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Childhood absence epilepsy: Elctroclinical features and diagnostic criteria
Brain & Development 33 (2011) 114–119 www.elsevier.com/locate/braindev
Original article
Childhood absence epilepsy: Elctroclinical features and diagnostic criteria Xiuwei Ma a,b, Yuehua Zhang a,*, Zhixian Yang a, Xiaoyan Liu a, Huihui Sun a, Jiong Qin a, Xiru Wu a, Jianmin Liang a,c,** a
Department of Pediatrics, Peking University First Hospital, No. 1, of Xian Men Street, Xicheng District, Beijing 100034, PR China b Bayi Children’s Hospital Affiliated to General Hospital of Beijing District, PLA 100710, PR China c Department of Pediatrics, First Hospital of Jilin University, Changchun 130021, PR China Received 6 July 2009; received in revised form 29 December 2009; accepted 16 February 2010
Abstract Objective: To analyze the electroclinical features of children with childhood absence epilepsy (CAE) and discuss the diagnostic criteria for CAE. Methods: The video-electroencephalogram (VEEG) database in our hospital was searched using “absence seizures” and “3-Hz generalized spike and waves (GSW)” as key-words. Other epileptic syndromes with typical absence seizures were carefully excluded. Children meeting the CAE diagnostic criteria of the International League Against Epilepsy (ILAE) in 1989 were further evaluated with the diagnostic criteria proposed by Panayiotopoulos in 2005. Results: Totally 37 children met the 1989 ILAE criteria of CAE. The onset age of absence seizures ranged from 3 to 11 years. All patients had frequent absence seizures (5–60 times per day). Two patients (5.4%) had generalized tonic-clonic seizures. Hyperventilation induced absences in all patients. VEEG confirmed that 7 patients (18.9%) had only simple absences, 25 patients (67.6%) had only complex absences, and 5 patients (13.5%) had both simple and complex absences. Ictal EEG showed 3 Hz GSW discharges in all patients. The seizure duration ranged from 3 to 40 s. Four patients (10.8%) had two spikes per wave in ictal EEG. GSW fragments were found in 29 patients (78.4%) during sleep. Interictal polyspikes and waves were present in 17 patients (45.9%). Focal discharges predominantly in the anterior regions, were found in 22 patients (56.8%). Only 7 patients (18.9%) met the diagnostic criteria proposed by Panayiotopoulos in 2005. Conclusions: Few patients meeting the 1989 ILAE diagnostic criteria for CAE meet the new diagnostic criteria proposed by Panayiotopoulos in 2005. The new criteria for CAE are too strict to appropriately classify some patients. Ó 2010 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved. Keywords: Childhood absence epilepsy; Electroencephalogram; Diagnosis
1. Introduction Childhood absence epilepsy (CAE) is an age-dependent, idiopathic form of generalized epilepsy, characterized by the following features: multiple typical absence seizures each day that accompanied with bilateral, sym*
Corresponding author. Tel.: +86 10 8357 3234; fax: +86 106613 4261. ** Corresponding author. E-mail addresses: [email protected] (Y. Zhang), jackyliangjm @126.com (J. Liang).
