Focal abnormalities in idiopathic generalized epilepsy: a critical review of the literature

Focal abnormalities in idiopathic generalized epilepsy: A

critical review of the literature*†Udaya Seneviratne, *Mark Cook, and *Wendyl D’Souza

Epilepsia, **(*):1–13, 2014doi: 10.1111/epi.12688

Dr. UdayaSeneviratne is aConsultantNeurologist andEpileptologist atMonashMedicalCentre and St.Vincent’s Hospital,Melbourne,Australia.

SUMMARY

Conventionally, epilepsy is dichotomized into distinct “focal” and “generalized” cate-

gories. However, many studies have reported so-called focal features among patients

with idiopathic generalized epilepsy (IGE) in the domains of semiology, electroenceph-

alography, neuropsychology, neuropathology, and neuroimaging.We sought to review

such features and clinical implications. A Web of Science database search was con-

ducted to identify relevant publications. Our search yielded 145 papers describing focal

features involving different domains in IGE, with 117 papers analyzed after excluding

abstracts and case reports. Focal semiologic features are commonly seen in IGE.

There are conflicting data from studies in the domains of electroencephalography,

neuroimaging, and neuropathology. Studies on neuropsychology are suggestive of

frontal lobe functional deficits in juvenile myoclonic epilepsy. Most advanced neuroi-

maging studies demonstrate the involvement of both the thalamus and the cortex dur-

ing generalized spike-wave discharges (GSWDs). A few electroencephalographic and

neuroimaging studies indicate that the cortex precedes the thalamus at the onset of

GSWD. Focal features may contribute to misdiagnosis of IGE as focal epilepsy. How-

ever there aremethodologic limitations in the studies that affect the results.

KEY WORDS: Electroencephalographic, Epilepsy semiology, Generalized seizures,

Partial seizures, Neuroimaging, Neuropsychology.

Idiopathic generalized epilepsy (IGE; genetic general-ized epilepsy) constitutes a rubric of several electroclinicalsyndromes based on specific clinical features and electro-encephalography (EEG) abnormalities.1,2 The traditionalapproach of classifying epilepsies into “focal” and “gener-alized” implies there can be no “focal” features in “gener-alized” epilepsies. However, there has been a gradualparadigm shift in the conceptualization of seizure genera-

tion and spread based on epileptic networks. This change isreflected in a recent publication by the International Lea-gue Against Epilepsy (ILAE) on revised terminology ofseizures and epilepsies.2 This paper conceptualizes focalseizures as those arising from networks confined to a singlecerebral hemisphere, whereas generalized seizures “origi-nate at some point within, and rapidly engage bilaterallydistributed networks” including cortical and subcorticalstructures, leaving open the possibility of a focal originwithin the network.

Amid the ongoing debate and discussion about the patho-genesis and classification of IGE, a body of literature high-lighting various focal features of IGE has graduallyaccumulated over the years. In this paper, we review the lit-erature on focal characteristics of IGE in the domains ofsemiology, EEG, neuropsychology, neuropathology, andneuroimaging.

AcceptedMay 13, 2014.*Department of Medicine, St. Vincent’s Hospital, University of Mel-

bourne, Melbourne, Victoria, Australia; and †Department of Neuroscience,MonashMedical Centre, Melbourne, Victoria, Australia

Address correspondence to Udaya Seneviratne, Department of Neuro-science, St. Vincent’s Hospital, PO Box 2900, Fitzroy, Melbourne, Vic.3065, Australia. E-mails: [email protected]; [email protected]

Wiley Periodicals, Inc.© 2014 International League Against Epilepsy

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CRITICALREVIEWAND INVITEDCOMMENTARY

MethodsWe searched the Web of Science database using search

terms “primary generaliz(s)ed epilepsy,” “idiopathic gener-aliz(s)ed epilepsy,” “absence epilepsy,” “juvenile myoclonicepilepsy,” “absence seizure,” “myoclonic seizure,” and “gen-eraliz(s)ed tonic–clonic seizure” in combination with “focal,”“aura,” “semiology,” “EEG,” “neuropsychology,” “magneticresonance imaging,” “volumetry,” “voxel-based morphome-try,” “functional magnetic resonance imaging,” “magneticresonance spectroscopy,” “pathology,” and “positron emis-sion tomography.” Publications in all years were taken intoconsideration. We also searched the reference lists of identi-fied publications for more papers relevant to the topic. Onlyoriginal papers published in English were included in thisreview. Single case reports and abstracts from conferenceswere excluded.

Results and DiscussionOur literature search yielded a total of 145 relevant publi-

cations describing focal features of IGE in differentdomains. Having excluded 16 abstracts and 12 case reports,117 publications were analyzed.

Semiology

AuraAn aura is a subjective symptom representing a seizure or

part of a seizure that can be recalled by the individual. The1981 ILAE seizure classification describes the aura as asimple partial seizure or the signal symptom of a complexpartial seizure.3 In the revised terminology, aura isdescribed as a focal seizure “without impairment of con-sciousness or awareness involving subjective sensory orpsychic phenomena only.”2 This implies auras are experi-enced only in focal epilepsies.

Our search yielded four papers on auras experienced bypatients with IGE. In a prospective study involving 19patients with IGE from an epilepsy monitoring unit (EMU),70% reported auras.4 This relatively high frequency couldbe an overestimate due to selection bias, as IGE patientswith auras are more likely to be referred to EMU with a pro-visional diagnosis of focal epilepsy. Another study foundspecial sensory, psychic, and autonomic auras among 54%of 37 patients diagnosed with juvenile myoclonic epilepsy(JME).5 A questionnaire was used to obtain information onauras. However, auras were reported during a structuredinterview by only 24% (n = 379) with “generalized epi-lepsy” from three population-based twin registries.6 Visualauras were experienced by 4 (10%) of 40 patients diagnosedwith JME.7 Phenomenologically, auras of temporal lobeepilepsy and IGE appeared to be different, except for risingepigastric sensation, which was reported by both groups.4

In the above studies, auras were elicited by systematic

questioning. It is possible that auras in IGE are under-reported, as patients may not volunteer this informationunless questioned in a systematic manner.

It is unclear what auras represent in IGE, particularly inthe absence of correlating video-EEG data. Auras may notnecessarily be due to focal seizure activity. It is possible thatpreictal prodromal symptoms may have been reported asictal “auras” by patients in these studies.

Generalized tonic–clonic seizuresIn classic generalized tonic–clonic seizures (GTCS) of

IGE, the tonic–clonic activity is expected to be symmetricaland generalized from the onset. Numerous focal featureshave been described in secondarily GTCS (focal seizuresevolving to bilateral convulsive seizures according to therevised terminology2) of focal epilepsies, helping lateraliza-tion and localization of the seizure focus. Several authorshave described similar focal features in GTCS of IGE aswell. These include forced head version, eye version, “fig-ure-4-sign” (contralateral elbow extension and ipsilateralflexion), focal clonic activity, asymmetry in tonic and clonicphases, hemiconvulsion, fencing posture, unilateral tonic/dystonic posturing, postictal nose wiping, postictal hemipa-resis, and asymmetric seizure termination.8–16 The fre-quency of such focal features ranges from 35% to 46%among three studies involving 20, 55, and 26 patients basedon video-EEG monitoring (VEM).12,14,15 However, itshould be noted that these studies were reported from ter-tiary referral centers, which were likely to receive moreatypical and complex cases of IGE. Therefore, the possibil-ity of overestimating the frequency due to selection biasshould be taken into consideration.

Myoclonic seizuresMyoclonic jerks of JME are characterized by bilateral,

arrhythmic, irregular jerks of proximal and distal musclespredominantly in the arms.1 However, focal (unilateral) andasymmetric jerks in JME have been reported. In a detailedvideo-polygraphic analysis of myoclonic seizures in JME,four of five patients had asymmetric myoclonic jerks.17

Three other studies have reported asymmetric myoclonus in61%,14 16.8%,18 and 14%19 of JME patients. Focal myo-clonic seizures were detected in 25% of patients with JMEwho underwent VEM.15 Study heterogeneity and samplingbias would account for this wide range.

Absence seizuresAutomatisms are generally considered to be an integral

component of complex partial seizures (focal seizures withimpairment of consciousness or awareness2). However, oraland manual automatisms have been well recognized in asso-ciation with typical absence seizures. In a cohort of 70untreated children with absence seizures, automatisms weredetected in 40% of seizures and 76% of patients.20 Automa-tisms were more likely to occur during hyperventilation and


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U. Seneviratne et al.

in longer absence seizures.20 The origin and underpinningmechanisms of automatisms are complex, and their pres-ence does not necessarily indicate a focal basis in IGE. Yet,it is important to be aware of this phenomenon to avoid mis-diagnosis of absences as complex partial seizures.

