Published Ahead of Print on July 17, 2015 as 10.1212/WNL.0000000000001841

Focal seizure symptoms in idiopathic generalized epilepsies

Udaya Seneviratne, MRCP(UK), FRACP Jia J. Woo, MD Ray C. Boston, PhD Mark Cook, MD, FRACP Wendyl D’Souza, FRACP, PhD

Correspondence to Dr. Seneviratne: [email protected]

ABSTRACT

Objective: We sought to study the frequency and prognostic value of focal seizure symptoms (FSS) in idiopathic generalized epilepsies (IGE) using a validated tool: Epilepsy Diagnostic Interview Questionnaire and Partial Seizure Symptom Definitions.

Methods: Participants with IGE were recruited from epilepsy clinics at 2 tertiary hospitals. The diagnosis was validated and classified into syndromes according to the International League Against Epilepsy criteria by 2 epileptologists independently with discordance resolved by consensus. The Epilepsy Diagnostic Interview Questionnaire utilizes both open- and closed-ended questions to elicit FSS in association with generalized tonic-clonic seizures, myoclonus, and absences. The elicited FSS were classified according to the Partial Seizure Symptom Definitions. Regression analysis was conducted to examine the relationship between the duration of seizure freedom and FSS. Results: A total of 135 patients were studied, of whom 70 (51.9%) reported FSS. Those symptoms occurred in association with generalized tonic-clonic seizures (53.1%) as well as myoclonus and absences (58%). FSS were reported with similar frequency in juvenile absence epilepsy (62.5%) and juvenile myoclonic epilepsy (60%), and with a lesser frequency in generalized epilepsy with tonic-clonic seizures only (39.5%) and childhood absence epilepsy (33.3%). A strong relationship between FSS and duration of seizure freedom was found (regression coefficient 20.665, p 5 0.037).

Conclusions: FSS are frequently reported by patients with IGE. A shorter duration of seizure freedom is associated with FSS. Recognition of the presence of FSS in IGE is important to avoid misdiagnosis and delayed diagnosis as well as to choose appropriate antiepileptic drug therapy. Neurology® 2015;85:1–7 GLOSSARY AED 5 antiepileptic drug; CAE 5 childhood absence epilepsy; FSS 5 focal seizure symptoms; GTCS 5 generalized tonicclonic seizures; GTCSO 5 generalized epilepsy with tonic-clonic seizures only; IGE 5 idiopathic generalized epilepsy; ILAE 5 International League Against Epilepsy; JAE 5 juvenile absence epilepsy; JME 5 juvenile myoclonic epilepsy; PSSD 5 Partial Seizure Symptom Definitions.

Epilepsies are dichotomized into “focal” and “generalized” groups in the International League Against Epilepsy (ILAE) classifications.1,2 This distinction suggests that focal and generalized features do not mix. However, there has been growing emphasis on epilepsy as a disorder of network dysfunction, as reflected in the recent ILAE terminology.2 According to the network hypothesis, focal seizures arise from networks confined to a single cerebral hemisphere, whereas generalized seizures involve bilaterally distributed networks.2 Hence, a “focal” onset within the bilateral network is possible in generalized epilepsies.2 Many publications have reported various focal features in idiopathic generalized epilepsies (IGE), despite representing generalized seizures. We recently highlighted the spectrum of focal features in IGE regarding semiology, EEG, neuropsychology, and neuroimaging.3 The presence of focal features in a patient with IGE may have far-reaching consequences such as unnecessary From the Department of Medicine, St. Vincent’s Hospital (U.S., R.C.B., M.C., W.D.S.), and St. Vincent’s Clinical School (J.J.W.), University of Melbourne; Department of Neuroscience (U.S.), Monash Medical Centre, Melbourne, Australia; Department of Clinical Studies (R.C.B.), New Bolton Center, School of Veterinary Medicine, University of Pennsylvania, Philadelphia. Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article. © 2015 American Academy of Neurology

