Generalized onset seizures with focal evolution (GOFE) — A unique seizure type in the setting of generalized epilepsy

Epilepsy & Behavior 54 (2016) 20–29

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Generalized onset seizures with focal evolution (GOFE) — A unique seizure type in the setting of generalized epilepsy Avriel Linane, Andre H. Lagrange, Cary Fu, Bassel Abou-Khalil ⁎ Department of Neurology, Vanderbilt University, Nashville, TN, USA

a r t i c l e

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Article history: Received 30 May 2015 Revised 7 October 2015 Accepted 8 October 2015 Available online xxxx Keywords: Generalized onset seizures with focal evolution (GOFE) Generalized onset Focal evolution Focal seizures Seizure classification Seizure types Interictal epileptiform discharges

a b s t r a c t Purpose: We report clinical and electrographic features of generalized onset seizures with focal evolution (GOFE) and present arguments for the inclusion of this seizure type in the seizure classification. Methods: The adult and pediatric Epilepsy Monitoring Unit databases at Vanderbilt Medical Center and Children's Hospital were screened to identify generalized onset seizures with focal evolution. We reviewed medical records for epilepsy characteristics, epilepsy risk factors, MRI abnormalities, neurologic examination, antiepileptic medications before and after diagnosis, and response to medications. We also reviewed ictal and interictal EEG tracings, as well as video-recorded semiology. Results: Ten patients were identified, 7 males and 3 females. All of the patients developed generalized epilepsy in childhood or adolescence (ages 3–15 years). Generalized onset seizures with focal evolution developed years after onset in 9 patients, with a semiology concerning for focal seizures or nonepileptic events. Ictal discharges had a generalized onset on EEG, described as either generalized spike-and-wave and/or polyspike-and-wave discharges, or generalized fast activity. This electrographic activity then evolved to focal rhythmic activity most commonly localized to one temporal or frontal region; five patients had multiple seizures evolving to focal activity in different regions of both hemispheres. The predominant interictal epileptiform activity included generalized spike-and-wave and/or polyspike-and-wave discharges in all patients. Taking into consideration all clinical and EEG data, six patients were classified with genetic (idiopathic) generalized epilepsy, and four were classified with structural/metabolic (symptomatic) generalized epilepsy. All of the patients had modifications to their medications following discharge, with three becoming seizure-free and five responding with N 50% reduction in seizure frequency. Conclusion: Generalized onset seizures may occasionally have focal evolution with semiology suggestive of focal seizures, leading to a misdiagnosis of focal onset. This unique seizure type may occur with genetic as well as structural/metabolic forms of epilepsy. The identification of this seizure type may help clinicians choose appropriate medications, avoiding narrow spectrum agents known to aggravate generalized onset seizures. © 2015 Elsevier Inc. All rights reserved.

1. Introduction While seizures are classified as focal or generalized based on their onset, it is recognized that focal seizures may evolve to become generalized [1,2]. The evolution of generalized onset seizures to become focal is much less recognized, though documented in several papers [3–6]. The phenomenon of focal evolution has been described as a generalized onset of spike-and-wave or polyspike-and-wave activity with ictal progression into lateralized rhythmic theta [6] or focal spike-and-wave activity [4]. This ictal transition from generalized to focal has been recognized in patients with childhood absence epilepsy (CAE), juvenile ⁎ Corresponding author at: Vanderbilt University Medical Center, Neurology Department A-0118 MCN 2551, Nashville, TN 37232-2551, USA. E-mail address: [email protected] (B. Abou-Khalil).

http://dx.doi.org/10.1016/j.yebeh.2015.10.005 1525-5050/© 2015 Elsevier Inc. All rights reserved.

absence epilepsy (JAE), and juvenile myoclonic epilepsy (JME) [4,6]. This subset of primary generalized seizures, referred to as generalized onset with focal evolution seizures (GOFE), is important to recognize as these patients are often misdiagnosed and treated with antiepileptic drugs (AEDs) specific for focal seizures, with incomplete control and risk of seizure aggravation. We identified patients with this seizure type who were evaluated in our epilepsy monitoring unit from 2007– 2014, and described their EEG and clinical features. This study expands upon a prior publication from Vanderbilt University Medical Center [6] in which GOFE are described in a smaller series. Following that publication, GOFE was recognized as a seizure type at our center. Here, we describe a larger, distinct cohort of patients with particular emphasis on comparing GOFE and generalized seizures without focal evolution (GS) in the same patient, and further explore potential mechanisms underlying this novel seizure pattern.

