Epilepsy & Behavior 17 (2010) 525–530

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Epilepsy & Behavior

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Seizure control in patients with idiopathic generalized epilepsies: EEGdeterminants of medication response

Jerzy P. Szaflarski a,b,c,d,e,*, Christopher J. Lindsell f, Tarek Zakaria a,1, Christi Banks a, Michael D. Privitera a,e

a Department of Neurology, University of Cincinnati, Cincinnati, OH, USAb Department of Psychiatry, University of Cincinnati, Cincinnati, OH, USAc Department of Psychology, University of Cincinnati, Cincinnati, OH, USAd Department of Neuroscience, University of Cincinnati, Cincinnati, OH, USAe Cincinnati Epilepsy Center, Cincinnati, OH, USAf Department of Emergency Medicine, University of Cincinnati, Cincinnati, OH, USA

a r t i c l e i n f o

Article history:Received 6 January 2010Revised 10 February 2010Accepted 12 February 2010Available online 12 March 2010

Keywords:ElectroencephalographyIdiopathic generalized epilepsiesJuvenile myoclonic epilepsyMedication responseValproic acid

1525-5050/$ - see front matter � 2010 Elsevier Inc. Adoi:10.1016/j.yebeh.2010.02.005

* Corresponding author. Address: Department oCincinnati, 260 Stetson Street, Room 2350, Cincinnat+1 513 558 4305.

E-mail address: Jerzy.Szaflarski@uc.edu (J.P. Szafla1 Present address: Mayo Clinic, Rochester, MN, USA.

a b s t r a c t

In a minority of patients with idiopathic generalized epilepsies (IGEs), seizures continue despite appro-priate treatment. We sought to determine the clinical and EEG factors associated with medicationresponse in these patients. All patients with IGEs evaluated by epilepsy specialists between 17 November2008 and 16 November 2009 were included. We collected information on seizure freedom (dependentvariable), EEG asymmetries, response to valproic acid (VPA), MRI characteristics, medication use, demo-graphics, and seizure history (predictors). We identified 322 patients with IGEs; 45 (14%) were excludedfrom analyses because they had always had a normal EEG (N = 26), there were no EEG data (N = 3), or theywere non-compliant with medication (N = 26). Patients with juvenile myoclonic epilepsy were morelikely to respond to VPA than were patients with other IGEs, and VPA response was associated with sei-zure freedom. When EEG characteristics were considered, presence of any focal EEG abnormalities (focalslowing, focal epileptiform discharges, or both) was associated with decreased odds of seizure freedom.These findings suggest that patients with IGEs with poor seizure control may have atypical IGEs with pos-sibly focal, for example, frontal, rather than thalamic onset.

� 2010 Elsevier Inc. All rights reserved.

1. Introduction

Approximately 30–40% of people with epilepsy have seizuresdefined by the International League Against Epilepsy as general-ized at onset [1,2]. These patients experience various types of sei-zures including absences, myoclonic seizures, and generalizedtonic–clonic seizures. Although idiopathic generalized epilepsies(IGEs) are thought to be relatively easy to control with antiepilep-tic drugs (AEDs), up to 30% of patients with IGEs have incompleteresponse to treatment with valproic acid (VPA) or other AEDs [3,4].Some patients continue to have seizures despite best medical ther-apy and suffer significant long-term consequences including poorquality of life, unemployment, lack of independence, and stigma[5,6].

The reasons for relative ‘‘medication resistance” in patients withIGEs have been shown to include poor adherence to medication

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f Neurology, University ofi, OH 45267-0525, USA. Fax:

rski).

regimens (sometimes called ‘‘pseudo-resistance” [3]), presence ofpsychiatric problems [4,7], early age at epilepsy onset [8], andpresence of generalized tonic–clonic seizures [8,9]. In patients withJME, multiple seizure types and EEG asymmetries are associatedwith worse seizure control [10]. In childhood or juvenile absenceepilepsy, lack of control of absence seizures is a risk factor for per-sistent generalized tonic–clonic seizures [11]. Studies examiningtreatment resistance in IGEs have been limited to a small numberof subjects [3,10], were conducted before newer AEDs becameavailable or were tested in patients with IGEs [3,4,9,10], and fo-cused on clinical [12,13] or EEG [14,15] aspects of IGEs, sometimeswithout providing full definitions that were used to describe EEGabnormalities [9,10].