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investigations, delayed diagnosis, misdiagnosis, and the use of inappropriate antiepileptic drugs (AEDs).3 We hypothesized that focal (partial) seizure symptoms (FSS) are compatible with the diagnosis of IGE and undertook a study to evaluate FSS experienced by patients diagnosed with IGE. The study was designed to eliminate the many limitations of previous data with the use of a validated, standardized questionnaire in a well-characterized cohort. METHODS We prospectively recruited patients through consecutive referrals from epilepsy specialists at 2 tertiary hospitals in Melbourne, Australia (St. Vincent’s Hospital and Monash Medical Centre). Patients recruited were part of an ongoing study on the prognosis of IGE. We established the diagnosis of IGE using ILAE criteria.1,2 Before recruitment, all patients had EEGs and brain MRI performed as per routine practice of the epileptologists. Some patients had further investigations such as videoEEG monitoring and PET scans to rule out focal epilepsy. All medical records including EEG and neuroimaging were reviewed independently by 2 epilepsy specialists (U.S. and W.D.S.) with any discordance on syndromic diagnosis resolved by consensus based on ILAE criteria.1,2 We included patients with a definitive diagnosis of IGE based on the combination of consistent clinical features and a positive EEG showing generalized epileptiform discharges at least on one occasion. Exclusion criteria were potentially epileptogenic structural abnormalities on MRI, coexistent focal and generalized epilepsies, secondary bilateral synchrony as defined by Blume and Pillay,4 and single seizure with generalized epileptiform abnormalities on EEG. A more recent ILAE report has defined a single unprovoked seizure with at least 60% recurrence risk as epilepsy.5 However, this definition was not established at the time the study was planned and launched. To study FSS, we used a validated tool, Epilepsy Diagnostic Interview Questionnaire and Partial Seizure Symptom Definitions (PSSD), developed for the Epilepsy Family Study of Columbia University.6 This diagnostic interview has been designed to elicit seizure types and symptoms. FSS elicited were then classified according to PSSD. This tool has been shown to have good validity and interrater reliability.6 The questionnaire contains 10 questions pertaining to “grand mal seizures” (major seizures: generalized tonic-clonic seizures [GTCS]) and 23 questions pertaining to “small seizures” (minor seizures: myoclonus and absences). Both open-ended questions to record patients’ verbatim and closed-ended questions to explore specific symptoms have been included. The PSSD has been designed to classify focal symptoms under 5 major categories: sensory, motor, speech, autonomic, and psychic. All participants were interviewed by 2 investigators (J.J.W. and U.S.) face-to-face or via telephone. The consensus opinion on FSS classification was arrived at by a panel discussion of investigators. The Epilepsy Diagnostic Interview Questionnaire contained questions to elicit the dates of last seizure. The seizure-free duration was calculated based on the date of the last seizure (grand mal or small) and the date of the interview. Most patients had 24-hour ambulatory EEG recordings, planned prospectively after obtaining the consent. The interviews were conducted on the date of EEG or close to the date. The international 10-20 electrode placement system was used for EEG recording. An experienced EEG reader (U.S.) reviewed and scored all ambulatory EEGs. For the purpose of the current study, the 2

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presence or absence of focal epileptiform discharges was taken into consideration. Focal epileptiform discharges were defined as those confined to a single lobe or part of a lobe. Bifrontal discharges (both symmetric and asymmetric) were considered to be fragments of frontal expression of generalized epileptiform activity and not classified as focal. We took caution to exclude frontal lobe epilepsy based on clinical and neuroimaging findings, as symmetric bifrontal discharges can also be found in frontal lobe epilepsies. Furthermore, we excluded focal epilepsies by ensuring the EEGs had typical generalized discharges in addition to focal and bifrontal discharges. Descriptive statistics included frequencies/percentages for categorical variables and mean/median and SD for continuous variables. We used x2 test for independence to explore the significance of the relationship between epilepsy syndrome and FSS. To quantitate the relationship between duration of seizure freedom and FSS, we used regression analysis. In keeping with common time-to-event investigations, the outcome variable, seizure-free duration, was logarithmically transformed. This rendered the outcome normally distributed. To explore the possible influence of confounders on the log duration of seizure freedom–FSS relationship, we admitted several contentious confounders (such as number of AEDs, age of seizure onset, age at interview, duration of epilepsy, presence of GTCS, and presence of focal discharges in EEG) into the log duration–FFS regression and monitored changes to the crude regression coefficient. Finally, to explore the potential impact of outliers on the robustness of our ordinary least squares regression analysis, we additionally examined the statistics of robust regression analysis on critical regression relationships. All data analyses were conducted with Stata (version 13.1) statistical software package (StataCorp LP, College Station, TX). A p value of 0.05 was deemed significant.

