understanding juvenile myoclonic epilepsy: contributions from neuroimaging

Epilepsy Research (2011) 94, 127—137

journa l homepage: www.e lsev ier .com/ locate /ep i lepsyres

REVIEW

Understanding juvenile myoclonic epilepsy:Contributions from neuroimaging

Joseph Anderson, Khalid Hamandi ∗

The Epilepsy Unit, University Hospital of Wales, Cardiff, CF14 4XW, UK

Received 1 September 2010; received in revised form 12 November 2010; accepted 9 March 2011Available online 8 April 2011

KEYWORDSJME;PET;SPECT;MRI;MRS;Frontal lobe

Summary Advanced neuroimaging techniques have been utilised with ever increasing fre-quency over the last 10 years. A range of structural and functional imaging modalities havebeen employed to study the neurobiological mechanisms and anatomical substrates underly-ing epileptic syndromes. Advanced neuroimaging studies of juvenile myoclonic epilepsy (JME)have utilised PET, SPECT, MRI, DTI and MRS, with all modalities revealing evidence of predom-inantly frontal lobe and thalamic changes. Abnormalities correlate with clinical features suchas seizure frequency and disease duration in some studies. Findings contribute to the ongoingdebate surrounding the classification of epileptic syndromes, suggesting JME is a predominantly
frontal thalamocortical network epilepsy, challenging the concept of a generalised epilepsy.Existing studies are limited by sample size and methodological considerations, and future stud-ies need to address these as well as pursue underlying mechanisms for phenotypic variationin this heterogenous disorder. The present review aims to outline the existing literature onadvanced neuroimaging in JME and highlight future directions for study. © 2011 Elsevier B.V. All rights reserved.
Contents

Introduction.............................................................................................................. 128Advanced neuroimaging — What is it? .................................................................................... 130

Positron emission tomography....................................................................................... 130
Single photon emission computed tomography .............Magnetic resonance imaging...............................
Structural MRI .......................................Diffusion tensor imaging ............................

∗ Corresponding author. Tel.: +44 29 2074 2834; fax: +44 29 2074 4166.E-mail addresses: j [email protected] (J. Anderson), haman

0920-1211/$ — see front matter © 2011 Elsevier B.V. All rights reserved.doi:10.1016/j.eplepsyres.2011.03.008

......................................................... 131.......................................................... 131......................................................... 131

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[email protected] (K. Hamandi).

dx.doi.org/10.1016/j.eplepsyres.2011.03.008

mailto:[email protected]

mailto:[email protected]

dx.doi.org/10.1016/j.eplepsyres.2011.03.008

128 J. Anderson, K. Hamandi

Functional MRI................................................................................................ 133Magnetic resonance spectroscopy............................................................................. 134

Magnetoencephalography ........................................................................................... 134Conclusions .............................................................................................................. 134

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References ................................................

ntroduction

his systematic review aims to outline the contributionsade by advanced neuroimaging techniques for understand-

ng the aetiology and pathophysiology of juvenile myoclonicpilepsy (JME), and the impact this potentially has on revi-ions to the classification of generalised and focal epilepsyyndromes. JME is a common idiopathic generalised epilepsy,haracterised by myoclonic jerks, generalised tonic cloniceizures and less frequent absence seizures, with character-stic electroencephalogram (EEG) findings and normal clinicrain imaging. Related syndromes include juvenile absencepilepsy (JAE) where absence seizures are prominent andyoclonic jerks do not or only rarely occur, and epilepsyith generalised tonic clonic seizures only. An overviewf JME is given below followed by a review of the lit-rature of advanced neuroimaging in JME. We performedseries of PubMed searches using the terms JME and/or

uvenile myoclonic epilepsy, together with DTI, MRI, MRS,euroimaging, PET, SPECT, VBM and MEG. Reference lists ofelevant studies were manually searched to identify studiesot detected by the PubMed search. Relevant review arti-les on related topics were identified for inclusion as furthereading in our reference list. Studies involving patients withME are covered in detail; in addition to studies of gen-ralised spike wave (GSW), the EEG hallmark of JME. Keyeatures of significant studies are summarised in Table 1

.The earliest description of JME is credited to Théodore

erpin, who in 1867 described a 13 year old boy who devel-ped upper body jerks and then generalised seizures threeonths later (Herpin, 1867; Pearce, 2005). Descriptions of

imilar patients by other authors followed but it was notntil 1957, 90 years later, that Janz and Christian pub-ished a report of 47 JME patients and the clinical featuresere recognised as a syndrome in their own right (Janznd Christian, 1957). They named the syndrome ‘‘impulsiveetit mal’’, and over the next 30 years various other namesere used, most notably ‘‘Janz Syndrome’’. It was not until989 that the terminology was unified to juvenile myoclonicpilepsy and the syndrome was admitted to the internationallassification of epileptic syndromes (ILAE, 1989).

The population prevalence of epilepsy in western pop-lations is 0.7—1% and JME can be expected to accountor 5—10% of all adult epilepsy patients, and 26% (theommonest) of all idiopathic generalised epilepsies (IGE)Panayiotopoulos et al., 1994; Montalenti et al., 2001;obayashi et al., 2008). Myoclonic jerks begin in adoles-ence (age 12—18) with a mean age of onset of 15.4 years.
pproximately 90—95% of patients have generalised tonic-lonic seizures (GTCS), mean age of onset 15.5 years, and0—50% have absence seizures (AS), mean age of onset 11.5ears (Renganathan and Delanty, 2003). Two to three percent
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ay have myoclonus only, and there are descriptions of JMEvolving out of childhood absence epilepsy (Martinez-Juarezt al., 2006).

Seizures occur in the first few hours after waking;yoclonic jerks are bilateral, irregular and arrhythmic,

ffecting predominantly the arms and occurring in single orlustered jerks, sometimes building to a GTCS. Seizures areommonly precipitated by alcohol, sleep deprivation andmotional stress and respond well to Valproate in 80% ofases. Whilst the generally held view is that treatment inost cases needs to be lifelong (Calleja et al., 2001), there

s more recent population based data to suggest that almostalf of patients may be able to discontinue drug treatmentn the long term (Camfield and Camfield, 2009). Photosensi-ivity is estimated to occur in 30—40% of JME patients, butan be elicited more commonly with more prolonged visualtimulation (Appleton et al., 2000).

Standard EEG in JME typically shows 3—6 Hz GSW orolyspike-wave activity, with a fronto-central predomi-ance, though frequencies outside this range are not unusualDelgado-Escueta and Enrile-Bacsal, 1984; Pedersen andetersen, 1998; Montalenti et al., 2001). Focal EEG dis-harges, have been reported in up to 45% of patientsAliberti et al., 1994; Jayalakshmi et al., 2010) and are aource of diagnostic errors (Panayiotopoulos et al., 1991).ore recently dense array EEG and quantitative analysisas suggested that ‘generalised’ discharges on standardEG originate in orbitofrontal, mesiofrontal, and to a lesserxtent, temporal lobe regions (Holmes et al., 2010). Visualnspection of standard clinical magnetic resonance imag-ng (MRI) shows no disease specific structural abnormalitiesILAE, 1989). Genetic studies indicate an interaction ofultiple susceptibility genes and the environment. Even

n families where a monogenic inheritance pattern doesccur, the phenotype often consists of other IGE sub-yndromes within the same family, including JME (Kobayashit al., 2008; Lu and Wang, 2009). Multiple genetic lociave been identified by linkage studies (Zifkin et al., 2005).mportant mutations have been identified in the EHFC1ene (6p12-11), encoding a calcium channel (Suzuki et al.,004); the GABRA1 gene (5q34-35) encoding the �1 sub-nit of GABAA receptors (causing autosomal dominant JME)Cossette et al., 2002); and the CACNB4 gene (2q22-23)ncoding the voltage gated calcium channel �4 sub-unit (andlso found in episodic ataxia pedigrees) (Escayg et al., 2000).otential mechanisms for these mutations causing JME areroposed; their place in the JME population as a whole andheir interactions with other genes and the environment aretill to be determined.