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2. Methods

3. Results

2.1. Patients and seizures

3.1. Patient clinical data

The adult and pediatric Epilepsy Monitoring Unit (EMU) databases and reports at Vanderbilt Medical Center and Children's Hospital were screened for the terms “generalized onset” and “focal evolution” to identify generalized onset seizures with focal evolution (GOFE). Medical records and video-EEG recordings were reviewed. The data collected from the medical records included: age of seizure onset, seizure description and frequency prior to EMU evaluation, family history of epilepsy, epilepsy risk factors, MRI abnormalities, neurologic examination, antiepileptic medications before and after video-EEG, and response to medications. We defined seizure freedom as the absence of seizures for the last 6 months of follow-up. We considered improvement in seizure frequency as ≥50% reduction in seizure frequency in the last 6 months as compared with seizure frequency before the EMU diagnosis of GOFE. The video-EEGs were evaluated for: clinical seizure semiology, duration of seizure, EEG pattern at ictal onset, evolution pattern, interictal epileptiform discharges, and nonepileptiform abnormalities. Patients with prior intracranial surgery were excluded from the study.

Ten patients with GOFE were identified over a seven-year time span, including seven males and three females (Table 1). They represented 4.5% of patients with generalized epilepsy with recorded seizures in our EMU. All of the patients developed epilepsy in childhood or adolescence, with onset ranging between 3 and 15 years. The age range for EMU evaluation was 7–56 years. The patients presented with a history of seizures suggestive of generalized tonic–clonic seizures and/or staring spells; eight of the ten patients also had seizures with focal clinical signs raising the possibility of focal seizures. Examples of these focal signs include early and versive head turning, automatisms (oral, verbal, and/or manual), or unilateral arm extension/clonic activity. The focal signs were noted several years after initial seizure onset, at ages 10–40 years. All of the patients had medically refractory seizures with a frequency ranging from 5–6 seizures per week to 1–2 seizures per year (Table 4).

2.2. Comparison of generalized onset seizures with and without focal evolution (GOFE vs GS)

3.1.1. Epilepsy risk factors and imaging Four of the patients had a first or second degree family member with epilepsy, while three patients had family members with febrile seizures (Table 1). Two of the patients had complex febrile seizures between the ages of one and three years. None of the patients had a history of meningitis/encephalitis, stroke, brain tumor, or complications during birth/maternal pregnancy. Two of the patients had head trauma in childhood associated with prolonged loss of consciousness, immediately preceding their first seizure. Patient 1 who fell from a roof at age 5 years had right mesial temporal sclerosis, and patient 8 who fell during a bicycle accident at age 13 years had a midline arachnoid cyst on MRI; neither of these MRI findings was likely related to the original traumatic brain injury. Six of the patients had a normal MRI, while two had an MRI at an outside institution with unknown results. Six of the patients had a normal neurologic exam, while four had a mild to moderate developmental delay. No focal neurologic features were noted in nine of the ten patients; patient 6 had mild right hand incoordination.

Each patient was evaluated for all recorded GS, such as absence, myoclonic, and tonic–clonic seizures, as well as GOFE. The seizure semiology, seizure duration, EEG pattern at ictal onset, and evolution pattern were evaluated in these two seizure groups. Institutional review board (IRB) approval was obtained for this retrospective review. 2.3. Statistical analysis The mean duration of GS and GOFE was compared using the Mann– Whitney test for nonparametric data. For patients with both GS and GOFE, we further compared the duration of GS to the generalized component of GOFE (onset of GOFE up to onset of focal evolution). A p-value of ≤0.05 was considered significant. We used GraphPad Prism (version 6, GraphPad software) for statistical calculations. Data are expressed as mean ± SD.

