[Show abstract][Hide abstract] ABSTRACT: To study the functional activity of the multidrug efflux transporter P-glycoprotein (Pgp) at the blood-brain barrier of patients with temporal lobe epilepsy using (R)-[(11)C]verapamil (VPM)-PET before and after temporal lobe surgery to assess whether postoperative changes in seizure frequency and antiepileptic drug load are associated with changes in Pgp function.
[Show abstract][Hide abstract] ABSTRACT: Objective
Assessment of language dominance using functional magnetic resonance imaging (fMRI) is a standard tool to estimate the risk of language function decline after epilepsy surgery. Although there has been considerable research in the characterization of language networks in bilingual individuals; little is known about the clinical usefulness of language mapping in a secondary language in patients with epilepsy, and how language lateralization assessed by fMRI may differ by the use of native or a secondary language paradigms. In this study we investigate language representation in a population of nonnative English speakers to assess differences in fMRI language lateralization between the first (native) and second language (English).Methods
Sixteen nonnative English-speaking patients with focal drug-resistant epilepsy underwent language fMRI in their first (native) language (L1) and in English (L2). Differences between language maps using L1 and L2 paradigms were examined at the single subject level by comparing within-subject lateralization indexes obtained for each language. Differences at the group level were examined for each of the tasks and languages.ResultsGroup maps for the second language (English) showed overlapping areas of activation with the native language, but with larger clusters, and more bilaterally distributed than for the first language. However, at the individual level, lateralization indexes were concordant between the two languages, except for one patient with bilateral hippocampal sclerosis who was left dominant in English and showed bilateral dominance for verb generation and right dominance for verbal fluency in his native tongue.SignificanceLanguage lateralization can generally be reliably derived from fMRI tasks in a second language provided that the subject can follow the task. Subjects with greater likelihood of atypical language representation should be evaluated more carefully, using more than one language paradigm.
[Show abstract][Hide abstract] ABSTRACT: Juvenile myoclonic epilepsy is a heritable idiopathic generalized epilepsy syndrome, characterized by myoclonic jerks and frequently triggered by cognitive effort. Impairment of frontal lobe cognitive functions has been reported in patients with juvenile myoclonic epilepsy and their unaffected siblings. In a recent functional magnetic resonance imaging study we reported abnormal co-activation of the motor cortex and increased functional connectivity between the motor system and prefrontal cognitive networks during a working memory paradigm, providing an underlying mechanism for cognitively triggered jerks. In this study, we used the same task in 15 unaffected siblings (10 female; age range 18-65 years, median 40) of 11 of those patients with juvenile myoclonic epilepsy (six female; age range 22-54 years, median 35) and compared functional magnetic resonance imaging activations with 20 age- and gender-matched healthy control subjects (12 female; age range 23-46 years, median 30.5). Unaffected siblings showed abnormal primary motor cortex and supplementary motor area co-activation with increasing cognitive load, as well as increased task-related functional connectivity between motor and prefrontal cognitive networks, with a similar pattern to patients (P < 0.001 uncorrected; 20-voxel threshold extent). This finding in unaffected siblings suggests that altered motor system activation and functional connectivity is not medication- or seizure-related, but represents a potential underlying mechanism for impairment of frontal lobe functions in both patients and siblings, and so constitutes an endophenotype of juvenile myoclonic epilepsy.