Diagnostic criteria of IGE is a confounding factor, asinadvertently mixed focal epilepsy patients will affect theresults on semiology. The 1989 ILAE criteria1 were used inmost studies on semiology, whereas criteria were not speci-fied in six studies.4,9,12,13,15,19

ElectroencephalographyThe existence of focal EEG features in IGE has been

known for many decades.21 In a large cohort of IGEpatients, EEG focal abnormalities were found in 56% andlocalized to temporal regions in most.22 In a series of IGEpatients studied with video-EEG, focal interictal epilepti-form discharges (IEDs) and semiologic features of focal sei-zure onset were observed in 35%. However, no seizureswith focal EEG onset were seen.12 Another study foundfocal interictal EEG abnormalities in 2 of 26 patients withJME.15 Other studies have reported EEG focalities in30–55% of JME patients.23–25 The reported frequency offocal or lateralized EEG abnormalities in patients withabsence seizures ranges from 16% to 37%.21,26–30 Temporalintermittent rhythmic delta activity was reported among13% of patients with juvenile absence epilepsy (JAE) com-pared to none in JME from a single study based on video-EEG.31 Focal EEG abnormalities appear to be state depen-dent, and Koutroumanidis et al.32 found focal discharges inchildren with childhood absence epilepsy (CAE) mainlyduring non–rapid eye movement sleep. Based on these stud-ies, it appears that focal interictal EEG abnormalities arefound among one third of patients with IGE.

However, it should be noted that patient populations ofthese studies were heterogeneous and the influence ofpotential confounding factors such as age, arousal state,length of recording, and AED therapy were not specified.Most studies employed diagnostic criteria consistent with1989 ILAE classification, although in the minority it wasnot specified.12,15,19,26,27 Another potential pitfall is label-ing bifrontal fragmented spike-wave discharges as focalIEDs. It should be noted that among the studies reviewedonly one provides a strict definition of focal IEDs.15

NeuropsychologyWorking memory, prospective memory, and executive

function are considered to be frontal lobe functions.33 Sev-eral neuropsychological studies have revealed functionaldeficits involving frontal lobes in JME. On neuropsycholog-ical testing, deficits in visual working memory were foundin both JME and frontal lobe epilepsy (FLE) compared tohealthy controls.34 Eight studies have reported deficits inexecutive functions in JME in comparison to healthycontrols.35–42 Another study compared frontal cognitive

function in JME with FLE, temporal lobe epilepsy (TLE),and healthy controls. The JME group had significant impair-ment in executive functions compared to TLE and healthycontrols. However, there was no difference between JMEand FLE.43

Prospective memory is closely linked to executive func-tions, and one study reported significant deficits in prospec-tive memory in JME patients and their unaffected siblingscompared to healthy controls.44

Verbal and nonverbal episodic memory reflecting func-tions of the temporal lobe did not appear to be impaired inJME in comparison to healthy controls.41,44

More recently, researchers used Iowa Gambling Task(IGT) to evaluate the decision making ability of patientswith JME. Worse performance was recorded from patientsin comparison to controls, and further analysis revealed atrend toward poor performance with poor seizure control.45

Another study found similar results in JME patients withongoing seizures.46 These results are suggestive of deficitsinvolving cortico-subcortical prefrontal networks in JME.45

Targeted neuropsychological studies in other IGE syn-dromes are scarce. One study compared intellectual capac-ity, verbal and nonverbal memory, language, and executivefunctions between benign childhood epilepsy with centro-temporal spikes (BECTS), CAE, and healthy controls. BothBECTS and CAE patients were in remission off antiepilep-tic drugs. Executive functions were evaluated with trail-marking, as well as Stroop and Wisconsin card sorting tests.No significant differences were found between the threegroups in the domains of memory, language, and executivefunctions.47

Another study compared neuropsychological functionsbetween children with absence epilepsy and healthy con-trols. Patients who had experienced seizures other thanabsences were excluded. Hence the patient group was likelyto consist of a mix of CAE and JAE. Compared to the con-trols, the patient group had significantly lower general cog-nition, visuospatial skills, nonverbal memory, and delayedrecall.48

Comparisons are difficult due to methodologic variations,particularly with respect to cohort differences in age ofonset, method of ascertainment (incident vs. prevalent,community vs. hospital, prospective vs. retrospective),duration of disease, treatment status, seizure control, lack ofpopulation control, and testing paradigms. As in otherdomains, diagnostic criteria employed have an influence onthe results. Among the 15 studies discussed, only 9 havedefined diagnostic features consistent with 1989 ILAE crite-ria.36–40,43,45–47 In general, there appears to be a tendencyfor frontal lobe functional deficits in JME on neuropsycho-logical testing.

Magnetic resonance imagingBy convention, magnetic resonance imaging (MRI) is not

expected to reveal abnormalities in IGE. More convincing


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Focal Features in IGE

evidence on focal features in IGE has emerged from studiesusing advanced neuroimaging techniques.

Magnetic resonance imaging volumetryStudies on volumetric analysis in IGE have yielded

mixed results. The most commonly reported abnormalitiesare in the thalamus. Two studies found reduced thalamicvolumes,40,49 whereas no changes were detected in threestudies.50–52 Both increased and decreased thalamic vol-umes were found in the cohort of another study.53 The samegroup reported increased volume in a larger cohort.54 Bothincreased55 and reduced56 lobar volumes have also beenreported. Volumetry technique is operator dependent, whichcan lead to variable results in different studies. With theexception of one study,52 all have used 1989 ILAE criteria.

Voxel-based morphometryVoxel-based morphometry (VBM) is an automated

technique of quantitative MRI analysis. It is widely used inepilepsy, and our search yielded 13 studies in IGE(Table 1).38,41,49,50,53,55,57–63 Both regional cortical graymatter and thalamic volume changes have been reported inthose studies. The most consistent finding is reduction isthalamic volumes seen across the majority of studies. Bothincreased and decreased frontal cortical gray mattervolumes have been found (Table 1), whereas one studydid not find any difference between JME patients andcontrols.41

These discrepancies could be due to several factorsincluding heterogeneity of study populations and methodol-ogy. Voxel-based morphometry findings in particular areaffected by covariates (such as total intracranial volume,

age, gender) and the size of control group.64 Artifacts canaffect comparisons, and gray matter volumes may varyacross different scanners.65 Furthermore, reporting bias inthe literature due to selective analysis, and reporting andpublication of positive results should also be taken into con-sideration when interpreting the studies on volumetry. Thisbias has been well demonstrated in the studies on brain vol-ume abnormalities in mental health conditions.66 With theexception of three studies,41,58,63 1989 ILAE diagnostic cri-teria were used.

Magnetic resonance spectroscopyMagnetic resonance spectroscopy (MRS) is a noninva-

sive technique of in vivo quantification of brain metabolites.Several studies have been carried out in IGE looking at glu-tamate plus glutamine (GLX), N-acetyl aspartate (NAA),creatine phosphocreatine (Cr), Choline (Cho), and c-amin-obutyric acid. Regional changes of these compounds reflectdifferences in local metabolism, cellular integrity, neuronalfunction, and excitability.67

From 13 published studies on MRS in IGE, the most con-sistent findings are reduced NAA in the thalamus and thefrontal lobe. There are conflicting results on GLX in thefrontal lobe, with studies showing both increased andreduced concentrations (Table 2).59,68–79

MRS results are influenced by several variables such asdifferences in data acquisition, post- processing techniques,and age and duration of epilepsy. The diagnostic criteria ofIGE are not defined in five studies,70–72,78,79 but other stud-ies have used 1989 ILAE criteria. These confounders shouldbe taken into consideration in the interpretation and compar-ison of results.

Table 1. Voxel-basedmorphometry studies in IGE

References Age range (mean) year Cohort Key findings in patients

38 (33.61) JME 28, Co 55 Reduced GM in supplementary motor area and posterior cingulate cortex

41 15–45 (24.2) JME 19, Co 20 No difference in GM volume

49 (33.6 � 8.6) GTCSO 19, Co 52 Reduced GM in frontal, parietal, temporal cortex, thalami and cerebellum

50 20–50 (30) JME 21, Co 20 Reduced volume anterior thalamus

53 9–60 (30) JME 7, AE 11, GTCSO 4 Focal GM abnormalities (frontal, parietal, temporal, occipital) in 77%

55 9–60 (30 � 11) JME 19, Co 19 Reduced GM in prefrontal lobe

57 JME (32 � 9)

AE (27 � 12)

GTCSO (12 � 11)

JME 44, AE 24,

GTCSO 15, Co 47

Increased GM in frontobasal (JME), superior mesiofrontal (AE),

no difference (GTCSO)

58 (17 � 8) CAE 13, Co 109 Reduced GM in thalami, subcallosal gyri of frontal lobe

ReducedWM in basal frontal lobe, anterior and posterior cingulate

59 (32) IGE 43, Co 38 Reduced volume in thalami

60 16–35 (22.7 � 5.1) JME 25, Co 44 Increased GMmesiofrontal lobe, reduced GM thalami

61 14–55 (26.6) JME 60, Co 30 Reduced GM thalami, insula, cerebellum

Increased GM superior frontal, orbital frontal, medial frontal gyri

62 (16) CAE 44, Co 257 Reduced GM in thalami

63 15–37 (25) JME 20, Co 30 Increased cortical GM in mesial frontal lobes

41 15–45 (24.2) JME 19, Co 20 No difference in GM volume

AE, absence epilepsy; CAE, childhood absence epilepsy; Co, controls; GM, gray matter; GTCSO, generalized tonic–clonic seizures only; IGE, idiopathic general-ized epilepsy; JME, juvenile myoclonic epilepsy;WM, white matter.