Table 1 Clinical characteristics of patients. Patient demographics

Mean (range)

Age at time of EMU (years) Age at seizure onset (years) Age of seizure onset (with focality, years)

23 (7–56) 9 (3–15) 20 (10–40)

Family history of epilepsy or febrile seizures

Other risk factors Cognitive/neurologic abnormalities

MRI abnormalities

Seizure classification prior to EMU

Seizure classification

Present (patient #)

Absent (patient #)

Epilepsy in 1st degree relative (1, 10) Epilepsy in 2nd degree relative (3, 8) Febrile seizure in 1st/2nd degree relatives (3, 4, 9) Head injury with LOC (1, 8) Febrile seizure (2, 3) Mild developmental delay (6, 7, 10) Moderate developmental delay (1) Dysarthric speech, ataxic gait (1) Brisk reflexes, mild incoordination of RUE (6) Right mesial temporal sclerosis (1) Left anterior middle cranial fossa arachnoid cyst (8)

4 patients

6 patients 6 patients

Normal imaging (2, 4–6, 9, 10) Unknown imaging results (3, 7)

GTCS (1, 2, 7, 8) Focal seizures with impaired awareness, with focal motor features, with or without evolution to bilateral convulsive seizure (1–6, 8–10) Focal seizures with impaired awareness only, with behavioral arrest versus generalized absence seizures (2, 3, 4, 7) GTCS and myoclonic seizures (3, 5, 9) Genetic (“idiopathic”) (2–5, 8–9) Structural/metabolic (“symptomatic”) (1, 6, 7, 10)

LOC, loss of consciousness; GTCS, generalized tonic–clonic seizures; RUE, right upper extremity.

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3.2. EMU data 3.2.1. GOFE Each patient had at least one recorded GOFE (Table 2). The semiology at generalized EEG onset consisted of behavioral arrest and/or staring (or appeared subclinical) in eight of the patients, while two patients had restless behavior associated with a subjective sensation, and one patient had a brief myoclonic jerk. The semiology at time of focal evolution was variable. Three of the patients had well-formed verbal automatisms during ictal activity, such as “I love you God…don't let me have a seizure” (patient 1), or “I'm seeing black…Really, I don't know” (patient 10). Patient 10 was able to read a test sentence and answer simple questions during GOFE. Chewing and lip-smacking occurred in two patients, and picking and grasping were observed in four patients. Versive head turn occurred in three patients, and early nonversive head turns in four patients. All ictal discharges had a generalized onset on EEG (Table 2); most often a 3- to 5-Hz spike-and-wave and/or polyspike-and-wave discharges. Generalized beta activity and/or generalized attenuation was noted in three patients, sometimes following a brief generalized polyspike-and-wave discharge. The focal evolution occurred with rhythmic 3- to 13-Hz activity. Electroencephalogram focality was predominant in frontal (7 patients) or temporal (5 patients) regions, although seizures in a few patients localized to occipital and parietal regions. Five patients had multiple GOFE localizing to different regions of the brain for each seizure (patients 3, 4, 6, 7, and 10). 3.2.2. GS Six of the ten patients also had their typical seizures with a generalized onset without focal evolution on EEG (Table 2). Seizure types included generalized absence, generalized tonic–clonic, myoclonic, and tonic seizures, with typical semiology. The most common ictal onset was 4- to 5-Hz generalized spike-and-wave and/or polyspike–wave activities.

Four patients did not have GS recorded during the EMU stay. One of these, patient 8, also had focal onset seizures although the interictal pattern was strictly generalized. The EEG onset involved left temporal delta–theta activity, which was similar to the evolution pattern in the GOFE. Both seizure types were clinically similar with chewing and right hand automatisms. Patient 9 also had several psychogenic nonepileptic seizures (PNES), involving hand tremor. 3.2.3. Statistical analysis Excluding myoclonic seizures, a total of 22 generalized seizures (GS) were recorded from five patients, with a mean duration of 51.32 s (±36.62, range: 5–130). Generalized onset seizures with focal evolution were significantly longer (p b 0.0001) with a mean duration of 146.3 s (± 160, range: 25–840) in 34 seizures recorded from ten patients. For statistical analysis, the brief myoclonic seizure of patient 9 was removed from the data set; in addition, for patient 3, the longest and shortest absence seizures for each of the three EMU admissions were used in the data set, given the uncountable number of seizures within seizure clusters. One may speculate that focal evolution may derive from prolonged GS; however, we found the duration of the generalized component in GOFE to be no different from the duration of GS. In the six patients with both GS and GOFE, there was no difference (p = 0.1422) between the mean time to onset of focal evolution (31.00 s ± 30.77, range: 5–136) and the mean GS duration. Thus, GOFE were longer than GS due to the additional focal evolution. 3.2.4. Interictal discharges All 10 patients had generalized spike-and-wave or polyspike-andwave discharges ranging from 2 to 9 Hz (Table 3), while one patient also had generalized paroxysmal fast activity. Three patients had focal epileptiform discharges localized to one or both temporal lobes. The bitemporal epileptiform discharges, as well as the nonepileptiform