[Show abstract][Hide abstract] ABSTRACT: Juvenile myoclonic epilepsy (JME) is a clinically and genetically heterogenous, generalized epilepsy syndrome usually starting in adolescence. An age-related, predominantly frontocortical-subcortical network dysfunction is likely to be the substrate of bilateral myoclonic seizures occurring at full consciousness within hours after awakening, which are the clinical hallmark of JME. Although essential features of JME were recognized by Herpin more than 140 years ago, it is still an enigmatic epilepsy syndrome in many ways; advanced imaging techniques reveal multi-focal abnormalities in this paradigmatic generalized epilepsy syndrome; clinical studies reveal a major role of genetics in etiology, but the underlying molecular changes are likely to be highly heterogeneous; many JME patients have psycho-social issues, even though their intelligence is normal; antiepileptic drugs (AEDs), notably valproic acid, achieve seizure remission in two thirds of patients, but more patients seem to relapse after stopping AEDs than in any other epilepsy syndrome. This pessimistic outlook has been challenged in recent population-based studies and needs to be assessed in randomized AED withdrawal trials. This review summarizes recent focus neuroimaging, genetic, and behavioral aspects of JME and re-appraises the entrenched view that remission off AEDs is exceptionally rare in JME.
Expert Review of Neurotherapeutics 06/2014; · 2.96 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Reduced deactivation within the default mode network (DMN) is common in individuals with primary affective disorders relative to healthy volunteers (HVs). It is unknown whether similar network abnormalities are present in temporal lobe epilepsy (TLE) patients with a history of affective psychopathology.
Journal of neurology, neurosurgery, and psychiatry. 05/2014;
[Show abstract][Hide abstract] ABSTRACT: Endocannabinoids are involved in normal cognition, and dysfunction in cannabinoid-receptor-mediated neurotransmission has been suggested in a variety of neurological and psychiatric pathologies. The type 1 cannabinoid receptor (CB1) is widely expressed in the human central nervous system. The objective of this study was to quantify the test-retest reproducibility of measures of the PET ligand [(11)C]MePPEP in order to assess the stability of CB1-receptor quantification in humans in vivo.
Fifteen healthy subjects (eight females; median age 32years, range 25 to 65years) had a 90-minute PET scan on two occasions after injection of a median dose of [(11)C]MePPEP of 364MBq. Metabolite-corrected arterial plasma input functions were obtained for all scans. Eight ROIs, reflecting different levels of receptor densities/concentrations, were defined automatically: hippocampus, anterior cingulate gyrus, inferior frontal gyrus, caudate nucleus, globus pallidus, nucleus accumbens, thalamus, and pons. We used seven quantification methods: reversible compartmental models with one and two tissue classes, two and four rate constants, and a variable blood volume term (2kbv; 4kbv); model-free (spectral) analyses with and without regularisation, including one with voxel-wise quantification; the simplified reference tissue model (SRTM) with pons as a pseudo-reference region; and modified standard uptake values (mSUVs) calculated for the period of ~30-60 minutes after injection. Percentage test-retest change and between-subject variability were both assessed, and test-retest reliability was quantified by the intraclass correlation coefficient (ICC). The ratio of binding estimates pallidum:pons served as an indicator of a method's ability to reflect binding heterogeneity.
Neither the SRTM nor the 4kbv model produced reliable measures, with ICCs around zero. Very good (>0.75) or excellent (>0.80) ICCs were obtained with the other methods. The most reliable were spectral analysis parametric maps (average across regions±standard deviation 0.83±0.03), rank shaping regularised spectral analysis (0.82±0.05), and the 2kbv model (0.82±0.09), but mSUVs were also reliable for most regions (0.79±0.13). Mean test-retest changes among the five well-performing methods ranged from 12±10% for mSUVs to 16% for 2kbv. Intersubject variability was high, with mean between-subject coefficients of variation ranging from 32±13% for mSUVs to 45% for 2kbv. The highest pallidum:pons ratios of binding estimates were achieved by mSUV (4.2), spectral analysis-derived parametric maps (3.6), and 2kbv (3.6).
Quantification of CB1 receptor availability using [(11)C]MePPEP shows good to excellent reproducibility with several kinetic models and model-free analyses, whether applied on a region-of-interest or voxelwise basis. Simple mSUV measures were also reliable for most regions, but do not allow fully quantitative interpretation. [(11)C]MePPEP PET is well placed as a tool to investigate CB1-receptor mediated neurotransmission in health and disease.