Personality traits such as impulsivity, poor planning, emo-ional instability, mental inflexibility and indifference wereoted in early descriptions (Janz and Christian, 1957), andave been borne out in systematic studies (Kim et al., 2007b;

Understanding juvenile myoclonic epilepsy: Contributions from neuroimaging 129

Table 1 Investigating the cause of juvenile myoclonic epilepsy (JME); neuroimaging studies.

Study Modality Subjects Findings Conclusions

Swartz et al.(1996)

PET [FDG] 9 JME vs. 14Controls

↓ Performance on delayed visualmemory task and reduced uptake inDLPFC, premotor and basal frontalcortex in JME group

Suggestion ofhypometabolism/hypofunctionalityin frontal lobes of JME patientscompared with controls

Kim et al.(2005)

PET [FDG] andEEG

19 JME vs. 19Controls

↑ Thalamic FDG uptake in JMEgroup; correlation between FDGuptake and GSW in JME group

Evidence that thalamus has a keyrole in the generation of GSWactivity in JME

Meschaks et al.(2005)

PET [Serotonin1A receptorbinding]


↓ Serotonin receptor binding inraphe nuclei, hippocampus* andDLPFC in JME group

Serotonergic system may beinvolved in JME. Findings couldequally reflect local neuronalloss/dysfunction

Ciumas et al.(2008)

PET [Dopaminetransporterbinding]


↓ Dopamine transporter binding insubstantia nigra and midbrain,impaired psychomotor speed andimpaired motor function in JMEgroup

↓ Motor and psychomotorperformance in JME group may berelated to impaired dopaminesignalling to striatal and frontalbrain regions

Tae et al.(2007)

SPECT[Interictal ECD]


↓ rCBF in thalami, midbrain, ponsand left hippocampus* in JME group.Negative correlation betweenfrontal rCBF and disease duration

Findings suggest regions of reducedrCBF involved in JME and changesmay be progressive. Findings notattributed to effects of AEDs as allpatients drug naïve

Woermannet al. (1999b)

MRI [VBM] 20 JME vs. 30Controls

↑ In mesial frontal GMC in JMEgroup. Comparison of individualpatients to control group showedabnormalities in 25%

Subtle but significant focal frontalcortical abnormalities in JME thatmay represent localised alteredneuronal connectivity and/ororganisation

Tae et al.(2006)


↓ GMC in rostral corpus collosum,left hippocampus and bilateralprefrontal regions in JME group

Frontal lobe pathology may lead toatrophy of rostal corpus callosum inJME. Hippocampal findings mayreflect serotononergic dysfunctionor reduced rCBF*

Betting et al.(2006)

MRI [VBM] 44 JME vs. 47Controls (andother IGEgroups)

↑ GMC in frontobasal regions inJME; not seen in other IGE group orcontrols.↑ GMC in anterior thalamus in JMEpatients with absences

Frontal lobe structural changes inJME patients not seen incontrols/other IGE. Suggestion ofdifferences in those with vs. thosewithout absences in JME group

Kim et al.(2007a)


↑ GMC in superior mesial frontalarea and ↓ GMC in thalamus in JME.Negative correlation betweenthalamic GMC and disease durationin JME

Similar to Woermann et al., 1999b,suggesting mesial frontalabnormalities. Suggestion thatthere may be progressive thalamicneuronal loss with time in JME

Tae et al.(2008)

MRI [CorticalThickness]


↓ Cortical thickness in widespreadfrontotemporal regions in JMEgroup; negative correlation withdisease duration in some areas

Frontal lobe changes; suggestionthat VBM methodological problemsexplain inconsistencies in otherstudies; cortical thickness methodmore reliable

Lin et al.(2009b)


↑ GMV in superior, orbito and mesialfrontal regions in JME and ↓ GMV inbilateral occipital (visual) corticesin photosensitive patients only

First evidence of sub-phenotypedifferences in brain structure(‘ictogenic network’) betweenphotosensitive andnon-photosensitive JME patients

Deppe et al.(2008)

MRI [DTI] 10 JME vs. 67Controls (vs. 8Cryptogenic)

↓ FA in white matter ROI connectingmedial and anterior thalami toprefrontal lobes in JME; negativecorrelation with number of seizures

Evidence of abnormal frontalthalamocortical networks aspathophysiological substrate forJME and evidence of white matterinvolvement


Table 1 (Continued)

Study Modality Subjects Findings Conclusions

Roebling et al.(2009)

MRI [VBM] andfMRI


↓ Semantic and verbal fluency inJME group but no statisticallysignificant changes in either theVBM or fMRI between groups

Failed to reproduce findings fromother MRI studies in JME. Caution ininterpreting studies; suggestgenetic heterogeneity may liebehind variability in results

Savic et al.(2000)

MRS 15 JME vs. 10Controls

↓ In prefrontal NAA concentrationsin JME. No difference in otherregions or metabolites

↓ NAA levels in JME group mayrepresent neuronal loss ordysfunction in these areas

Mory et al.(2003)


More detailed assessment ofthalamus showed significant ↓ inNAA/Cr ratio in JME group

Greater spatial resolution thanSavic et al., suggestion of neuronalloss or dysfunction in thalamus

Haki et al.(2007)


↓ In absolute NAA value in leftthalamus in JME. NAA/Cr ratiodecreased bilaterally

Attempt to repeat Savic et al. withdifferent sequencing, showing adifference in thalamus of JME groupsuggesting neuronal loss ordysfunction

Lin et al.(2009a)


↑ Resolution and number of ROIthan other MRS studies. ↓ NAA/Crratio in mesial prefrontal andprimary motor cortex and thalamusin JME

Further evidence of frontalthalamocortical networks ofneuronal dysfunction or loss. MRIstudies suggest this more likelyreflects neuronal dysfunction

JME, juvenile myoclonic epilepsy; PET, positron emission topography; FDG, fluorodeoxyglucose; ↓, decreased; DLPFC, dorsolateral pre-frontal cortex; EEG, electroencephalography; ↑, increased; GSW, generalised spike wave; SPECT, single photon emission computedtopography; ECD, 99mTc-ethylcysteinate dimer; rCBF, regional cerebral blood flow; MRI, magnetic resonance imaging; VBM, voxel based

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morphometry; GMC, grey matter concentration; GMV, grey matterregion of interest; fMRI, functional MRI; MRS, magnetic resonance

* rCBF regional cerebral blood flow.

ascalicchio et al., 2007; Plattner et al., 2007; Iqbal et al.,009). Frontal lobe cognitive performance in JME has beenound to be similarly impaired to those with frontal lobepilepsy (Piazzini et al., 2008), and in the clinically moreeverely affected JME patients increased rates of personalityisorders have been found (de Araujo Filho et al., 2007).