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Functional magnetic resonance imagingFunctional magnetic resonance imaging (fMRI) is a non-

invasive technique measuring cerebral activity linked tocerebral blood flow based on oxygenated and deoxygenatedhemoglobin ratio (blood oxygenation level–dependentcontrast, BOLD).67 Increased synaptic activity associatedwith epileptiform discharges is expected to increase theBOLD signal in the corresponding region (“activation”).This principle is used in simultaneous recording of EEG andfMRI to compare BOLD signal changes with ictal and inte-rictal epileptiform discharges. The reasons for decreasedBOLD signal (“deactivation”) in EEG-fMRI are lessclear. Researchers have postulated it to be a reflection ofinterruptions to the “default state of the brain” by epilepticdischarges.80

Activation of various brain regions during cognitive taskshas also been tested with fMRI in IGE patients.41 Our litera-ture search yielded 16 fMRI studies in IGE.41,80–94 Despitestudy heterogeneity, common trends emerge from EEG-fMRI results. First, almost all studies demonstrate thalamicactivation with generalized spike-wave discharges (GSWDs).Second, GSWDs are also associated with activation ofcertain cortical areas, mainly frontal, parietal, temporal,and insular. Two studies found that cortical activationpreceded thalamic changes.83,92 Third, there is deactivationof certain regions recognized as “default mode areas”(Table 3).

The activation of certain cortical regions in EEG-fMRIcan be interpreted as evidence supporting the theory of focalbasis in IGE. However, these studies should be interpretedand compared with caution due to some limitations.

First, most studies have used GSWD for simultaneousEEG-fMRI. Although GSWD is the electrographic hall-mark, there are other specific EEG features in IGE. Only aminority of research studies address other electrographicmarkers such as polyspike-wave discharges and photopar-oxysmal response (Table 3). Hence, the inferences drawnfrom studies involving GSWDs alone may not provide acomplete functional picture.

Second, the findings are affected by various methodolog-ic differences such as fMRI paradigms, image processing,data acquisition (continuous vs. spike triggered EEG-fMRI,amount and length of GSWD acquired) and statistical analy-sis.

Finally, as in all other domains, diagnostic criteria willaffect the sample and results. Among the studies discussed,the majority have defined diagnostic features consistentwith 1989 ILAE criteria.80–85,87,90–93

Positron emission tomographyPositron emission tomography (PET) scans are com-

monly used in the presurgical evaluation of focal epilepsies.Only a few studies have employed this technique in IGE.Two early studies demonstrated increased cerebral meta-bolic rate for glucose during GSWD without any focalchanges.95,96 A later study evaluated fluorodeoxyglucose(FDG) uptake with visual working memory paradigms innine JME patients in comparison to 14 healthy controls.Only the controls demonstrated increased uptake in frontalregions during the task. The absence of uptake in JME wasinterpreted as “cortical disorganization” in the region.97 Amore recent study found increased FDG uptake in the

Table 2. Studies onmagnetic resonance spectroscopy in IGE

References

Age range

(mean) years Cohort On AED Key findings in patients

59 (32) JME 23, GTCSO 20, Co 38 Yes Increased GLX and reducedNAA in thalamus

68 20–52 (37) JME 12, GTCSO 8, Co 11 NS ReducedNAA/Cr in thalamus

69 (27.2) JME 57, Co 30 Yes ReducedNAA/Cr in frontal lobe; increased GLX/Cr

in insula and striatum

70 18–39 (28) IGE 18, Co 25 Yes ReducedNAA, GLX, CHO and MI in frontal lobe,

reduced NAA in thalamus

71 25–43 (32.3) AE 9, Co 9 Yes ReducedNAA/Cr in thalamus

72 16–30 (20.3) JME 15, Co 16 Yes ReducedNAA/Cr in thalamus

73 11–19 (14.9) JAE 14, Co 10 Yes ReducedNAA/Cr in thalamus

74 (26.6) JME 60, Co 30 Yes ReducedNAA/Cr in thalamus, motor cortex and

medial prefrontal cortex; reduced GLX/Cr in motor

cortex, medial prefrontal cortex and posterior cingulate gyrus

75 17–44 (31.6) JME 10, Co 10 NS ReducedNAA/Cr in thalamus

76 26–42 JME 15, Co 10 Yes ReducedNAA in prefrontal cortex

77 18–51 JME 25, GTCSO 20, Co 10 Yes (43), no (2) ReducedNAA in frontal lobe (JME); reducedNAA in thalamus

(GTCSO); reduced CHO and MI (JME and GTCSO)

78 17–55 (27) IGE 15, OLE 15, Co 15 Yes Increased GLX and GABA in occipital lobe (both IGE and OLE)

79 NS IGE 21, Co 17 Yes Increased GLX and reducedNAA in frontal lobe

AE, absence epilepsy; AEDs, antiepileptic drugs; CHO, choline; Co, controls; Cr, creatine; GABA, c-aminobutyric acid; GLX, glutamate plus glutamine; GTCSO,generalized tonic–clonic seizures only; IGE, idiopathic generalized epilepsy; JAE, juvenile absence epilepsy; JME, juvenile myoclonic epilepsy; MI, myo-inositol; NAA,N-acetyl aspartate; NS, not specified; OLE, occipital lobe epilepsy.


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thalamus during GSWD as well as interictally in JMEpatients.98 No cortical abnormalities were reported in thisstudy. In this study, EEG monitoring was done before, dur-ing, and after the isotope injection. In contrast, anotherstudy did not find any difference between JME patients andhealthy controls in resting (interictal) FDG-PET scans.99

However, EEG monitoring was not done, and the interictalstate was decided on clinical observation, thereby limitingthe validity of data.

A major drawback in FDG-PET is its limited temporalresolution due to delayed tracer uptake.98 It is of limitedvalue in evaluating focal abnormalities in IGE.

Among the studies discussed, only one has used 1989ILAE diagnostic criteria in patient selection.98

NeuropathologyMicrodysgenesis refers to specific microscopic abnor-

malities of brain reported in people with epilepsy as well asnormal subjects. Early neuropathologic studies indicatedthat microdysgenesis was found in most patients with

IGE.100 However, a later autopsy study comparing the his-tology of brain from people who had IGE with healthy con-trols found no significant difference in microdysgenesisfeatures between the two groups.101

Focal features in IGE: what does it mean?There are four possible explanations for the presence of

focal features in studies on IGE; (1) misdiagnosis of focalepilepsy as IGE due to poor diagnostic criteria, (2) focal fea-tures as an integral component of IGE compatible with thatdiagnosis, (3) coexistence of both IGE and focal epilepsy inthe same patient, and (4) generalized seizures in IGE havinga focal onset.

Misdiagnosis of focal epilepsy as IGEPoor case selection with imprecise diagnostic criteria

may result in the inclusion of focal epilepsy cases in IGEstudy cohorts and one might interpret focal features on thatbasis. However, most studies from tertiary centers haveincluded patients based on established ILAE criteria. Hence,

Table 3. Studies on functionalmagnetic resonance imaging in IGE

References

Age range

(mean) year Cohort On AED Key findings in patients

41 15–45 (24.2) JME 19, Co 20 Yes 16, no 3 fMRI done with cognitive tests; no difference between JME and controls in

fMRI activation with working memory paradigms

80 18–66 (35) IGE 15 Yes 14, no 1 Activation in thalamus, mesial frontal, insula and cerebellum; deactivation

in anterior frontal, parietal, posterior cingulate gyri

81 18–66 (35) IGE 15 Yes 14, no 1 Multiregional activation and deactivation in 14, thalamus activation in 8,

deactivation in 2, both in 2

82 16–34 CAE 4, IGEU 1 Yes 4, no 1 Deactivation in posterior cingulate, no activation in thalamus

83 6–15 (11.9) CAE 42 NS Activation in orbital/medial frontal and medial/lateral parietal cortices >5 s

before seizure onset; thalamus activation follows

84 6–15 CAE 9 Yes 5, no 4 Activation in thalamus, frontal, primary visual, auditory, somatosensory

and motor cortices; deactivation in parietal cortex, cingulate gyrus,

and basal ganglia

85 18–74 IGE 32, SGE 14 Yes 43, no 3 Activation in thalamus; deactivation in frontal, parietal, and temporal cortices

86 11–14 (10.25) EMA 4 Yes Activation in thalamus, cerebellum, mesial frontal, middle parietal,

temporal and insula r cortices; deactivation in anterior frontal cortex,

posterior parietal cortex, and posterior cingulate gyrus

87 NS CAE 8, JAE 1

(17 AS studied)

Yes 3, no 6 Activation in thalamus (94%), frontal and parietal cortex (59%);

deactivation in caudate (59%), default mode areas (88%)

88 19–58 (35.2) IGE 27, Co 30 Yes 25, no 2 Activation in thalamus, mesial frontal cortex, cerebellum;

deactivation in default mode areas

89 8–22 (14) Generalized PPR 6 Yes 2, no 4 Activation in visual, parietal and premotor cortices (with PPR)

90 4–7 (9) CAE 3, MAE 1,

JME 1, IGEU 1

Yes 5, no 1 Activation in thalamus; deactivation in frontal, parietal regions,

and precuneus (with generalized polyspike and wave discharges)

91 4–12 (8) CAE 10 No Activation in thalamus; deactivation in parietal lobe, precuneus, caudate

92 15–55 JME 5, JAE 1, IGEU 3 Yes Activation in prefrontal and dorsolateral cortex followed by thalamus

93 (31.8) JME 12, IGE

(non-JME) 13

Yes Valproate-responsive and valproate-resistant groups were compared.