metrical, and synchronous discharges of 3-Hz generalized spike and waves (GSW) in the electroencephalogram (EEG). CAE accounts for 2% to 10% of all childhood epilepsies and 8–15% of school-aged childhood epilepsies [1]. The idiopathic generalized epileptic (IGE) syndromes with typical absences defined by the International League Against Epilepsy (ILAE) in 2001 include CAE, juvenile absence epilepsy (JAE), juvenile myoclonic epilepsy (JME) and myoclonic absence epilepsy (MAE) [2]. The syndromes with typical absences that are not officially recognized by ILAE include eyelid myoclonia with absences (EMA) and perioral myoclonia with absences
0387-7604/$ - see front matter Ó 2010 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.braindev.2010.02.004
X. Ma et al. / Brain & Development 33 (2011) 114–119
(PMA) [3]. The clinical features and prognosis of these epileptic syndromes are different, so it is important to define the syndromic classification for every patient rigorously. The criteria for CAE proposed by ILAE in 1989 are still broadly used. Panayiotopoulos proposed stricter inclusion and exclusion criteria for CAE in 2005 [4]. Whether the new diagnostic criteria for CAE are suitable or not is still controversial. In this study, we analyzed the clinical and EEG features of the CAE patients diagnosed in our hospital meeting the 1989 ILAE criteria and further evaluated these patients using the new criteria with an attempt to explore the feasibility of applying the new criteria for CAE in clinical practice. 2. Subject and methods 2.1. The diagnostic criteria for CAE The criteria proposed by ILAE in 1989 include [5] (1) Onset in children of school age (peak age 5–7 years); (2) Very frequent absence seizures (several to many per day); (3) Ictal EEG reveals bilateral, synchronous and symmetrical spike and waves, usually 3 Hz, on a normal background activity; (4) GTCS often develop during adolescence. The detailed inclusion criteria of this study are as follows: (1) Onset ages range from 3 to12 years; (2) Typical absence seizures as the initial seizure type; (3) Frequent absence seizures per day (=5 times); (4) Absence seizures are associated with bilateral, synchronous and symmetrical 3 Hz GSW discharges in the EEG with normal background; (5) Neurological examinations are normal; (6) Neuroradiological examinations (CT or MRI) are normal. 2.2. The inclusion and exclusion criteria for CAE proposed by Panayiotopoulos in 2005 [4] Inclusion criteria: (1) Age at onset between 4 and 10 years and a peak at 5–7 years; (2) Normal neurological state and development; (3) Brief and frequent absence seizures with abrupt and severe impairment of consciousness; (4) EEG ictal discharges of generalized highamplitude spike and double (maximum occasional 3 spikes are allowed) spike and slow wave complexes. Spike-wave is rhythmic at around 3 Hz with a gradual and regular slowdown from the initial to the terminal phase of the discharge. The duration of the discharges varies from 4 to 20 s. Exclusion criteria: (1) Other than typical absence seizures such as GTCS, or myoclonic jerks before or during the active stage of absences; (2) Eyelid myoclonia, perioral myoclonia, rhythmic massive limb jerking, and single or arrhythmic myoclonic jerks of the head, trunk or limbs; (3) Mild or no impairment of consciousness during the 3–4 Hz discharges; (4) Brief EEG 3–4 Hz spike-wave paroxysms of <4 s, multiple spikes
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(>3) or ictal discharge fragmentations; (5) Visual (photic) and other sensory precipitation of clinical seizures. 2.3. Patients The video-electroencephalogram (VEEG) database between January 1999 and August 2008 in our hospital was searched by using “absence seizures” and “3 Hz GSW” as key-words. The hospital records of all eligible patients were reviewed and other epileptic syndromes with typical absence seizures were excluded. 2.4. VEEG records The total length of the EEG recording was 3–4 h. Hyperventilation (HV) was performed in all patients, and intermittent photic stimulation (IPS) in a part of the patients. All the EEGs were read by two pediatric neurologists and one pediatric specialist in EEG. 2.5. Follow-up The effectiveness of medical treatment on seizures and the prognosis of the patients were followed up through outpatient service. 3. Results A total of 57 patients were searched in the database, and 20 of them were excluded for the following reasons: 15 patients had other epileptic syndromes with typical absence (4 JAE, 6 MAE, 3 EMA, 2 PMA), 3 patients had neck myoclonia with absences, and 2 patients had absence status epilepticus. As a result, 37 patients met the 1989 ILAE criteria. During the EEG examinations, 26 patients were naive to anti-epileptic drugs and 11 had received drug therapy but their seizures were still not well controlled. 3.1. Clinical features Among the whole cohort of 37 patients (15 male and 22 female), the onset age of absence seizures was from 3 to 11 years (medium, 6 years). The onset age of 35 patients ranged from 4 to 10 years, and the other 2 patients were 3 and 11 years, respectively. The absence seizures ranged from 5 to 60 times per day. Two patients (5.4%) had generalized tonic-clonic seizures (GTCS) which occurred after absence seizures. Seven patients (18.9%) had a history of febrile seizures. Family history of epilepsy or (and) febrile seizures in a first or second degree relative was reported in 5 patients (13.5%). All the patients had normal neurological development and brain imaging (CT or MRI). Absence seizures were recorded in all of the children by VEEG. The seizure duration ranged from 3 to 40 s,
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predominantly around 10 s. Seven children (18.9%) had only simple absences, consisting mainly of loss of consciousness, arrest of activity, and staring eyes. Twentyfive children (67.6%) had only complex absences. Five children (13.5%) had both simple and complex absences. Automatisms were seen in 24 children (80%). Six patients (16.2%) had absences with mild myoclonic components which showed jerking of the eyelids. Three patients (8.1%) had absences with atonic components, which showed dropping of the head. One patient (2.7%) had absences with the autonomic components which showed flushing on the face. Three patients (8.1%) had absence with myoclonic components and automatism simultaneously. One patient (2.7%) had absence with atonic components and automatism during one seizure. Absence seizures were provoked by HV in all patients. IPS was performed in 10 patients and no absence seizures were precipitated in any of them.