Regionally distributed dystopic neurones, termedmicrodysgenesis’, are described in a small post-mortemistological series of IGE cases (Meencke and Janz, 1984).he significance of this report is disputed (Lyon and Gastaut,985) and further reports have not been forthcoming, asost-mortem studies in this group (with a non-terminalondition) are difficult to obtain.

dvanced neuroimaging — What is it?

dvanced neuroimaging refers to techniques used to objec-ively determine aspects of the brains structure, functionnd chemical composition, over and above visual inspec-ion of standard structural clinical brain scans. This typicallynvolves systematic comparison between individuals androups in the search for neurobiological mechanisms under-inning diseases of the nervous system. This is done withnumber of open source and commercial software pack-

ges employing signal processing and statistical methods,ith graphical displays and reconstructions of brain scansnd statistical maps. The advanced imaging modalities con-idered here are positron emission tomography (PET), singlehoton emission computed tomography (SPECT), structural

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me; DTI, diffusion tensor imaging; FA, fractional anisotropy; ROI,troscopy; NAA, N-acetyl aspartate; Cr, creatine phosphocreatine

RI (MRI), diffusion tensor imaging (DTI), functional MRIfMRI) and MR spectroscopy (MRS). Magnetoencephalogra-hy (MEG), because it is used to generate images overlaidnto MRI is included briefly for completeness.

ositron emission tomography

ET uses intravenous injection of radio-labelled ligandsollowed by detection of their positron decay in tissuey a tomographic camera, with resultant images basedn the physiological distribution of the ligand in brainissue. Imaging cerebral glucose metabolism with 18F-fluoro--deoxyglucose (FDG) is a standard clinical evaluation inocal epilepsy in many epilepsy surgery centres (la Fougeret al., 2009), with areas of glucose hypometabolism indicat-ng the epileptogenic zone.

Ligands that measure receptor density or neurotransmit-er and related enzyme activity hold greater promise in thetudy of the neurobiology underpinning epilepsy (Duncan,009). Early ligand PET studies using 11C-diprenorphine, anpioid agonist, found a reduction compared with controlsf 11C-diprenorphine binding in areas of association cor-ex at the time of absence seizures (Bartenstein et al.,993), thought to represent displacement by endogenous
pioids during absences. No differences in 11C-diprenorphineere seen between patients and controls in interictal
tudies (Prevett et al., 1994). Observation that serotoninntoxication can lead to myoclonus has led to the postu-ation that serotonergic systems may be involved in JME

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Understanding juvenile myoclonic epilepsy: Contributions fr

also. Carbonyl-11C-WAY-100635 PET measures serotonin 1Areceptor binding, in JME significant reduction in bindingin the raphe nuclei (where serotonergic neurones arise),hippocampus and dorsolateral pre-frontal cortex (DLPFC) isseen, representing either receptor down regulation due toincreased serotonergic activity, focal developmental abnor-malities, neuronal loss in these areas or receptor occupationby endogenous ligand (Meschaks et al., 2005). 11C-flumazanilPET, a benzodiazepine antagonist, maps GABAA receptordensity and has been shown to be globally increased in thecortex of IGE patients compared with controls, more so inthe frontal lobes of JME patients whilst not in other IGEsyndromes (Koepp, 2005).

More recently dopaminergic systems have also been sug-gested to have a role in JME. Twelve patients studied withthe dopamine transporter ligand 11C-PE2I showed significantreductions in binding in the midbrain and substantia nigracompared with controls (Ciumas et al., 2008). Reductionscorrelated with impaired psychomotor function suggestinga functionally significant impairment of dopamine transmis-sion.

FDG PET in JME patients has shown increased glucosemetabolism in bilateral thalami compared to controls, whichcorrelated with the amount of GSW on their EEG (Kim etal., 2005). Blood flow measured with H2

15O PET and con-current EEG showed regional thalamic increases during GSW(Prevett et al., 1995). Regional glucose hypometabolism wasalso seen in the DLPFC, premotor cortex and basal frontalcortex of 9 JME patients scanned immediately following avisual working memory paradigm when compared with 14controls (Swartz et al., 1996). Patients failed to show thenormal increased activity in these areas on PET followingthe delayed visual matching task, and performed worse onthe task, suggesting a clinically significant frontal cognitivedysfunction in JME. A similar study failed to show thesebetween-group FDG PET differences but did find a positivecorrelation between frontal lobe FDG uptake and perfor-mance on some frontal lobe (executive) tasks within thepatient group (McDonald et al., 2006).

In summary, the use of PET in studying JME has con-tributed evidence of increased thalamic metabolic activityduring GSW, and reduced metabolic activity in regionalfrontal networks. Neurotransmitter ligand studies showalterations in the opioid, serotonin and dopamine systemsin JME, with brainstem and basal ganglia involvement inaddition to the commonly implicated thalamo—cortical sys-tems. Other targets of PET ligands for example precursorsand intracellular synthetic pathways have potential but areyet to be explored in IGE (Yu, 2007).

Single photon emission computed tomography

SPECT images map cerebral blood flow, using detection of�-energy rays emitted by injected radiotracers, typicallyhexamethyl propylene-amine-oxime (99mTc-HMPAO) or ethylcysteinate dimer (99mTc-ECD). Images do not have the spa-
tial resolution of PET but unlike PET, the radiotracer remainsstable for some hours after injection making ictal stud-ies possible, primarily used in the pre-surgical setting forlocalising the epileptogenic zone (la Fougere et al., 2009).The logistics, and invasiveness (namely drug withdrawal to
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euroimaging 131

recipitate seizures in the absence of potential clinical ben-fit) of ictal studies limit their use in research imagingf JME. Furthermore, interictal SPECT studies in JME arecant.

An interictal ECD SPECT comparison of 19 drug naiveatients to 25 controls showed significantly reduced regionalerebral blood flow (rCBF) in bilateral thalami, brain stem,erebellum, left hippocampus, bilateral parahippocampalyri, both lingual and fusiform gyri and the left gyrus rec-us of frontal lobe (Tae et al., 2007). A negative correlationas been seen between disease duration and frontal lobend thalamic rCBF; the raphe nuclei showed reduced rCBFhich may be related to the serotonergic system involve-ent described in PET studies (Meschaks et al., 2005).

agnetic resonance imaging

RI sequences used in advanced imaging studies include highesolution structural MRI, diffusion MRI, fMRI and MRS. Struc-ural MRI involves novel and high resolution MRI sequencesith quantitative analysis to compare volumes, distributionsnd morphology of cortical and subcortical structures. Dif-usion MRI sequences give a measure of self-diffusivity ofater in tissue; this diffusion is hindered by cellular struc-

ures, most notably nerve fibre bundles, and in diffusionensor imaging (DTI) this property is used to make infer-nces on white matter directionality, micro-structure andonnectivity (Jones, 2008). Functional MRI (fMRI) utiliseshe differing magnetic properties of deoxygenated andxygenated haemoglobin to map haemodynamic changeselated to neural activity — the blood oxygen level depen-ant (BOLD) response. fMRI can be used to measure taskr stimulus related neural responses or in conjunction withEG (EEG-fMRI) to localise BOLD changes related to interic-al epileptiform discharges (Hamandi et al., 2004; Gotmant al., 2005). Magnetic resonance spectroscopy (MRS) givesnformation on the chemical composition of brain tissue byetecting resonance signals of metabolites.