[Show abstract][Hide abstract] ABSTRACT: Working memory is a crucial cognitive function that is disrupted in temporal lobe epilepsy. It is unclear whether this impairment is a consequence of temporal lobe involvement in working memory processes or due to seizure spread to extratemporal eloquent cortex. Anterior temporal lobe resection controls seizures in 50-80% of patients with drug-resistant temporal lobe epilepsy and the effect of surgery on working memory are poorly understood both at a behavioural and neural level. We investigated the impact of temporal lobe resection on the efficiency and functional anatomy of working memory networks. We studied 33 patients with unilateral medial temporal lobe epilepsy (16 left) before, 3 and 12 months after anterior temporal lobe resection. Fifteen healthy control subjects were also assessed in parallel. All subjects had neuropsychological testing and performed a visuospatial working memory functional magnetic resonance imaging paradigm on these three separate occasions. Changes in activation and deactivation patterns were modelled individually and compared between groups. Changes in task performance were included as regressors of interest to assess the efficiency of changes in the networks. Left and right temporal lobe epilepsy patients were impaired on preoperative measures of working memory compared to controls. Working memory performance did not decline following left or right temporal lobe resection, but improved at 3 and 12 months following left and, to a lesser extent, following right anterior temporal lobe resection. After left anterior temporal lobe resection, improved performance correlated with greater deactivation of the left hippocampal remnant and the contralateral right hippocampus. There was a failure of increased deactivation of the left hippocampal remnant at 3 months after left temporal lobe resection compared to control subjects, which had normalized 12 months after surgery. Following right anterior temporal lobe resection there was a progressive increase of activation in the right superior parietal lobe at 3 and 12 months after surgery. There was greater deactivation of the right hippocampal remnant compared to controls between 3 and 12 months after right anterior temporal lobe resection that was associated with lesser improvement in task performance. Working memory improved after anterior temporal lobe resection, particularly following left-sided resections. Postoperative working memory was reliant on the functional capacity of the hippocampal remnant and, following left resections, the functional reserve of the right hippocampus. These data suggest that working memory following temporal lobe resection is dependent on the engagement of the posterior medial temporal lobes and eloquent cortex.
[Show abstract][Hide abstract] ABSTRACT: 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.
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.
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.
Current opinion in neurology 02/2014; · 5.43 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: N-methyl d-aspartate (NMDA) ion channels play a key role in a wide range of physiologic (e.g., memory and learning tasks) and pathologic processes (e.g., excitotoxicity). To date, suitable PET markers of NMDA ion channel activity have not been available. (18)F-GE-179 is a novel radioligand that selectively binds to the open/active state of the NMDA receptor ion channel, displacing the binding of (3)H-tenocyclidine from the intrachannel binding site with an affinity of 2.4 nM. No significant binding was observed with 10 nM GE-179 at 60 other neuroreceptors, channels, or transporters. We describe the kinetic behavior of the radioligand in vivo in humans.
Nine healthy participants (6 men, 3 women; median age, 37 y) each underwent a 90-min PET scan after an intravenous injection of (18)F-GE-179. Continuous arterial blood sampling over the first 15 min was followed by discrete blood sampling over the duration of the scan. Brain radioactivity (KBq/mL) was measured in summation images created from the attenuation- and motion-corrected dynamic images. Metabolite-corrected parent plasma input functions were generated. We assessed the abilities of 1-, 2-, and 3-compartment models to kinetically describe cerebral time-activity curves using 6 bilateral regions of interest. Parametric volume-of-distribution (VT) images were generated by voxelwise rank-shaping regularization of exponential spectral analysis (RS-ESA).
A 2-brain-compartment, 4-rate-constant model best described the radioligand's kinetics in normal gray matter of subjects at rest. At 30 min after injection, 37% of plasma radioactivity represented unmetabolized (18)F-GE-179. The highest mean levels of gray matter radioactivity were seen in the putamina and peaked at 7.5 min. A significant positive correlation was observed between K1 and VT (Spearman ρ = 0.398; P = 0.003). Between-subject coefficients of variation of VT ranged between 12% and 16%. Voxelwise RS-ESA yielded similar VTs and coefficients of variation.
