-resistant epilepsy. Keywords connectivity, functional MRI, MRI, PET
INTRODUCTION
syndromes, and potentially to a better understanding of the anatomy of epileptic networks [3 ]. &&
Imaging research has focused primarily on patients undergoing presurgical evaluations, as postoperative seizure freedom is conceptualized as ‘gold standard’ for identifying the ‘epileptogenic zone’. Electrophysiological and imaging data suggest that changes beyond the temporal lobe may affect outcome negatively, supporting the concept of disordered distributed brain networks [1 ]. A network perspective helps also to understand not only ‘surgical failure’, but also the development and progression (epileptogenesis) of epilepsy: focal epilepsies show highly diffuse, often bilateral, structural and functional disturbances, which may contribute to the development and maintenance of chronic or drug-resistant epilepsy [2 ]. In addition to identifying pathogenic mechanisms in the development of chronic epilepsy, imaging studies of structural and functional connectivity may also lead to a better understanding of the cognitive and behavioral problems commonly associated with specific &&
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FROM ZONES TO NETWORKS Resting-state investigations suggest functional connectivity alterations in regions that comprise the ‘default mode’ network (DMN) [4]. During interictal epileptiform discharges (IEDs), DMN regions decrease their metabolic demand and undergo an electroencephalogram (EEG) change consisting of decreased gamma and increased lower frequencies. Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, National Hospital for Neurology & Neurosurgery, Queen Square, London, UK Correspondence to Matthias J. Koepp, Epilepsy Society, Chalfont Centre for Epilepsy, Gerrard’s Cross, Buckinghamshire SL9 0RJ, UK. Tel: +44 601344; e-mail: [email protected] Curr Opin Neurol 2014, 27:192–198 DOI:10.1097/WCO.0000000000000072 Volume 27 Number 2 April 2014
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Neuroimaging of drug resistance in epilepsy Koepp
KEY POINTS fMRI approaches can identify underlying networks in patients with specific epileptic syndromes. fMRI and IAT are generally congruent, but fMRI may be more sensitive than IAT to right hemisphere language processing. fMRI provides evidence for importance of functional adequacy of ipsilateral structures rather than functional reserve of the contralateral hemisphere, and for a node within the ipsilateral piriform cortex common to focal epilepsies of different cortical origin. Structural and functional neuroimaging techniques can differentiate between responder and nonresponder to surgical interventions and detects effects specific to particular AEDs. Molecular imaging with [11C]verapamil (VPM)-PET can differentiate between drug-responsive and drug-resistant patients, and identifies individual patients with increased Pgp activity in vivo.
These findings, specific to DMN regions, indicate that epileptic activity may momentarily reduce the consciousness level and cognitive reserve [5]. There are important common features in the networks involved in IEDs. Flanagan et al. [6 ] confirmed previous observations from functional MRI (fMRI) and PET studies [7] of a node within the ipsilateral piriform cortex, as well as patterns involving distant cortical or subcortical areas common to patients with a heterogeneous range of epileptogenic foci. Resting-state studies are particularly sensitive to detect disruptions of brain organization, which are closely linked with impaired neuropsychological function [8]. In children with frontal lobe epilepsy [9], changes in intrinsic connectivity network (ICN) explained cognitive impairments caused by generalized spike-and-wave discharge (GSWD): GSWDrelated increase of intra-network connectivity was found only in the thalamus, and extensive decreases were found in the ICNs corresponding to higherorder cognitive processes including the DMN, dorsal attention network and central executive network. The perceptive and motor networks were less affected by GSWD [10]. Network changes are detected early in the disease process, suggesting that the neurodevelopmental impact of new-onset epilepsies alters largescale brain networks, resulting in greater vulnerability to network failure and cognitive impairment, or reflective of alteration even before the onset of epilepsy contributing to epileptogenesis and cognitive impairment. Children with new-onset epilepsy &
showed a suboptimal topological structural organization with enhanced network segregation and reduced global integration compared with controls [3 ]. A subgroup of children with epilepsy, namely those with lower IQ and poorer executive function, had a reduced balance between network segregation and integration. &&