tructural MRIarly use of MRI volumetry in focal epilepsies due to corti-al dysgenesis found structural abnormalities that extendedeyond those apparent on visual inspection of standard clin-cal MRI (Sisodiya et al., 1995). Woermann et al. used thisechnique in IGE patients (including JME) and comparedo controls found increased regional grey matter volumesGMV), though precise localisation was not feasible with theechnology available (Woermann et al., 1998). Voxel-basedorphometry (VBM) is a method for registration of images

n standard space and statistical voxel-by-voxel compari-on between individuals or groups (Ashburner and Friston,000); in 20 JME patients from this same cohort increases inrey matter localised to the mesial frontal lobes were seenompared to controls using the VBM method (Woermannt al., 1999a; Woermann et al., 1999b). A larger study in3 patients with IGE, 44 with JME, found increased grey
atter concentration (GMC) in the frontobasal regions of
ME patients that was not seen in the controls or otherGE groups (Fig. 1) (Betting et al., 2006); no changes wereeen in the mesial frontal regions reported by Woermannt al. JME patients with absences also had increased GMC


Figure 1 Results of the voxel-based morphometry analysis comparing patients with JME (A) and absence epilepsy (B) versus 47healthy controls, showing areas of increased GMC located in the frontobasal (A) and superior mesiofrontal regions (B). Panel C showsa region of interest comparison between patients with absence seizures (23 JME and 24 AE) and controls, showing areas of increasedGMC mainly at the anterior portion of both thalami. The results of these comparisons are displayed as a statistic parametric mapof the t statistic (SPM(t)). This figure illustrates the results superimposed in multislice axial T1 template images of a normal brain.T parea ate).w

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n the anterior thalamus, whereas those without did not.further study of 25 JME patients found increased GMC in

redominantly medial frontal regions and showed a nega-ive correlation between disease duration and thalamic GMCKim et al., 2007a). Similar results have been seen in chil-ren with recently diagnosed JME suggesting abnormalitiesre present early on in the disease (Pulsipher et al., 2009).educed GMC in multiple pre-frontal regions have beeneported in a further study of 19 JME patients comparedo controls using VBM (Tae et al., 2006). Atrophy of the ros-rum of the corpus callosum was also found, and postulatedo be linked to the prefrontal volume loss given their exten-ive connections. The cortical areas involved were closelyelated to those seen in the groups SPECT study (Tae et al.,
007). The most recent VBM based MRI study has revealedncreased GMV in right superior frontal, orbitofrontal andedial frontal gyri. There were also decreases in GMV
n bilateral thalami, insular cortices and cerebellar hemi-

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d to controls (z score). The level of significance selected wasReprinted from Neuroimage, Betting et al., Copyright (2006),

pheres. An important additional finding was that of reducedMV in the occipital (visual) cortices of those JME patientsith photosensitivity, not seen in those without (Lin et al.,009b). In JME cases with focal epileptiform discharges sub-le grey matter abnormalities are reported co-localising withhe EEG dipole locations (Betting et al., 2010). An alterna-ive methodological approach to VBM has been to measureortical thickness (Hutton et al., 2008; Hutton et al., 2009),hich has shown reduced thickness of superior, middle andedial frontal gyri as well as superior, middle and inferior

emporal gyri in 19 JME patients compared to controls (Taet al., 2008).

Overall frontal lobe changes are seen in JME comparedo controls, affecting superior mesial and orbito-frontal
reas. The imaging metrics used in structural MRI scans (grayatter volumes, gray matter concentration, cortical thick-
ess) vary between studies. Results can be confusing withncreases in gray matter measurements in some studies and

om neuroimaging 133

Figure 2 EEG-fMRI of GSW group analysis of 17 patients withIGE. A box-car model based in the occurrence of visually iden-tified spike wave activity on the simultaneously recorded EEGduring fMRI scanning, convolved with a haemodynamic responsefunction was used to model the fMRI data. Areas of significant(p < 0.001 uncorrected) BOLD signal increase or ‘‘activation’’(shown in red) are seen in thalamus and BOLD signal decreaseor ‘‘deactivation’’ (shown in green) are seen in bilateral pos-terior parietal areas and the precuneus; areas of associationcortex sometimes referred to as the ‘default mode’ network.A

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decreases in others. The rapidly evolving nature of the anal-ysis methods employed makes comparing studies over a 10year period difficult. VBM studies may not for example takeinto account the effect of cortical folding or opposing gyri ina way that cortical thickness measures might. Furthermoresmall sample size and phenotypic heterogeneity complicatecomparisons. Whilst frontal lobe changes predominate find-ings in other regions like those found in occipital corticesshould not be ignored (Lin et al., 2009b).

Diffusion tensor imagingDTI gives the fractional anisotropy (FA), a measure of direc-tionality of water diffusion and mean diffusivity (MD), ameasure of the degree of hindrance to water diffusion bycellular structures. Statistical algorithms can ‘trace’ the dif-fusion directionality between voxels to infer white mattertracts — giving us MRI tractography. One study using DTI inJME has been published to date. Statistical comparison usingvoxel-based analysis of FA values, rather than tractography,showed significantly reduced FA bilaterally in the anteriorlimb of the internal capsule of 10 JME patients. These whitematter regions contain the anterior radiations of the thala-mus that connect the medial and anterior thalamic nucleito the prefrontal cortex (Deppe et al., 2008). The findingswere not seen in the cohort of patients with cryptogenicpartial epilepsy (8) or controls (67) concurrently studied.The authors conclude this reflects reduced ‘white matterintegrity’ in fronto—thalamic connections, but clearly withonly one small and limited DTI study this is a key area forfurther research. A further recent study reports altered con-nectivity, as indexed by reduced FA and increased MD tothe supplementary motor area in JME but not patients withfrontal lobe epilepsy, when compared to matched controls(Vulliemoz et al., 2010).

Functional MRISimultaneous EEG-fMRI has been applied to the study ofGSW activity. Similar findings across several centres are ofthalamic activation and widespread deactivation of associ-ation cortex, the so called ‘default mode’ networks (Fig. 2)(Archer et al., 2003; Aghakhani et al., 2004; Gotman et al.,2005; Hamandi et al., 2006; Laufs et al., 2007). These mayrepresent downstream consequences of GSW, and to datelimitations on the temporal resolution of fMRI have failedto detect putative areas of origin of spike wave activity.It is notable that the posterior cingulate deactivation mir-rors the decreased opioid PET binding related to absenceseizures seen by Bartenstein et al. (Bartenstein et al., 1993).Specific differences in GSW related fMRI responses were notseen between IGE sub-syndromes or secondary generalisedepilepsies (Hamandi et al., 2006). More recent EEG-fMRI ofGSW have elegantly shown the time course and evolutionof GSW related BOLD changes, with initially mesial frontaland thalamic ‘‘activations’’ occurring up to several sec-onds before EEG spike wave activity, followed by widespread‘‘deactivations’’ affecting frontal, parietal and cingulate
areas, (areas of association cortex). More recent EEG-fMRIof GSW have elegantly shown the time course and evolutionof GSW related BOLD changes (Bai et al., 2010) and individ-ual with patient specific ‘signatures’ of GSW related BOLDpatterns (Moeller et al., 2010).
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dapted from Hamandi et al., 2006.