The AED of choice for patients with IGEs is VPA [16]; however,some patients remain poorly controlled despite large doses of thisor other syndrome-appropriate AEDs. Fernando-Dongas et al. re-ported that EEG asymmetries and intellectual deficiencies are asso-ciated with VPA resistance [10], but the intellectual deficiencieswere not well defined, suggesting the possibility that some of thesepatients may have had symptomatic rather than idiopathic gener-alized epilepsy. Therefore, the main aim of this retrospective studywas to explore factors associated with medication resistance in a

526 J.P. Szaflarski et al. / Epilepsy & Behavior 17 (2010) 525–530

large sample of patients with IGEs, with particular focus on identi-fying likely predictors of poor medication response in patients withJME and identifying differences in predictors between patientswith JME and those with other IGEs. The main hypothesis was thatpatients who respond to VPA and are well controlled show verytypical IGE characteristics including symmetric EEG abnormalities,with the opposite noted in patients with poorly controlled IGEs.Such findings, if present, could be due at least in part to focal epi-lepsies presenting clinically as IGEs.

2. Methods

2.1. Subjects

This retrospective observational study was approved by theinstitutional review board of the University of Cincinnati. Patientsseen in the outpatient clinic of the Cincinnati Epilepsy Center be-tween 17 November 2008 and 16 November 2009 were eligibleto participate if they were treated by an epilepsy specialist andhad a diagnosis of IGE as defined by the International LeagueAgainst Epilepsy [1,2]. We focused only on patients treated by epi-lepsy specialists, as epilepsy outcomes have been shown to differbetween patients treated by general neurologists and those treatedby epilepsy specialists [17,18]. Study subjects were identified viareview of the electronic health records; paper charts were re-viewed for missing data if needed (<10% of subjects with IGEs re-quired additional paper chart review). All charts were reviewedfor diagnosis based on the impression of the treating clinician. Incases where the chart entry was not clear, the treating physicianwas contacted directly with questions and/or a request for addi-tional records (<5% of the charts). If the diagnosis was still uncer-tain (e.g., frontal lobe vs generalized epilepsy), patients wereexcluded from the study.

Four hundred fifty-six patients with a clinical diagnosis of gen-eralized epilepsy were identified from 2522 reviewed charts (2107with epilepsy, 415 with diagnoses other than epilepsy, e.g., spellsor nonepileptic seizures). Of the 456 patients, 134 were excludedbecause they carried the diagnosis of symptomatic generalized epi-lepsy based on clinical presentation, EEG findings, or presence ofcognitive handicaps. Presence of cognitive handicaps was definedas IQ < 70 (if available), need for special education, or poor schoolperformance evidenced by the need to repeat grades. The remain-ing 322 patients were diagnosed with IGEs based on clinical andEEG criteria, and complete review of their charts was conducted(7 of these patients were included in the analyses of their EEG/fMRIdata as a part of a larger study evaluating generalized spike-and-wave discharge generators in patients with IGEs [19]).

2.2. Data collection and definitions

All charts were abstracted by a single investigator (J.P.S.) using astandardized case report form and data dictionary with explicit, pre-specified data definitions. Disease- and treatment-specific dataincluding type of epilepsy, AED therapy before and during treatmentwith VPA, duration of epilepsy, outcomes (as defined below), EEG,and neuroimaging were extracted. For the purpose of this study,IGEs were divided into four groups: (1) possible IGE but EEG alwaysnormal, (2) JME, (3) absence epilepsy (childhood or juvenile, AE), (4)other IGEs [20]. All charts were reviewed within 1 week of a patient’sepilepsy clinic visit, and charts of all patients enrolled were re-re-viewed on the last day of the study for any new data or findings (sei-zures, EEGs, study results, medication changes, etc.).