(18)F-GE-179 exhibits high and rapid brain extraction, with a relatively homogeneous distribution in gray matter and acceptable between-subject variability. Despite its rapid peripheral metabolism, quantification of (18)F-GE-179 VT is feasible both within regions of interest and at the voxel level. The specificity of (18)F-GE-179 binding, however, requires further characterization with in vivo studies using activation and disease models.
Journal of Nuclear Medicine 02/2014; · 5.77 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Multidrug resistance-associated protein 1 (MRP1) is a drug efflux transporter that has been implicated in the pathology of several neurological diseases, and is associated with development of multidrug resistance. To enable measurement of MRP1 function in the living brain, a series of 6-halopurines decorated with fluorinated side chains have been synthesized and evaluated as putative pro-drug tracers. The tracers were designed to undergo conjugation with glutathione within the brain, and hence form the corresponding MRP1 substrate tracers in situ. 6-Bromo-7-(2-[(18)F]fluoroethyl)purine showed good brain uptake and rapid metabolic conversion. Dynamic PET imaging demonstrated a marked difference in brain clearance rates between wild-type and mrp1 knockout mice, suggesting that the tracer can allow non-invasive assessment of MRP1 activity in vivo.
Journal of Medicinal Chemistry 01/2014; · 5.61 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background
Neuronal networks involved in seizure generation, maintenance and spread of epileptic activity comprise cortico-subcortical circuits. Although epileptic foci vary in location across focal epilepsy syndromes, there is evidence for common structures in the epileptogenic networks. We recently reported evidence from functional neuroimaging for a unique area in the piriform cortex, common to focal epilepsies in humans, which might play a role in modulating seizure activity.
In this study, we aimed to identify common areas of structural abnormalities in patients with frontal lobe epilepsy (FLE)
T1-weighted MRI scans of 43 FLE patients and 25 healthy controls were analysed using voxel based morphometry. Differences in regional grey matter volume were examined across the whole brain, and correlated with age at epilepsy onset, duration and frequency of seizures.
We detected areas of increased grey matter volume in the piriform cortex, amygdala parahippocampal gyrus and left id temporal yrus of patients relative to controls, which did not correlate with any of the clinical variables tested. No common areas of atrophy were detected across the FLE group.
Although epileptic foci vary in location across focal epilepsy syndromes, there is evidence for common underlying major hubs in the epileptogenic networks. We recently reported evidence from functional neuroimaging for a unique area in the piriform cortex, common to focal epilepsies in humans, which might play a role in modulating seizure activity. Our study shows structural abnormalities within the piriform cortex and adjacent structures of patients with FLE. These findings provide further evidence for the involvement of this area in the epileptogenic network of focal epilepsies. Lack of correlation with duration or age of onset of epilepsy suggests that this area of abnormality is not a consequence of seizure activity.
[Show abstract][Hide abstract] ABSTRACT: Patients with juvenile myoclonic epilepsy (JME) often present with risk-taking behavior, suggestive of frontal lobe dysfunction. Recent studies confirm functional and microstructural changes within the frontal lobes in JME. This study aimed at characterizing decision-making behavior in JME and its neuronal correlates using functional magnetic resonance imaging (fMRI).
We investigated impulsivity in 21 JME patients and 11 controls using the Iowa Gambling Task (IGT), which measures decision making under ambiguity. Performance on the IGT was correlated with activation patterns during an fMRI working memory task.
Both patients and controls learned throughout the task. Post hoc analysis revealed a greater proportion of patients with seizures than seizure-free patients having difficulties in advantageous decision making, but no difference in performance between seizure-free patients and controls. Functional imaging of working memory networks showed that overall poor IGT performance was associated with an increased activation in the dorsolateral prefrontal cortex (DLPFC) in JME patients. Impaired learning during the task and ongoing seizures were associated with bilateral medial prefrontal cortex (PFC) and presupplementary motor area, right superior frontal gyrus, and left DLPFC activation.