Recently combined structural and functional MRI witheuropsychological testing in 19 JME patients foundecreased semantic and verbal fluency but did not find anytatistically significant structural or functional imaging dif-erences as seen in other studies (Roebling et al., 2009). Theuthors conclude that conflicting study results may reflecthe well recognised genetic heterogeneity of JME, althought may also reflect the ability of their fMRI task to discrim-nate differences, the relatively small sample sizes or thetatistical power of the studies to date.

In summary fMRI studies show predominantly deacti-ation of association cortex networks during GSW. Thesetudies have focused more commonly on GSW in absencepilepsy rather than JME because of the relative frequencyf GSW former. Frontal lobe activations are seen in someases and the significance of these remains to be seen. Toate there have been strikingly few cognitive or task related
MRI studies in JME, particularly in comparison to the vastiterature in healthy volunteers and other disease states.

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agnetic resonance spectroscopyRS gives information on the chemical composition of brain

issue by detecting resonance signals of metabolites includ-ng N-acetyl aspartate (NAA), creatine plus phosphocreatineCr), choline containing compounds (Cho) and lactate (Lac).AA is synthesised in mitochondria and is highly specific toeural tissue. Where cell loss or dysfunction occurs it under-oes enzymatic degradation. Cr on the other hand remainstable, even in disease states, and so the absolute NAA sig-al or the NAA/Cr ratio is often used as a marker of focaleuronal loss or dysfunction, with the use of NAA/Cr ratioimed at reducing differences in values between individuals.

Building on then recent PET evidence of frontal lobeathology in JME (Swartz et al., 1996), 15 JME patients weretudied and compared to controls and showed decreasedAA signals in prefrontal cortex but not other regions of

nterest (ROI), including the thalamus, or other metabo-ites (Savic et al., 2000). This might represent local neuronaloss/dysfunction and extension of the study to include otherGE syndromes showed normal NAA signals suggesting therontal lobe findings were specific to JME (Savic et al., 2004).ubsequent more focussed MRS of the thalamus in 10 JMEatients showed reduced NAA/Cr signal ratio in the patientroup (Mory et al., 2003), which further supports the notionf thalamic involvement in the disease, and in particularay correlate to structural MRI evidence of progressive tha-

amic volume loss (Betting et al., 2006; Kim et al., 2007a; Taet al., 2007; Deppe et al., 2008). The previous lack of suchndings (Savic et al., 2000) has been attributed to inferiorost-processing techniques (Haki et al., 2007).

A multi-voxel MRS study of 60 JME patients showededuced NAA/Cr signals in medial frontal lobes and thalamushat negatively correlated with age and disease duration (Lint al., 2009a). Also the degree of NAA/Cr signal decreasend therefore supposed neuronal dysfunction in JME haseen correlated to personality traits to suggest that thoseith the greatest degree of neuronal dysfunction have more

evere epilepsy and more significant personality disordersde Araujo Filho et al., 2009).

MRS findings support thalamo-frontal cortical hypothesesf JME from an in vivo functional level. Acquisition and postrocessing methods continue to improve and offer promisen larger studies of elucidating correlates of JME diseasetates and heterogeneity.

agnetoencephalography

agnetoencephalography (MEG) is not strictly speaking anmaging but rather a neurophysiological technique. It isncluded here for completeness because it is used to cre-te images that allow visual inferences of brain functionn the same way as fMRI. MEG utilises superconductinguantum interference devices (SQUIDS) placed outside thekull to detect the miniscule magnetic fields from the brainStufflebeam et al., 2009). Two small case studies have beenublished to date using MEG to study JME. The first, a study
f source localisation of spike-wave discharges in 2 JMEatients found dipolar sources of MEG paroxysmal activityn cerebellar regions in both patients (Kotini et al., 2010),his finding is unusual and need replication but bears rela-ion to reduced rCBF in the same areas in SPECT studies (Tae
dogyi

J. Anderson, K. Hamandi

t al., 2007; Joo et al., 2008). The second study of seven IGE2 JME) patients found paroxysmal MEG activity in frontalegions in all patients, with a specific central and pre-motoristribution in the JME patients (Stefan et al., 2009), moren line with EEG studies (Holmes et al., 2010).

MEG has been predominantly used in the study ofre-surgical focal epilepsy, but new analysis methods, inarticular with beamformer techniques (Singh et al., 2003)pen up possibilities of functional task related studies akino fMRI with the advantage of being a more direct mea-ure of neural function and having a much greater temporalesolution, down to the millisecond scale.

onclusions

dvanced neuroimaging shows evidence of predominantlyrontal lobe changes/dysfunction in JME. This is consis-ent with the frontal predominance of EEG abnormalities,europsychological profiles and neuro-pathological reports.tructural and biochemical changes are also reported in tha-amic and brain stem structures in JME. Both frontal lobend thalamic structures are involved in GSW EEG dischargend seizure propagation and whilst identifying the area ofeizure onset is important, this could vary between patientsnd even within patients at different times. Advanced brainmaging has the potential to shed more light on multiregionalnd network changes underpinning JME.

A reclassification of JME from a generalised epilepsy tofrontal lobe variant of a multi-regional, thalamocortical

network’ epilepsy has been suggested (Blumenfeld, 2003;lumenfeld, 2005; Koepp, 2005). The recent revision fromhe International League Against Epilepsy Commission onlassification and Terminology proposes ‘‘such findings willncourage a change in the notion of a ‘generalised’ epilepsyo that of a disorder arising from a bilaterally distributedetwork that needn’t involve the whole cortex’’ (Berg et al.,010).

Advanced neuroimaging studies in JME, and epilepsy ineneral, to date have suffered similar limitations in theirmall sample sizes, selection difficulties and variable anal-sis methods. This has led to often conflicting results ands particularly problematic given that JME is a biologicallyomplex and heterogeneous disorder. Evidence from furthermaging studies will inform this debate further, and shouldnclude improved attempts to replicate/confirm existingtudy findings in addition to developing new study designs.uture studies need to tackle issues of a priori sample sizend the statistical power of neuro-imaging methods. Largertudies are needed to address the biological variability,ikely underlying genetic heterogeneity, and signal-to-noiseatio of imaging measures. The aim of such studies wouldnclude correlation of clinical phenotypes to imaging met-ics, and to bridge the gap between genotype and phenotypen newly discovered mutations causing epilepsy (Siniatchkinnd Koepp, 2009). Opportunities include multimodal stud-es of JME patients with identified mutations, to look for
iscriminating imaging metrics in an attempt to separateut neuroimaging endo-phenotypes. Little is known of theenetic status of most patients included in existing studies,et this information is likely to be sought in future stud-es. Drug responsiveness, seizure severity and frequency,

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predominant seizure types are all examples of factors thatcan and need to be correlated with future imaging studiesto better understand disease pathophysiology. Studying thecorrelates of neuroimaging abnormalities to anti-epilepticdrug treatment response might shed light on the strikingdifferences in drug efficacy in JME (Nicolson and Marson,2010), and moreover, advanced imaging methods might beused in assessing the mechanisms of action and efficacy ofnew drugs, and predicting outcome of drug withdrawal.