Standard protocol approvals, registrations, and patient consents. This study was approved by the human research ethics committees of St. Vincent’s Hospital and Monash Health. Written informed consent was obtained from all patients to participate in all components of the study.

A total of 152 patients were invited to participate in the study and 140 consented. Five patients were excluded because of structural abnormalities in 2 (hippocampal sclerosis, polymicrogyria) and presentation with a single seizure although the EEG showed generalized epileptiform discharges in 3. The cohort consisted of 49 (36.3%) males and 86 (63.7%) females with mean age of 33.2 6 13.7 years. The mean age of seizure onset was 13.6 6 5 years with median duration of seizure freedom of 215 days. The age distribution in relation to syndromes and seizure types is given in table 1. Juvenile myoclonic epilepsy (JME) was the most common epilepsy syndrome in the cohort accounting for 37%, followed by generalized epilepsy with tonicclonic seizures only (GTCSO) (28.1%), juvenile absence epilepsy (JAE) (23.7%), and childhood absence epilepsy (CAE) (11.1%). The majority (43%) received monotherapy whereas 39.3% and 10.4% were treated with 2 and 3 AEDs, respectively. At the time of interview, 7.3% were not receiving AED therapy. Sodium valproate was the most frequently used AED in 73.3%. RESULTS

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Table 1

Age at interview in relation to syndromes and seizure types Age at interview, y Mean (SD)

Median (IQR)

Childhood absence epilepsy

35.5 (13.2)

29 (28–42)

Juvenile absence epilepsy

34.2 (16.3)

30 (20–44.8)

Juvenile myoclonic epilepsy

32.7 (12.3)

29 (23–40.5)

Generalized epilepsy with tonic-clonic seizures only

32 (13.9)

28.5 (20.8–39.3)

Generalized tonic-clonic seizures

33.3 (13.9)

29.5 (22.3–41.5)

Myoclonic and/or absence seizures

34 (14)

30 (22.3–42)

Abbreviation: IQR 5 interquartile range.

Eighty-three patients underwent 24-hour ambulatory EEG recordings, of which 18 (21.7%) demonstrated focal epileptiform discharges in addition to generalized discharges. Table 2

Major seizures (GTCS) were reported by 94.8% of patients, whereas 65.2% had experienced minor seizures (absence and/or myoclonic seizures). In describing FSS, we followed the scheme adopted by the Epilepsy Family Study of Columbia University.6 FSS were equally common in association with both major (53.1%) and minor (58%) seizures (table 2). Syndromic breakdown of FSS is contained in table 3. Overall, 70 patients (51.9%) reported FSS. Aphasia, both receptive and expressive, was the most frequent symptom in response to a closed-ended question. FSS were more common in JAE (62.5%) and JME (60%) than GTCSO (39.5%) and CAE (33.3%). However, these differences failed to reach statistical significance (p 5 0.07). We found a strong relationship between FSS and the duration of seizure freedom, indicating that shorter duration of seizure freedom was associated with FSS. None of the confounders had a significant

Summary of focal seizure symptoms reported by patients

Symptom type

Descriptions by patients

With GTCS

With MS/AS Total

Focal tonic/clonic/ myoclonic

Stiffening, jerks, twitch, sudden shakes, sharp movements

10 (7.8)

5 (5.7)

10 (7.4)

Automatisms

Lip smacking, twirling fingers, chewing, flicking clothes, rearranging things, walking around in circles

5 (3.9)

