Clinical Neurophysiology 126 (2015) 446–455

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Ictal ontogeny in Dravet syndrome Se Hee Kim, Douglas R. Nordli Jr., Anne T. Berg, Sookyong Koh, Linda Laux ⇑ Epilepsy Center, Department of Pediatrics, Ann & Robert H. Lurie Children’s Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA

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Article history: Accepted 8 June 2014 Available online 30 June 2014 Keywords: SCN1A Channelopathy Epilepsy Postictal generalized EEG suppression (PGES) Sudden unexpected death in epilepsy (SUDEP)

h i g h l i g h t s  Seizures in Dravet syndrome (DS) defy characterization as purely focal or generalized as presentation

was mixed semiologically and electrographically.  Seizures in DS change with age in their phenotype, duration, and EEG features.  Postictal EEG suppression happen frequently after a generalized seizure in all ages.

a b s t r a c t Objective: To define seizure characteristics of Dravet syndrome (DS) with video-electroencephalographic (EEG) recording in different age groups. Methods: We reviewed 23 patients with 63 seizures in different age groups: group 1 (0–5 years old); group 2 (6–10 years old); and group 3 (11 or above). Results: We included 7, 11 and 5 patients in groups 1, 2, and 3 respectively. Younger children had seizures while awake (p = 0.005), provoked seizures (p = 0.05), focal seizure semiology (p = 0.02) and long seizure duration (p = 0.0004). Older children had seizures from sleep (p = 0.004), generalized seizure semiology (p = 0.01) and short seizure duration (p = 0.0007). A generalized ictal discharge was the most commonly observed EEG pattern (15/23, 65%), more frequently found in older children (p = 0.01). Ten patients (43%) had unclassified seizures or seizures with discordant EEG results. Postictal EEG suppression was found in 9 (39%). Conclusion: The phenotype of seizures and ictal EEG patterns in DS vary with age. Significance: These findings will enhance the recognition of DS in the adolescent population. The incidence of postictal EEG suppression seen in DS is significant because it is a possible biomarker for sudden unexpected death in epilepsy. Ó 2014 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

1. Introduction Dravet syndrome (DS) is an SCN1A mutation related, infantileonset epilepsy syndrome, characterized by a distinctive seizure history: prolonged febrile or afebrile seizures beginning in the first year of life, followed by subsequent multiple seizure types. Most patients develop intractable epilepsy and a high incidence of sudden unexpected death in epilepsy (SUDEP) has been reported (Skluzacek et al., 2011). Early diagnosis of DS is critical in order

⇑ Corresponding author. Address: Epilepsy Center, Ann & Robert H. Lurie Children’s Hospital of Chicago, 225 E. Chicago Avenue, Box 29, Chicago, IL 60611, USA. Tel.: +1 312 227 3540; fax: +1 312 227 9644. E-mail address: [email protected] (L. Laux).

to avoid anticonvulsants that may aggravate seizures and increase morbidity and mortality (Brunklaus et al., 2012). Recognizing the changing pattern of seizures with age can be important for the diagnosis of DS. In young children, DS can be strongly suspected, especially when the infant presents with alternating hemiconvulsive seizures or prolonged febrile seizures. By contrast, in adolescents or adults, diagnosis is often under recognized because details of the earlier seizure history may be forgotten, and later seizure characteristics of DS are less well documented (Jansen et al., 2006). Defining an evolutionary pattern of epilepsy in DS has been challenging, because of polymorphic and complex nature of seizures and ill-defined ictal electroencephalographic (EEG) findings. Previous studies have primarily focused on describing seizures exclusively either in children or in adults. Seizures were described at different levels of detail, rendering 1388-2457/Ó 2014 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

S.H. Kim et al. / Clinical Neurophysiology 126 (2015) 446–455


Fig. 1. A clinically focal onset seizure in a 5-year-old boy with correlating focal ictal EEG pattern on the right hemisphere. (a) Repetitive spike discharges, maximum on the right fronto-temporal region at the onset, (b) progress to more varied waveforms admixed with spike discharges with a persistent right predominance. Parameters include; longitudinal bipolar montatge and sensitivity (a) 20 lV, (b) 15 lV.