References

Aghakhani, Y., Bagshaw, A.P., Benar, C.G., Hawco, C., Andermann,F., Dubeau, F., et al., 2004. fMRI activation during spike and wavedischarges in idiopathic generalized epilepsy. Brain 127 (May (Pt5)), 1127—1144.

Aliberti, V., Grunewald, R.A., Panayiotopoulos, C.P., Chroni, E.,1994. Focal electroencephalographic abnormalities in juvenilemyoclonic epilepsy. Epilepsia 35 (March—April (2)), 297—301.

Appleton, R., Beirne, M., Acomb, B., 2000. Photosensitivity in juve-nile myoclonic epilepsy. Seizure 9 (March (2)), 108—111.

Archer, J.S., Abbott, D.F., Waites, A.B., Jackson, G.D., 2003.fMRI ‘‘deactivation’’ of the posterior cingulate during gener-alized spike and wave. Neuroimage 20 (December (4)), 1915—1922.

Ashburner, J., Friston, K.J., 2000. Voxel-based morphometry—Themethods. Neuroimage 11 (June (6 Pt 1)), 805—821.

Bai, X., Vestal, M., Berman, R., Negishi, M., Spann, M., Vega, C.,et al., 2010. Dynamic time course of typical childhood absenceseizures: EEG, behavior, and functional magnetic resonanceimaging. J. Neurosci. 30 (April (17)), 5884—5893.

Bartenstein, P.A., Duncan, J.S., Prevett, M.C., Cunningham, V.J.,Fish, D.R., Jones, A.K., et al., 1993. Investigation of theopioid system in absence seizures with positron emission tomog-raphy. J. Neurol. Neurosurg. Psychiatry 56 (December (12)),1295—1302.

Berg, A.T., Berkovic, S.F., Brodie, M.J., Buchhalter, J., Cross, J.H.,van Emde Boas, W., et al., 2010. Revised terminology and con-cepts for organization of seizures and epilepsies: report of theILAE Commission on Classification and Terminology, 2005—2009.Epilepsia 51 (April (4)), 676—685.

Betting, L.E., Mory, S.B., Li, L.M., Lopes-Cendes, I., Guerreiro,M.M., Guerreiro, C.A., et al., 2006. Voxel-based morphometryin patients with idiopathic generalized epilepsies. Neuroimage32 (August (2)), 498—502.

Betting, L.E., Li, L.M., Lopes-Cendes, I., Guerreiro, M.M., Guer-reiro, C.A., Cendes, F., 2010. Correlation between quantitativeEEG and MRI in idiopathic generalized epilepsy. Hum. BrainMapp. 31 (January (9)), 1327—1338.

Blumenfeld, H., 2003. From molecules to networks: corti-cal/subcortical interactions in the pathophysiology of idiopathicgeneralized epilepsy. Epilepsia 44 (Suppl 2), 7—15.

Blumenfeld, H., 2005. Cellular and network mechanisms of spike-wave seizures. Epilepsia 46 (Suppl 9), 21—33.

Calleja, S., Salas-Puig, J., Ribacoba, R., Lahoz, C.H., 2001. Evolu-tion of juvenile myoclonic epilepsy treated from the outset withsodium valproate. Seizure 10 (September (6)), 424—427.

Camfield, C.S., Camfield, P.R., 2009. Juvenile myoclonic epilepsy 25years after seizure onset: a population-based study. Neurology73 (September (13)), 1041—1045.

Ciumas, C., Wahlin, T.B., Jucaite, A., Lindstrom, P., Halldin,
C., Savic, I., 2008. Reduced dopamine transporter bindingin patients with juvenile myoclonic epilepsy. Neurology 71(September (11)), 788—794.
Cossette, P., Liu, L., Brisebois, K., Dong, H., Lortie, A., Vanasse,M., et al., 2002. Mutation of GABRA1 in an autosomal dominant

J

euroimaging 135

form of juvenile myoclonic epilepsy. Nat. Genet. 31 (June (2)),184—189.

e Araujo Filho, G.M., Pascalicchio, T.F., Sousa Pda, S., Lin, K.,Ferreira Guilhoto, L.M., Yacubian, E.M., 2007. Psychiatric dis-orders in juvenile myoclonic epilepsy: a controlled study of 100patients. Epilepsy Behav. 10 (May (3)), 437—441.

e Araujo Filho, G.M., Lin, K., Lin, J., Peruchi, M.M., Caboclo, L.O.,Guaranha, M.S., et al., 2009. Are personality traits of juvenilemyoclonic epilepsy related to frontal lobe dysfunctions? A protonMRS study. Epilepsia 50 (May (5)), 1201—1209.

elgado-Escueta, A.V., Enrile-Bacsal, F., 1984. Juvenile myoclonicepilepsy of Janz. Neurology 34 (March (3)), 285—294.

eppe, M., Kellinghaus, C., Duning, T., Moddel, G., Mohammadi, S.,Deppe, K., et al., 2008. Nerve fiber impairment of anterior tha-lamocortical circuitry in juvenile myoclonic epilepsy. Neurology71 (December (24)), 1981—1985.

uncan, J., 2009. The current status of neuroimaging for epilepsy.Curr. Opin. Neurol. 22 (April (2)), 179—184.

scayg, A., De Waard, M., Lee, D.D., Bichet, D., Wolf, P., Mayer,T., et al., 2000. Coding and noncoding variation of the humancalcium-channel beta4-subunit gene CACNB4 in patients withidiopathic generalized epilepsy and episodic ataxia. Am. J. Hum.Genet. 66 (May (5)), 1531—1539.

otman, J., Grova, C., Bagshaw, A., Kobayashi, E., Aghakhani, Y.,Dubeau, F., 2005. Generalized epileptic discharges show tha-lamocortical activation and suspension of the default state ofthe brain. Proc. Natl. Acad. Sci. U.S.A. 102 (October (42)),15236—15240.

aki, C., Gumustas, O.G., Bora, I., Gumustas, A.U., Parlak, M.,2007. Proton magnetic resonance spectroscopy study of bilat-eral thalamus in juvenile myoclonic epilepsy. Seizure 16 (June(4)), 287—295.

amandi, K., Salek-Haddadi, A., Fish, D.R., Lemieux, L., 2004.EEG/functional MRI in epilepsy: the Queen Square Experience.J. Clin. Neurophysiol. 21 (July—August (4)), 241—248.

amandi, K., Salek-Haddadi, A., Laufs, H., Liston, A., Friston,K., Fish, D.R., et al., 2006. EEG-fMRI of idiopathic and secon-darily generalized epilepsies. Neuroimage 31 (July (4)), 1700—1710.

erpin, T., 1867. Des accès incomplets d’épilepsie. Baillière, Paris.olmes, M.D., Quiring, J., Tucker, D.M., 2010. Evidence that

juvenile myoclonic epilepsy is a disorder of frontotempo-ral corticothalamic networks. Neuroimage 49 (January (1)),80—93.

utton, C., De Vita, E., Ashburner, J., Deichmann, R., Turner, R.,2008. Voxel-based cortical thickness measurements in MRI. Neu-roimage 40 (May (4)), 1701—1710.

utton, C., Draganski, B., Ashburner, J., Weiskopf, N., 2009. A com-parison between voxel-based cortical thickness and voxel-basedmorphometry in normal aging. Neuroimage 48 (November (2)),371—380.