6 (6.8)

11 (8.1)

5 (3.9)

0

5 (3.7)

Eyes roll to one side

1 (0.8)

0

1 (0.7)

Somatosensory

Numbness, tingling

2 (3.1)

7 (7.9)

9 (6.7)

Auditory

Ringing, echoing, noises getting louder

7 (5.5)

4 (4.5)

11 (8.1)

Motor

Focal weakness Eye version Sensory

Olfactory

Bad smell

1 (0.8)

0

1 (0.7)

Gustatory

Metallic taste, bitter taste

2 (1.6)

1 (1.1)

2 (1.5)

Vision

Black and white spots, colorful spots, wiggly lines, see only half

18 (14.1)

8 (9.1)

24 (17.8)

Cephalic

Funny feeling in head, hard to describe

3 (2.3)

0

3 (2.2)

Visceral/epigastric

Rising sensation, butterflies, rush, electric surge, tingling, queasy, sick, tingling in stomach

14 (10.9)

3 (3.4)

16 (11.9)

Chest tightness

Tightness in chest with panic sensation

2 (1.6)

1 (1.1)

3 (2.2)

Cardiac

Palpitations

2 (1.6)

1 (1.1)

3 (2.2)

Diaphoresis/flushing/ warmth

Sweaty feet, hot flush, feel warm

4 (3.1)

0

4 (3)

Familiar feeling, being there before

4 (3.1)

0

4 (3)

Autonomic

Psychic Déjà vu Autoscopy

Feeling out of body, like watching yourself

1 (0.8)

0

1 (0.7)

Euphoria

Overwhelming happiness

1 (0.8)

0

1 (0.7)

19 (21.5)

33 (24.4)

Speech Aphasia

Wanted to talk but could not, slower processing of speech, 20 (15.6) slurred speech, difficulty in understanding, could not speak the right word

Abbreviations: AS 5 absence seizures; GTCS 5 generalized tonic-clonic seizures; MS 5 myoclonic seizures. Data are presented as n (%). Neurology 85

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Table 3

Summary of focal seizure symptoms in syndromes CAE (n 5 15)

JAE (n 5 32)

JME (n 5 50)

Focal tonic/clonic/myoclonic

0

3 (9.4)

6 (12)

1 (2.6)

Automatisms

1 (6.7)

4 (12.5)

6 (12)

0

Focal weakness (postictal)

0

3 (9.4)

0

2 (5.3)

Eye version

0

0

0

1 (2.6)

Somatosensory

0

2 (6.3)

5 (10)

2 (5.3)

Auditory

1 (6.7)

3 (9.4)

5 (10)

2 (5.3)

Olfactory

0

1 (3.1)

0

0

Gustatory

0

0

1 (2)

1 (2.6)

Vision

2 (13.3)

6 (18.8)

8 (16)

8 (21.1)

Cephalic

0

0

3 (6)

0

Visceral/epigastric

0

5 (15.6)

3 (6)

8 (21.1)

Chest tightness

0

1 (3.1)

1 (2)

1 (2.6)

Cardiac

0

1 (3.1)

0

2 (5.3)

Diaphoresis/flushing/warmth

0

1 (3.1)

0

3 (7.9)

Déjà vu

0

0

2 (4)

2 (5.3)

Autoscopy

0

1 (3.1)

0

0

Euphoria

0

0

0

1 (2.6)

2 (13.3)

12 (37.5)

14 (28)

5 (13.2)

Symptom type

GTCSO (n 5 38)

Motor

Sensory

Autonomic

Psychic

Speech Aphasia

Abbreviations: CAE 5 childhood absence epilepsy; GTCSO 5 generalized epilepsy with tonic-clonic seizures only; JAE 5 juvenile absence epilepsy; JME 5 juvenile myoclonic epilepsy. Data are presented as n (%).

