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Juvenile myoclonic epilepsy — Neuroimaging findings
Epilepsy & Behavior 28 (2013) S40–S44
Contents lists available at SciVerse ScienceDirect
Epilepsy & Behavior journal homepage: www.elsevier.com/locate/yebeh
Review
Juvenile myoclonic epilepsy — Neuroimaging findings Matthias J. Koepp a,⁎, Friedrich Woermann c, Ivanka Savic d, Britta Wandschneider b a
Department of Clinical Experimental Epilepsy, Institute of Neurology, University College London, London, UK Epilepsy Society MRI-Unit, Epilepsy Society, Chalfont St Peter, UK c Bethel Epilepsy Center, Mara Hospital, Bielefeld, Germany d Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden b
a r t i c l e
i n f o
Article history: Accepted 28 June 2012 Keywords: Functional magnetic resonance imaging Idiopathic generalized epilepsy Juvenile myoclonic epilepsy JME Positron emission tomography Proton magnetic resonance spectroscopy Quantitative magnetic resonance imaging
a b s t r a c t 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. 1H-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? © 2012 Elsevier Inc. All rights reserved.
1. Introduction Juvenile myoclonic epilepsy (JME) is characterized by myoclonic jerks, generalized tonic-clonic seizures, and, less frequently, absence seizures, with a typical sleep and wake pattern in relationship to seizures. The seizures may be precipitated by a variety of stimuli, including sleep deprivation, fatigue, alcohol intake, menses and stress, but more specifically following complex cognitive tasks, described as praxis-induction. Thalamocortical dysfunction is considered to be the major mechanism of JME, and, as with other IGE syndromes, JME is defined by electrophysiological features that show involvement of both cerebral hemispheres from the beginning of seizures. According to the criteria of the International League Against Epilepsy, structural brain abnormalities using magnetic resonance imaging (MRI) and computed tomography (CT) are not found in JME. Juvenile myoclonic epilepsy is associated with normal intelligence. However, it has been noted that JME is associated with a particular personality profile, and behavioral and neuropsychological studies ⁎ Corresponding author at: UCL Institute of Neurology, 33 Queen Square, London WC1N 3BG, UK. E-mail address: [email protected] (M.J. Koepp). 1525-5050/$ – see front matter © 2012 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.yebeh.2012.06.035
have suggested subtle frontal lobe dysfunction. Moreover, neuropathological studies have provided evidence of microdysgenesis in IGE, in the form of cortical and subcortical dystopic neurons and other microscopic structural abnormalities. The development of highly sensitive neuroimaging techniques has allowed the identification of subtle functional and structural abnormalities, providing a means of elucidating the underlying mechanisms of JME and the relative contribution of focal versus generalized dysfunction. 2. Neuroimaging in JME 2.1. Positron emission tomography Positron emission tomography (PET) allows the tomographic delineation of cerebral structures and the measurement of tissue concentrations of injected radioactive tracers at the molecular level and may be performed when the subject is at rest or during or following the occurrence of a seizure, the undertaking of a cognitive or motor task, or the administration of a drug. A study using PET and bolus injections of H215O was used to measure cerebral blood flow in patients with IGE and a history of absence seizures [1]. It showed that in
M.J. Koepp et al. / Epilepsy & Behavior 28 (2013) S40–S44
addition to a global increase in cerebral blood flow during absence seizures, there was a significant focal increase in thalamic blood flow, providing evidence that the thalamus plays a key role in the pathogenesis of typical absence seizures. Swartz and colleagues [2] performed a 18FGD-PET study using a visual working memory paradigm in nine JME patients and 14 controls. Pairs of abstract images were presented and subjects had to indicate by pressing a button whether the images were matching or not. Defined by the delay between the two images, two conditions were created: the immediate match to sample task (IMS), with an image delay of 100 ms, controlled for attention, motivation, motor function, and habituation, whereas the delayed match to sample task (DMS; delay 8000 ms) evaluated the visual working memory. Two categories of mistakes (match-on-mismatch and mismatch-on-match) were recorded as well as reaction times for correct and incorrect answers. The JME patients' performance was comparable to controls on the IMS task but impaired during the working memory condition. Considering possible confounders, groups showed no significant age difference. The authors concluded that dysfunctional thalamo-fronto-cortical networks might account for both ictogenesis and poor working memory performance. At resting state, 18FDG uptake in patients was decreased in the ventral premotor cortex, caudate, the dorsolateral prefrontal cortex (DLPFC) bilaterally, and the left premotor area, representing widespread frontal impairment. Controls activated areas which are thought to support working memory function, whereas patients presented with a “hypofrontality state” in keeping with poorer performance in the DMS task. Increased metabolism of the lateral orbital and medial temporal regions was interpreted as compensatory mechanisms for prefrontal dysfunction. In a resting FDG-PET study [3], regional cerebral rates of glucose