FROM SEIZURES TO SYNDROMES EEG–fMRI has been applied mainly to localize generators of IEDs in focal and generalized epilepsies with varying success depending on time of seizure and frequency of IEDs [11], but is ideally suited to detect underlying networks in patients with specific epileptic syndromes [12]. A specific fingerprint of hemodynamic changes was detected in association with several syndromes: (1) In Lennox–Gastaut syndrome, characteristic paroxysmal fast activity was associated with diffuse network activity that includes association cortices as well as an unusual pattern of simultaneous activation of subcortical structures (brainstem, thalamus, basal ganglia) [13]. (2) In West syndrome, the neuronal network underlying hypsarrhythmia involved the brainstem, putamen and cortical regions, supporting the theory that hypsarrhythmia results from ascending brainstem pathways projecting widely to basal ganglia and cortex [14]. (3) In Dravet syndrome, IEDs were not associated with common activation patterns, despite a common genetic cause, suggestive of different neuronal networks underlying individual IEDs [15]. (4) In rolandic epilepsy, connectivity was decreased between the left sensorimotor area and right inferior frontal gyrus, which correlated with lower language scores, linking rolandic (sensorimotor) pathology to syndrome-specific language problems [16]. (5) In atypical benign partial epilepsy, fMRI signal changes across patients were similar to studies in rolandic epilepsy with focal changes in the spike field, as well as similar to patterns observed in patients with continuous spikes and waves during slow sleep with distant fMRI signal changes in cortical and subcortical structures. This similarity of findings supports the notion that idiopathic focal epilepsies of childhood form a spectrum of overlapping syndromes [17]. Structural imaging abnormalities, such as subtle variation in hippocampal morphology and asymptomatic hippocampal sclerosis, were observed in
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close relatives of patients with mesial temporal lobe epilepsy (mTLE) due to hippocampal sclerosis [18]. Findings in asymptomatic siblings provide evidence for a hereditary component for hippocampal sclerosis, and may provide imaging markers for future studies seeking susceptibility genes in specific syndromes. Investigating specific imaging phenotypes in epilepsy can therefore potentially help to understand how gene variations may lead to epilepsy or, vice versa, imaging phenotypes may help to identify common mechanism in complex inherited epilepsy syndromes.
FROM LATERALIZATION OF COGNITIVE FUNCTIONS TO IDENTIFICATION OF NETWORKS In addition to identifying robust and specific patterns of functional and structural connectivity underlying the development and progression of specific syndromes, imaging can help to understand how disease-related mechanisms or therapeutic interventions, such as resective surgery or antiepileptic drugs (AEDs), may lead to specific cognitive, in particular language and memory, impairments. Thus, imaging may serve as a useful prediction tool, or surrogate marker, of treatment or rehabilitation efficacy and as marker of treatment resistance. Functional MRI is sensitive to the variation in language network patterns, but large populations are needed to rigorously assess atypical patterns, exemplified by the following two studies: &&
(1) Berl et al. [19 ] studied 220 children with focal epilepsy and 118 healthy volunteers who performed an auditory description decision task and found six patterns of atypical language: a symmetrically bilateral, two unilaterally crossed, and three right dominant patterns. Beyond the established association of left-handedness, early seizure onset, and vascular pathology with atypical language, cluster analysis identified an association of handedness with right frontal/left temporal lateralization, early seizure onset with left frontal/right temporal lateralization, and left hemisphere focus with a unilateral right pattern. (2) Janecek et al. [20] studied 229 patients prospectively with both a standardized intracarotid amobarbital test (IAT) and a semantic decision fMRI language protocol. Discordant results were observed in 14% of patients. Discordance was highest among those categorized by either test as having bilateral language. In a multivariate model, the only factor that predicted 194