impact on this association (table 4, figure). Focal discharges in EEG and the number of AEDs were negatively related to the duration of seizure freedom, whereas the presence of GTCS was positively related (table 4). No differences between ordinary least squares and robust regression results were observed. DISCUSSION Our study demonstrates that FSS are common in IGE with 51.9% of patients reporting such symptoms based on a validated questionnaire. Aphasia, visual aura, epigastric sensation, auditory symptoms, automatisms, and focal motor activity are the most common FSS reported. Patients with JAE and JME more frequently experience these symptoms than those with CAE and GTCSO. The presence of FSS suggests a worse disease course with a shorter duration of seizure freedom. These findings are consistent with previous studies indicating that FSS are common in IGE.7 In addition, our study reports 3 novel findings. First, FSS occur in 4

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association with both major and minor seizures equally. Second, such symptoms are more common in JAE and JME than CAE and GTCSO. Third, the presence of FSS is associated with a shorter period of seizure freedom. Focal abnormalities are not uncommon in IGE. Many focal features in the domains of semiology, EEG, neuropsychology, neuroimaging, and neuropathology have been reported.3 In our recently published literature review,3 4 studies reported auras experienced by patients with IGE, ranging from 10% to 70%.8–11 However, small sample size and the lack of a standardized protocol to elicit symptoms of auras are major limitations in these studies. A more recent study has reported auras in 64.3% of patients diagnosed with generalized epilepsy.7 This wide range can be explained on the basis of differences in methodology, in particular the protocol to elicit symptoms. In response to open-ended questions, 21.3% diagnosed with generalized epilepsy reported auras, which increased to 64.3% with the use of a closed-ended questionnaire in the same cohort.7 We used a validated tool using both open-ended and closed questions to elicit FSS in order to avoid this pitfall. Aphasia was the most frequent FSS reported in association with both major and minor seizures, a finding concordant with a recent study.7 Automatisms, epigastric sensation, and déjà vu are usually considered to be features of focal epilepsy. However, our study shows that such symptoms also occur in IGE. This has practical implications because the presence of FSS may prompt the clinician to diagnose focal epilepsy and treat with narrow-spectrum AEDs. Delayed diagnosis and misdiagnosis of IGE as focal epilepsy with adverse consequences have been reported.12 Because of the presence of FSS, patients with IGE may be prescribed carbamazepine resulting in exacerbation of myoclonic and absence seizures.13 In JME, the mean diagnostic delay ranges from 5.9 to 15 years exposing the patient to the risk of ongoing seizures.3 The lack of seizure remission is a critical risk factor in the morbidity associated with injury, burns, drowning, and vehicular crashes in patients with epilepsy.14 Even though epilepsy onset was characterized by typical absence seizures, 60% of patients with CAE reported subsequent GTCS. This finding is concordant with previous research, and a recent literature review has reported GTCS among 8% to 69% of patients with CAE.15 The most interesting and novel finding in our study is the association between FSS and duration of seizure freedom. A shorter duration of seizure freedom was significantly associated with FSS. This relationship was unaffected by confounders such as number of AEDs, age of seizure onset, age at

August 18, 2015

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Table 4

Results of regression analysis demonstrating the relationship between duration of seizure freedom and focal seizure symptoms as well as the impact of potential confounders

Exposure/confounder

RC

95% CI

p

1. Focal symptoms (crude association)

20.665

21.290 to 20.040

0.037

2. Focal symptoms

20.536

21.155 to 0.083

0.089

20.531

20.929 to 20.134

0.009

20.634

21.265 to 20.003

0.049

20.039 to 0.087

0.456

No. of AEDs 3. Focal symptoms Age at onset

0.024

4. Focal symptoms

20.623

21.243 to 20.004

0.049

Age at interview

0.023

0.0001 to 0.045

0.049

5. Focal symptoms

20.656

Duration of epilepsy 6. Focal symptoms Presence of GTCS 7. Focal symptoms Presence of FDs in EEG

21.277 to 20.034

0.039

0.018

20.004 to 0.039

0.108

20.740

21.36 to 20.120

0.020

0.16 to 2.953

0.029

1.556 20.773

21.53 to 20.0165

0.045

20.610

21.528 to 0.308

0.190

Abbreviations: AED 5 antiepileptic drug; CI 5 confidence interval; FD 5 focal discharge; GTCS 5 generalized tonic-clonic seizures; RC 5 regression coefficient.