Activation in thalamus, frontal region (all); activation in mesial frontal

cortex, paracingulate gyrus, and anterior insula (valproate-resistant patients)

94 (32.8) JME 30, Co 26 Yes 29, no 1 fMRI was done with spatial working memory paradigm. Activation in

primary motor cortex and supplementary motor area; impaired

deactivation in default mode network

AED, antiepileptic drugs; AS, absence seizures; CAE, childhood absence epilepsy; Co, controls; EMA, eyelid myoclonia with absences; fMRI, functional magneticresonance imaging; IGE, idiopathic generalized epilepsy; IGEU, idiopathic generalized epilepsy unspecified; JAE, juvenile absence epilepsy; JME, juvenile myoclonicepilepsy; MAE, myoclonic astatic epilepsy; NS, not specified; PPR, photoparoxysmal response; SGE, secondary generalized epilepsy (please note only two fMRIstudies, Refs 41 and 94, were done with cognitive tasks. Others were EEG-fMRI studies).


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this does not appear to be a major confounding factor. Yet,this aspect needs attention in the interpretation of studyresults.

Focal features as an integral component of IGEIn general, studies indicate that the presence of focal fea-

tures is not incompatible with the diagnosis of IGE, whenstandard ILAE criteria are fulfilled. This is illustrated inFigure 1, demonstrating both generalized and focal EEGabnormalities in a 22-year-old patient with JME. The under-lying mechanism of focal abnormalities on neuropsycholog-ical testing and neuroimaging are unclear. Whether suchfocal abnormalities are caused by the impact of repetitiveseizure activity, effect of antiepileptic medications, orgenetic factors remain speculative.

Coexistence of both IGE and focal epilepsy in the samepatient

There are case reports and case series describing coexis-tence of proven focal epilepsy and well-characterized IGEin the same patient.102,103 However, this phenomenonappears to be rare, accounting for <1% of the IGE popula-tion in the studies.102,103 Given the tertiary center referralbias, the true prevalence is likely to be even smaller. Hence,this phenomenon is unlikely to be responsible for all thefocal features of IGE reported in the studies.

Focal onset of generalized seizures in IGEWhether seizures of IGE have focal onset is a highly con-

tentious subject. It is not possible to draw any conclusionsbased on the data from studies discussed in this article.However, despite some inconsistencies and methodologiclimitations, one common trend seen across most of the neu-roimaging studies is the involvement of the thalamus andfrontal cortex. Further evaluation of these findings mayimprove our understanding on the pathophysiologic basis of

IGE. It would be useful to look at different hypotheses ofIGE pathophysiology and relevant animal and human datain this context.

Cellular and network mechanisms of GSWD are com-plex. There are several seizure types and EEG markers inIGE. Underlying pathophysiologic mechanisms of all dif-ferent types may not be the same. What has been mostlystudied is the typical GSWDs of absence seizure, the elec-troclinical prototype of IGE.

Several hypotheses have been proposed to explain theGSWDs of absence seizures. Historically, the “centrence-phalic theory” was the first mechanism proposed, whichsuggested origin of GSWDs from subcortical midline struc-tures, in particular thalamus and brainstem.104 Buzsaki105

refined this theory further by localizing the pacemaker toreticular thalamic nucleus (“thalamic clock theory”). Theuse of intracarotid and intravertebral injections of amobar-bital sodium and pentamethylenetetrazol in patients withgeneralized seizures106 as well as the advent of feline gener-alized penicillin epilepsy (FGPE) model107 lead to the “cor-ticoreticular theory” describing the genesis of GSWD in athalamocortical circuitry. This theory postulated a key roleplayed by the cortex in a more diffuse manner rather than afocal abnormality. According to “corticoreticular theory,”the cortex is in a hyperexcitable state so that thalamic sleepspindles reaching the cortex are transformed into GSWD.108

More recently, the “cortical focus theory” was proposed toindicate the origin of GSWD in a frontal corticalfocus.109,110 Using a rat genetic model of absence epilepsy,Meeren et al.110 demonstrated that a cortical focus withinthe perioral region of the somatosensory cortex lead thethalamus by a mean time of 8.1 msec during the first500 msec of an absence seizure. According to this hypothe-sis, GSWDs originate from a focus in the somatosensorycortex followed by rapid generalization over the cortexbilaterally via corticocortical networks and paroxysmal

A BC

Figure 1.

EEG of a patient with typical juvenile myoclonic epilepsy demonstrating both generalized and focal abnormalities. (A) Typical generalized

spike-wave and polyspike-wave discharges. (B) Focal bitemporal sharp-wave discharges (X and Y) captured in sleep. (C) The magnetic

resonance imaging of the brain does not reveal any focal structural abnormality.

Epilepsia ILAE


7


oscillations through thalamocortical loops. At the onset thecortex drives the thalamus, but subsequently the couplingbecomes bidirectional, with both structures driving eachother. This mechanism provides a circuitry to amplify andsustain GSWDs.109,110 It is important to distinguish corticalonset of GSWD in IGE from focal frontal lobe epilepsy withrapid generalization, based on a thorough assessmentincluding clinical details, neuroimaging, and EEG.111,112

There has been a growing body of literature supportingthe theory of GSWD origin from a cortical, in particularfrontal, focus. Most of the data come from experimentsinvolving animal models including FGPE and genetic ratmodels of absence epilepsy such as Genetic Absence Epi-lepsy Rats from Strasbourg (GAERS) and Wistar AlbinoGlaxo/Rijswijk (WAG/Rij).

Using nonlinear association analysis, Meeren et al.110

have demonstrated a focus of GSWD origin within the per-ioral region of somatosensory cortex in the WAG/Rijmodel. Concordant findings have been reported from theGAERSmodel as well.113 Several other animal studies havesupported this hypothesis. Upregulation of sodium channelexpression114 and increased excitability on electrical stimu-lation115 have been demonstrated in the same region. In theWAG/Rij model, focal microinfusions of phenytoin116 andethosuximide117,118 into the somatosensory cortex abol-ished GSWD, but intrathalamic microinfusion failed toachieve this result.117,118 Further evidence for the impor-tance of cortex in the generation of GSWD has been demon-strated in the FGPE model. In decorticated cats, penicillinfailed to trigger GSWD in the thalamus.119 Furthermore,systemic injection and bilateral diffuse cortical application,but not thalamic injection of penicillin triggered GSWD.107

In cats and monkeys, creation of acute bilateral cortical sei-zure foci by chemicals and freezing generated typicalGSWD.120

Human data from invasive EEG recordings are scarceand a few studies support the cortical focus theory. In a caseseries of four patients with GSWD on scalp EEG, depthelectrode records demonstrated focal frontal onset intwo.121 Another depth electrode study in patients with gen-eralized seizures revealed cortical onset of GSWD.122 Withstereo-EEG implanted in 10 patients, Bancaud et al.123 wereable to induce typical GSWD accompanied by clinicalabsences and generalized tonic–clonic seizures by stimulat-ing the mesial frontal cortex. Tukel and Jasper124 observedGSWD among 26 of 31 patients with parasagittal lesions.However, those cases could be focal frontal lobe epilepsywith secondary bilateral synchrony rather than IGE.