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discordance was the degree of atypical language dominance on fMRI. In a meta-analysis of 22 studies totaling 504 patients [21], fMRI language lateralization was found to be generally concordant with IAT. fMRI and IAT agreed in 94% for typical, but in only 51% for atypical language lateralization. The degree of rightward shift of language dominance on fMRI strongly correlated with IAT/fMRI discordance, suggesting that fMRI may be more sensitive than IAT to right hemisphere language processing, although the clinical significance of this increased sensitivity is unknown. Surprisingly, many patients fail to show rightward shift of language despite epileptogenic lesions in close proximity to eloquent cortex. Neuroanatomical asymmetries were linked to human language dominance with the size of the right, contra-lesional planum temporale region reflecting a ’reserve capacity’ for interhemispheric language reorganization in the presence of a seizure focus and lesions within left perisylvian regions [22]. Little is known of the extra-temporal networks involved in reorganization of memory. Activations within anterior cingulate and insula correlated with better verbal and visual subsequent memory in patients with left and right hippocampal sclerosis, respectively, representing effective extra-temporal recruitment [23]. Stretton et al. [24 ] reported disrupted segregation of task-positive and task-negative functional connectivity networks supporting working memory in mTLE, associated with working memory dysfunction. In patients with small lesions centered on the left anterior temporal lobe before surgery, dynamic causal modeling revealed selective network adjustments highlighting the role of feedback connections in enabling the integration of the semantic information: backward connectivity from anterior to posterior temporal lobe was decreased in the ipsilesional hemisphere, whereas it was enhanced in the contralesional hemisphere [25]. &
FROM CORRELATION WITH FUNCTION TO PREDICTION OF FUNCTIONAL OUTCOME Despite the widespread use of fMRI, evidence of its usefulness in predicting postoperative language performance is scant: (1) Functional MRI predicted postsurgical naming outcome with relatively better accuracy compared to the IAT [26] in those 10 of 229 patients with discordant language lateralization results who underwent left anterior temporal Volume 27 Number 2 April 2014
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Neuroimaging of drug resistance in epilepsy Koepp
lobectomy, studied preoperatively by Janecek et al. [20]. (2) Decreased left lateralization preoperatively was predictive of better naming performance at 6 and 12 months after surgery in a subgroup of 17 left TLE patients who underwent surgery, out of 72 patients studied preoperatively [27]. The relative lack or of predictive studies for postoperative language functions might be due to technical constraints. In a systematic comparison of fMRI for covert (silent) and overt (spoken) versions of a language task, the overt task was advantageous for presurgical fMRI assessments of language; it produced higher-quality scans, was more sensitive for identifying activation in core language regions on an individual basis, and provided an online measure of performance crucial for improving the yield of preoperative fMRI [28 ]. In contrast to the paucity of studies predicting postoperative language functions, fMRI has advanced and expanded our understanding of material-specific memory deficits and hemispheric lateralization in mTLE [29], and is now being applied to pre and postoperative mapping of memory functions. Bonelli et al. [30,31 ] found evidence for effective preoperative reorganization of verbal memory function to the ipsilateral posterior medial temporal lobe due to the underlying disease, suggesting that it is the capacity of the posterior remnant of the ipsilateral hippocampus rather than the functional reserve of the contralateral hippocampus that is important for maintaining verbal memory function after anterior temporal lobe resection. Despite the negative effects of epilepsy, memory functioning was better supported by the affected hemisphere than the hemisphere contralateral to the seizure focus. In postoperative studies, early (3 month) postoperative reorganization to ipsilateral posterior or contralateral medial temporal lobe structures did not underpin better performance [32]. &
&
PREDICTION OF DRUG RESPONSE Functional imaging is primarily used to predict cognitive sequelae of surgery for refractory TLE. The stage is now set to extend these methodologies to predict response to drug therapies. Similar neuropsychological responses and disruption of taskrelated DMN deactivations were observed in patients and healthy controls after both chronic administration and a single dose of the AED topiramate (TPM), which indicates a specific effect of TPM in DMN areas that may be essential components of the language network. This suggests
a mechanism by which TPM impairs cognitive processing during language function and highlights the sensitivity of fMRI to detect the effects of AEDs on cognitive brain networks [33]. Szaflarski et al. [34 ] compared patients with sodium valproate (VPA)-refractory and VPA-responsive idiopathic generalized epilepsy, suggesting that VPA-resistant and VPA-responsive patients may have different GSWD generators, and that these differences in GSWD generators may be the reason for different responses to VPA. Connectivity negatively correlated with duration of epilepsy, and reduced connectivity was more pronounced in treatment-resistant epilepsy. The use of VPA was also found to be associated with reduced parietal lobe thickness, total brain volume, and white matter volume, which might be related to the effects this drug has on neurodevelopment [35]. &