Seizure freedom was the outcome variable. As previously, weassessed charts for the presence/absence of seizures in the 3-month period preceding the last chart review [18]. The choice of

a 3-month cutoff was based on the fact that in our geographic area,a 3-month seizure-free period is required for driving. Further, thiscutoff was chosen to minimize the potential bias due to referral ofpatients with increased seizure frequency as this time is approxi-mately three to six times longer than our current wait time foran initial appointment. Expanding this variable to 12 monthswould be impractical as many charts do not contain such informa-tion. The seizure freedom variable was evaluated at each visit andchanged from seizure-free to non-seizure-free if there were calls orreports of seizures, if medication changes were instituted by thetreating physician for possible seizures, or if there was EEG evi-dence of seizures (e.g., 24-h ambulatory EEG showing absence sei-zures or bursts of generalized epileptiform discharges lasting morethan 2 s) [15,19,21,22]. Age at onset was defined as the first age atwhich seizures were observed (absence, myoclonus, or generalizedtonic–clonic seizures; febrile seizures clearly different from thediagnosis of IGE were excluded from age at onset calculations). Fi-nally, VPA response was defined as at least 3 months of seizurefreedom while being treated with this AED. Many patients eitherwere not able to tolerate this AED despite being seizure free (e.g.,because of tremor, weight gain, or hair loss) or had other reasonsfor discontinuation (e.g., women of childbearing age desiring to be-come pregnant).

Abnormal MRI was defined as any study with focal findings(e.g., medial temporal sclerosis, cortical dysplasia, areas of enceph-alomalacia) that could potentially have an effect on the diagnosis.All available EEG reports were reviewed for evidence of any abnor-malities; attempts were made to review the last performed EEG(routine, ambulatory, or video/EEG monitoring). We developedseparate definitions for review of the EEG report and for direct re-view of the EEG itself. For review of the EEG report, we defined thefollowing variables as reported by the interpreting physician: (1)normal EEG, (2) focal EEG abnormalities (e.g., focal slowing and/or focal epileptiform discharges), (3) focal epileptiform discharges,or (4) generalized epileptiform discharges. For review of the avail-able EEGs themselves, a more precise classification of abnormali-ties was developed [23,24]. This included four categories: (1)generalized spike-and-wave discharges or polyspike-and-wavedischarges (GSWDs) were defined as any epileptiform dischargesoccurring in bisynchronous fashion with maximum amplitudeusually over the F3 and F4 electrodes (possibly with bifrontaland paracentral or bi-occipital predominance). Focal epileptiformdischarges were considered spike fragments if they had clearlythe same morphology as GSWDs with the exception of the more fo-cal (e.g., predominantly over one hemisphere) appearance. (2)Spike fragments were defined as ‘‘asymmetric” GSWDs, as wereany GSWDs with more than 30% amplitude difference as measuredover the electrodes with the maximum GSWD amplitude. (3) Allother epileptiform discharges were labeled as ‘‘focal.” (4) Focalslowing was defined as any regional EEG abnormality that wasnot epileptiform in nature. Finally, current AEDs were divided intotwo groups to examine whether AED choices were affected by EEGabnormalities and whether the use of AEDs not indicated for thetreatment of IGEs led to better seizure control in patients withasymmetric EEG findings [25,26]. One group of AEDs included syn-drome-appropriate AEDs (VPA, lamotrigine, topiramate, zonisa-mide, levetiracetam, felbamate, and benzodiazepines); the secondgroup included other AEDs.