interview, duration of epilepsy, presence of GTCS, and presence of focal discharges in the EEG. We acknowledge that 95% confidence interval includes zero when adjusted for some confounders such as number of AEDs. However, we believe it is attributable to the relatively small sample size, and the association between the duration of seizure freedom and FSS is still clinically relevant. Overall, our study raises the possibility that the presence of FSS may be an important prognostic factor associated with the duration of seizure freedom. Previous studies have reported conflicting results on the presence of focal

Figure

Influence of confounders on the relationship between duration of seizure freedom and FSS

A strong relationship between FSS and the duration of seizure freedom is demonstrated (regression coefficient 20.665). Note none of the confounders has a significant impact on this association. AED 5 antiepileptic drug; CI 5 confidence interval; FSS 5 focal seizure symptoms; GTCS 5 generalized tonic-clonic seizures.

EEG abnormalities as a predictor of prognosis.3 To our knowledge, the prognostic significance of FSS in IGE has not been previously published. However, an alternative explanation is recall bias, whereby those with a shorter duration of seizure freedom and more frequent seizures may be more likely to remember their FSS. Patients with shorter durations of seizure freedom have had more recent seizures, hence, are more likely to be able to reinforce their perceptions and recall subtle FSS. Although there was no statistically significant difference, FSS were more common in JME and JAE (table 3). It is possible that the presence of myoclonic seizures may be a contributory factor to this difference. As shown in table 3, focal motor activity was most frequently reported in JAE and JME. This observation is in keeping with previous studies indicating that unilateral and asymmetric myoclonic seizures are detected in 14% to 61% of patients with JME.3 Furthermore, it is also possible that patients who experience seizures without alteration of consciousness, such as myoclonic jerks, may remember their FSS better. Our study also highlights practical challenges in semiology-based epilepsy classification. We studied a well-characterized cohort with an unequivocal diagnosis of IGE and found FSS in more than 50% of cases. This might lead to misdiagnosis as focal epilepsy, if the clinician relies too much on focal symptoms in the classification. Hence, we emphasize the critical role of EEG in the confirmation of diagnosis of IGE. We acknowledge some limitations of this study. First, the study was conducted in 2 tertiary centers introducing a potential selection bias. Patients recruited were in the pilot phase of an ongoing study on IGE prognosis, hence, with a referral bias. It is possible that patients with more complex IGE with atypical features such as FSS were overrepresented in our centers. In our cohort, JME was the most frequent IGE syndrome followed by GTCSO, JAE, and CAE. A large, adult, hospital-based cohort study reported GTCSO in 52%, and 16% each of the other 3 IGE syndromes.16 On the contrary, a populationbased study of children found prevalence rates of 0.2 per 1,000 in CAE and 0.1 per 1,000 in JME, JAE, and GTCSO.17 These discordances reflect the potential for selection bias in hospital cohorts as in our study. However, cohorts from tertiary hospitals are likely to be well-characterized and better investigated yielding more reliable results. Second, there is recall bias. This study predominantly captured prevalent disease and the questionnaire depended on the participants’ memory to recall their previous FSS. Those with a shorter duration of seizure freedom may be more likely to remember their symptoms. Third, Neurology 85