LAE, 1989. Proposal for revised classification of epilepsies andepileptic syndromes. Commission on Classification and Termi-nology of the International League Against Epilepsy. Epilepsia 30(July—August (4)), 389—399.

qbal, N., Caswell, H.L., Hare, D.J., Pilkington, O., Mercer, S.,Duncan, S., 2009. Neuropsychological profiles of patients withjuvenile myoclonic epilepsy and their siblings: a preliminary con-trolled experimental video-EEG case series. Epilepsy Behav. 14(March (3)), 516—521.

anz, D., Christian, W., 1957. Impulsiv- petit mal. DeutscheZeitschrift für Nervenheilkunde 176, 346—386.

ayalakshmi, S.S., Srinivasa Rao, B., Sailaja, S., 2010. Focal clinical
and electroencephalographic features in patients with juvenilemyoclonic epilepsy. Acta Neurol. Scand 122 (October), 115—123.
ones, D.K., 2008. Studying connections in the living humanbrain with diffusion MRI. Cortex 44 (September (8)),936—952.

1

J

K

K

K

K

K

K

l

L

L

L

L

L

M

M

M

M

M

M

M

N

P

P

P

P

P

P

P

P

P

P

R

R

S

S

S

S

S

36

oo, E.Y., Tae, W.S., Hong, S.B., 2008. Cerebral blood flow abnor-mality in patients with idiopathic generalized epilepsy. J.Neurol. 255 (April (4)), 520—525.

im, J.H., Im, K.C., Kim, J.S., Lee, S.A., Kang, J.K., 2005. Correla-tion of interictal spike-wave with thalamic glucose metabolismin juvenile myoclonic epilepsy. Neuroreport 16 (August (11)),1151—1155.

im, J.H., Lee, J.K., Koh, S.B., Lee, S.A., Lee, J.M., Kim, S.I.,et al., 2007a. Regional grey matter abnormalities in juvenilemyoclonic epilepsy: a voxel-based morphometry study. Neuroim-age 37 (October (4)), 1132—1137.

im, S.Y., Hwang, Y.H., Lee, H.W., Suh, C.K., Kwon, S.H., Park, S.P.,2007b. Cognitive impairment in juvenile myoclonic epilepsy. J.Clin. Neurol. 3 (June (2)), 86—92.

obayashi, E., Zifkin, B.G., Andermann, F., Andermann, E., 2008.Juvenile Myoclonic Epilepsy. In: Engel, J., Pedley, T.A. (Eds.),Epilepsy: A Comprehensive Textbook. , Second Edition. Lippin-cott Williams & Wilkins, Philidelphia, pp. 2455—2460.

oepp, M.J., 2005. Juvenile myoclonic epilepsy — A generalizedepilepsy syndrome? Acta Neurol. Scand. Suppl. 181, 57—62.

otini, A., Mavraki, E., Anninos, P., Piperidou, H., Prassopoulos, P.,2010. Magnetoencephalographic findings in two cases of juvenilemyoclonus epilepsy. Brain Topogr. 23 (March (1)), 41—45.

a Fougere, C., Rominger, A., Forster, S., Geisler, J., Bartenstein,P., 2009. PET and SPECT in epilepsy: a critical review. EpilepsyBehav. 15 (May (1)), 50—55.

aufs, H., Hamandi, K., Salek-Haddadi, A., Kleinschmidt, A.K., Dun-can, J.S., Lemieux, L., 2007. Temporal lobe interictal epilepticdischarges affect cerebral activity in ‘‘default mode’’ brainregions. Hum. Brain Mapp. 28 (October (10)), 1023—1032.

in, K., Carrete Jr., H., Lin, J., Peruchi, M.M., de Araujo Filho, G.M.,Guaranha, M.S., et al., 2009a. Magnetic resonance spectroscopyreveals an epileptic network in juvenile myoclonic epilepsy.Epilepsia 50 (May (5)), 1191—1200.

in, K., Jackowski, A.P., Carrete Jr., H., de Araujo Filho, G.M., Silva,H.H., Guaranha, M.S., et al., 2009b. Voxel-based morphometryevaluation of patients with photosensitive juvenile myoclonicepilepsy. Epilepsy Res. 86 (October (2—3)), 138—145.

u, Y., Wang, X., 2009. Genes associated with idiopathic epilep-sies: a current overview. Neurol. Res. 31 (March (2)), 135—143.

yon, G., Gastaut, H., 1985. Considerations on the significanceattributed to unusual cerebral histological findings recentlydescribed in eight patients with primary generalized epilepsy.Epilepsia 26 (July—August (4)), 365—367.

artinez-Juarez, I.E., Alonso, M.E., Medina, M.T., Duron, R.M.,Bailey, J.N., Lopez-Ruiz, M., et al., 2006. Juvenile myoclonicepilepsy subsyndromes: family studies and long-term follow-up.Brain 129 (May (Pt 5)), 1269—1280.

cDonald, C.R., Swartz, B.E., Halgren, E., Patell, A., Daimes,R., Mandelkern, M., 2006. The relationship of regional frontalhypometabolism to executive function: a resting fluorodeoxyglu-cose PET study of patients with epilepsy and healthy controls.Epilepsy Behav. 9 (August (1)), 58—67.

eencke, H.J., Janz, D., 1984. Neuropathological findings in pri-mary generalized epilepsy: a study of eight cases. Epilepsia 25(February (1)), 8—21.

eschaks, A., Lindstrom, P., Halldin, C., Farde, L., Savic, I.,2005. Regional reductions in serotonin 1A receptor bindingin juvenile myoclonic epilepsy. Arch. Neurol. 62 (June (6)),946—950.

oeller, F., LeVan, P., Muhle, H., Stephani, U., Dubeau, F., Sini-atchkin, M., et al., 2010. Absence seizures: individual patterns
revealed by EEG-fMRI. Epilepsia 51 (October (10)), 2000—2010.
ontalenti, E., Imperiale, D., Rovera, A., Bergamasco, B., Benna,P., 2001. Clinical features, EEG findings and diagnostic pitfalls injuvenile myoclonic epilepsy: a series of 63 patients. J. Neurol.Sci. 184 (February (1)), 65—70.