2.3. Data analyses

Data were initially characterized using descriptive statistics(means and SD or frequencies and percentages as appropriate).We compared groups of patients using Fisher’s exact test or Pear-son’s v2 test for categorical data, and Student’s t test for continuousdata. When data departed from normality, the Mann–Whitney U

J.P. Szaflarski et al. / Epilepsy & Behavior 17 (2010) 525–530 527

test was used for between-group comparisons and the Wilcoxonsigned-rank test was used for comparisons within groups. Wemodeled the effect of EEG abnormalities and VPA use on seizurefreedom using logistic regression. All analyses were a priori,planned comparisons and derived from the main hypotheses;therefore no corrections for multiple comparisons were madeand the significance level was set at 5% (a = 0.05) for all analyses(see below). All data management and analyses were performedusing SPSS Version 17.0 (SPSS Inc., Chicago, IL, USA).

3. Results

Twenty-nine patients (29/322, 9%) with a presumptive diagno-sis of IGE were excluded from analyses because either they alwayshad a normal EEG (26/29) or there was a lack of EEG data (3/29). Anadditional 26 (26/293, 9%) patients were excluded from analyseswith a history of medication noncompliance or inadequate lifestyleregulation (e.g., sleep deprivation or alcohol use) leading to possi-ble pseudo-resistance. Hence, the final sample included 267 sub-jects with IGEs (106 with JME, 55 with AE, and 106 with otherIGEs). There were no differences between the included and ex-cluded subjects in age at epilepsy onset (15.8 years vs 14.4 years,P = 0.07), age at enrollment (34.2 years vs 32.5 years, P = 0.27), gen-der (P = 0.06), or proportion with a JME diagnosis (P = 0.57). Finally,these analyses were repeated on all subjects with EEG data, includ-ing patients with normal EEGs (N = 293), to eliminate the influenceof non-inclusion of IGE patients with normal EEGs (N = 26) on theresults of the study. No significant differences were noted in age atepilepsy onset (16.0 vs 14.4, P = 0.379), age at enrollment (34.0 vs33.1, P = 0.729), gender (P = 0.069), or proportion of patients withJME (P = 0.687) between the included and excluded patients,respectively; there were no differences in seizure freedom(P = 0.913) or in VPA response (P = 0.682) between patients withalways normal EEGs and other patients.

Relatively minor differences were noted between patients withJME and other IGEs (Table 1). Patients with IGEs other than JMEhad a slightly higher chance of having GSWDs on their most recentEEG report (69.8% vs 57.1%, P = 0.04) and being older at epilepsyonset (17.2 years vs 13.7 years, P = 0.001); no differences werenoted in the frequency of incidental MRI findings, percentage of fe-males, or family history of epilepsy. Clinical differences were fur-

Table 1Demographic, clinical, and EEG/MRI characteristics of enrolled patientsa

Not JME JME P value No

Sei

Age at onset 17.16 11.30 13.70 5.51 0.001 1Male 53 32.9 39 36.8 0.514 4Female 108 67.1 67 63.2 8Generalized tonic–clonic seizures 149 92.5 98 92.5 1.000 12Absence seizures 97 60.2 51 48.1 0.059 7Family history of epilepsy (any type) 72 44.7 54 50.9 0.119 5GSWDs on most recent EEG 92 57.1 74 69.8 0.040 7Other abnormalities on most recent EEG 30 18.6 13 12.3 0.178 2GSWDs on first EEG 50 78.1 33 80.5 0.811 4Other abnormalities on first EEG 10 15.4 5 12.2 0.778Any EEG—other abnormalities 72 44.7 35 33.0 0.074 4Any EEG—focal slowing 29 18.0 15 14.2 0.501 1Any EEG—focal EDs 47 29.2 28 26.4 0.677 3MRI normal 142 88.2 93 87.7 0.931 11Reviewed—last EEG 129 80.1 75 70.8 0.105 10Reviewed—GSWDs present 69 53.5 47 62.7 0.241 5Reviewed—asymmetric EDs 32 24.8 18 24.0 1.000 1Reviewed—other focal abnormalities 14 10.9 7 9.3 0.815Reviewed—normal last EEG 55 42.6 24 32.0 0.140 5