zures recorded had only one spike per wave. Four patients (10.8%) had double spikes per wave, mainly in occipital area. 3.2.2. Interictal EEG Fragments of GSW (<4 s) were found in 29 patients (78.4%) during sleep (Fig. 1). Among them fragments of GSW occurred when the patients were either drowsy (n = 10) or awaked (n = 9). The GSW could be irregular and asymmetric, and the frequency ranged from 1.5– 4 Hz. Interictal polyspikes (2–3 spikes per wave) were seen in 17 (45.9%) children. Focal epileptiform discharges were seen in 22 (56.8%) children, which predominantly in the anterior areas (Fig. 1). Posterior delta rhythm (2.5–4 Hz) was found in three patients. Interictal EEG was normal in three patients (8.1%). The EEG background was normal in all patients. 3.3. Application of 2005 Panayiotopoulos criteria
3.2. EEG features 3.2.1. Ictal EEG In all 37 patients, the ictal EEG consisted of high amplitude, bilateral, synchronous, symmetrical 3 Hz GSW discharges, with the highest voltage observed in the anterior regions. The duration of the discharges varied from 4 to 20 s in 33 patients (89.2%). 3 Hz GSW discharges shorter than 4 s were recorded in 1 patient (2.7%) and longer than 20 s recorded in 3 patients (5.4%); however, in these 4 patients, most 3 Hz GSW discharges varied from 4 to 20 s. The majority of sei-
We also applied the 2005 Panayiotopoulos criteria for CAE to evaluate these 37 patients. The following findings met the 2005 Panayiotopoulos criteria: All the patients had consciousness loss during absence seizures; and no one had obvious myoclonic features, photosensitivity, or polyspikes more than 3 spikes per wave. However, the following findings showed that not all the patients met the 2005 Panayiotopoulos criteria: the onset age of 2 patients was out of the range of 4 to 10 years; GTCS occurred during absence active stage in 2 patients; the duration of 3 Hz GSW did not range
Fig. 1. GSW fragment and focal discharge in frontal area in CAE patient during sleep.