Some evidence supporting focal onset of GSWD has beenreported from studies based on noninvasive scalp EEG. Indense-array EEG, source analysis localized the ictal onsetof absence seizures to dorsolateral, orbital, and mesial fron-tal regions.125 Source analysis of conventional EEG yieldedsimilar results.126 Electrical field mapping of GSWD local-ized the field maximum to the frontal region.127

More recently, data from advanced neuroimaging studiesprovide further evidence in this area. Most studies showinvolvement of both the thalamus and cortex in relation toGSWDs, although the relative importance of each compo-nent is less clear. At least two EEG-fMRI studies haveshown BOLD activity in the frontal cortex before thalamicactivation, which could be interpreted as evidence support-ing the “cortical focus theory.”83,92

However, some studies are not in favor of cortical focustheory. In the rat model, some studies have shown that tha-lamic activity precedes the cortical activation at the onset ofGSWDs.128,129 Some of the early experiments on anesthe-tized cats demonstrated generation of 3-Hz bilateral spike-wave discharges over the anterior cortical regions with mid-line thalamic stimulation supporting centrencephalic the-ory.130 One depth electrode study reported capturing 3-HzGSWDs synchronously from the scalp surface electrode andthalamic depth electrodes.131

The crucial role played by the reticular thalamic nucleus(RTN) has been demonstrated with lesional studies resultingin abolition of GSWDs in both the GAERS132 and theWAG/Rij models.133 Based on the lesional studies,researchers have postulated that even though GSWDs areinitiated in the cortex, RTN is necessary to self-sustain thedischarges.133

No further conclusions can be drawn from the data pre-sented with regard to the pathophysiology of IGE. Yet, it isimportant to emphasize that even if there is a focal onset asindicated in some studies discussed earlier, IGE cannot beinterpreted as a form of focal epilepsy. The key feature is“origin within and rapid engagement of bilateral networks”in generalized seizures as opposed to “origin within net-works limited to one hemisphere” in focal seizures as con-ceptualized in a recent ILAE report.2

Misdiagnosis of focal epilepsy as IGEThe converse problem would be the misdiagnosis of focal

epilepsy as IGE with potential treatment implications suchas denial of epilepsy surgery. However, in this review, wehave confined our literature search and discussion only tofocal features of IGE and its implications.

Clinical implications of focal abnormalities in IGE

PrognosisThe value of focal EEG abnormalities as a predictor of

prognosis in IGE is not well defined, with studies reportingvariable and conflicting results.27,83,134–140 Some studieshave reported focal EEG abnormalities as a predictor ofpoor prognosis in IGE, although contradicted by others(Table 4). All were hospital-based retrospective studies,except for a single community based cohort.27 Most studiesinvolved patients diagnosed with absence epilepsy, butthere appears to be an equal mix of syndromes in the twogroups (poor prognosis vs. good prognosis).


8


Many variables including the recording technique, acti-vation procedures, circadian rhythm, and length of record-ing affect the yield of EEG abnormalities in IGE.141 Thisfact along with heterogeneity of studies, particularly inmethodology and diagnostic criteria, should be taken intoaccount in evaluating the prognostic value of focal EEGchanges in IGE.

There are no data available on the prognostic value ofother focal features in IGE.

Misdiagnosis and delayed diagnosisFocal abnormalities could potentially lead to delayed

diagnosis and misdiagnosis of IGE as focal epilepsy withinappropriate AED choice as a result. These pitfalls havebeen highlighted in several studies involving JME patients(Table 5).5,18,19,142–146 In those studies, the reported meandiagnostic delay ranged from 5.9 to 15 years. A fair propor-tion of patients had been originally misdiagnosed as havingfocal epilepsy (range 5.3–91.4%). As a result, many hadbeen on inappropriate AEDs prior to the correct diagnosiswas established, resulting in seizure exacerbation. Focaland asymmetric EEG and semiologic features were majorcontributory factors responsible for delayed diagnosis andmisdiagnosis. It should be noted that all studies except

one19 included patients based on diagnostic criteria consis-tent with 1989 ILAE guidelines.

Study limitationsThere is a growing body of literature on various focal fea-

tures of IGE in different domains. However, certain studylimitations compromise the value of those data. First, almostall studies have been conducted in tertiary centers, introduc-ing a potential for selection bias. It is possible that morecomplex IGE patients with atypical features such as focalabnormalities are overrepresented in such centers. Second,there is bias toward JME, with other IGE syndromes beingless well studied. Hence, the results may not be extrapolatedto all IGE syndromes. This is most likely because JME isthe most common IGE syndrome. Third, there is wide heter-ogeneity in study methodology, which could explain thevariable and sometimes conflicting results across differentstudies. In particular, inclusion and diagnostic criteria arelikely to affect the results. Less stringent diagnostic criteriaof IGE may result in inclusion of patients with focal epi-lepsy in the cohort contaminating the results. It should benoted, as detailed in previous sections, diagnostic criteriaare not clearly defined in some studies. Finally, there ispotential reporting and publication bias with selective

Table 4. Studies on prognostic value of EEG focal abnormalities

References

Age range

(mean) year Total number Cohort

FA is a predictor

of poor prognosis

27 ≤15 97 AE Yes

83 (34.2) 267 IGE Yes

134 NS 80 CAE, JAE No

135 (39.9 � 9.5) 48 JME No

136 14–27 (23.1) 119 CAE Yes

137 (23.2) 28 JME No

138 NS 32 JME Yes

139 NS 962 IGE No

140 NS 119 AE No

AE, absence epilepsy; CAE, childhood absence epilepsy; FA, focal abnormalities; IGE, idiopathic generalized epilepsy; JAE, juvenile absence epilepsy; JME, juvenilemyoclonic epilepsy; NS, not specified.

Table 5. Studies onmisdiagnosis and diagnostic delay due to focal features of IGE

References Cohort Design

Mean diagnostic

delay (year)

Misdiagnosis as

focal epilepsy (%) Use of inappropriate AED

5 JME 37 R 15 46 59.4%

18 JME 131 P 6.8 � 6.3 5.3 NS

19 JME 85 R 9.5 19 PHTmost frequently

used (number NS)

142 JME 76 R 5.9 15.8 52.6%

143 JME 15 R 14.5 26.7 33%

144 JME 90 R 9 17.8 58.8% (PHT), 16.6% (CBZ)

145 JME 63 R 13.3 52.4 NS

146 JME 70 P 8.3 � 5.5 91.4 NS

AED, antiepileptic drugs; CBZ, carbamazepine; IGE, idiopathic generalized epilepsy; JME, juvenile myoclonic epilepsy; NS, not specified; P, prospective; PHT,phenytoin; R, retrospective.


9


reporting and publication of positive studies of focal fea-tures. It is evident in the publications discussed in this articlethat there are very few negative studies. Hence, it is possiblethat focal features in IGE may be overreported and over-emphasized.

ConclusionsThere is a large body of literature describing various

focal abnormalities in IGE. Some studies shed light onunderpinning pathophysiologic mechanisms of GSWD.Whether the onset of GSWD is in the cortex or the thala-mus is controversial, but more recently cortical focustheory, mostly backed by animal data, has received muchemphasis. EEG-fMRI studies have shown activation ofthalamus and frontal cortex with spike-wave activitysupporting the hypothesis of both cortical and thalamicinvolvement in IGE. There are conflicting data on focaland asymmetric EEG abnormalities as a predictor ofprognosis. No information is available on the prognosticrelevance of other focal features in IGE. Focal features,particularly in EEG and semiology, may result in misdiag-nosis and delayed diagnosis of IGE. As a result, the patientmay receive an inappropriate AED, leading to poor seizurecontrol. This perhaps is the most important practical impli-cation of focal features in IGE. Clinicians need to be awareof this pitfall.

Conflict of InterestA/Professor D’Souza has received travel, investigator-initiated, and

speaker honoraria from UCB Pharma; educational grants from NovartisPharmaceuticals and Pfizer Pharmaceuticals; educational, travel, and fel-lowship grants from GlaxoSmithKline Neurology Australia; and honorariafrom SciGen Pharmaceuticals. Professor Cook has received speaker hono-raria from UCB Pharma and Sanofi Australia and travel honoraria fromUCB Pharma and SciGen. He has received research grants from NationalHealth and Medical Research Council (Australia), and Australian ResearchCouncil. He has also received a Science, Technology, and Innovation Grantfrom the State Government of Victoria, Australia. Dr. Seneviratne hasreceived an educational grant and speaker honoraria from UCB Pharma.We confirm that we have read the Journal’s position on issues involved inethical publication and affirm that this report is consistent with those guide-lines.

FundingNone.

References1. Commission on Classification and Terminology of the International

League Against Epilepsy. Proposal for revised classification ofepilepsies and epileptic syndromes. Epilepsia 1989;30:389–399.

2. Berg AT, Berkovic SF, Brodie MJ, et al. Revised terminology andconcepts for organization of seizures and epilepsies: report of theILAE Commission on Classification and Terminology, 2005–2009.Epilepsia 2010;51:676–685.

3. Commission on Classification and Terminology of the InternationalLeague Against Epilepsy. Proposal for revised clinical and

electroencephalographic classification of epileptic seizures..Epilepsia 1981;22:489–501.

4. Boylan LS, Labovitz DL, Jackson SC, et al. Auras are frequent inidiopathic generalized epilepsy.Neurology 2006;67:343–345.

5. Vazquez B, Devinsky O, Luciano D, et al. Juvenile myoclonicepilepsy – clinical features and factors related to misdiagnosis.J Epilepsy 1993;6:233–238.