On the left side of the table, all patients with JME are compared with patients with otheseizure-free patients with JME or other IGEs. GSWD, generalized spike and wave discha

a N = 267; patients with normal EEGs not included

ther evaluated. In patients with JME, having absences wasassociated with decreased odds of seizure freedom (OR = 0.100,95% CI = 0.021–0.465, P = 0.003) and of VPA response (OR 0.241,95% CI = 0.078–0.748, P = 0.014). Absence seizures were marginallyassociated with decreased odds of seizure freedom among all otherIGEs (OR = 0.419, 95 CI = 0.167–1.048, P = 0.063), but were notassociated with VPA response (OR = 0.880, 95% CI = 0.372–2.084,P = 0.771). Generalized tonic–clonic seizures were not included instatistical models as a predictor of seizure freedom because all pa-tients who were free of generalized seizures were also overall sei-zure free (JME and other IGEs), and in only one patient who neverhad generalized seizures was VPA not successful in controlling sei-zures. Inclusion of patients with normal EEGs resulted in only oneminor difference: the family history tended to be more common inthose with other IGEs than in those with JME (P = 0.055). Inclusionof patients with normal EEGs did not significantly change any ofthe subsequent results; hence the results of these analyses arenot reported.

In patients with JME, seizure freedom occurred in 85%, and inpatients with other IGEs seizure freedom occurred in 82% of cases(31 of 44 [70.5%] patients with juvenile AE were successfully con-trolled with VPA, 95% CI = 54.6–82.8%). Seizure freedom was notdependent on whether the patient had JME (P = 0.543). Finally,VPA was successful in controlling seizures in 78% of patients withJME and in 67% of patients with other IGEs. The success of VPAtended to depend on whether the patient had JME or not; the oddsof VPA being successful were 1.763 times higher for those with JMEthan those with other IGEs (95% CI = 0.923–3.370, P = 0.086). Thesuccess of VPA was a significant predictor of seizure freedom(OR = 6.05, 95% CI = 2.7–13.6, P < 0.001), and whether or not thesuccess of VPA predicted seizure freedom was independent ofJME (P = 0.725). Of note, from among 138 patients initially success-fully treated with VPA, 77 had to be weaned off this AED for sideeffects or other reasons. Although many remained seizure free, in12 this AED change resulted in loss of seizure freedom. For the pur-pose of this study these patients were labeled ‘‘VPA responders.”

3.1. Initial EEG

Results of the first EEG were available for 106 patients (41 withJME). Overall, there were no differences in the first EEG between

t JME JME

zure free Not seizure free P value Seizure free Not seizure free P value

7.80 11.85 14.24 7.90 0.125 13.98 5.62 12.13 4.70 0.2163 32.6 10 34.5 0.831 35 38.9 4 25.0 0.4029 67.4 19 65.5 55 61.1 12 75.00 90.9 29 100.0 0.126 82 91.1 16 100.0 0.6045 56.8 22 75.9 0.063 37 41.1 14 87.5 0.0019 44.7 13 44.8 0.990 43 47.8 11 68.8 0.2810 53.0 22 75.9 0.037 59 65.6 15 93.8 0.0350 15.2 10 34.5 0.032 7 7.8 6 37.5 0.0046 80.7 4 57.1 0.171 32 80.0 1 100.0 1.0006 10.3 4 57.1 0.008 5 12.5 0 .0 1.0009 37.1 23 79.3 0.000 24 26.7 11 68.8 0.0039 14.4 10 34.5 0.016 8 8.9 7 43.8 0.0021 23.5 16 55.2 0.001 19 21.1 9 56.3 0.0116 87.9 26 89.7 0.850 78 86.7 15 93.8 0.5636 80.3 23 79.3 1.000 62 68.9 13 81.3 0.3862 49.1 17 73.9 0.038 35 56.5 12 92.3 0.0248 17.0 14 60.9 0.000 11 17.7 7 53.8 0.0118 7.5 6 26.1 0.019 4 6.5 3 23.1 0.0950 47.2 5 21.7 0.035 23 37.1 1 7.7 0.050

r IGEs; on the right side of the table, seizure-free patients are compared with non-rge; ED, epileptiform discharge.