X. Ma et al. / Brain & Development 33 (2011) 114–119
from 4 to 20 s in 4 patients; GSW paroxysms fragments shorter than 4 s in 29 patients. As a result, only 7 patients (18.9%) met the 2005 Panayiotopoulos criteria (Table 1). 3.4. Medical treatment and follow-up Totally 29 patients were followed. Although valproic acid (VPA) monotherapy in 28 patients, the seizures were well controlled after 3 days-3 months. In 5 patients who responded poorly to VPA, another drug was added in 4 patients (lamotrigine in 3 and clonazepam in 1 patient) and lamotrigine replaced VPA in 1 patient, and then the seizures were controlled. The following period was from 6 months to 9 year and 6 months. Nineteen patients had withdrawn anti-epileptic drugs and no relapse occurred. Complete remission maintained for more than 1 year in 11 patients. Two children accompanied with GTCS also got their seizures controlled; among them 1 patient had withdrawn anti-epileptic drugs for 1 year. 4. Discussion CAE is a common IGE syndrome with female preponderance. The onset age was not defined clearly in the 1989 ILAE criteria, although it is widely recognized as 3 to 10 years [6–7]. In the 2005 Panayiotopoulos criteria, the onset age was limited to 4–10 years. Some authors argued the children with typical absence seizures before 3 years should be classified as early-onset absence epilepsy, which should be regarded as an independent IGE syndrome [8–9]. Onsets of CAE between 3 to 4 years have been widely reported [10–11]. In our study, we also noted a patient who presented absence seizures when he was 3 years old, while his clinical features met the 2005 CAE criteria. Although most authors classified patients with onset age after 10 years as JAE, the child
Table 1 Re-evaluation of 37 children using the 2005 Panayiotopoulos criteria for CAE. 2005 criteria
Cases met the new criteria
Onset age from 4 to 10 years Normal general physical and neurological examinations Consciousness lost during absence seizures No GTCS or myoclonic jerks prior to or during the active stage of absences No myoclonic features in seizures except mild in eyes, eyebrows and eyelids 53 spikes per wave Duration of 3 Hz GSW 4–20 s No brief 3–4 Hz spike-wave paroxysms of less than 4 s Cases fulfilled the 2005 criteria
35 37 37 35 37 37 33 8 7/37
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whose onset age was 11 years in this cohort had many absence seizures (>10 times) per day, and her clinical features met CAE rather than JAE; therefore, it is inappropriate to classify her to other epileptic syndromes. Impairment of consciousness is severe in CAE, but may be mild or inconspicuous in other syndromes with typical absences such as EMA or MAE. All the patients in this cohort showed consciousness loss, demonstrating that consciousness impairment is severe in CAE patients. Mild or no impairment of consciousness during 3–4 Hz discharges is an exclusion criterion in 2005 Panayiotopoulos criteria. Complex absences are much more common than simple absences, especially absences with automatisms. A single patient may have both simple and complex absences [12]. That is also true in our study: the complex absences were all absences with automatisms in the patients who had both simple and complex absences. Absence with automatisms and absence with mild myoclonic components occurred at the same time in 3 patients and with atonic components occurred in 1 patient, suggesting that several components may occur during a given complex absence seizure. Mild myoclonic elements of the eyes, eyelids and eyebrows are common during absence. However, severe eyelid or perioral myoclonus, rhythmic limb jerking and single or arrhythmic myoclonic jerks of the head, trunk or limbs during absence ictus may indicate other IGE syndromes with absences. In 3 patients who showed neck myoclonia with absence and excluded from this cohort, their absence seizures were not frequent and the duration of absences was short, consciousness impairment was mild, the duration of 3 Hz GSW was 3–5 s; therefore, they can not be classified as CAE. In CAE, the absence seizures generally occur many times each day (up to 200 per day) [4], while the absence seizures are fewer than 5 times per day in JAE. Duration of the absences varies from 4 to 20 s, mainly around 10 s in CAE [13]. Typical absence seizures of CAE are easy to precipitate by HV. HV is very important in the diagnosis of CAE. A diagnosis of CAE should be questioned in an untreated