S

J. Anderson, K. Hamandi

ory, S.B., Li, L.M., Guerreiro, C.A., Cendes, F., 2003. Thalamicdysfunction in juvenile myoclonic epilepsy: a proton MRS study.Epilepsia 44 (November (11)), 1402—1405.

icolson, A., Marson, A.G., 2010. When the first antiepileptic drugfails in a patient with juvenile myoclonic epilepsy. Pract. Neurol.10 (August (4)), 208—218.

anayiotopoulos, C.P., Tahan, R., Obeid, T., 1991. Juvenilemyoclonic epilepsy: factors of error involved in the diagnosis andtreatment. Epilepsia 32 (September—October (5)), 672—676.

anayiotopoulos, C.P., Obeid, T., Tahan, A.R., 1994. Juvenilemyoclonic epilepsy: a 5-year prospective study. Epilepsia 35(March—April (2)), 285—296.

ascalicchio, T.F., de Araujo Filho, G.M., da Silva Noffs, M.H., Lin,K., Caboclo, L.O., Vidal-Dourado, M., et al., 2007. Neuropsy-chological profile of patients with juvenile myoclonic epilepsy:a controlled study of 50 patients. Epilepsy Behav. 10 (March (2)),263—267.

earce, J.M., 2005. Theodore Herpin: neglected contributions in theunderstanding of epilepsy. Eur. Neurol. 54 (3), 135—139.

edersen, S.B., Petersen, K.A., 1998. Juvenile myoclonic epilepsy:clinical and EEG features. Acta Neurol. Scand. 97 (March (3)),160—163.

iazzini, A., Turner, K., Vignoli, A., Canger, R., Canevini, M.P., 2008.Frontal cognitive dysfunction in juvenile myoclonic epilepsy.Epilepsia 49 (April (4)), 657—662.

lattner, B., Pahs, G., Kindler, J., Williams, R.P., Hall, R.E., Mayer,H., et al., 2007. Juvenile myoclonic epilepsy: a benign disorder?Personality traits and psychiatric symptoms. Epilepsy Behav. 10(June (4)), 560—564.

revett, M.C., Cunningham, V.J., Brooks, D.J., Fish, D.R., Duncan,J.S., 1994. Opiate receptors in idiopathic generalised epilepsymeasured with [11C]diprenorphine and positron emission tomog-raphy. Epilepsy Res. 19 (September (1)), 71—77.

revett, M.C., Duncan, J.S., Jones, T., Fish, D.R., Brooks, D.J.,1995. Demonstration of thalamic activation during typicalabsence seizures using H2

(15)O and PET. Neurology 45 (July (7)),1396—1402.

ulsipher, D.T., Seidenberg, M., Guidotti, L., Tuchscherer, V.N.,Morton, J., Sheth, R.D., et al., 2009. Thalamofrontal circuitryand executive dysfunction in recent-onset juvenile myoclonicepilepsy. Epilepsia 50 (May (5)), 1210—1219.

enganathan, R., Delanty, N., 2003. Juvenile myoclonic epilepsy:under-appreciated and under-diagnosed. Postgrad. Med. J. 79(February (928)), 78—80.

oebling, R., Scheerer, N., Uttner, I., Gruber, O., Kraft, E., Lerche,H., 2009. Evaluation of cognition, structural, and functional MRIin juvenile myoclonic epilepsy. Epilepsia 50 (November (11)),2456—2465.

avic, I., Lekvall, A., Greitz, D., Helms, G., 2000. MR spectroscopyshows reduced frontal lobe concentrations of N-acetyl aspartatein patients with juvenile myoclonic epilepsy. Epilepsia 41 (March(3)), 290—296.

avic, I., Osterman, Y., Helms, G., 2004. MRS shows syndrome differ-entiated metabolite changes in human-generalized epilepsies.Neuroimage 21 (January (1)), 163—172.

ingh, K.D., Barnes, G.R., Hillebrand, A., 2003. Group imagingof task-related changes in cortical synchronisation using non-parametric permutation testing. Neuroimage 19 (August (4)),1589—1601.

iniatchkin, M., Koepp, M., 2009. Neuroimaging and neurogenet-ics of epilepsy in humans. Neuroscience 164 (November (1)),164—173.

isodiya, S.M., Free, S.L., Stevens, J.M., Fish, D.R., Shorvon, S.D.,
1995. Widespread cerebral structural changes in patients withcortical dysgenesis and epilepsy. Brain 118 (August (Pt 4)),1039—1050.
tefan, H., Paulini-Ruf, A., Hopfengartner, R., Rampp, S., 2009.Network characteristics of idiopathic generalized epilepsies in

om n

V

W

W

W

Y


combined MEG/EEG. Epilepsy Res. 85 (August (2—3)), 187—198.

Stufflebeam, S.M., Tanaka, N., Ahlfors, S.P., 2009. Clinical applica-tions of magnetoencephalography. Hum. Brain Mapp. 30 (June(6)), 1813—1823.

Suzuki, T., Delgado-Escueta, A.V., Aguan, K., Alonso, M.E.,Shi, J., Hara, Y., et al., 2004. Mutations in EFHC1 causejuvenile myoclonic epilepsy. Nat. Genet. 36 (August (8)),842—849.

Swartz, B.E., Simpkins, F., Halgren, E., Mandelkern, M., Brown, C.,Krisdakumtorn, T., et al., 1996. Visual working memory in pri-mary generalized epilepsy: an 18FDG-PET study. Neurology 47(November (5)), 1203—1212.

Tae, W.S., Hong, S.B., Joo, E.Y., Han, S.J., Cho, J.W., Seo, D.W.,et al., 2006. Structural brain abnormalities in juvenile myoclonicepilepsy patients: volumetry and voxel-based morphometry.Korean J. Radiol. 7 (July—September (3)), 162—172.

Tae, W.S., Joo, E.Y., Han, S.J., Lee, K.H., Hong, S.B., 2007. CBF
changes in drug naive juvenile myoclonic epilepsy patients. J.Neurol. 254 (August (8)), 1073—1080.
Tae, W.S., Kim, S.H., Joo, E.Y., Han, S.J., Kim, I.Y., Kim, S.I.,et al., 2008. Cortical thickness abnormality in juvenile myoclonicepilepsy. J. Neurol. 255 (April (4)), 561—566.

Z

euroimaging 137

ulliemoz, S., Vollmar, C., Koepp, M.J., Yogarajah, M.,O’Muircheartaigh, J., Carmichael, D.W., et al., 2010. Connec-tivity of the supplementary motor area in juvenile myoclonicepilepsy and frontal lobe epilepsy. Epilepsia (November).

oermann, F.G., Sisodiya, S.M., Free, S.L., Duncan, J.S., 1998.Quantitative MRI in patients with idiopathic generalizedepilepsy, Evidence of widespread cerebral structural changes.Brain 121 (September), 1661—1667.

oermann, F.G., Free, S.L., Koepp, M.J., Ashburner, J., Duncan,J.S., 1999a. Voxel-by-voxel comparison of automatically seg-mented cerebral gray matter—A rater-independent comparisonof structural MRI in patients with epilepsy. Neuroimage 10 (Octo-ber (4)), 373—384.

oermann, F.G., Free, S.L., Koepp, M.J., Sisodiya, S.M., Duncan,J.S., 1999b. Abnormal cerebral structure in juvenile myoclonicepilepsy demonstrated with voxel-based analysis of MRI. Brain122 (November), 2101—2108.

u, M., 2007. Recent developments of the PET imaging agents for
metabotropic glutamate receptor subtype 5. Curr. Top. Med.Chem. 7 (18), 1800—1805.
ifkin, B., Andermann, E., Andermann, F., 2005. Mechanisms, genet-ics, and pathogenesis of juvenile myoclonic epilepsy. Curr. Opin.Neurol. 18 (April (2)), 147—153.

understanding juvenile myoclonic epilepsy: contributions from neuroimaging

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