Our study provides evidence that patients with JME and ongoing seizures learn significantly less from previous experience. Interictal dysfunction within "normal" working memory networks, specifically, within the DLPFC and medial PFC structures, may affect their ability to learn.
[Show abstract][Hide abstract] ABSTRACT: To investigate cerebral grey matter (GM) abnormalities in temporal lobe epilepsy (TLE) patients who develop de novo depression following TLE surgery using voxel-based morphometry (VBM).
We retrospectively examined the pre-surgical grey matter (GM) abnormalities in 45 patients with TLE due to unilateral left-sided hippocampal sclerosis using a 1.5 T MRI scanner, which were segmented with optimised VBM parameters using SPM8 software. Grey matter maps were normalised to a sample template using DARTEL. Voxel-wise GM differences between patients that developed de novo post-surgical depression (n=6) were compared with patients with no pre- or postoperative psychiatric diagnoses (n=25), using independent samples t-tests. Analysis of covariance with age and gender as covariates was adopted for the VBM statistics; the level of statistical significance was set at p<.001, uncorrected.
Reduced preoperative GM in both the ipsilateral thalamic and orbitofrontal cortices (OFC) were significantly associated with the development of de novo depression within 4 years postoperatively. Further analyses revealed that GM atrophy of these structures was unrelated to a history or frequency of secondary generalised tonic-clonic seizures (SGTCS). We observed no differences in seizure freedom (ILAE 1 vs 2-6) or seizure recurrence (ILAE 2 vs 3-6) between the groups.
Although the development of postoperative de novo depression following TLE surgery is likely to be multi-factorial, our results suggest that ipsilateral thalamic and OFC atrophy in LTLE patients may play a modulatory role. Structural and functional abnormalities in these areas have also been implicated in primary mood disorders (1). Prospective studies with larger cohorts utilising in vivo imaging techniques are warranted to replicate these results, and further elucidate the neural correlates of de novo postoperative mood disorders.
Journal of neurology, neurosurgery, and psychiatry 09/2013; 84(9):e1. · 4.87 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To explore the neural substrates of affective psychopathology in temporal lobe epilepsy (TLE), using functional MRI (fMRI).
A visuo-spatial "n-back" paradigm was used to compare working-memory network activation in 17 TLE patients (Median age: 40, 14 female) with a lifetime diagnosis of depression and/or anxiety with 31 TLE patients (Median age: 38, 17 female) with no formal psychiatric history and 30 healthy controls (Median age: 37, 18 female). There were no significant differences between the TLE groups with respect to age, gender, handedness, epilepsy onset/duration or pre-morbid IQ. All subjects completed the Beck Depression Inventory Fast Screen (BDI-FS) and Beck Anxiety Inventory (BAI) on the day of scanning. Imaging data were analysed using SPM8 software.
Each group activated the fronto-parietal working memory networks, and deactivated the typical default mode network (DMN) in response to the increasing task demands. Group comparison revealed that TLE patients with a lifetime history of affective disorders showed significantly greater deactivation in bilateral subgenual prefrontal cortex than either the TLE without any psychiatric history and the healthy control groups (p<.001). Post-hoc analyses indicated that this main group effect persisted after co-varying for current psychotropic medication and severity of current depressive/anxiety symptoms (all p-values<.001). Correlational analysis revealed that this finding was not driven by differences in task performance (r=.49, p=.33). There were no significant differences in hippocampal volume or amygdala T2 signal between the TLE groups.