uptake values (rCMRGlc) were regressed on various executive function test scores in patients with frontal lobe epilepsy (FLE; n = 18), JME (n = 10), and healthy controls (n = 14). The executive function battery included measures of cognitive flexibility, fluency, response inhibition, working memory, and sustained attention. In the JME group, frontal hypometabolic values predicted impairment on measures of figural fluency and cognitive flexibility. Flumazenil (FMZ), a specific, reversibly bound, high-affinity neutral antagonist of cBZR, can be 11C-labeled and used with PET to provide a marker for the integrity of γ-amino butyric acid (GABA) — the principal inhibitory neurotransmitter in the brain. A study using 11 C-FMZ-PET demonstrated that GABAA–cBZR binding is globally increased in the cerebral cortex of patients with JME and other forms of IGE [4]. Frontal lobe GABAA–cBZR binding was particularly elevated in patients with JME but not in patients with other forms of IGE [5]. At a neurotransmission level, evidence exists that serotonergic processes may be involved in the pathophysiology of myoclonus. In human subjects, serotonin 1A receptor binding can be examined in vivo with positron emission tomography (PET) and the radioligand 11 C‐WAY-100635. Testing the hypothesis that JME may be associated with a disturbance (a hyperreactivity) of serotonergic neurons, leading to altered serotonin 1A receptor binding, Meschaks et al. [6] observed reduced WAY-100635 binding potential in the dorsolateral prefrontal cortex, raphe nuclei, and hippocampus, but not motor cortex (Fig. 1). The observed reductions in serotonin 1A receptor binding suggest that the serotonin system is affected in JME, although provide no definitive information about underlying mechanisms. Based on previous data showing that the dopamine system is involved in motor as well as cognitive functions, Ciumas et al. [7] investigated the binding potential to the dopamine transporter (DAT) in the midbrain, substantia nigra, caudate, and putamen, and if such changes are linked to dysfunctions in 12 patients with JME compared to 12 healthy controls. Dopamine signaling seemed impaired in the target regions for dopaminergic neurons with reduced
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Fig. 1. Late uptake images. 11C‐WAY-100635 in a patient with juvenile myoclonic epilepsy (JME) and control. The images illustrate low uptake in the hippocampus and raphe in the patient. The patient's right side is to the left in the image.
binding potential in the substantia nigra and midbrain (p = 0.009 and 0.007), but normal values in the caudate and putamen. In a second study of Ciumas et al. [8], JME patients were compared with patients with epilepsy with generalized tonic-clonic seizures (GTCS) only. Both patient groups showed a reduced BP compared to controls, albeit in different locations. Juvenile myoclonic epilepsy patients had a lower tracer binding than controls in the midbrain (0.8+/− 0.1 vs. 1.0 +/− 0.2, p = 0.019), whereas GTCS patients had reduced tracer binding in the putamen (5.9+/− 1.6 vs. 7.1 +/− 1.2, p = 0.023). While GTCS patients showed impaired performance in motor functions and on one test of executive function, JME patients performed poorly also in tests of working memory and several tests of executive function. Alterations in the DA system seem to exist in both GTCS and JME. However, the regional distribution of these changes differs between the two syndromes, as does their association with psychomotor and working memory performance. 2.2. Proton magnetic resonance spectroscopy Whereas conventional MRI provides structural information based on signals from water protons, proton magnetic resonance spectroscopy ( 1H-MRS) provides information on the chemical composition of the brain. Since N-acetyl aspartate (NAA) is found exclusively in neurons and neuronal processes, a reduction in the level of NAA can be an indication of neuronal damage or dysfunction [9]. Using this technique, thalamic NAA concentrations were found to be significantly lower in IGE patients than in controls [10]. Volumetric MRI did not identify a significant loss in thalamic volume in these patients, indicating thalamic neuronal dysfunction, rather than loss, in agreement with previous neuropathological studies [11]. Moreover, a negative correlation was found between NAA levels and duration of epilepsy, indicating that thalamic dysfunction in IGE may be progressive. Proton magnetic resonance spectroscopy has indicated that NAA levels are reduced in the thalami of JME patients, supporting the idea that thalamic dysfunction is part of the underlying mechanism of epileptogenesis in JME [12]. However, 1H-MRS has also demonstrated that patients with JME have significantly reduced prefrontal concentrations of NAA, compared with controls, demonstrating that prefrontal cerebral