Table 2 Seizures recorded in EMU — comparison of seizures with and without focal evolution (GS vs GOFE). Generalized only (GS)

Generalized onset focal evolution (GOFE)

Patient Semiology (# seizures)

EEG onset + evolution

Mean duration, seconds

Semiology (# seizures)

1

GTCS (1)

4- to 5-Hz GSW +

117

2

–

GPSW –

3

Generalized absence with eye flutter (numerous clusters)

GBA/GPS ± 3- to 4-Hz GSW/GPSW

Tonic seizure (1)

GBA → 3-Hz GSW

4

5 6

Absence (1) Tonic → GTCS (6)

4- to 5-Hz GSW 3- to 4-Hz GSW ±

Focal evolution

Mean duration, (focal onset mean duration) seconds

WFVA, lip smacking, BL grasping (3) 3- to 4-Hz GPSW

Right temporal theta

223 (43)

–

Right arm clonic activity (1)

Left temporal alpha

70 (35)

18

Left versive head turn → GTCS (2)

Right frontal theta

378 (58)

18

15 55

GBA → generalized attenuation 7

–

–

–

8 9

– – Myoclonic seizures (1) 4- to 5-Hz GSW

– 1.5

10

–

–

–

Right clonic head jerking (1) Right head deviation with eye flutter (1) Right head/eye deviation, vocalization, BL picking (2)

Left versive head turn → GTCS (1) Right clonic head jerking (1), behavioral arrest (1), left head deviation + blinking (2) Left clonic head jerking (2) Myoclonic jerk, BL grasping (1) Staring (1) Chewing (9) Right hand picking, WFVA, left versive head turn → GTCS (1) Right head turn (1), staring (1) Staring, WFVA (2) Continues conversation (1) Left eye blinking, left head turn (1)

Generalized EEG onset

3- to 4-Hz GSW/GPSW GBA/GPS ± 4- to 5-Hz GSW/GPSW Same Same 3- to 5-Hz GPSW → GBA Same

Left frontal delta Left frontal theta Right frontotemporal delta (1)

110 (42)

Shifting delta right/left hemisphere (1) Right frontal beta Left frontal theta

147 (29) 45 (18)

Same 2- to 3-Hz GPSW →

Right frontal theta Right temporal delta

139 (19)

attenuation GBA → attenuation 6- to 7-Hz GSW 5- to 6-Hz GSW

Left temporal theta Left temporal theta Right frontal theta

77 (35) 202 (30)

3- to 4-Hz GSW Same Same Same

Right occipital theta 181 (17) Left frontocentral theta Right centroparietal theta Bilateral frontocentral delta

3- to 4-Hz GSW GBA or generalized attenuation

GTCS, generalized tonic–clonic seizure; GSW, generalized spike-and-wave; GPSW, generalized polyspike-and-wave; GBA, generalized beta activity; WFVA, Well-formed verbal automatism; BL, bilateral; GPS, generalized polyspike discharges.