child whose typical absence seizures can not be provoked by HV [14]. In our study, absence seizures were provoked by HV in all 37 patients, which further highlighted the importance oh HV in the diagnosis of CAE. The 1989 ILAE criteria states that GTCSs often develop during adolescence in CAE patients. Many authors still believe GTCS is a risk factor of worse prognosis in CAE [6,15]. However, also some studies found that the occurrence of GTCS had no obvious relationship with final outcome [10,11,16]. According to Panayiotopoulos, about 10% of patients may develop a few solitary or infrequency GTCS in adolescence or adult life [12]. In our cohort, GTCS occurred during the active stage of absences in 2 children, but their initial seizures were all absences and GTCS were few. The 2 children were fol-
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lowed up for 3–4 years, and they were all seizure-free. One patient had withdrawn anti-epileptic drugs for 1 year, and the other patient was still using drugs but remained clinical seizure-free. Therefore, these 2 patients can not be classified to other epileptic syndromes. Photosensitivity was not mentioned in 1989 ILAE criteria, although it was considered as a risk factor of poor prognosis in some studies [17–18]. Clinical photosensitivity or consistent provocation of typical absence by IPS was considered as an exclusion criterion for CAE in 2005 Panayiotopoulos criteria. Photosensitivity was far fewer in CAE than that in other epileptic syndromes with typical absences such as EMA and MAE [17]. In our study, IPS was performed in 10 patients and there was no photic induction of seizures, indicating that photosensitivity is seldom in CAE. The diagnosis of CAE should be questioned in a child whose absence seizures are photosensitive. Ictal EEG consists of high amplitude 3 Hz GSW discharges, which are of higher voltage in the anterior regions. There are rhythmic at around 3 Hz (2.5–4 Hz) with a regular slowing down of the frequency by 0.5– 1 Hz from the initial to the terminal phase of the discharge [11]. The children in our cohort completely met the above features. The number of polyspikes was not mentioned in the 1989 ILAE criteria, but was mentioned in the 2005 Panayiotopoulos criteria, which states that EEG ictal discharges of generalized high-amplitude spike and double (maximum occasional three spikes are allowed) spike and slow wave complexes is an inclusion criterion. In this study, 4 patients had double spikes and waves in ictal EEG and no one had polyspikes (3 or more than 3 spikes per wave), indicating that polyspikes more than 3 spikes per wave are rare in ictal EEG. The duration of the discharges varies from 4 to 20 s was considered as an inclusion criterion in the 2005 Panayiotopoulos criteria. In this cohort, the duration of 3 Hz GSW shorter than 4 s was noted in 1 patient and longer than 20 s in 3 patients in ictal EEG; however, the majority of their duration of 3 Hz GSW was 4–20 s. These 4 children still fit the clinical features of CAE. It seemed more reasonable to make “the majority duration of 3 Hz GSW is 4–20 s ” as an inclusion criterion. The interictal discharges are found in almost all children with active CAE, especially GSW fragments during sleep and drowsiness. The GSW may be irregular and asymmetric [14]. Sadlier et al. [13] found that fragments of GSW were seen in all but 4 of the 47 children, among which 97% in sleep and 70% in drowsiness. In our study, fragments of GSW occurred in 29 patients during sleep, including fragments of GSW during drowsiness in 10 patients, demonstrating that fragments of GSW are common during sleep and drowsiness in CAE patients. In the 2005 Panayiotopoulos criteria, brief 3–4 Hz spike-wave paroxysms of less than 4 s is regarded as an exclusion criterion. Our study showed it would be