6. Nakken KO, Solaas MH, Kjeldsen MJ, et al. The occurrence andcharacteristics of auras in a large epilepsy cohort. Acta Neurol Scand2009;119:88–93.

7. Taylor I, Marini C, Johnson MR, et al. Juvenile myoclonic epilepsyand idiopathic photosensitive occipital lobe epilepsy: is thereoverlap? Brain 2004;127:1878–1886.

8. Aguglia U, Gambardella A, Le Piane E, et al. Idiopathic generalizedepilepsies with versive or circling seizures. Acta Neurol Scand1999;99:219–224.

9. Casaubon L, Pohlmann-Eden B, Khosravani H, et al. Video-EEGevidence of lateralized clinical features in primary generalizedepilepsy with tonic-clonic seizures. Epileptic Disord 2003;5:149–156.

10. Chin PS, Miller JW. Ictal head version in generalized epilepsy.Neurology 2004;63:370–372.

11. Kiley MA, Smith SJ, Sander JW. Idiopathic generalized epilepsypresenting with hemiconvulsive seizures. Epilepsia 2000;41:1633–1636.

12. Leutmezer F, Lurger S, Baumgartner C. Focal features in patients withidiopathic generalized epilepsy.Epilepsy Res 2002;50:293–300.

13. Niaz FE, Abou-Khalil B, Fakhoury T. The generalized tonic-clonicseizure in partial versus generalized epilepsy: semiologicdifferences. Epilepsia 1999;40:1664–1666.

14. Park KI, Lee SK, Chu K, et al. The value of video-EEG monitoringto diagnose juvenile myoclonic epilepsy. Seizure 2009;18:94–99.

15. Usui N, Kotagal P, Matsumoto R, et al. Focal semiologic andelectroencephalographic features in patients with juvenilemyoclonic epilepsy. Epilepsia 2005;46:1668–1676.

16. Walser G, Unterberger I, Dobesberger J, et al. Asymmetric seizuretermination in primary and secondary generalized tonic-clonicseizures. Epilepsia 2009;50:2035–2039.

17. Oguni H, Mukahira K, Oguni M, et al. Video-polygraphic analysisof myoclonic seizures in juvenile myoclonic epilepsy. Epilepsia1994;35:307–316.

18. Murthy JM, Rao CM, Meena AK. Clinical observations of juvenilemyoclonic epilepsy in 131 patients: a study in South India. Seizure1998;7:43–47.

19. Lancman ME, Asconape JJ, Penry JK. Clinical and EEGasymmetries in juvenile myoclonic epilepsy. Epilepsia1994;35:302–306.

20. Sadleir LG, Scheffer IE, Smith S, et al. Automatisms in absenceseizures in children with idiopathic generalized epilepsy. ArchNeurol 2009;66:729–734.

21. O’Brien JL, Goldensohn ES, Hoefer PF. Electroencephalographicabnormalities in addition to bilaterally synchronous 3 per secondspike and wave activity in petit mal. Electroencephalogr ClinNeurophysiol 1959;11:747–761.

22. Lombroso CT. Consistent EEG focalities detected in subjects withprimary generalized epilepsies monitored for two decades. Epilepsia1997;38:797–812.

23. Aliberti V, Grunewald RA, Panayiotopoulos CP, et al. Focalelectroencephalographic abnormalities in juvenile myoclonicepilepsy. Epilepsia 1994;35:297–301.

24. Jayalakshmi SS, Srinivasa Rao B, Sailaja S. Focal clinical andelectroencephalographic features in patients with juvenilemyoclonic epilepsy. Acta Neurol Scand 2010;122:115–123.

25. Panayiotopoulos CP, Obeid T, Tahan AR. Juvenile myoclonicepilepsy: a 5-year prospective study. Epilepsia 1994;35:285–296.

26. Covanis A, Skiadas K, Loli N, et al. Absence epilepsy: earlyprognostic signs. Seizure 1992;1:281–289.

27. Hedstrom A, Olsson I. Epidemiology of absence epilepsy: EEGfindings and their predictive value. Pediatr Neurol 1991;7:100–104.

28. Matur Z, Baykan B, Bebek N, et al. The evaluation of interictal focalEEG findings in adult patients with absence seizures. Seizure2009;18:352–358.


10


29. Tezer FI, Sahin G, Ciger A, et al. Focal EEG findings in juvenileabsence syndrome and the effect of antiepileptic drugs. Clin EEGNeurosci 2008;39:33–38.

30. Vierck E, Cauley R, Kugler SL, et al. Polyspike and waves do notpredict generalized tonic-clonic seizures in childhood absenceepilepsy. J Child Neurol 2010;25:475–481.

31. Gelisse P, Serafini A, Velizarova R, et al. Temporal intermittentdelta activity: a marker of juvenile absence epilepsy? Seizure2011;20:38–41.

32. Koutroumanidis M, Tsiptsios D, Kokkinos V, et al. Focal andgeneralized EEG paroxysms in childhood absence epilepsy:topographic associations and distinctive behaviors during the firstcycle of non-REM sleep. Epilepsia 2012;53:840–849.

33. Stuss DT, Levine B. Adult clinical neuropsychology: lessons fromstudies of the frontal lobes. Annu Rev Psychol 2002;53:401–433.

34. Swartz BE, Halgren E, Simpkins F, et al. Primary memory inpatients with frontal and primary generalized epilepsy. J Epilepsy1994;7:232–241.

35. Iqbal N, Caswell HL, Hare DJ, et al. Neuropsychological profiles ofpatients with juvenile myoclonic epilepsy and their siblings: apreliminary controlled experimental video-EEG case series.Epilepsy Behav 2009;14:516–521.

36. Kim JH, Suh SI, Park SY, et al. Microstructural white matterabnormality and frontal cognitive dysfunctions in juvenilemyoclonic epilepsy. Epilepsia 2012;53:1371–1378.

37. Moschetta SP, Valente KD. Juvenile myoclonic epilepsy: the impactof clinical variables and psychiatric disorders on executive profileassessed with a comprehensive neuropsychological battery. EpilepsyBehav 2012;25:682–686.

38. O’Muircheartaigh J, Vollmar C, Barker GJ, et al. Focal structuralchanges and cognitive dysfunction in juvenile myoclonic epilepsy.Neurology 2011;76:34–40.

39. Pascalicchio TF, de Araujo Filho GM, da Silva Noffs MH, et al.Neuropsychological profile of patients with juvenile myoclonicepilepsy: a controlled study of 50 patients. Epilepsy Behav2007;10:263–267.

40. Pulsipher DT, Seidenberg M, Guidotti L, et al. Thalamofrontalcircuitry and executive dysfunction in recent-onset juvenilemyoclonic epilepsy. Epilepsia 2009;50:1210–1219.

41. Roebling R, Scheerer N, Uttner I, et al. Evaluation of cognition,structural, and functional MRI in juvenile myoclonic epilepsy.Epilepsia 2009;50:2456–2465.

42. Sonmez F, Atakli D, Sari H, et al. Cognitive function in juvenilemyoclonic epilepsy. Epilepsy Behav 2004;5:329–336.

43. Piazzini A, Turner K, Vignoli A, et al. Frontal cognitive dysfunctionin juvenile myoclonic epilepsy. Epilepsia 2008;49:657–662.

44. Wandschneider B, Kopp UA, Kliegel M, et al. Prospective memoryin patients with juvenile myoclonic epilepsy and their healthysiblings.Neurology 2010;75:2161–2167.

45. Zamarian L, Hofler J, Kuchukhidze G, et al. Decision making injuvenile myoclonic epilepsy. J Neurol 2013;260:839–846.

46. Wandschneider B, Centeno M, Vollmar C, et al. Risk-takingbehavior in juvenile myoclonic epilepsy. Epilepsia 2013;54:2158–2165.

47. Hommet C, Billard C, Motte J, et al. Cognitive function inadolescents and young adults in complete remission from benignchildhood epilepsy with centro-temporal spikes. Epileptic Disord2001;3:207–216.

48. Pavone P, Bianchini R, Trifiletti RR, et al. Neuropsychologicalassessment in children with absence epilepsy. Neurology2001;56:1047–1051.

49. Ciumas C, Savic I. Structural changes in patients with primarygeneralized tonic and clonic seizures.Neurology 2006;67:683–686.

50. Mory SB, Betting LE, Fernandes PT, et al. Structural abnormalitiesof the thalamus in juvenile myoclonic epilepsy. Epilepsy Behav2011;21:407–411.

51. Natsume J, Bernasconi N, Andermann F, et al. MRI volumetry of thethalamus in temporal, extratemporal, and idiopathic generalizedepilepsy.Neurology 2003;60:1296–1300.

52. Seeck M, Dreifuss S, Lantz G, et al. Subcortical nuclei volumetry inidiopathic generalized epilepsy. Epilepsia 2005;46:1642–1645.