A. Linane et al. / Epilepsy & Behavior 54 (2016) 20–29 Table 3 Interictal EEG abnormalities. Interictal abnormality

Present (patient #)

Generalized epileptiform Generalized polyspike–wave ± spike-and-wave (1–10) discharges GPFA (7) Focal epileptiform discharges Right temporal sharp waves (1) Bitemporal, independent sharp waves (4, 6) Nonepileptiform Right temporal delta (1) abnormalities Left temporal delta (7) GRDA (6, 7, 10) GRDA, generalized rhythmic delta activity; GPFA, generalized paroxysmal fast activity.

abnormalities such as irregular delta activity, did not correlate with a particular GOFE pattern, except in patient 1. His right temporal sharp waves and irregular delta activity were associated with right temporal localization in the GOFE, likely related to the right mesial temporal sclerosis on MRI. 3.3. Epilepsy classification

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3.4.2. AED changes following GOFE diagnosis All of the patients had AED changes or dose adjustments of their current AED regimen following EMU discharge (Table 4). Three patients became seizure-free: patient 5 following the addition of divalproex, patient 2 with a decreased dose of lamotrigine (prior dose possibly supratherapeutic) and avoidance of energy drinks, and patient 9 following increased dose of lamotrigine. Five patients showed improvement in seizure frequency: patient 4 after discontinuation of oxcarbazepine and addition of clobazam, patient 8 after discontinuation of oxcarbazepine, patient 1 after increasing dose of lamotrigine, patient 3 after addition of divalproex and clobazam, and patient 10 after addition of clobazam. The three patients on oxcarbazepine or carbamazepine prior to admission stopped these medications upon discharge; patients 4 and 8 had improved seizure frequency, while no change was noted in patient 7. However, it is important to clarify that patient 7 continued to have PNES that were difficult for the patient to distinguish from her epileptic seizures. Patient 6 continues to have daily seizures despite subsequent AED trials of seven different medications, although he remains on narrow spectrum AEDs. 3.5. Case examples

Taking into consideration all clinical and EEG data (Tables 1 and 2), six patients were classified with genetic (idiopathic) generalized epilepsy, and four patients were classified with structural/metabolic (symptomatic) generalized epilepsy. These latter 4 patients (1, 6, 7, and 10) had abnormal cognitive and neurologic exams, but no specific MRI abnormality to correlate with cognitive dysfunction. None of the patients had a slow spike-and-wave pattern as may be seen in the Lennox–Gastaut population. 3.4. AED therapy 3.4.1. AEDs prior to EMU admission Eight of ten patients were currently on two or more AEDs, having tried 1–6 other AEDs in the past (Table 4). The majority of patients were on levetiracetam (seven patients), topiramate (five patients), and lamotrigine (five patients), often in combination, at the time of their EMU admission. Only one patient was on divalproex, but seizures in four patients had previously failed to improve with this medication prior to EMU admission, though it was unclear if side effects versus efficacy led to termination. Three patients were on either oxcarbazepine or carbamazepine. The majority of patients were tapered off AEDs during their EMU admission.

3.5.1. Patient 3 A 17-year-old woman began having seizures at age 7 years. Initially, she had absence seizures characterized by blinking, staring, and unresponsiveness. However, by age 11 years, her seizures began to change in semiology, involving unilateral clonic activity or aversive head turn into tonic–clonic activity. She was initially diagnosed with CAE then JME; however, new onset focal seizures were suspected. Seizure risk factors included a complex febrile seizure lasting 45 min at age 18 months and multiple febrile seizures until age 3 years. She also had a family history of absence seizures in a maternal aunt and febrile seizures in multiple paternal cousins. Her neurologic examination was normal. An MRI was not completed at Vanderbilt, although recommended. The seizures captured during three EMU admissions were consistent with absence seizures and generalized tonic–clonic seizures. The clinical features of the absence seizures involved motionless staring, behavioral arrest, and eyelid fluttering, associated with generalized polyspike activity (7–15 Hz) that evolved into a 3- to 4-Hz spike-and-wave and polyspikeand-wave patterns (Fig. 1). These seizures typically lasted 5–30 s; however, seizures often were found in repetitive clusters for 20–120 min. Generalized onset seizures with focal evolution were also recorded (Figs. 2 and 3). The GOFE semiology and EEG pattern included right clonic head jerking (associated with left frontal delta activity), right

Table 4 Seizure frequency and AEDs before and after GOFE diagnosis. Patients were grouped by seizure outcome. Patient

Before Seizure frequency

Seizure freedom 2 5 9

4–6/year 1–2/month 1–2/year

After AEDs Broad spectrum

AEDs Narrow spectrum

Broad spectrum

Narrow spectrum

Seizure frequency

LEV, LTG LEV, TPM LTG

LEV, LTG LEV, VPA LTG (incr. dose)