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changes – neuronal in origin – also exist in JME [13,14]. This finding seems to be specific to JME, compared with other forms of IGE, such as pure primarily generalized tonic–clonic epilepsy [15]. In addition, 1H-MRS has revealed frontal lobe metabolite changes in IGE, by demonstrating increased levels of glutamate plus glutamine (GLX), an indication of increased neuronal excitability in this region [14]. Proton magnetic resonance spectroscopy has also demonstrated elevated levels of GLX and GABA in the occipital lobes of patients with IGE [15]. 2.3. Functional MRI Electroencephalography-correlated functional MRI (EEG–fMRI) provides a means of identifying and studying the neural correlates of spontaneously occurring generalized spike–wave discharges (GSWD). This technique has been used to study a patient with IGE and frequent absences, demonstrating the reciprocal participation of focal thalamic blood flow increases and symmetrical cortical deactivation, with a frontal maximum time-locked with prolonged runs of GSWD [16]. Subsequently, two EEG–fMRI series, conducted in Australia [17] and Canada [18], have replicated these findings of altered thalamic and cortical blood flow, in larger groups of patients with IGE. In the Australian series, signal reductions in the posterior cingulate were observed in four out of five patients, whereas the Canadian series reported a variable, but – in the majority of patients – symmetrical, deactivation in the cortex of both hemispheres, involving the anterior as much as posterior head regions. A more recent functional imaging study examined 19 JME patients using a verbal and non-verbal functional MRI (fMRI) working memory paradigm [19]. During the visuo-spatial paradigm, subjects were assessed with a modified version of the Sternberg Item Recognition Test. A virtual grid was presented, holding either a triangle or a square, and subjects were asked to memorize the positions of the items within the grid. After an interval, the grid was presented again, containing either a triangle or a square. Participants had to decide whether one of the symbols had been in the same position in the previous grid, irrespective of its shape. During the verbal memory task, phonologically similar letters were shown, either capitalized or not. During the response condition, a single letter was presented, and subjects had to decide whether it had been shown in the previous condition, irrespective if capitalized or not. Both groups performed well on these tasks and no significant group differences were detected on fMRI activation patterns. Roebling and colleagues compared patients on valproic acid (VPA) to untreated patients or patients on lamotrigine (LTG) monotherapy respectively. The VPA group was significantly more impaired, and the authors concluded that cognitive dysfunction in this cohort is at least partially caused by medication side-effects, especially of VPA. The authors suggested that these inconsistent findings may indicate a heterogeneous epilepsy syndrome, in which frontal lobe dysfunction is only present in a JME subgroup. However, they acknowledge that absence of group differences might be caused by a working memory task that is not sufficiently challenging. Vollmar et al. [20] investigated a larger JME population (n = 30) with a different and, probably, more challenging working memory fMRI paradigm. During the task, dots were randomly presented on a screen. There were three different response conditions: during the “0-back” task, participants were instructed to move a joystick toward the current position of the dot; in the “1-back” condition to the previous position of the dot; and in the “2-back” condition to its second previous position. Patients and controls performed equally well on all three tasks and showed significant fMRI activation of working memory networks, after subtracting “0-back” from “1-back” and “2-back” in order to control for the motor component. However, their fMRI cortical activation patterns differed significantly with increasing task demand. During the “2-back” condition, the motor cortex and
supplementary motor area (SMA) increasingly co-activated with working memory networks in patients. The authors also described increased functional connectivity between the motor system and areas of higher cognitive functions within the frontal and parietal lobes. Precipitation of myoclonic jerks by cognitive tasks is a known clinical feature in some JME patients [21]. Therefore, the increased functional connectivity was interpreted as possible mechanism for seizures triggered by cognitive effort. Regions of cortical hyper-excitability may overlap with areas physiologically activated during cognitive or motor activities. Hence, a complex task involving several functional cortical systems may summon a “critical mass of cortex activated” which leads to seizure precipitation [22]. The abnormal motor cortex co-activation during a working memory task may represent the functional correlate of this mechanism. In keeping with being the drug of choice, VPA had a beneficial effect in JME: abnormal left motor cortex co-activation correlated negatively with an increasing daily VPA dose, implying a normalization of function and possibly reflecting the positive effect VPA has on controlling myoclonic jerks. 2.4. Quantitative MRI Although visual inspection of routine MRI in patients with IGE appears normal, neuropathological autopsy studies have provided evidence of gray and white matter microdysgenesis [11]. Quantitative MRI can elucidate subtle changes in the ratio of cortical and subcortical matter in specified volumes of interest, providing a means of detecting structural changes not normally visible using high-resolution MRI [23]. This technique has been used to demonstrate subtle but widespread cerebral structural changes in patients with IGE [24]. Of the patients with JME included in this study, 40% (8/20) had a significant abnormality of cerebral structure. When voxel-based statistical parametric mapping was used to analyze structural MRI data, patients with JME were shown to have an increase in cortical gray matter in the mesial frontal lobes compared with healthy subjects [25]. This objective technique revealed