528 J.P. Szaflarski et al. / Epilepsy & Behavior 17 (2010) 525–530

patients with JME and those with other IGEs (Table 1). GSWDs andfocal EEG abnormalities (focal slowing and/or focal epileptiformdischarges) were noted more frequently on the first EEG in patientswith IGEs who later did not achieve seizure-free status (P = 0.037and 0.032, respectively); focal EEG abnormalities were also notedmore frequently in non-seizure-free patients with JME (P = 0.004).

3.2. All EEGs

Several significant differences between seizure-free and non-seizure-free patients were noted when the EEG variables werecompared (Table 1). Overall, patients with JME and those withother IGEs with focal EEG abnormalities (focal slowing, focal epi-leptiform discharges, or both) were less likely to be seizure free.On the basis of EEG reports, focal slowing or focal epileptiform dis-charges individually did not significantly decrease the odds of sei-zure freedom (OR = 0.776, 95% CI = 0.311–1.94, P = = 0.588;OR = 0.563, 95% CI = 0.248–1.277, P = 0.169, respectively), but thepresence of any focal EEG abnormalities (combined focal slowingand focal epileptiform discharges) was associated with decreasedodds of seizure freedom (OR = 0.241, 95% CI= 0.084–0.695,P = 0.008). Based on the review of the last EEG, asymmetry inGSWDs and focal findings (focal slowing or focal epileptiform dis-charges) were significantly associated with decreased odds of sei-zure freedom (OR = 0.209, 95% CI = 0.083–0.526, P = 0.001, andOR = 0.244, 95% CI = 0.074–0.805, P = 0.021, respectively), whereasGSWDs and normal findings were not (OR = 0.258, 95% CI = 0.036–1.859, P = 0.179, and OR = 0.386, 95% CI = 0.045–3.311, P = 0.385).Thus, the findings indicate that seizure-free patients are morelikely to have an EEG that either is normal or shows only symmet-ric GSWDs. Finally, EEG asymmetry variables were not associatedwith type of AED used based on logistic regression (all P P 0.093for all), and the use of non-syndrome-specific AEDs in these pa-tients was not associated with decreased seizure control (allP P 0.178).

4. Discussion

In this retrospective study we explored EEG findings associatedwith seizure freedom and medication response in patients withJME and other types of IGE. Our main finding is that any EEG asym-metries in patients with IGEs, whether focal slowing, focal epilepti-form discharges, or asymmetric GWSDs (defined as more than 30%amplitude asymmetry), are associated with poor VPA responseand decreased chance of seizure freedom. Although these findingsmay not be surprising as they are supported by literature, theyprovide additional evidence for clinical and possibly functional dif-ferences between patients with medication-responsive and medica-tion-resistant IGEs.

Several studies have evaluated factors associated with poor sei-zure control in patients with IGEs. The concept is that because pa-tients with IGEs are thought to have the same location and type ofseizure and GSWD generators and the seizures and other clinicalpresentations of IGEs are a continuum that starts in childhoodand persists throughout lifetime [27], then these patients shoulduniformly respond to the same AED. The notion of an IGE contin-uum is further supported by human EEG triggered functionalMRI (EEG/fMRI) data revealing that seizures or GSWDs in eitherdrug-naïve children [28] or AED-treated adult patients [29] arepossibly generated in the thalami, indicating the same underlyingetiology as part of such a continuum. Recent human [19,30] datasuggest that in some patients the frontal lobes may be the seizureand GSWD generators. These authors suggest that the thalamusmay be involved in GSWD generation as a part of the network thatparticipates in seizure propagation rather than being the main

component of such a network. If patients with IGEs represent acontinuum of the same disorder with thalamic onset then, at leasttheoretically, they should respond to one and possibly the sameAED, especially VPA, the prototypical AED used in IGEs [31]. Whydo so many patients require AEDs other than VPA or remain poorlycontrolled despite multiple therapeutic trials [32,33]? This retro-spective study has attempted to shed light on the underlying fac-tors leading to AED resistance.