53. Betting LE, Li LM, Lopes-Cendes I, et al. Correlation betweenquantitative EEG and MRI in idiopathic generalized epilepsy. HumBrain Mapp 2010;31:1327–1338.

54. Betting LE, Mory SB, Lopes-Cendes I, et al. MRI volumetry showsincreased anterior thalamic volumes in patients with absenceseizures. Epilepsy Behav 2006;8:575–580.

55. Tae WS, Hong SB, Joo EY, et al. Structural brain abnormalities injuvenile myoclonic epilepsy patients: volumetry and voxel-basedmorphometry.Korean J Radiol 2006;7:162–172.

56. Caplan R, Levitt J, Siddarth P, et al. Frontal and temporal volumesin Childhood Absence Epilepsy. Epilepsia 2009;50:2466–2472.

57. Betting LE, Mory SB, Li LM, et al. Voxel-based morphometry inpatients with idiopathic generalized epilepsies. Neuroimage2006;32:498–502.

58. Chan CH, Briellmann RS, Pell GS, et al. Thalamic atrophy inchildhood absence epilepsy. Epilepsia 2006;47:399–405.

59. Helms G, Ciumas C, Kyaga S, et al. Increased thalamus levels ofglutamate and glutamine (Glx) in patients with idiopathicgeneralised epilepsy. J Neurol Neurosurg Psychiatry 2006;77:489–494.

60. Kim JH, Lee JK, Koh SB, et al. Regional grey matter abnormalitiesin juvenile myoclonic epilepsy: a voxel-based morphometry study.Neuroimage 2007;37:1132–1137.

61. Lin K, Jackowski AP, Carrete H Jr, et al. Voxel-based morphometryevaluation of patients with photosensitive juvenile myoclonicepilepsy. Epilepsy Res 2009;86:138–145.

62. Pardoe H, Pell GS, Abbott DF, et al. Multi-site voxel-basedmorphometry: methods and a feasibility demonstration withchildhood absence epilepsy.Neuroimage 2008;42:611–616.

63. Woermann FG, Free SL, Koepp MJ, et al. Abnormal cerebralstructure in juvenile myoclonic epilepsy demonstrated with voxel-based analysis of MRI. Brain 1999;122:2101–2108.

64. Pell GS, Briellmann RS, Chan CH, et al. Selection of the controlgroup for VBM analysis: influence of covariates, matching andsample size.Neuroimage 2008;41:1324–1335.

65. Yasuda CL, Betting LE, Cendes F. Voxel-based morphometry andepilepsy. Expert Rev Neurother 2010;10:975–984.

66. Ioannidis JP. Excess significance bias in the literature on brainvolume abnormalities. Arch Gen Psychiatry 2011;68:773–780.

67. Richardson M. Update on neuroimaging in epilepsy. Expert RevNeurother 2010;10:961–973.

68. Bernasconi A, Bernasconi N, Natsume J, et al. Magnetic resonancespectroscopy and imaging of the thalamus in idiopathic generalizedepilepsy. Brain 2003;126:2447–2454.

69. de Araujo Filho GM, Lin K, Lin J, et al. Are personality traits ofjuvenile myoclonic epilepsy related to frontal lobe dysfunctions? AprotonMRS study. Epilepsia 2009;50:1201–1209.

70. Doelken MT, Mennecke A, Stadlbauer A, et al. Multi-voxelmagnetic resonance spectroscopy at 3 T in patients with idiopathicgeneralised epilepsy. Seizure 2010;19:485–492.

71. Fojtikova D, Brazdil M, Horky J, et al. Magnetic resonancespectroscopy of the thalamus in patients with typical absenceepilepsy. Seizure 2006;15:533–540.

72. Haki C, Gumustas OG, Bora I, et al. Proton magnetic resonancespectroscopy study of bilateral thalamus in juvenile myoclonicepilepsy. Seizure 2007;16:287–295.

73. Kabay SC, Gumustas OG, Karaman HO, et al. A proton magneticresonance spectroscopic study in juvenile absence epilepsy in earlystages. Eur J Paediatr Neurol 2010;14:224–228.

74. Lin K, Carrete H Jr, Lin J, et al. Magnetic resonance spectroscopyreveals an epileptic network in juvenile myoclonic epilepsy.Epilepsia 2009;50:1191–1200.

75. Mory SB, Li LM, Guerreiro CA, et al. Thalamic dysfunction injuvenile myoclonic epilepsy: a proton MRS study. Epilepsia2003;44:1402–1405.

76. Savic I, Lekvall A, Greitz D, et al. MR spectroscopy shows reducedfrontal lobe concentrations of N-acetyl aspartate in patients withjuvenile myoclonic epilepsy. Epilepsia 2000;41:290–296.

77. Savic I, Osterman Y, Helms G. MRS shows syndrome differentiatedmetabolite changes in human-generalized epilepsies. Neuroimage2004;21:163–172.


11


78. Simister RJ, McLean MA, Barker GJ, et al. A proton magneticresonance spectroscopy study of metabolites in the occipital lobes inepilepsy. Epilepsia 2003;44:550–558.

79. Simister RJ, McLean MA, Barker GJ, et al. Proton MRS revealsfrontal lobe metabolite abnormalities in idiopathic generalizedepilepsy.Neurology 2003;61:897–902.

80. Gotman J, Grova C, Bagshaw A, et al. Generalized epilepticdischarges show thalamocortical activation and suspension of thedefault state of the brain. Proc Natl Acad Sci U S A 2005;102:15236–15240.

81. Aghakhani Y, Bagshaw AP, Benar CG, et al. fMRI activation duringspike and wave discharges in idiopathic generalized epilepsy. Brain2004;127:1127–1144.

82. Archer JS, Abbott DF, Waites AB, et al. fMRI “deactivation” of theposterior cingulate during generalized spike and wave. Neuroimage2003;20:1915–1922.

83. Bai X, Vestal M, Berman R, et al. Dynamic time course of typicalchildhood absence seizures: EEG, behavior, and functional magneticresonance imaging. J Neurosci 2010;30:5884–5893.

84. Berman R, Negishi M, Vestal M, et al. Simultaneous EEG, fMRI,and behavior in typical childhood absence seizures. Epilepsia2010;51:2011–2022.

85. Hamandi K, Salek-Haddadi A, Laufs H, et al. EEG-fMRI ofidiopathic and secondarily generalized epilepsies. Neuroimage2006;31:1700–1710.

86. Liu Y, Yang T, Liao W, et al. EEG-fMRI study of the ictal andinterictal epileptic activity in patients with eyelid myoclonia withabsences. Epilepsia 2008;49:2078–2086.

87. Moeller F, LeVan P, Muhle H, et al. Absence seizures: individualpatterns revealed by EEG-fMRI. Epilepsia 2010;51:2000–2010.

88. Moeller F, Maneshi M, Pittau F, et al. Functional connectivity inpatients with idiopathic generalized epilepsy. Epilepsia2011;52:515–522.

89. Moeller F, Siebner HR, Ahlgrimm N, et al. fMRI activation duringspike and wave discharges evoked by photic stimulation.Neuroimage 2009;48:682–695.

90. Moeller F, Siebner HR, Wolff S, et al. Changes in activity of striato-thalamo-cortical network precede generalized spike wavedischarges.Neuroimage 2008;39:1839–1849.

91. Moeller F, Siebner HR, Wolff S, et al. Simultaneous EEG-fMRI indrug-naive children with newly diagnosed absence epilepsy.Epilepsia 2008;49:1510–1519.

92. Szaflarski JP, DiFrancesco M, Hirschauer T, et al. Cortical andsubcortical contributions to absence seizure onset examined withEEG/fMRI. Epilepsy Behav 2010;18:404–413.

93. Szaflarski JP, Kay B, Gotman J, et al. The relationship between thelocalization of the generalized spike and wave discharge generatorsand the response to valproate. Epilepsia 2013;54:471–480.

94. Vollmar C, O’Muircheartaigh J, Barker GJ, et al. Motor systemhyperconnectivity in juvenile myoclonic epilepsy: a cognitivefunctional magnetic resonance imaging study. Brain 2011;134:1710–1719.

95. Engel J Jr, Lubens P, Kuhl DE, et al. Local cerebral metabolic ratefor glucose during petit mal absences. Ann Neurol 1985;17:121–128.

96. Ochs RF, Gloor P, Tyler JL, et al. Effect of generalized spike-and-wave discharge on glucose metabolism measured by positronemission tomography. Ann Neurol 1987;21:458–464.

97. Swartz BE, Simpkins F, Halgren E, et al. Visual working memory inprimary generalized epilepsy: an 18FDG-PET study. Neurology1996;47:1203–1212.

98. Kim JH, Im KC, Kim JS, et al. Correlation of interictal spike-wavewith thalamic glucose metabolism in juvenile myoclonic epilepsy.Neuroreport 2005;16:1151–1155.

99. McDonald CR, Swartz BE, Halgren E, et al. The relationship ofregional frontal hypometabolism to executive function: a restingfluorodeoxyglucose PET study of patients with epilepsy and healthycontrols. Epilepsy Behav 2006;9:58–67.