significant abnormalities in the cortical gray matter of a quarter (5/20) of the JME patients studied; four of whom had previously been shown to have widespread abnormalities using quantitative MRI. Two patients had bilateral areas of increased gray matter volume: one in the temporal posterior and the other in the mesioparietal region, while three had areas of decreased gray matter volume: two in the frontopolar area and one in the frontomesial region. For the correct interpretation of these voxel-based techniques, it has to be emphasized that unilateral or bilateral findings very much depend on the level of thresholding chosen for the analysis. Further structural imaging studies in JME repeatedly reported subtle changes in the mesial frontal lobe of patients with JME. Morphometric studies based on T1‐weighted MRI reported both gray matter decreases [26] and increases [25]. This may not only reflect changes in image analysis methodology, but also supports the existence of micro-structural changes in mesio-frontal regions. This could be shown in a meta-analysis of seven voxel-based morphometric studies using Signed Differential Mapping (Fig. 2) (SDM; http://sdmproject. com/). Pulsipher et al. [27] aimed to investigate the integrity of thalamo‐ fronto‐cortical networks in correlation to executive function in recent-onset JME. 20 newly-diagnosed JME patients (diagnosis within the last 12 months) were compared to an epilepsy “control group” of 12 patients with recent onset Benign Childhood Epilepsy with Centrotemporal Spikes (BECTS) and 51 healthy controls (first degree cousins). Groups were comparable for gender, duration of epilepsy, and IQ. Due to characteristic ages of onset, JME patients were significantly older than both BECTS patients and healthy controls, yet no significant correlations between standardized test scores and age were observed. Participants were assessed with three subtests of the
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3. Conclusions Sensitive neuroimaging techniques provide qualitative and quantitative methods of elucidating the underlying pathological mechanisms involved in JME. Although JME has characteristics of a form of generalized epilepsy, such techniques provide evidence of the involvement of additional, possibly multi-focal disease mechanisms – in particular involving the frontal lobes – in accordance with the findings of behavioral and neuropsychological studies. Increased functional connectivity between prefrontal cognitive areas and the motor system in JME suggests that connectivity alterations in the SMA might be the “missing link” between seizure‐facilitating mechanisms and seizure type. The increased connectivity between the anterior cluster, which is part of the prefrontal cognitive network, and the central region reflects the structural basis for increased functional connectivity in these patients and helps to explain why, why cognitive activity elicits epileptiform discharges and seizures in these patients. The increased connectivity to the occipital cortex may reflect a pathway, via which photic stimulation can elicit discharges and seizures. The reduced connectivity within the prefrontal cortex, on the other hand, may be the basis for impaired frontal lobe functioning in these patients. Conflict of interest Fig. 2. Meta-analysis of voxel‐based MRI studies showing increased gray matter in mesio-frontal regions (upper row) and reduced gray matter in perisylvian regions bilaterally.
The authors declare that there are no conflicts of interest. References
Delis–Kaplan Executive Function System (D-KEFS) and a parent questionnaire, the Behavior Rating Inventory of Executive Function (BRIEF). Age-adjusted scores demonstrated poorer performance in JME patients than in controls on D-KEFS Inhibition. Behavioral regulation and metacognition scores of the BRIEF were also significantly lower in the JME group. Quantitative MRI measurements revealed smaller thalamic volumes and greater frontal CSF in JME patients than in healthy controls and BCECTS patients. Only in the JME group, thalamic and frontal volumes predicted D-KEFS performance. Interestingly, JME patients showed volumetric abnormalities already within 12 months of seizure onset, suggesting a clinically significant disruption of the thalamo‐fronto‐cortical circuitry, leading to both seizures and neuro-cognitive deficits. How early structural abnormalities present in disease evolution remains uncertain, though, in as much as the distinct volumetric abnormalities seem to be unlikely the result of chronic seizures.
2.5. DTI-tractography In a recent analysis of T1‐weighted MRI and diffusion tensor imaging (DTI), we could replicate the finding of decreased mesial frontal gray matter volume and also found a reduced fractional anisotropy (FA) in underlying white matter tracts, which are considered to form the basis for the observed neuropsychological and psychiatric changes observed in patients with JME [26]. Vollmar et al. [28] investigated the structural segregation of SMA and preSMA in JME using DTI‐based connectivity fingerprinting and clustering techniques. Patients with JME showed reduced connectivity of the anterior SMA cluster to prefrontal and frontopolar areas. Connectivity was increased to the central region, occipital lobe, and descending motor pathways and cerebellum. The posterior SMA cluster showed relatively decreased connectivity to the primary motor cortex and increased connectivity to the parietal lobe and temporal neocortex explaining several imaging findings and clinical observations in JME.