FROM IMAGING DRUG-RESISTANT PATIENTS TO STUDYING MECHANISMS OF DRUG RESISTANCE Elucidating basic mechanisms of drug response and development of drug resistance is the strength of preclinical and clinical molecular imaging. Substantial progress has been made in support of the transporter hypothesis, which maintains that broad resistance to AEDs might relate to overactivity of nonspecific transporter mechanisms at the blood– brain barrier (BBB) that reduce the local concentration of AEDs within the brain tissue below a therapeutic level. The recently developed P-glycoprotein (P-gp) PET radiotracer, [11C]N-desmethylloperamide ([11C]dLop), was assessed for measuring P-gp function in the rat brain and showed significantly increased uptake of [11C]dLop after P-gp inhibition, suggesting that [11C]dLop is a P-gp substrate [36]. Several P-gp inhibitor-based PET tracers ([11C]laniquidar [37], [11C]elacridar and [11C]tariquidar [38]) were characterized either as P-gp and/or BCRP substrates with biodistribution studies in animal models of naı¨ve, transporter knock-out and epileptic rodents [39]. Using the established PET radiotracer [11C]verapamil (VPM) as a model P-gp substrate and the PET receptor ligand [11C]flumazenil, partial inhibition of P-gp function the BBB by administration of half-maximum inhibitor dose allowed detection of regional differences in P-gp functionality at the rat BBB [40]. Findings in animal models were successfully translated to the human condition, with [11C]VPM-PET studies in healthy controls showing that tariquidar-induced P-gp modulation at the human BBB appeared to be transient and its
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magnitude directly proportionate to serum drug exposure [41]. In patients with TLE, the brain uptake of [11C]VPM in drug-sensitive patients was higher than in drug-resistant patients. This increase in brain uptake was restricted to the temporal lobes both on the ipsilateral and contralateral sides, which suggests more efficient P-gp function in drugrefractory patients resulting in lower drug concentrations in the brain [42 ]. [11C]VPM uptake increases were attenuated following P-gp blockade in the drug-resistant patients compared to healthy volunteers, suggestive of overexpression of P-gp function, with the ipsilateral epileptogenic hippocampus being most significantly affected. This change in VPM uptake after P-gp inhibition with tariquidar in the hippocampus correlated inversely with P-gp-immunopositive labeling. &&
PREDICTION OF POSTOPERATIVE SEIZURE OUTCOME The main clinical indication for imaging remains the identification of a potential surgical target in drug-resistant focal epilepsies, and with this, the prediction of postoperative outcome. Reasons for failure of epilepsy surgery are multifactorial. Complete resection of the abnormality detected by preoperative MRI is generally considered the most important predictor of a favorable postoperative outcome, and additional outcome predictors are hard to identify [43]. Evidence for disease progression in the mesiotemporal lobe is mainly derived from global volumetry of the hippocampus, but extent of hippocampal atrophy is not a good predictor of postoperative outcome. Longitudinal and cross-sectional surface-shape analysis of mesiotemporal structures showed consistent patterns of progressive atrophy in hippocampal CA1, amygdala, and entorhinal cortex. Progression of hippocampal atrophy was faster in patients with a seizure frequency of at least 6 per month. High rates of contralateral entorhinal cortex atrophy predicted postsurgical seizure relapse [44 ]. A similar pattern of network re-organization was detected using presurgical brain connectome calculated through probabilistic connectivity from MRI– diffusion tensor imaging [45]. Patients exhibited a decrease in connectivity involving ipsilateral thalamocortical regions, with a pathologic increase in ipsilateral medial temporal lobe, insular, and frontal connectivity. Among patients, those not seizure-free exhibited a higher connectivity between structures in the ipsilateral medial and lateral temporal lobe, the ipsilateral medial temporal and parietal lobe, and the contralateral temporal pole and parietal lobe. &&