100. Meencke HJ, Janz D. The significance of microdysgenesia inprimary generalized epilepsy: an answer to the considerations ofLyon and Gastaut. Epilepsia 1985;26:368–371.

101. Opeskin K, Kalnins RM, Halliday G, et al. Idiopathic generalizedepilepsy: lack of significant microdysgenesis. Neurology 2000;55:1101–1106.

102. Jeha LE, Morris HH, Burgess RC. Coexistence of focal andidiopathic generalized epilepsy in the same patient population.Seizure 2006;15:28–34.

103. Nicolson A, Chadwick DW, Smith DF. The coexistence ofidiopathic generalized epilepsy and partial epilepsy. Epilepsia2004;45:682–685.

104. Penfield WG, Jasper HH. Epilepsy and functional anatomy of thehuman brain. Boston, MA: Little Brown& Co; 1954.

105. Buzsaki G. The thalamic clock: emergent network properties.Neuroscience 1991;41:351–364.

106. Gloor P. Generalized cortico-reticular epilepsies. Someconsiderations on the pathophysiology of generalized bilaterallysynchronous spike and wave discharge. Epilepsia 1968;9:249–263.

107. Quesney LF, Gloor P. Generalized penicillin epilepsy in the cat:correlation between electrophysiological data and distribution of14C-penicillin in the brain. Epilepsia 1978;19:35–45.

108. Kostopoulos GK. Spike-and-wave discharges of absence seizures asa transformation of sleep spindles: the continuing development of ahypothesis. Clin Neurophysiol 2000;111 (Suppl. 2):S27–S38.

109. Meeren H, van Luijtelaar G, Lopes da Silva F, et al. Evolvingconcepts on the pathophysiology of absence seizures: the corticalfocus theory. Arch Neurol 2005;62:371–376.

110. Meeren HK, Pijn JP, Van Luijtelaar EL, et al. Cortical focus driveswidespread corticothalamic networks during spontaneous absenceseizures in rats. J Neurosci 2002;22:1480–1495.

111. Niedermeyer E. Primary (idiopathic) generalized epilepsy andunderlying mechanisms.Clin Electroencephalogr 1996;27:1–21.

112. Pavone A, Niedermeyer E. Absence seizures and the frontal lobe.Clin Electroencephalogr 2000;31:153–156.

113. Polack PO, Guillemain I, Hu E, et al. Deep layer somatosensorycortical neurons initiate spike-and-wave discharges in a geneticmodel of absence seizures. J Neurosci 2007;27:6590–6599.

114. Klein JP, Khera DS, Nersesyan H, et al. Dysregulation of sodiumchannel expression in cortical neurons in a rodent model of absenceepilepsy. Brain Res 2004;1000:102–109.

115. Luttjohann A, Zhang S, de Peijper R, et al. Electrical stimulation ofthe epileptic focus in absence epileptic WAG/Rij rats: assessment oflocal and network excitability.Neuroscience 2011;188:125–134.

116. Gurbanova AA, Aker R, Berkman K, et al. Effect of systemic andintracortical administration of phenytoin in two genetic models ofabsence epilepsy. Br J Pharmacol 2006;148:1076–1082.

117. Manning JP, Richards DA, Leresche N, et al. Cortical-area specificblock of genetically determined absence seizures by ethosuximide.Neuroscience 2004;123:5–9.

118. Richards DA, Manning JP, Barnes D, et al. Targeting thalamicnuclei is not sufficient for the full anti-absence action ofethosuximide in a rat model of absence epilepsy. Epilepsy Res2003;54:97–107.

119. Avoli M, Gloor P. Interaction of cortex and thalamus in spike andwave discharges of feline generalized penicillin epilepsy. ExpNeurol 1982;76:196–217.

120. Marcus EM, Watson CW, Simon SA. An experimental model ofsome varieties of petit mal epilepsy. Electrical-behavioralcorrelations of acute bilateral epileptogenic foci in cerebral cortex.Epilepsia 1968;9:233–248.

121. Niedermeyer E, Laws ER Jr, Walker EA. Depth EEG findings inepileptics with generalized spike-wave complexes. Arch Neurol1969;21:51–58.

122. Hayne RA, Belinson L, Gibbs FA. Electrical activity of subcorticalareas in epilepsy. Electroencephalogr Clin Neurophysiol 1949;1:437–445.

123. Bancaud J, Talairach J, Morel P, et al. “Generalized” epilepticseizures elicited by electrical stimulation of the frontal lobe in man.Electroencephalogr Clin Neurophysiol 1974;37:275–282.

124. Tukel K, Jasper H. The electroencephalogram in parasagittal lesions.Electroencephalogr Clin Neurophysiol 1952;4:481–494.

125. Holmes MD, Brown M, Tucker DM. Are “generalized” seizurestruly generalized? Evidence of localized mesial frontal andfrontopolar discharges in absence. Epilepsia 2004;45:1568–1579.

126. Rodin EA, Rodin MK, Thompson JA. Source analysis of generalizedspike-wave complexes. Brain Topogr 1994;7:113–119.

127. Rodin E, Ancheta O. Cerebral electrical fields during petit malabsences. Electroencephalogr Clin Neurophysiol 1987;66:457–466.


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128. Inoue M, Duysens J, Vossen JM, et al. Thalamic multiple-unitactivity underlying spike-wave discharges in anesthetized rats. BrainRes 1993;612:35–40.

129. Vergnes M, Marescaux C, Depaulis A, et al. Spontaneous spike andwave discharges in thalamus and cortex in a rat model of geneticpetit mal-like seizures. Exp Neurol 1987;96:127–136.

130. Pollen DA, Perot P, Reid KH. Experimental bilateral wave and spikefrom thalamic stimulation in relation to level of arousal.Electroencephalogr Clin Neurophysiol 1963;15:1017–1028.

131. Laws E, Niedermeyer E, Walker AE. Depth EEG findings inepileptics with generalized spike-wave complexes.Electroencephalogr Clin Neurophysiol 1970;28:94–95.

132. Avanzini G, Vergnes M, Spreafico R, et al. Calcium-dependentregulation of genetically determined spike and waves by the reticularthalamic nucleus of rats. Epilepsia 1993;34:1–7.

133. Meeren HK, Veening JG, Moderscheim TA, et al. Thalamiclesions in a genetic rat model of absence epilepsy: dissociationbetween spike-wave discharges and sleep spindles. Exp Neurol2009;217:25–37.

134. Bartolomei F, Roger J, Bureau M, et al. Prognostic factors forchildhood and juvenile absence epilepsies. Eur Neurol1997;37:169–175.

135. Baykan B, Altindag EA, Bebek N, et al. Myoclonic seizures subsidein the fourth decade in juvenile myoclonic epilepsy. Neurology2008;70:2123–2129.

136. Grosso S, Galimberti D, Vezzosi P, et al. Childhood absenceepilepsy: evolution and prognostic factors. Epilepsia2005;46:1796–1801.

137. Letourneau K, Cieuta-Walti C, Deacon C. Epileptiform asymetriesand treatment response in juvenile myoclonic epilepsy. Can J NeurolSci 2010;37:826–830.

138. Matsuoka H. The seizure prognosis of juvenile myoclonic epilepsy.Jpn J Psychiatry Neurol 1992;46:293–296.

139. Nicolson A, Appleton RE, Chadwick DW, et al. The relationshipbetween treatment with valproate, lamotrigine, and topiramate andthe prognosis of the idiopathic generalised epilepsies. J NeurolNeurosurg Psychiatry 2004;75:75–79.

140. Sinclair DB, Unwala H. Absence epilepsy in childhood:electroencephalography (EEG) does not predict outcome. J ChildNeurol 2007;22:799–802.

141. Seneviratne U, Cook M, D’Souza W. The electroencephalogram ofidiopathic generalized epilepsy. Epilepsia 2012;53:234–248.

142. Atakli D, Sozuer D, Atay T, et al. Misdiagnosis and treatment injuvenile myoclonic epilepsy. Seizure 1998;7:63–66.

143. Grunewald RA, Chroni E, Panayiotopoulos CP. Delayed diagnosisof juvenile myoclonic epilepsy. J Neurol Neurosurg Psychiatry1992;55:497–499.

144. Lancman ME, Asconape JJ, Brotherton T, et al. Juvenilemyoclonic epilepsy – an underdiagnosed syndrome. J Epilepsy1995;8:215–218.

145. Montalenti E, Imperiale D, Rovera A, et al. Clinical features, EEGfindings and diagnostic pitfalls in juvenile myoclonic epilepsy: aseries of 63 patients. J Neurol Sci 2001;184:65–70.

146. Panayiotopoulos CP, Tahan R, Obeid T. Juvenile myoclonicepilepsy: factors of error involved in the diagnosis and treatment.Epilepsia 1991;32:672–676.


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Focal abnormalities in idiopathic generalized epilepsy: a critical review of the literature

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