Seizure-free Seizure-free Seizure-free

Decreased seizure frequency 1 5–6/month 3 4–6/month 4 2/month 8 2/month 10 1/month

LEV, LTG, TPM LEV LTG, TPM, LEV, TPM LEV, LTG

OXC, PGB OXC LCM

LTG (incr. dose), LEV, TPM CLB, LEV, VPA CLB, LTG, TPM LEV, TPM CLB, LEV, LTG

2/year 2/month 1 per 3 months 2/year 1–2/year

No change 6 7

VPA, ZNS TPM, LEV,

CBZ

CZP, LEV, RFM TPM, LEV, LTG

5–6/week 2/month

GBP, LCM

Daily to weekly 2/month

TPM, topiramate; LTG, lamotrigine; LEV, levetiracetam; PhB, phenobarbital; VPA, valproic acid; PHT, phenytoin; ZNS, zonisamide; RFM, rufinamide; ETX, ethosuximide; CLB, clobazam; PRM, primidone; PGB, pregabalin; OXC, oxcarbazepine; FBM, felbamate; GBP, gabapentin; CZP, clonazepam; CBZ, carbamazepine; LCM, lacosamide. Lacosamide was tentatively included as a “narrow spectrum” AED because its mechanism of action partially overlaps that of carbamazepine and phenytoin.

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Fig. 1. Absence seizure noted in patient 3, associated with behavioral arrest and blinking (linked ear referential montage).

head turn with eye flutter (associated with left frontal theta activity), and left versive head turn (associated with right frontal theta activity) into tonic–clonic activity. While these GOFE appeared clinically different from GS, the EEG onset pattern was similar with 4- to 5-Hz spikeand-wave and polyspike-and-wave discharges. The interictal activity consisted of 3- to 4-Hz spike-and-wave or polyspike-and-wave discharges (Fig. 4). Seizure frequency improved with the addition of divalproex and clobazam (Table 4). 3.5.2. Patient 2 A 34-year-old man began having seizures at age 6 years. He had a risk factor of febrile seizures at age 2 years. With the first recognized afebrile seizure, he was discovered lethargic on the floor, after a presumed generalized tonic–clonic seizure. He had a normal neurologic examination as well as a normal MRI. He began having absence seizures with brief staring and blinking, captured on EEG, consistent with idiopathic generalized epilepsy. In adolescence, he had recurrent generalized tonic–clonic seizures. However, at age 33 years, he developed a new seizure type associated with an aura of a “mental feeling” (“like seeing inside the subconscious”) followed by confusion, head turning in different directions for different seizures, and unilateral arm or foot extension. Sometimes, these events were followed by full body shaking. He had 4–6 such seizures in one year. The semiology was variable and often changing from seizure to seizure, causing the practitioner to question a diagnosis of new onset focal seizures or PNES. His EMU admission captured one of these new atypical events, with unresponsiveness and right arm clonic activity. The EEG demonstrated generalized spike/polyspikeand-wave activity at onset, followed by focal evolution in the left temporal region (Fig. 5). He had frequent generalized 3- to 9-Hz spikeand-wave and polyspike-and-wave interictal discharges (Fig. 6). His lamotrigine dose, thought to be supratherapeutic, was decreased, and he refrained from consumption of energy drinks, which was a known trigger. He has remained seizure-free for 3 years on lamotrigine and levetiracetam. 4. Discussion The current study further confirms the existence of GOFE, in ten additional patients. This generalized seizure type, characterized by