more reasonable if the sleep and drowsiness stages were excluded when using this exclusion criterion. Focal discharges were seen in 22 patients (56.8%) and consisted mainly of anterior areas in this study, which was consistent with the previous report [19]. Polyspikes often occurred in the interictal EEG of CAE patients. Interictal polyspikes (2 to 5 spikes per wave) were seen in 40% of children in Sadleir’s report [13]. Multiple spikes (>3) was an exclusion criterion in the 2005 Panayiotopoulos criteria. In our study, multiple spikes (2–3 per wave) were found in the interictal EEG in 17 patients; however, no one had more than 3 spikes per wave, which provided supportive evidence to the 2005 Panayiotopoulos criteria. According to Sadleir et al. [13], only 5 of 47 (11%) patients classified as 1989 CAE criteria met the 2005 Panayiotopoulos criteria. According to Grosso et al. [15], the 2005 Panayiotopoulos criteria applied to 62/ 118 (52.1%) CAE patients. In our study, among 37 patients meeting 1989 ILAE criteria, only 7 (18.9%) met the 2005 Panayiotopoulos criteria. The other 30 patients did not meet these criteria due to: 3–4 Hz GSW paroxysms lasting less than 4 s (n = 29); onset before 4 years (n = 1) or after 10 years (n = 1); GTCS occurred during the active stage of absences (n = 2); and 3–4 Hz GSW < 4 s (n = 1) or >20 s (n = 3). Our study demonstrates basically the new inclusion and exclusion criteria of the 2005 Panayiotopoulos criteria are suitable for diagnosis of CAE; however, the exclusion criterion “brief EEG 3–4 Hz paroxysms lasting less than 4 s” does not properly interpret the patients’ status (awaking, drowsiness or sleep), which may rule out many patients, making the diagnosis even more difficult. In conclusion, more efforts should be made to further optimize the 2005 Panayiotopoulos criteria. Acknowledgment This study was supported by a Grant from the Research Foundation of Peking University First Hospital. References [1] Callenbach P, Geerts A, Arts W, et al. Familial occurrence of epilepsy in children with newly diagnosed multiple seizures: dutch study of epilepsy in childhood. Epilepsia 1998;39:331–6. [2] Engel J. A proposed diagnostic scheme for people with epileptic seizures and with epilepsy: report of the ILAE task force on classification and terminology. Epilepsia 2001;42:796–803. [3] Panayiotopoulos CP. Syndromes of idiopathic generalized epilepsies not recognized by the International League Against Epilepsy. Epilepsia 2005;46:57–66. [4] Loiseau P, Panayiotopoulos CP. Childhood Absence Epilepsy. Available at www.ilae-epilepsy.org/Visitors/Centre/ctf. Ret Type: Internet Communication. [5] Commission on classification and terminology of the International League Against Epilepsy. Proposal for revised classification of epilepsies and epileptic syndromes. Epilepsia 1989;30:389–99.
X. Ma et al. / Brain & Development 33 (2011) 114–119 [6] Valentin A, Hindocha N, Osei-Lah A, et al. Idiopathic generalized epilepsy with absences: syndrome classification. Epilepsia 2007;48:2187–90. [7] Coppola G, Licciardi F, Sciscio N, et al. Lamotrigine as first-line drug in childhood absence epilepsy: a clinical and neurophysiological study. Brain Dev 2004;26:26–9. [8] Shahar E, Genizi J, Nevo Y, et al. Typical absence epilepsy presenting prior to age of 3 years: an uncommon form of idiopathic generalized epilepsy. Eur J Paediatr Neurol 2007;11:346–532. [9] Ferna´ndez-Torre JL, Herranz JL, Martı´nez-Martı´nez M, et al. Early-onset absence epilepsy: clinical and electroencephalographic features in three children. Brain Dev 2006;28:311–4. [10] Chen Q, Li EZ, Wang LW, et al. The effectiveness of valproate on the therapy to childhood absence epilepsy. Chin J Prac Pediatr 2006;21:541–2. [11] Callenbach PM, Bouma PA, Geerts AT, et al. Long-term outcome of childhood absence epilepsy: dutch study of epilepsy in childhood. Epilepsy Res 2009;83:249–56. [12] Panayiotopoulos CP. Idiopathic generalized epilepsies. In: Panayiotopoulos CP, editor. The epilepsies: seizures, syndromes and
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management. Oxford: Bladon Medical Publishing; 2005. p. 296–303. Sadleir LG, Farrell K, Smith S, et al. Electroclinical features of absence seizures in childhood absence epilepsy. Neurology 2006;67:413–8. Liu XY. Clinical electroencephalography. 1st ed. Peking: People’ health publishing; 2006, p. 251–254. Grosso S, Galimberti D, Vezzosi P, et al. Childhood absence epilepsy: evolution and prognostic factors. Epilepsia 2005;46:1796–801. Ma XW, Zhang YH, Liu XY, et al. Treatment and prognosis of childhood absence epilepsy in 240 patients: application of modified diagnostic criteria of childhood absence epilepsy 1989. Chin J Evid Based Pediatr 2008;3:419–25. Covanis A. Photosensitivity in idiopathic generalized epilepsies. Epilepsia 2005;46:67–72. Agathonikou A, Giannakodimos S, Koutroumanidis M, et al. Idiopathic generalized epilepsies in adults with onset of typical absences before the age of 10 years. Epilepsia 1997;38:213. Yoshinaga H, Ohtsuka Y, Tamai K, et al. EEG in childhood absence epilepsy. Seizure 2004;13:296–302.