Relatively little is known about the prevalence and the risk fac-tors associated with drug resistance or intractability in patientswith IGEs. Few studies have tried to address this question in se-lected groups of patients with IGEs (mainly patients with JME).For example, in a retrospective review of 155 consecutive patientswith newly diagnosed JME, 15.5% had persisting seizures despiteadequate therapy and lifestyle adjustment [4]. Clinical featuresassociated with drug resistance were the presence of psychiatricproblems and the combination of three seizure types (absence,myoclonic, and generalized tonic–clonic). Further, in concordancewith our findings, family history of epilepsy, age at seizure onset,gender, and results of conventional neuroimaging (CT and MRI)were not significantly associated with drug resistance in JME. Astudy of risk factors associated with VPA resistance in childhoodepilepsy found that experiencing generalized seizures and highpretreatment absence frequency were associated with poor seizurecontrol [11]. Another retrospective review of patients with JMEwith intractable epilepsy found that 10 of 33 patients (30%) wereVPA resistant [10], and as a group, the VPA-resistant patients hada higher frequency of EEG asymmetries, although the asymmetrieswere not clearly defined. Atypical seizure characteristics, includingauras and postictal confusion and intellectual deficiency, were alsoassociated with medication resistance. This brings the issue of EEGasymmetries into light. In our study, we performed two separateanalyses of EEG data: one based on review of the EEG report andone based on review of the EEG itself. Although we do not seeany substantial differences in EEG characteristics between patientswith JME and those with other IGEs, there is clear evidence thatEEG asymmetries, whether based on review of the EEG report orof the EEG itself (initial or all EEG data), are associated with resis-tance to VPA and/or other AEDs. This may be related to differencesin localization of the GSWD generators. If, in fact, IGE-like epilep-sies can be a manifestation of focal lesions, this would explainthe presence of focal EEG abnormalities and also the lower re-sponse to VPA [34–36]. Finally, IGEs as a group of epilepsies areconsidered to be of primarily genetic origin, but specific geneticabnormalities have thus far been identified in only a minority ofpatients with IGEs [37]. Although some of the families with identi-fied genetic abnormalities have mendelian or monogenetic abnor-malities [38–40], other, complex modes of inheritance (e.g., single-nucleotide polymorphisms) were also identified [41]. Because thegenetic abnormalities and associated molecular abnormalities arelikely widespread, we would expect these patients to have sym-metric EEG abnormalities more frequently than other patientsdiagnosed with IGEs. Such molecular differences may also underliedifferences in VPA response between the patients with genetic epi-lepsies and those with other etiologies of their epilepsies, but cur-rently such data are not available.

To our knowledge, there have been few large studies that haveincluded patients with multiple IGEs subtypes and their EEG data.In an analysis of 962 pediatric and adult patients with IGEs, Nicol-son et al. found that an age at onset younger than 5 years or an‘‘atypical” presentation was associated with poor outcome [31].These authors also reviewed EEG data as a part of syndromic clas-sification and did not find any EEG differences between patientswith controlled seizures and patients with persistent seizures(their EEG data description for analysis was very limited: GSWDs,photoparoxysmal responses, or focal abnormalities). A study by

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Wolf and Inoue noted that asymmetric GSWDs were associatedwith lack of response to medications in patients with absence sei-zures [9]. Another, aforementioned study by Fernando–Dongaset al. noted that EEG asymmetries are associated with medicationresistance in patients with JME [10]. Finally, Leutmezer et al. notedfocal EEG features in 30–35% of patients with IGEs and poorly con-trolled seizures [20]. Our finding of an association between focalEEG abnormalities and poor seizure control is in concordance withthese studies. Based on the above, a pattern appears to be emerg-ing: focal EEG abnormalities are associated with an increased riskof poor seizure control. So, the question remains: Is there other evi-dence to support focal, possibly frontal lobe dysfunction in patientswith IGEs and, therefore, to support the theory that the frontallobes and not the thalamus may be the reason for AED resistancein atypical patients with IGEs? Based on the notion that patientswith asymmetric EEG findings could have focal onset epilepsy,we conducted additional analyses to evaluate the effect of syn-drome-appropriate versus syndrome-inappropriate AED use inthese patients, as syndrome-inappropriate AEDs were observedpreviously to lead to poor seizure control [25,26]. The lack of thisrelationship in our data may be related to the fact that these anal-yses were performed based on the current status of seizure controlafter AEDs were adjusted by epilepsy-trained physicians who havebeen shown to afford patients with better seizure control thannon-epilepsy-trained physicians [18].