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there is ascertainment bias. Patients with FSS might have been overrepresented in the sample because they were more likely to identify their seizures and seek treatment. Fourth, the sample size could be considered relatively small, and a larger sample using the same methodology could potentially yield more robust results. The cohort shows skewed sex distribution with a higher proportion of females. Previous epidemiologic studies have shown that females are more likely to participate in research than males.18 Hence, we believe the higher proportion of females in the cohort is a reflection of bias in participation and small sample size rather than a biologically driven phenomenon. Finally, our questionnaire gathered self-reported FSS. Many focal semiologic features such as head version, figure-4 sign, hemiconvulsions, fencing posture, unilateral tonic/dystonic posturing, and postictal nose wiping have been reported in IGE.3 Because we did not collect data from eyewitnesses, some of those focal features may not have been included. A recent study reported head or eye version in 101 patients based on responses to closed-ended questions, whereas only 7 responded positively to open-ended questions.7 They used a modified version of the Epilepsy Diagnostic Interview Questionnaire. In the original version used by us, there were no specific closed-ended questions on head version. Patients are more likely to respond positively to closed-ended questions,7 which may explain why we did not have any cases of self-reported head version. Automatisms are better classified as clinical signs, but we opted to keep them under the umbrella of reported FSS in keeping with the original FSSD classification. We used a sensitive tool to elicit seizure symptoms. However, perceptions of patients may differ from investigators’ interpretation in some situations. For example, questions on speech disturbances have been designed to elicit dysphasia in relation to seizures, but not due to alteration of awareness. However, patients with interruptions of speech due to absence seizures may record a positive response to the question. We included patients with a confirmed diagnosis of IGE based on a typical history and an EEG showing generalized epileptiform discharges before recruitment. Twenty-four–hour ambulatory EEGs were done as part of the research protocol. All abnormal 24-hour EEG recordings showed typical generalized epileptiform discharges in addition to focal discharges. Hence, a prolonged EEG for at least 24 hours should be considered if any doubt about the diagnosis of IGE is raised because of FSS or focal discharges on routine EEG. The main strength of our study is its uniform and rigorous methodology. All patients were diagnosed and classified into IGE syndromes based on ILAE criteria independently by 2 epilepsy specialists with any 6

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discordance resolved by consensus with a positive EEG recording necessary to confirm the diagnosis. FSS were elicited using a validated tool. Our study demonstrates that FSS are often reported by patients with IGE in association with both major and minor seizures. The duration of seizure freedom is associated with FSS. Our findings have implications for clinical practice. First, we emphasize that clinicians need to be aware of FSS in IGE to avoid misdiagnosis and delayed diagnosis as well as to choose appropriate AED treatment. Second, FSS may lead to inappropriate investigations for focal epilepsy including evaluation for epilepsy surgery. Third, the presence of FSS should alert the clinician as a potential marker of reduced likelihood of prolonged seizure freedom. Further studies are needed to confirm these findings, preferably in incident cases with prospective follow-up, and to examine the underlying pathophysiologic and network mechanisms of focal abnormalities in IGE. A greater understanding of these network mechanisms may assist in long-term management of IGE. AUTHOR CONTRIBUTIONS U.S.: study concept and design, literature search, data collection, data analysis, data interpretation, drafting and critical revision of manuscript. J.J.W.: study concept and design, data collection, literature search. R.C.B.: data analysis and interpretation, critical revision of manuscript. M.C.: study concept and design, data interpretation, critical revision of manuscript. W.D.S.: study concept and design, data interpretation, critical revision of manuscript.

ACKNOWLEDGMENT The authors thank Dr. Ruth Ottman for granting permission to use the PSSD and Epilepsy Diagnostic Interview Questionnaire.

STUDY FUNDING No targeted funding reported.

DISCLOSURE U. Seneviratne has received travel and speaker honoraria from UCB Pharma. J. Woo and R. Boston report no disclosures relevant to the manuscript. M. Cook has received speaker honoraria from UCB Pharma and Sanofi Australia and travel honoraria from UCB Pharma and SciGen. He has received research grants from National Health and Medical Research Council (Australia) and Australian Research Council. He has also received a Science, Technology, and Innovation Grant from the State Government of Victoria, Australia. W. D’Souza has received travel, investigator-initiated, and speaker honoraria from UCB Pharma, educational grants from Novartis Pharmaceuticals and Pfizer Pharmaceuticals, educational, travel, and fellowship grants from GSK Neurology Australia, and honoraria from SciGen Pharmaceuticals. Go to Neurology.org for full disclosures.