the results between the studies largely incomparable (Nabbout et al., 2008; Akiyama et al., 2010; Gaily et al., 2013). For example, generalized tonic–clonic seizures (GTCS) were reported in nearly all of the patients in earlier studies (Jansen et al., 2006; Ragona et al., 2010), while other studies either did not see GTCS (Bureau and Dalla Bernardina, 2011) or described this seizure type less frequently (Caraballo and Fejerman, 2006; Catarino et al., 2011). Here, we describe the variation across different age groups of patients with respect to seizure semiology and electrographic features based on video-EEG recordings. We examined the proportion of patients for whom the seizure semiology and the corresponding electrographic patterns were discordant in order to better understand the conflicting results of previous studies. Identifying generalized convulsions and postictal generalized EEG suppression (PGES) can be important as they can be associated with sudden unexpected death in epilepsy (SUDEP).

2. Methods 2.1. Patients Fifty-nine patients with DS had available video-EEG data which were performed at our institution for various reasons including evaluation for background activity, seizures, and treatment efficacy. We reviewed our archived video-EEGs to identify patients whose motor seizures were recorded during the video-EEG study. Twenty-three patients with DS had motor seizures captured by a video-EEG study. Patients were diagnosed as DS according to the following criteria: (1) febrile and afebrile, generalized and unilateral, clonic or tonic–clonic seizures that occur in the first year of life in an otherwise normal infant; (2) development of drug-resistant myoclonus, atypical absences and focal seizures; (3) developmental delay within the second year of life; and (4) subsequent development of cognitive impairment or other neuropsychiatric and


S.H. Kim et al. / Clinical Neurophysiology 126 (2015) 446–455

behavioral disorders. All, but three, patients had an identified SCN1A mutations. Patients were then divided into 3 groups according to their age at the time of EEG: (1) 0–5 years old; (2) 6–10 years old; (3) 11 or above. This study was approved by the institutional review board. 2.2. Study design For each subject, data regarding age, sex and SCN1A mutation were obtained from the medical record and a total number of recorded motor or convulsive seizures was counted from each EEG record in the archived video EEG. For each seizure, time of day of seizure onset, sleep state immediately before seizure, presence of triggering factors for the seizure (e.g. temperature change, photic stimulation), duration of seizure and seizure semiology were analyzed by review of the archived video EEG. EEGs were reviewed independently by two epileptologists (S.H and L.L), and consensus was reached for final classification. All EEG recordings were obtained according to the 10–20 international system, using a 21 channel digital EEG system (Xltek, Natus Medical Incorporated, San Carlos, California). The data was recorded using a sampling rate of 200 Hz with filter settings of 1–70 Hz. The semiology of each seizure was reviewed and classified according to the following: (1) focal onset seizure with or without secondary generalization; (2) onset with bilateral body involvement (generalized seizure) with or without asymmetry; (3) onset with dyscognitive features of unclear generalized or focal origin. For each seizure, the presence of preceding myoclonus was evaluated. Ictal EEG pattern of each seizure were analyzed and classified into 2 categories: (1) focal with or without bilateral evolution (Figs. 1 and 2); and (2) generalized and diffuse (Figs. 3–5). Ictal termination pattern was evaluated per the following parameters: (1) termination pattern: abrupt versus gradual; (2) symmetry: bilateral versus hemispheric; (3) postictal EEG suppression: present or absent. Postictal EEG suppression was defined as absence of electroencephalographic activity >10 lV immediately after seizure termination (Lhatoo et al., 2010). Preceding burst of irregular, generalized polyspike/spike-wave was marked separately from the subsequent ictal discharges.