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[19] Roebling R, Scheerer N, Uttner I, Gruber O, Kraft E, Lerche H. Evaluation of cognition, structural, and functional MRI in juvenile myoclonic epilepsy. Epilepsia 2009;50: 2456-65. [20] Vollmar C, O'Muircheartaigh J, Barker GJ, et al. Motor system hyperconnectivity in juvenile myoclonic epilepsy: a cognitive functional magnetic resonance imaging study. Brain 2011;134:1710-9. [21] Inoue Y, Kubota H. Juvenile myoclonic epilepsy with praxis-induced seizures. Juvenile myoclonic epilepsy. The Janz Syndrome. Petersfield, UK: Wrightson Biomedical Publishing; 2000. p. 73-81. [22] Ferlazzo E, Zifkin BG, Andermann E, Andermann F. Cortical triggers in generalized reflex seizures and epilepsies. Brain 2005;128:700-10. [23] Sisodiya SM, Free SL, Stevens JM, Fish DR, Shorvon SD. Widespread cerebral structural changes in patients with cortical dysgenesis and epilepsy. Brain 1995;118:1039-50.
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Contents lists available at SciVerse ScienceDirect
Epilepsy & Behavior journal homepage: www.elsevier.com/locate/yebeh
Review
Juvenile myoclonic epilepsy — Neuroimaging findings Matthias J. Koepp a,⁎, Friedrich Woermann c, Ivanka Savic d, Britta Wandschneider b a
Department of Clinical Experimental Epilepsy, Institute of Neurology, University College London, London, UK Epilepsy Society MRI-Unit, Epilepsy Society, Chalfont St Peter, UK c Bethel Epilepsy Center, Mara Hospital, Bielefeld, Germany d Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden b
a r t i c l e
i n f o
Article history: Accepted 28 June 2012 Keywords: Functional magnetic resonance imaging Idiopathic generalized epilepsy Juvenile myoclonic epilepsy JME Positron emission tomography Proton magnetic resonance spectroscopy Quantitative magnetic resonance imaging
a b s t r a c t 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. 1H-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? © 2012 Elsevier Inc. All rights reserved.
1. Introduction Juvenile myoclonic epilepsy (JME) is characterized by myoclonic jerks, generalized tonic-clonic seizures, and, less frequently, absence seizures, with a typical sleep and wake pattern in relationship to seizures. The seizures may be precipitated by a variety of stimuli, including sleep deprivation, fatigue, alcohol intake, menses and stress, but more specifically following complex cognitive tasks, described as praxis-induction. Thalamocortical dysfunction is considered to be the major mechanism of JME, and, as with other IGE syndromes, JME is defined by electrophysiological features that show involvement of both cerebral hemispheres from the beginning of seizures. According to the criteria of the International League Against Epilepsy, structural brain abnormalities using magnetic resonance imaging (MRI) and computed tomography (CT) are not found in JME. Juvenile myoclonic epilepsy is associated with normal intelligence. However, it has been noted that JME is associated with a particular personality profile, and behavioral and neuropsychological studies ⁎ Corresponding author at: UCL Institute of Neurology, 33 Queen Square, London WC1N 3BG, UK. E-mail address: [email protected] (M.J. Koepp). 1525-5050/$ – see front matter © 2012 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.yebeh.2012.06.035
have suggested subtle frontal lobe dysfunction. Moreover, neuropathological studies have provided evidence of microdysgenesis in IGE, in the form of cortical and subcortical dystopic neurons and other microscopic structural abnormalities. The development of highly sensitive neuroimaging techniques has allowed the identification of subtle functional and structural abnormalities, providing a means of elucidating the underlying mechanisms of JME and the relative contribution of focal versus generalized dysfunction. 2. Neuroimaging in JME 2.1. Positron emission tomography Positron emission tomography (PET) allows the tomographic delineation of cerebral structures and the measurement of tissue concentrations of injected radioactive tracers at the molecular level and may be performed when the subject is at rest or during or following the occurrence of a seizure, the undertaking of a cognitive or motor task, or the administration of a drug. A study using PET and bolus injections of H215O was used to measure cerebral blood flow in patients with IGE and a history of absence seizures [1]. It showed that in
M.J. Koepp et al. / Epilepsy & Behavior 28 (2013) S40–S44
addition to a global increase in cerebral blood flow during absence seizures, there was a significant focal increase in thalamic blood flow, providing evidence that the thalamus plays a key role in the pathogenesis of typical absence seizures. Swartz and colleagues [2] performed a 18FGD-PET study using a visual working memory paradigm in nine JME patients and 14 controls. Pairs of abstract images were presented and subjects had to indicate by pressing a button whether the images were matching or not. Defined by the delay between the two images, two conditions were created: the immediate match to sample task (IMS), with an image delay of 100 ms, controlled for attention, motivation, motor function, and habituation, whereas the delayed match to sample task (DMS; delay 8000 ms) evaluated the visual working memory. Two categories of mistakes (match-on-mismatch and mismatch-on-match) were recorded as well as reaction times for correct and incorrect answers. The JME patients' performance was comparable to controls on the IMS task but impaired during the working memory condition. Considering possible confounders, groups showed no significant age difference. The authors concluded that dysfunctional thalamo-fronto-cortical networks might account for both ictogenesis and poor working memory performance. At