Received December 17, 2014. Accepted in final form March 27, 2015. REFERENCES 1. Proposal for revised classification of epilepsies and epileptic syndromes. Commission on Classification and Terminology of the International League Against Epilepsy. Epilepsia 1989;30:389–399. 2. Berg AT, Berkovic SF, Brodie MJ, et al. Revised terminology and concepts for organization of seizures and

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3.

4.

5.

6.

7.

8.

9.

epilepsies: report of the ILAE Commission on Classification and Terminology, 2005–2009. Epilepsia 2010;51: 676–685. Seneviratne U, Cook M, D’Souza W. Focal abnormalities in idiopathic generalized epilepsy: a critical review of the literature. Epilepsia 2014;55:1157–1169. Blume WT, Pillay N. Electrographic and clinical correlates of secondary bilateral synchrony. Epilepsia 1985;26: 636–641. Fisher RS, Acevedo C, Arzimanoglou A, et al. ILAE official report: a practical clinical definition of epilepsy. Epilepsia 2014;55:475–482. Choi H, Winawer MR, Kalachikov S, Pedley TA, Hauser WA, Ottman R. Classification of partial seizure symptoms in genetic studies of the epilepsies. Neurology 2006;66:1648–1653. Dugan P, Carlson C, Bluvstein J, Chong DJ, Friedman D, Kirsch HE. Auras in generalized epilepsy. Neurology 2014;83:1444–1449. Boylan LS, Labovitz DL, Jackson SC, Starner K, Devinsky O. Auras are frequent in idiopathic generalized epilepsy. Neurology 2006;67:343–345. Nakken KO, Solaas MH, Kjeldsen MJ, Friis ML, Pellock JM, Corey LA. The occurrence and characteristics of auras in a large epilepsy cohort. Acta Neurol Scand 2009;119:88–93.

10.

11.

12.

13.

14.

15.

16. 17.

18.

Taylor I, Marini C, Johnson MR, Turner S, Berkovic SF, Scheffer IE. Juvenile myoclonic epilepsy and idiopathic photosensitive occipital lobe epilepsy: is there overlap? Brain 2004;127:1878–1886. Vazquez B, Devinsky O, Luciano D, Alper K, Perrine K. Juvenile myoclonic epilepsy: clinical features and factors related to misdiagnosis. J Epilepsy 1993;6:233–238. Panayiotopoulos CP, Tahan R, Obeid T. Juvenile myoclonic epilepsy: factors of error involved in the diagnosis and treatment. Epilepsia 1991;32:672–676. Perucca E, Gram L, Avanzini G, Dulac O. Antiepileptic drugs as a cause of worsening seizures. Epilepsia 1998;39: 5–17. Tan M, D’Souza W. Seizure-related injuries, drowning and vehicular crashes: a critical review of the literature. Curr Neurol Neurosci Rep 2013;13:361. Seneviratne U, Cook M, D’Souza W. The prognosis of idiopathic generalized epilepsy. Epilepsia 2012;53: 2079–2090. Bauer G. Seizure types and epileptic syndromes in adults. Eur Neurol 1994;34(suppl 1):13–17. Sidenvall R, Forsgren L, Heijbel J. Prevalence and characteristics of epilepsy in children in northern Sweden. Seizure 1996;5:139–146. Galea S, Tracy M. Participation rates in epidemiologic studies. Ann Epidemiol 2007;17:643–653.

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Focal seizure symptoms in idiopathic generalized epilepsies Udaya Seneviratne, Jia J. Woo, Ray C. Boston, et al. Neurology published online July 17, 2015 DOI 10.1212/WNL.0000000000001841 This information is current as of July 17, 2015 Updated Information & Services

including high resolution figures, can be found at: http://www.neurology.org/content/early/2015/07/17/WNL.0000000000 001841.full.html

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Neurology ® is the official journal of the American Academy of Neurology. Published continuously since 1951, it is now a weekly with 48 issues per year. Copyright © 2015 American Academy of Neurology. All rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X.

Focal seizure symptoms in idiopathic generalized epilepsies.

We sought to study the frequency and prognostic value of focal seizure symptoms (FSS) in idiopathic generalized epilepsies (IGE) using a validated too...
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