Hypometabolismof the subgenual prefrontal cortex bilaterally has been reported in association with primary mood disorders (1), and our findings further implicate this region. The subgenual prefrontal cortex shares extensive and reciprocal anatomical connections with areas implicated in emotional and behavioural regulation, such as the posterior orbitofrontal cortex, amygdala, hippocampus and hypothalamus. We hypothesise that altered modulation of this region with increased deactivation may be associated with a predisposition to develop mood disturbance. Our findings suggest that the same neurobiological substrate involved in the pathogenesis of primary mood disorders may also underpin affective psychopathology in TLE.
Journal of neurology, neurosurgery, and psychiatry 09/2013; 84(9):e1. · 4.87 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The long-term outcome of chronic epilepsy remains largely unknown, despite a long historical experience. We report the lifelong course of epilepsy of an historical cohort of 235 subjects who were in residential care at the Chalfont Centre for Epilepsy: 122 had comprehensive post-mortem examination. The populations admitted as resident to the centre over time followed the evolution of society's perception of epilepsy. 'Early residents' (before 1972) were admitted for sheltered employment, escaping stigmatization, whereas 'later' residents with more severe epilepsies were admitted for care. Subjects admitted before 1972 were similar to subjects followed nowadays as outpatients, whereas patients admitted later with a higher burden of disabilities are often those in residential care. This long follow-up allowed exploration of a wide spectrum of epilepsies, affecting both subjects who were otherwise healthy and those with co-morbidities. Age at death showed a bimodal distribution with an early peak of mortality between 45-50 years old, whilst the remainder had life expectancy comparable to the general population. As a group, subjects who had post-mortem examination were not significantly different from patients who did not have post-mortem examination, but post-mortem examination provided data that were otherwise unavailable. For those who had post-mortem examination, sudden unexpected death in epilepsy (SUDEP, 18% of all deaths) did not fully explain the early mortality, to which co-morbidities contributed. High seizure frequency was a significant independent predictor of early death even after excluding SUDEP (e.g. reduction in years of life for those who had >4 seizures/month compared with those who had <1 seizure/month: 13 years; 95% confidence interval: 6-19; overall P = 0.0006). Those who survived to older age increasingly went into spontaneous remission lasting until death (in the whole cohort, 38/166, 23% of those who died in or after sixth decade). In subjects who had post-mortem examination, older age (odds ratio = 1.13; 95% confidence interval: 1.06-1.20) and presence of neuropathologically confirmed degenerative changes (that were not the cause of epilepsy) (odds ratio 7.14; 1.95-26.2) were independent predictors of terminal remission. Epilepsy may cause premature death indirectly through co-morbid conditions. Terminal remission occurs even without prior remissions; ageing may improve epilepsy drug responsiveness although unknown factors related to the natural history may also play a role.
[Show abstract][Hide abstract] ABSTRACT: Juvenile myoclonic epilepsy (JME) has been classified as a syndrome of idiopathic generalized epilepsy and is characterized by specific types of seizures, showing a lack of pathology using magnetic resonance imaging (MRI) and computed tomography scanning. However, JME is associated with a particular personality profile, and behavioral and neuropsychological studies have suggested the possible involvement of frontal lobe dysfunction. The development of highly sensitive neuroimaging techniques has provided a means of elucidating the underlying mechanisms of JME. Positron emission tomography demonstrated metabolic and neurotransmitter changes in the dorsolateral prefrontal cortex reflecting the particular cognitive and behavioral profile of JME patients. (1)H-magnetic resonance spectroscopy has shown evidence of thalamic dysfunction, which appears to be progressive. Such techniques provide evidence of multi-focal disease mechanisms, suggesting that JME is a frontal lobe variant of a multi-regional, thalamocortical 'network' epilepsy, rather than a generalized epilepsy syndrome. Quantitative MRI revealed significant abnormalities of cortical gray matter in medial frontal areas close to the supplementary motor area and diffusion abnormalities with increased functional coupling between the motor and prefrontal cognitive systems. This altered structural connectivity of the supplementary motor area provides an explanatory framework for the particular imaging findings, seizure type, and seizure-provoking mechanisms in JME. This article is part of a supplemental special issue entitled Juvenile Myoclonic Epilepsy: What is it Really?