generalized onset with focal evolution, is not yet recognized in the international classifications of the International League Against Epilepsy [1,2]. Some epileptic syndromes include generalized and focal seizures in the same patients; however, GOFE are not focal seizures in patients with generalized epilepsy; they are generalized-onset seizures with focal evolution. Patients with GOFE typically have a childhood or adolescence onset presenting with absence, myoclonic, or tonic–clonic seizures, with confirmed initial diagnosis of generalized epilepsy on EEG, prior to GOFE onset. Generalized onset seizures with focal evolution seem to appear as a late manifestation in the course of generalized epilepsy; each patient experienced GOFE as a new onset seizure pattern years later, sometimes in adulthood. Some of these patients were thought to have developed nonepileptic events given the change in semiology; patient 2 was initially thought to have PNES, while patient 10 was diagnosed with complicated migraines. For other patients, the focal semiology resulted in suspicion of focal seizures with subsequent narrow spectrum AEDs chosen for treatment. One limitation of our study is that generalized seizure onsets on scalp EEG may be due to secondary bilateral synchrony. While it is difficult to rule out the possibility that GOFE reflect secondary bilateral synchrony in focal epilepsy [7], there are a number of arguments that favor generalized epilepsy in patients with GOFE. Generalized onset seizures with focal evolution are generalized at onset on EEG, with generalized spike-and-wave, generalized polyspike-and-wave, or generalized fast activity. They may be due to the activation of broadly distributed cortical networks producing generalized seizures with late focal buildup. All of the patients also had generalized interictal epileptiform discharges. There was no focal lead or lateralization of the generalized spike-andwave or polyspike–wave discharges seen at seizure onset. Focal epileptiform activity, seen in only three patients, and focal slow activity, in only two patients, were temporal; secondary bilateral synchrony is more common with frontal foci. The generalized discharges described with secondary bilateral synchrony were most often reported to be less than 3 Hz in frequency, while spike-and-wave discharges were most often N3 Hz in the current patient group [7]. The focality upon ictal evolution often varied in laterality in the same patient, which would be unusual in secondary bilateral synchrony. The pattern of AED response with improvement after removal of narrow spectrum sodium channel blockers is another feature favoring generalized epilepsy.

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Fig. 2. Absence seizure with generalized onset and focal evolution of left frontal delta associated with blinking and right head turn in patient 3 (linked ear referential montage). A. Seizure onset. B. Continuation of same seizure noted in A, with focal evolution of left frontal delta associated with right clonic head movements (linked ear referential montage).

Finally, there was a suggestion of genetic predisposition in many patients; 7 of the 16 (44%) patients with GOFE (including prior published series in [6]) had a first or second degree family member with epilepsy, similar to the reported incidence in generalized epilepsy [8]. Even though the new epilepsy classification abandoned “focal” and “generalized” as modifiers of the epilepsies themselves, because some epilepsies may include focal and generalized seizures, it has endorsed the division of seizures into focal and generalized based on onset, and it has recognized that seizures are consistently generalized in certain epilepsies [2]. Most generalized epilepsies are considered genetically determined. Nevertheless, it is quite possible that there is an interaction of genetic and environmental factors in patients with GOFE [7]. While focal features during generalized seizures are not a new concept [9–13], electrographic evolution from generalized onset to focal

activity is not well recognized. This novel pattern of EEG evolution resulted in a semiology that is not currently recognized for generalized seizure types. Generalized onset seizures with focal evolution are likely underreported and unrecognized, at times misdiagnosed as focal seizures and treated with inappropriate AEDs. Narrow spectrum AEDs, such as carbamazepine, oxcarbazepine, gabapentin, and pregabalin are probably not appropriate for patients with GOFE. Seizure aggravation has been reported when carbamazepine or oxcarbazepine is introduced in adults or children with generalized epilepsy [14–17]. Patient 4 improved considerably when oxcarbazepine was replaced with clobazam, while patient 8 improved with the discontinuation of oxcarbazepine. Wide spectrum AEDs such as valproate are most appropriate for patients with GOFE. Valproate is established as one of the most effective AEDs for generalized epilepsy [18]. Other appropriate AEDs include lamotrigine, levetiracetam, zonisamide, topiramate, and clobazam. In

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Fig. 3. Generalized tonic–clonic seizure with generalized onset and focal evolution of right frontal theta, associated with left versive head turn prior to tonic–clonic activity in patient 3 (linked ear referential montage).