2.3. Statistical analysis Data analyses were performed using SAS version 9.3 (SAS Inc., Cary, NC, USA). The number of recorded seizures per EEG in each group was analyzed using Kruskall–Wallis test. All categorical variables including number of girls, number of patients who had seizures from sleep/daytime sleep, patients with provoked seizures, duration of seizures, seizure semiology and EEG findings of each group were evaluated by chi-square test. Certain data were assessed further, by using Mantel–Haenszel chi-square test for trend in association with age groups. P values < 0.05 were regarded as statistically significant. Data are expressed as mean ± standard deviation (median, maximum, interquartile range (IQR)) or number (%). 3. Results 3.1. Demographics Twenty-three patients with 63 motor seizures were analyzed. The patients ranged in age from nine months to 19 years (mean 7.5 ± 4.6 years old, median = 6.5, maximum 19, IQR = 4–10). Group 1 (0–5 years) consisted of seven children, Group 2 (6–10), eleven and Group 3 (11+), five. There were 13 boys and 10 girls. The median number of seizures per EEG was 2.7 ± 2.4 (median = 2, maximum = 9, IQR 1–4). SCN1A mutation was identified in 20 (87%) patients: (1) missense in 11; (2) nonsense in five; (3) frame shift in one; (4) splice site in two; and (5) deletion in one. A significantly lower number of patients in the adolescent group had identified SCN1A mutation, compared to the other groups (p = 0.004). Demographics of each group are summarized in Table 1. 3.2. Interictal EEG finding and photosensitivity Older children were more likely to have a slowed posterior dominant rhythm for age (p = 0.02) and diffuse background slowing (p = 0.049). Photoparoxysmal response was observed more frequently in the younger children (p = 0.047). With one exception, all patients showed some form of interictal epileptiform discharges

Fig. 2. A clinically generalized onset seizure in a 9-month-old girl with focal ictal EEG pattern. Seizure began with a cry and diffuse stiffening of her whole body, followed by asynchronous and asymmetric clonic movements of all limbs. A burst of heralding polyspike-wave followed by rhythmic theta activity in the right frontal region (F4) is observed. Parameters include; longitudinal bipolar montatge and sensitivity 15 lV.

S.H. Kim et al. / Clinical Neurophysiology 126 (2015) 446–455


Fig. 3. A clinically generalized onset seizure in a 5-year-old girl with generalized ictal EEG pattern. Seizure started with an extension of her bilateral arms followed by staring with eyelid flutters. (a) Admixture of polyspike and polyspike wave discharges are followed by gradual increase of diffuse repetitive spikes on EEG. (b) Electrographic seizure ended symmetrically and gradually after slow sharp wave discharges. Parameters include; longitudinal bipolar montatge and sensitivity (a) 30 lV, (b) 20 lV.

(22/23, 95%). Multifocal spike discharges were the most commonly observed finding (19/23, 82%) (Table 2). 3.3. Clinical seizure characteristics and semiology Twelve patients (52%) had seizures while they were awake, and 12 patients (52%) had seizures from sleep (one had seizures both from sleep and awake). Older patients were more likely to have seizures from sleep (p = 0.005), including seizures from daytime sleep (p = 0.004). Prolonged seizures, lasting over 3 min were observed only in children younger than 5 years of age (p < 0.0001), while brief seizures lasting less than 1 min were not seen in group 1 but in children older than six (p = 0.0007). Two patients in group 1 and 2 had seizures triggered by photic stimulation while photic stimulation failed to trigger seizures in group 3 (p = 0.047). Two other patients in group 1 and 2 had seizures provoked by temperature changes after a hot bath or exposure to hot temperatures.