resting state, 18FDG uptake in patients was decreased in the ventral premotor cortex, caudate, the dorsolateral prefrontal cortex (DLPFC) bilaterally, and the left premotor area, representing widespread frontal impairment. Controls activated areas which are thought to support working memory function, whereas patients presented with a “hypofrontality state” in keeping with poorer performance in the DMS task. Increased metabolism of the lateral orbital and medial temporal regions was interpreted as compensatory mechanisms for prefrontal dysfunction. In a resting FDG-PET study [3], regional cerebral rates of glucose uptake values (rCMRGlc) were regressed on various executive function test scores in patients with frontal lobe epilepsy (FLE; n = 18), JME (n = 10), and healthy controls (n = 14). The executive function battery included measures of cognitive flexibility, fluency, response inhibition, working memory, and sustained attention. In the JME group, frontal hypometabolic values predicted impairment on measures of figural fluency and cognitive flexibility. Flumazenil (FMZ), a specific, reversibly bound, high-affinity neutral antagonist of cBZR, can be 11C-labeled and used with PET to provide a marker for the integrity of γ-amino butyric acid (GABA) — the principal inhibitory neurotransmitter in the brain. A study using 11 C-FMZ-PET demonstrated that GABAA–cBZR binding is globally increased in the cerebral cortex of patients with JME and other forms of IGE [4]. Frontal lobe GABAA–cBZR binding was particularly elevated in patients with JME but not in patients with other forms of IGE [5]. At a neurotransmission level, evidence exists that serotonergic processes may be involved in the pathophysiology of myoclonus. In human subjects, serotonin 1A receptor binding can be examined in vivo with positron emission tomography (PET) and the radioligand 11 C‐WAY-100635. Testing the hypothesis that JME may be associated with a disturbance (a hyperreactivity) of serotonergic neurons, leading to altered serotonin 1A receptor binding, Meschaks et al. [6] observed reduced WAY-100635 binding potential in the dorsolateral prefrontal cortex, raphe nuclei, and hippocampus, but not motor cortex (Fig. 1). The observed reductions in serotonin 1A receptor binding suggest that the serotonin system is affected in JME, although provide no definitive information about underlying mechanisms. Based on previous data showing that the dopamine system is involved in motor as well as cognitive functions, Ciumas et al. [7] investigated the binding potential to the dopamine transporter (DAT) in the midbrain, substantia nigra, caudate, and putamen, and if such changes are linked to dysfunctions in 12 patients with JME compared to 12 healthy controls. Dopamine signaling seemed impaired in the target regions for dopaminergic neurons with reduced
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Fig. 1. Late uptake images. 11C‐WAY-100635 in a patient with juvenile myoclonic epilepsy (JME) and control. The images illustrate low uptake in the hippocampus and raphe in the patient. The patient's right side is to the left in the image.
binding potential in the substantia nigra and midbrain (p = 0.009 and 0.007), but normal values in the caudate and putamen. In a second study of Ciumas et al. [8], JME patients were compared with patients with epilepsy with generalized tonic-clonic seizures (GTCS) only. Both patient groups showed a reduced BP compared to controls, albeit in different locations. Juvenile myoclonic epilepsy patients had a lower tracer binding than controls in the midbrain (0.8+/− 0.1 vs. 1.0 +/− 0.2, p = 0.019), whereas GTCS patients had reduced tracer binding in the putamen (5.9+/− 1.6 vs. 7.1 +/− 1.2, p = 0.023). While GTCS patients showed impaired performance in motor functions and on one test of executive function, JME patients performed poorly also in tests of working memory and several tests of executive function. Alterations in the DA system seem to exist in both GTCS and JME. However, the regional distribution of these changes differs between the two syndromes, as does their association with psychomotor and working memory performance. 2.2. Proton magnetic resonance spectroscopy Whereas conventional MRI provides structural information based on signals from water protons, proton magnetic resonance spectroscopy ( 1H-MRS) provides information on the chemical composition of the brain. Since N-acetyl aspartate (NAA) is found exclusively in neurons and neuronal processes, a reduction in the level of NAA can be an indication of neuronal damage or dysfunction [9]. Using this technique, thalamic NAA concentrations were found to be significantly lower in IGE patients than in controls [10]. Volumetric MRI did not identify a significant loss in thalamic volume in these patients, indicating thalamic neuronal dysfunction, rather than loss, in agreement with previous neuropathological studies [11]. Moreover, a negative correlation was found between NAA levels and duration of epilepsy, indicating that thalamic dysfunction in IGE may be progressive. Proton magnetic resonance spectroscopy has indicated that NAA levels are reduced in the thalami of JME patients, supporting the idea that thalamic dysfunction is part of the underlying mechanism of epileptogenesis in JME [12]. However, 1H-MRS has also demonstrated that patients with JME have significantly reduced prefrontal concentrations of NAA, compared with controls, demonstrating that prefrontal cerebral