[Show abstract][Hide abstract] ABSTRACT: To analyse the impact of both epilepsy and pharmacological modulation of P-glycoprotein on brain uptake and kinetics of positron emission tomography (PET) radiotracers [(11)C]quinidine and [(11)C]laniquidar.
Metabolism and brain kinetics of both [(11)C]quinidine and [(11)C]laniquidar were assessed in naive rats, electrode-implanted control rats, and rats with spontaneous recurrent seizures. The latter group was further classified according to their response to the antiepileptic drug phenobarbital into "responders" and "non-responders". Additional experiments were performed following pre-treatment with the P-glycoprotein modulator tariquidar.
[(11)C]quinidine was metabolized rapidly, whereas [(11)C]laniquidar was more stable. Brain concentrations of both radiotracers remained at relatively low levels at baseline conditions. Tariquidar pre-treatment resulted in significant increases of [(11)C]quinidine and [(11)C]laniquidar brain concentrations. In the epileptic subgroup "non-responders", brain uptake of [(11)C]quinidine in selected brain regions reached higher levels than in electrode-implanted control rats. However, the relative response to tariquidar did not differ between groups with full blockade of P-glycoprotein by 15mg/kg of tariquidar. For [(11)C]laniquidar differences between epileptic and control animals were only evident at baseline conditions but not after tariquidar pretreatment.
We confirmed that both [(11)C]quinidine and [(11)C]laniquidar are P-glycoprotein substrates. At full P-gp blockade, tariquidar pre-treatment only demonstrated slight differences for [(11)C]quinidine between drug-resistant and drug-sensitive animals.
Nuclear Medicine and Biology 07/2013; · 2.52 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: An international workshop on juvenile myoclonic epilepsy (JME) was conducted in Avignon, France in May 2011. During that workshop, a group of 45 experts on JME, together with one of the founding fathers of the syndrome of JME ("Janz syndrome"), Prof. Dr. Dieter Janz from Berlin, reached a consensus on diagnostic criteria and management of JME. The international experts on JME proposed two sets of criteria, which will be helpful for both clinical and scientific purposes. Class I criteria encompass myoclonic jerks without loss of consciousness exclusively occurring on or after awakening and associated with typical generalized epileptiform EEG abnormalities, with an age of onset between 10 and 25. Class II criteria allow the inclusion of myoclonic jerks predominantly occurring after awakening, generalized epileptiform EEG abnormalities with or without concomitant myoclonic jerks, and a greater time window for age at onset (6-25years). For both sets of criteria, patients should have a clear history of myoclonic jerks predominantly occurring after awakening and an EEG with generalized epileptiform discharges supporting a diagnosis of idiopathic generalized epilepsy. Patients with JME require special management because their epilepsy starts in the vulnerable period of adolescence and, accordingly, they have lifestyle issues that typically increase the likelihood of seizures (sleep deprivation, exposure to stroboscopic flashes in discos, alcohol intake, etc.) with poor adherence to antiepileptic drugs (AEDs). Results of an inventory of the different clinical management strategies are given. This article is part of a supplemental special issue entitled Juvenile Myoclonic Epilepsy: What is it Really?