The issue of frontal lobe dysfunction in patients with frontallobe epilepsy and JME was previously examined using neuropsy-chological testing and PET [4,42–46]. These studies found frontallobe dysfunction in patients with JME to be similar to the abnor-malities seen in patients with frontal lobe epilepsy. Furthermore,previously mentioned MRI studies confirmed that up to 40% of pa-tients with JME have structural abnormalities [47–49], but neitherthese nor other studies have questioned whether the functionaland structural abnormalities are more prevalent in patients withVPA-resistant or VPA-controlled JME. These studies confirmedthe autopsy findings from two case series of patients with IGEand/or JME that have shown frontal cortical and subcortical dys-topic neurons and microdysgenesis in some of these patients[50,51]. Several studies have examined the psychiatric comorbidi-ties and cognitive profiles of patients with IGEs. One study foundthat patients with JME as a group had more psychiatric disorders,psychosocial problems, and anxiety and mood disorders whencompared with matched healthy controls [52], whereas other stud-ies showed maladaptive behavioral consequences and overall fron-tal lobe dysfunction in patients with JME [42,53]. Such psychiatricproblems are more likely to exist in patients with JME who arepoorly responsive to AEDs (58.3% vs 19%, P < 0.001) [4]. Further-more, symptoms of frontal lobe dysfunction seen in patients withpsychiatric conditions, which include depression, apathy, lack ofdrive, inertia, and irritability, are also seen in patients with epi-lepsy, especially frontal lobe epilepsy [54,55]. Therefore, the avail-able clinical, EEG, and neuroimaging evidence appears to point tothe frontal lobes as the sources of GSWDs and possibly seizuresin patients with poorly controlled IGEs.

Limitations of this study should be noted. First, not all EEGswere reviewed and not all reports were identified. This is relatedto some patients being older and treated by many physicians priorto their visits to our center. Therefore, we cannot exclude the pos-sibility that some EEGs with focal features were missed. Further,EEG interpretation can sometimes be subjective, especially wheninvolving interpretation of subtle spike–wave asymmetries. Wewere surprised at the consistency between the EEG reports andour direct analysis of EEG; thus we believe subtle differences ininterpretation did not have a major effect on our results. Second,as in all retrospective studies, selection bias may have led to inclu-sion of patients who are more likely to be referred to a tertiary epi-

lepsy center, that is, patients with poorly controlled IGEs. Again,this appears to be unlikely as the proportion of patients with sei-zures controlled with medications in our study is similar to thosein other reports. Another limitation related to the retrospectivenature of the study is lack of a standardized approach to diagnosisand selection of appropriate AEDs; hence, it is possible that somepatients were misclassified as having IGEs while having othertypes of epilepsies and/or were treated with medications thatmay not be indicated for patients with IGEs.

In summary, our study showed that in patients with IGEs, theprognosis for long-term seizure freedom may depend on initial re-sponse to VPA and EEG characteristics. Failure of VPA or presenceof EEG asymmetries may indicate the diagnosis of frontal lobe epi-lepsy rather than IGEs.

Acknowledgments

This work was supported in part by a Career DevelopmentGrant to J.P.S. (NIH K23 NS052468). This work was presented inpart at the 134th Annual Meeting of the American NeurologicalAssociation and in part at the 38th Annual Meeting of the AmericanEpilepsy Society.

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