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changes – neuronal in origin – also exist in JME [13,14]. This finding seems to be specific to JME, compared with other forms of IGE, such as pure primarily generalized tonic–clonic epilepsy [15]. In addition, 1H-MRS has revealed frontal lobe metabolite changes in IGE, by demonstrating increased levels of glutamate plus glutamine (GLX), an indication of increased neuronal excitability in this region [14]. Proton magnetic resonance spectroscopy has also demonstrated elevated levels of GLX and GABA in the occipital lobes of patients with IGE [15]. 2.3. Functional MRI Electroencephalography-correlated functional MRI (EEG–fMRI) provides a means of identifying and studying the neural correlates of spontaneously occurring generalized spike–wave discharges (GSWD). This technique has been used to study a patient with IGE and frequent absences, demonstrating the reciprocal participation of focal thalamic blood flow increases and symmetrical cortical deactivation, with a frontal maximum time-locked with prolonged runs of GSWD [16]. Subsequently, two EEG–fMRI series, conducted in Australia [17] and Canada [18], have replicated these findings of altered thalamic and cortical blood flow, in larger groups of patients with IGE. In the Australian series, signal reductions in the posterior cingulate were observed in four out of five patients, whereas the Canadian series reported a variable, but – in the majority of patients – symmetrical, deactivation in the cortex of both hemispheres, involving the anterior as much as posterior head regions. A more recent functional imaging study examined 19 JME patients using a verbal and non-verbal functional MRI (fMRI) working memory paradigm [19]. During the visuo-spatial paradigm, subjects were assessed with a modified version of the Sternberg Item Recognition Test. A virtual grid was presented, holding either a triangle or a square, and subjects were asked to memorize the positions of the items within the grid. After an interval, the grid was presented again, containing either a triangle or a square. Participants had to decide whether one of the symbols had been in the same position in the previous grid, irrespective of its shape. During the verbal memory task, phonologically similar letters were shown, either capitalized or not. During the response condition, a single letter was presented, and subjects had to decide whether it had been shown in the previous condition, irrespective if capitalized or not. Both groups performed well on these tasks and no significant group differences were detected on fMRI activation patterns. Roebling and colleagues compared patients on valproic acid (VPA) to untreated patients or patients on lamotrigine (LTG) monotherapy respectively. The VPA group was significantly more impaired, and the authors concluded that cognitive dysfunction in this cohort is at least partially caused by medication side-effects, especially of VPA. The authors suggested that these inconsistent findings may indicate a heterogeneous epilepsy syndrome, in which frontal lobe dysfunction is only present in a JME subgroup. However, they acknowledge that absence of group differences might be caused by a working memory task that is not sufficiently challenging. Vollmar et al. [20] investigated a larger JME population (n = 30) with a different and, probably, more challenging working memory fMRI paradigm. During the task, dots were randomly presented on a screen. There were three different response conditions: during the “0-back” task, participants were instructed to move a joystick toward the current position of the dot; in the “1-back” condition to the previous position of the dot; and in the “2-back” condition to its second previous position. Patients and controls performed equally well on all three tasks and showed significant fMRI activation of working memory networks, after subtracting “0-back” from “1-back” and “2-back” in order to control for the motor component. However, their fMRI cortical activation patterns differed significantly with increasing task demand. During the “2-back” condition, the motor cortex and
supplementary motor area (SMA) increasingly co-activated with working memory networks in patients. The authors also described increased functional connectivity between the motor system and areas of higher cognitive functions within the frontal and parietal lobes. Precipitation of myoclonic jerks by cognitive tasks is a known clinical feature in some JME patients [21]. Therefore, the increased functional connectivity was interpreted as possible mechanism for seizures triggered by cognitive effort. Regions of cortical hyper-excitability may overlap with areas physiologically activated during cognitive or motor activities. Hence, a complex task involving several functional cortical systems may summon a “critical mass of cortex activated” which leads to seizure precipitation [22]. The abnormal motor cortex co-activation during a working memory task may represent the functional correlate of this mechanism. In keeping with being the drug of choice, VPA had a beneficial effect in JME: abnormal left motor cortex co-activation correlated negatively with an increasing daily VPA dose, implying a normalization of function and possibly reflecting the positive effect VPA has on controlling myoclonic jerks. 