this study, one patient (patient 5) became seizure-free with the addition of valproate, and two others with further adjustments of lamotrigine dosing. Other patients improved with the addition of valproate or clobazam and titration of lamotrigine (Table 4). By identifying GOFE as a particular seizure type, we hope to support further work in elucidating the best treatment for GOFE. In this patient series, drug-resistance was common, and seizures in these patients often presented a management challenge. Patients with GOFE from the current and the prior series had seizures that were medically refractory prior to EMU admission [6]. There may be a selection bias, since

seizure-free patients are unlikely to be referred to an epilepsy center and are unlikely to be evaluated in the EMU. It is also possible that appearance of GOFE is predictive of challenging seizure control. Parallel examples in generalized epilepsy syndromes are the appearance of generalized tonic– clonic seizures in children with childhood absence or the evolution of childhood absence epilepsy into juvenile myoclonic epilepsy; both are unfavorable prognostic indicators [19–23]. However, 30–50% of patients with GOFE achieved long seizure-free remissions with appropriate AED adjustments. In addition to the diagnostic and therapeutic importance of recognizing this seizure pattern, GOFE offer an opportunity to expand our

Fig. 4. Generalized interictal discharges, patient 3 (linked ear referential montage).

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Fig. 5. A. Seizure onset in patient 2, with generalized frontal dominant spike-and-wave and polyspike-and-wave discharges (linked ear referential montage). B. Seizure evolution of in same seizure as A, with left temporal predominance at T7 and P7, approximately 46 s later (average referential montage).

understanding of how epilepsy circuits interact with each other [4,6]. There is a large body of literature exploring the way that focal seizures spread and become generalized, but to our knowledge, relatively little work has focused on the reverse process of focalization of generalized discharges. Perhaps the explanation that first comes to mind for GOFE is that these patients have experienced some sort of acquired neurological insult causing them to develop a localized seizure generator that is activated by the generalized discharges. This idea is supported by the finding that two patients in the current series had focal MRI abnormalities, at least one of which was potentially epileptogenic. However, the rarity of focal seizures without GOFE in our patients (only patient 8) makes this possibility less likely. Alternatively, even if these abnormal areas are unable to generate seizures de novo, perhaps they lack the inhibitory machinery that helps terminate ictal discharges, resulting in persistent seizures in this area well after the initial generalized seizure

had ended [23–25]. While the later onset of the focal evolution may suggest that the insult occurred later in life, there was no historical or radiologic evidence for such a neurological injury in the remaining 8 patients in our series. Functional and advanced structural imaging, like magnetic source imaging (MSI), voxel-based morphometry (VBM), diffusion tensor imaging (DTI), fMRI, or ictal SPECT may help identify focal abnormalities not seen on structural MRI. The cohort of patients with multiple focal semiologies correlating with various independent regions of focal evolution on EEG suggests that these circuits may have acquired multiple functional and/or microanatomical abnormalities that lead to GOFE. An alternative explanation for the relatively late onset of focal seizures is that the tendency toward GOFE was present since birth and that maturational processes, like synaptic pruning, may have simply unmasked a focal network anomaly that was present since birth.

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Fig. 6. Interictal epileptiform activity in patient 2 was consistently generalized (linked ear referential montage).

Much of the synchronous firing seen during generalized seizures is driven by aberrant thalamocortical pathways in idiopathic generalized epilepsies, and advances in fMRI and nuclear medicine imaging have identified specific thalamic nuclei activated during generalized discharges. Moreover, these same thalamic nuclei can become involved in complex partial seizures and subsequently produce deactivation of focal cortical regions, such as the default mode network [25]. If we think of focal evolution as an extension of the generalized seizure, perhaps this connectivity between the thalamus and cortical/limbic networks allows the generalized discharges to selectively engage specific thalamocortical pathways in the frontal, peri-insular, and temporal regions [24,26,27]. Once again, functional imaging with FDG–PET and functional resting connectivity analysis might help delineate pathological connections specific to these patients. Regardless of the pathophysiology of GOFE, the potential for generalized onset seizures to become focal should be recognized in the epilepsy classification, so clinicians can appropriately diagnose them as generalized seizures and treat them with appropriate AEDs. Disclosure None of the authors report a conflict of interest in relation to the current work. References [1] Proposal for revised clinical and electroencephalographic classification of epileptic seizures. From the Commission on Classification and Terminology of the International League Against Epilepsy. Epilepsia 1981;22:489–501. [2] Berg AT, Berkovic SF, Brodie MJ, Buchhalter J, Cross JH, van Emde Boas W, et al. Revised terminology and concepts for organization of seizures and epilepsies: report of the ILAE Commission on Classification and Terminology, 2005–2009. Epilepsia 2010; 51:676–85.

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