Fourteen patients had generalized onset seizures (60%) (Figs. 2 and 3), while six had clinically focal seizures (26%) (Figs. 1 and 4). Six patients (26%) had seizures that began with dyscognitive features (Fig. 5), including two patients whose seizures started with unresponsiveness followed by a focal seizure punctuated by multiple myoclonic seizures (Fig. 6). Some seizures had generalized seizure semiology, but with shifting focality or multifocality. This phenomenon was found in all age groups (p = 0.1). A myoclonic jerk preceded the main seizure manifestations in seven patients (30%) and occurred often in younger children and diminished with age (p = 0.04). Detailed data are provided in Table 3. 3.4. Ictal EEG findings A generalized discharge was the most commonly observed ictal EEG pattern (15/23, 65%), and was more likely to be found in the older children (p = 0.01) (Figs. 3–5). A focal pattern was more likely


S.H. Kim et al. / Clinical Neurophysiology 126 (2015) 446–455

Fig. 4. A clinically focal onset seizure in an 18-month-old girl with generalized ictal EEG pattern. Erratic myoclonus of both arms was followed by left arm stiffening and clonic movement. (a) Heralding myoclonic seizure with correlating polyspike-wave bursts. (b) Generalized, repetitive spike discharges, seen during stiffening of her left arm. Parameters include; longitudinal bipolar montatge, sensitivity (a) 30 lV and (b) 30 lV.

to be seen in younger children (p = 0.05) (Figs. 1 and 2). EEGs of dyscognitive onset seizures were reviewed in detail, and they showed either generalized (3/6, 50%) (Fig. 5) or focal (3/6, 50%) (Fig. 6) ictal EEG pattern. In addition to seizures that began with dyscognitive features, two patients with focal seizure semiology showed generalized ictal EEG onset while the other two patients with generalized seizure semiology showed a mismatching EEG pattern of focal ictal onset. Overall, 10 patients (43%) showed seizures which were either unclassifiable due to onset with dyscognitive features or seizures which had discordant semiology and EEG findings. As noted in Figs. 3 and 4, the obvious ictal EEG changes were often preceded by a burst of polyspike or spike-wave discharges in a majority of patients (65%, 15/23). These heralding spike-wave discharges were more commonly found in the younger children (p = 0.03). Details are provided in Table 4.

3.5. Postictal EEG findings Postictal EEG suppression was found in nearly half of patients (39%, 9/23). While 6 out of 9 had generalized EEG suppression after generalized convulsions, three young patients aged one, three and four, showed unilateral postictal EEG suppression following either primarily or secondarily generalized seizures (Fig. 7). In addition, six patients (26%) showed an asymmetric postictal pattern after primary or secondarily generalized seizures. Seizures ended symmetrically in majority of patients (18/23, 78%). 4. Discussion Three main points emerged from the current study. Seizure phenotype, duration, and concurrent EEG features all changed with


S.H. Kim et al. / Clinical Neurophysiology 126 (2015) 446–455

Fig. 5. A seizure with dyscognitive feature followed by generalized tonic–clonic movement in an 8-year-old boy. Generalized ictal EEG pattern was observed. (a) Diffuse delta rhythm with intermixed rhythmic low voltage fast activity maximal in the fronto-temporal region during unresponsiveness and rightward eye gaze (b) progresses and becomes intermingled with muscle artifacts as he develops tonic posturing. Parameters include; longitudinal bipolar montatge, sensitivity (a) 10 lV, (b) 10 lV.

Table 1 Demographics of patients in each group.

N of patients Total N of recorded seizures per patient Median N of recorded seizures per patient Female (%) Mean age (years) Patients with positive SCN1A mutation (%)


Group 1 (0–5 years)

Group 2 (6–10 years)

Group 3 (11 or above)

23 2.8 ± 2.5 2 (9, 1–4) 10 (44) 7.5 ± 4.6 20 (87)

7 1.3 ± 0.5 1 (2, 1–2) 4 (57) 2.3 ± 1.8 7 (100)

11 3.0 ± 2.7 2 (9, 1–4) 4 (36) 7.9 ± 1.3 11 (100)

5 4.4 ± 2.9 5 (8, 2–6) 2 (40) 13.8 ± 3.1 2 (40)

age. Seizures often defied characterization as focal or generalized, as their presentation was mixed clinically and electrographically or discordant. Postictal EEG suppression happened frequently after a generalized seizure in all ages.


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Ictal ontogeny in Dravet syndrome.

To define seizure characteristics of Dravet syndrome (DS) with video-electroencephalographic (EEG) recording in different age groups...
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