[Show abstract][Hide abstract] ABSTRACT: An international workshop on juvenile myoclonic epilepsy (JME) was conducted in Avignon, France in May 2011. During that workshop, a group of 45 experts on JME, together with one of the founding fathers of the syndrome of JME (“Janz syndrome”), Prof. Dr. Dieter Janz from Berlin, reached a consensus on diagnostic criteria and management of JME.The international experts on JME proposed two sets of criteria, which will be helpful for both clinical and scientific purposes.Class I criteria encompass myoclonic jerks without loss of consciousness exclusively occurring on or after awakening and associated with typical generalized epileptiform EEG abnormalities, with an age of onset between 10 and 25. Class II criteria allow the inclusion of myoclonic jerks predominantly occurring after awakening, generalized epileptiform EEG abnormalities with or without concomitant myoclonic jerks, and a greater time window for age at onset (6–25 years).For both sets of criteria, patients should have a clear history of myoclonic jerks predominantly occurring after awakening and an EEG with generalized epileptiform discharges supporting a diagnosis of idiopathic generalized epilepsy.Patients with JME require special management because their epilepsy starts in the vulnerable period of adolescence and, accordingly, they have lifestyle issues that typically increase the likelihood of seizures (sleep deprivation, exposure to stroboscopic flashes in discos, alcohol intake, etc.) with poor adherence to antiepileptic drugs (AEDs).Results of an inventory of the different clinical management strategies are given.This article is part of a supplemental special issue entitled Juvenile Myoclonic Epilepsy: What is it Really?
[Show abstract][Hide abstract] ABSTRACT: Studies in rodent models of epilepsy suggest that multidrug efflux transporters at the blood-brain barrier, such as P-glycoprotein, might contribute to pharmacoresistance by reducing target-site concentrations of antiepileptic drugs. We assessed P-glycoprotein activity in vivo in patients with temporal lobe epilepsy.
We selected 16 patients with pharmacoresistant temporal lobe epilepsy who had seizures despite treatment with at least two antiepileptic drugs, eight patients who had been seizure-free on antiepileptic drugs for at least a year after 3 or more years of active temporal lobe epilepsy, and 17 healthy controls. All participants had a baseline PET scan with the P-glycoprotein substrate (R)-[(11)C]verapamil. Pharmacoresistant patients and healthy controls then received a 30-min infusion of the P-glycoprotein-inhibitor tariquidar followed by another (R)-[(11)C]verapamil PET scan 60 min later. Seizure-free patients had a second scan on the same day, but without tariquidar infusion. Voxel-by-voxel, we calculated the (R)-[(11)C]verapamil plasma-to-brain transport rate constant, K1 (mL/min/cm(3)). Low baseline K1 and attenuated K1 increases after tariquidar correspond to high P-glycoprotein activity.
Between October, 2008, and November, 2011, we completed (R)-[(11)C]verapamil PET studies in 14 pharmacoresistant patients, eight seizure-free patients, and 13 healthy controls. Voxel-based analysis revealed that pharmacoresistant patients had lower baseline K1, corresponding to higher baseline P-glycoprotein activity, than seizure-free patients in ipsilateral amygdala (0·031 vs 0·036 mL/min/cm(3); p=0·014), bilateral parahippocampus (0·032 vs 0·037; p<0·0001), fusiform gyrus (0·036 vs 0·041; p<0·0001), inferior temporal gyrus (0·035 vs 0·041; p<0·0001), and middle temporal gyrus (0·038 vs 0·044; p<0·0001). Higher P-glycoprotein activity was associated with higher seizure frequency in whole-brain grey matter (p=0·016) and the hippocampus (p=0·029). In healthy controls, we noted a 56·8% increase of whole-brain K1 after 2 mg/kg tariquidar, and 57·9% for 3 mg/kg; in patients with pharmacoresistant temporal lobe epilepsy, whole-brain K1 increased by only 21·9% for 2 mg/kg and 42·6% after 3 mg/kg. This difference in tariquidar response was most pronounced in the sclerotic hippocampus (mean 24·5% increase in patients vs mean 65% increase in healthy controls, p<0·0001).
Our results support the hypothesis that there is an association between P-glycoprotein overactivity in some regions of the brain and pharmacoresistance in temporal lobe epilepsy. If this relation is confirmed, and P-glycoprotein can be identified as a contributor to pharmacoresistance, overcoming P-glycoprotein overactivity could be investigated as a potential treatment strategy.
EU-FP7 programme (EURIPIDES number 201380).
The Lancet Neurology 06/2013; · 23.92 Impact Factor