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PET tracer for important neurotransmitter systems was assessed primarily in drug-resistant epilepsies, with a view not only to identifying a surgical target and understanding mechanisms of seizure generation in chronic epilepsies, but also in parallel to identify molecular substrates and networks resulting in psychiatric comorbidities: (1) [18F]-flumazenil-PET showed high specificity (94%) and moderate sensitivity (68%) for the localization of the epileptogenic zone, with a more restricted abnormality than [18F]-FDG PET, but falsely localized in 3 of 31 patients (10%) [46]. (2) a-[11C]-methyl-L-tryptophan (AMT) hotspots correlated with the duration of seizure intractability in tuberous sclerosis: the longer the duration of seizure intractability, the greater the number of AMT hotspots, regardless of tuberours sclerosis complex mutation [47 ]. (3) Using the same tracer, AMT, a case report of a patient with new-onset refractory status epilepticus illustrated the value of PET imaging with AMT changes overlapping with the epileptogenic cortex mapped by chronic intracranial electroencephalographic monitoring [48]. Resection of the epileptic focus resulted in long-term seizure freedom, and the nonresected portion of the PET-documented abnormality normalized. Histopathology showed reactive gliosis and inflammatory markers in the AMT-PET-positive cortex, reflecting increased tryptophan transport and metabolism via the inflammatory and immunosuppressive kynurenine pathway. (4) 5-hydroxytryptamine transporter (HTT) activity was lower in the insula and fusiform gyrus on the epileptogenic side, more so in depressed patients with TLE than in nondepressed patients with TLE. In the insular cortex, there was a correlation between 5-HTT asymmetry and 5-HT1A asymmetry for patients with TLE, but not for healthy controls, suggesting greater loss of 5-HT1A receptors to compensate for reduced transport, such that higher synaptic serotonin levels will be maintained at the sites that have fewer 5-HT1A receptors [49]. &
Although magnetic resonance spectroscopy (MRS) has had success in earlier studies in refractory TLE, there has only been one recent study evaluating the use of high-resolution 7T MRS imaging in 25 surgically treated patients studied over a 3.5-year period: outcome was better if the resected tissue was metabolically abnormal, consistent with the seizure-onset zone being characterized by metabolic dysfunction [50]. Volume 27 Number 2 April 2014
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Neuroimaging of drug resistance in epilepsy Koepp
Neurophysiological imaging modalities, such as magnetoencephalography (MEG)/magnetic source imaging (MSI), have clinical value in predicting seizure-free outcome, especially in nonlesional TLE or extra-temporal lobe epilepsies. Jung et al. [51 ] evaluated whether the spatial congruence between the spiking volume determined by MEG and the localization of the seizure-onset zone determined by stereo-electroencephalography (SEEG) could predict outcome of surgical treatment. Patients with focal MEG results and volumetric imaging of epileptic spikes had good outcome, if the implantation strategy incorporated volumetric imaging of epileptic spikes results. In contrast, patients with nonfocal MEG results were less likely to have a localized seizure-onset zone and SEEG is not advised unless clear localizing information is provided by other presurgical investigation methods. Similarly, a more complete removal of MEG source cluster area was associated with better clinical outcome in patients with small focal cortical dysplasias [52]. In contrast, number and density of clustered spike dipole sources within the surgical resection volume were not associated with postoperative seizure-free outcome in 22 children. MSI successfully localized the perilesional epileptogenic zone in cases with localized MRI lesions, but not in cases with nonlesional MRI [53]. &
CONCLUSION Our understanding of the mechanisms underlying drug resistance benefits from investigating global disturbances of structural and functional connectivity of the entire brain and specific molecular mechanisms. Combined measurements of aberrant functional and structural connections offer the potential of outcome predictors that can improve the selection of more suitable treatment options, and provide more adequate patient counseling about prognosis individually. Elucidation of epileptic networks in specific syndromes and fundamental mechanisms underlying the development of pharmacoresistance and behavioral comorbidities in individual patients will support the development of novel therapies and treatment strategies. Acknowledgements The author received funding from Wellcome Trust (project grant 083148), Medical Research Council, EU-FP7 framework program (201380), Department of Health’s NIHR UCLH Biomedical Research Centre funding scheme, Deutsche Forschungsgemeinschaft, FundacionCaja Madrid.
Conflicts of interest There are no conflicts of interest.
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Volume 27 Number 2 April 2014
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