2.4. Quantitative MRI Although visual inspection of routine MRI in patients with IGE appears normal, neuropathological autopsy studies have provided evidence of gray and white matter microdysgenesis [11]. Quantitative MRI can elucidate subtle changes in the ratio of cortical and subcortical matter in specified volumes of interest, providing a means of detecting structural changes not normally visible using high-resolution MRI [23]. This technique has been used to demonstrate subtle but widespread cerebral structural changes in patients with IGE [24]. Of the patients with JME included in this study, 40% (8/20) had a significant abnormality of cerebral structure. When voxel-based statistical parametric mapping was used to analyze structural MRI data, patients with JME were shown to have an increase in cortical gray matter in the mesial frontal lobes compared with healthy subjects [25]. This objective technique revealed significant abnormalities in the cortical gray matter of a quarter (5/20) of the JME patients studied; four of whom had previously been shown to have widespread abnormalities using quantitative MRI. Two patients had bilateral areas of increased gray matter volume: one in the temporal posterior and the other in the mesioparietal region, while three had areas of decreased gray matter volume: two in the frontopolar area and one in the frontomesial region. For the correct interpretation of these voxel-based techniques, it has to be emphasized that unilateral or bilateral findings very much depend on the level of thresholding chosen for the analysis. Further structural imaging studies in JME repeatedly reported subtle changes in the mesial frontal lobe of patients with JME. Morphometric studies based on T1‐weighted MRI reported both gray matter decreases [26] and increases [25]. This may not only reflect changes in image analysis methodology, but also supports the existence of micro-structural changes in mesio-frontal regions. This could be shown in a meta-analysis of seven voxel-based morphometric studies using Signed Differential Mapping (Fig. 2) (SDM; http://sdmproject. com/). Pulsipher et al. [27] aimed to investigate the integrity of thalamo‐ fronto‐cortical networks in correlation to executive function in recent-onset JME. 20 newly-diagnosed JME patients (diagnosis within the last 12 months) were compared to an epilepsy “control group” of 12 patients with recent onset Benign Childhood Epilepsy with Centrotemporal Spikes (BECTS) and 51 healthy controls (first degree cousins). Groups were comparable for gender, duration of epilepsy, and IQ. Due to characteristic ages of onset, JME patients were significantly older than both BECTS patients and healthy controls, yet no significant correlations between standardized test scores and age were observed. Participants were assessed with three subtests of the
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3. Conclusions Sensitive neuroimaging techniques provide qualitative and quantitative methods of elucidating the underlying pathological mechanisms involved in JME. Although JME has characteristics of a form of generalized epilepsy, such techniques provide evidence of the involvement of additional, possibly multi-focal disease mechanisms – in particular involving the frontal lobes – in accordance with the findings of behavioral and neuropsychological studies. Increased functional connectivity between prefrontal cognitive areas and the motor system in JME suggests that connectivity alterations in the SMA might be the “missing link” between seizure‐facilitating mechanisms and seizure type. The increased connectivity between the anterior cluster, which is part of the prefrontal cognitive network, and the central region reflects the structural basis for increased functional connectivity in these patients and helps to explain why, why cognitive activity elicits epileptiform discharges and seizures in these patients. The increased connectivity to the occipital cortex may reflect a pathway, via which photic stimulation can elicit discharges and seizures. The reduced connectivity within the prefrontal cortex, on the other hand, may be the basis for impaired frontal lobe functioning in these patients. Conflict of interest Fig. 2. Meta-analysis of voxel‐based MRI studies showing increased gray matter in mesio-frontal regions (upper row) and reduced gray matter in perisylvian regions bilaterally.
The authors declare that there are no conflicts of interest. References
Delis–Kaplan Executive Function System (D-KEFS) and a parent questionnaire, the Behavior Rating Inventory of Executive Function (BRIEF). Age-adjusted scores demonstrated poorer performance in JME patients than in controls on D-KEFS Inhibition. Behavioral regulation and metacognition scores of the BRIEF were also significantly lower in the JME group. Quantitative MRI measurements revealed smaller thalamic volumes and greater frontal CSF in JME patients than in healthy controls and BCECTS patients. Only in the JME group, thalamic and frontal volumes predicted D-KEFS performance. Interestingly, JME patients showed volumetric abnormalities already within 12 months of seizure onset, suggesting a clinically significant disruption of the thalamo‐fronto‐cortical circuitry, leading to both seizures and neuro-cognitive deficits. How early structural abnormalities present in disease evolution remains uncertain, though, in as much as the distinct volumetric abnormalities seem to be unlikely the result of chronic seizures.
2.5. DTI-tractography In a recent analysis of T1‐weighted MRI and diffusion tensor imaging (DTI), we could replicate the finding of decreased mesial frontal gray matter volume and also found a reduced fractional anisotropy (FA) in underlying white matter tracts, which are considered to form the basis for the observed neuropsychological and psychiatric changes observed in patients with JME [26]. Vollmar et al. [28] investigated the structural segregation of SMA and preSMA in JME using DTI‐based connectivity fingerprinting and clustering techniques. Patients with JME showed reduced connectivity of the anterior SMA cluster to prefrontal and frontopolar areas. Connectivity was increased to the central region, occipital lobe, and descending motor pathways and cerebellum. The posterior SMA cluster showed relatively decreased connectivity to the primary motor cortex and increased connectivity to the parietal lobe and temporal neocortex explaining several imaging findings and clinical observations in JME.
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