Original article
Childhood absence epilepsy: Elctroclinical features and diagnostic criteria Xiuwei Ma a,b, Yuehua Zhang a,*, Zhixian Yang a, Xiaoyan Liu a, Huihui Sun a, Jiong Qin a, Xiru Wu a, Jianmin Liang a,c,** a
Department of Pediatrics, Peking University First Hospital, No. 1, of Xian Men Street, Xicheng District, Beijing 100034, PR China b Bayi Children’s Hospital Affiliated to General Hospital of Beijing District, PLA 100710, PR China c Department of Pediatrics, First Hospital of Jilin University, Changchun 130021, PR China Received 6 July 2009; received in revised form 29 December 2009; accepted 16 February 2010
Abstract Objective: To analyze the electroclinical features of children with childhood absence epilepsy (CAE) and discuss the diagnostic criteria for CAE. Methods: The video-electroencephalogram (VEEG) database in our hospital was searched using “absence seizures” and “3-Hz generalized spike and waves (GSW)” as key-words. Other epileptic syndromes with typical absence seizures were carefully excluded. Children meeting the CAE diagnostic criteria of the International League Against Epilepsy (ILAE) in 1989 were further evaluated with the diagnostic criteria proposed by Panayiotopoulos in 2005. Results: Totally 37 children met the 1989 ILAE criteria of CAE. The onset age of absence seizures ranged from 3 to 11 years. All patients had frequent absence seizures (5–60 times per day). Two patients (5.4%) had generalized tonic-clonic seizures. Hyperventilation induced absences in all patients. VEEG confirmed that 7 patients (18.9%) had only simple absences, 25 patients (67.6%) had only complex absences, and 5 patients (13.5%) had both simple and complex absences. Ictal EEG showed 3 Hz GSW discharges in all patients. The seizure duration ranged from 3 to 40 s. Four patients (10.8%) had two spikes per wave in ictal EEG. GSW fragments were found in 29 patients (78.4%) during sleep. Interictal polyspikes and waves were present in 17 patients (45.9%). Focal discharges predominantly in the anterior regions, were found in 22 patients (56.8%). Only 7 patients (18.9%) met the diagnostic criteria proposed by Panayiotopoulos in 2005. Conclusions: Few patients meeting the 1989 ILAE diagnostic criteria for CAE meet the new diagnostic criteria proposed by Panayiotopoulos in 2005. The new criteria for CAE are too strict to appropriately classify some patients. Ó 2010 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved. Keywords: Childhood absence epilepsy; Electroencephalogram; Diagnosis
1. Introduction Childhood absence epilepsy (CAE) is an age-dependent, idiopathic form of generalized epilepsy, characterized by the following features: multiple typical absence seizures each day that accompanied with bilateral, sym*
Corresponding author. Tel.: +86 10 8357 3234; fax: +86 106613 4261. ** Corresponding author. E-mail addresses: [email protected] (Y. Zhang), jackyliangjm @126.com (J. Liang).
metrical, and synchronous discharges of 3-Hz generalized spike and waves (GSW) in the electroencephalogram (EEG). CAE accounts for 2% to 10% of all childhood epilepsies and 8–15% of school-aged childhood epilepsies [1]. The idiopathic generalized epileptic (IGE) syndromes with typical absences defined by the International League Against Epilepsy (ILAE) in 2001 include CAE, juvenile absence epilepsy (JAE), juvenile myoclonic epilepsy (JME) and myoclonic absence epilepsy (MAE) [2]. The syndromes with typical absences that are not officially recognized by ILAE include eyelid myoclonia with absences (EMA) and perioral myoclonia with absences
0387-7604/$ - see front matter Ó 2010 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.braindev.2010.02.004
X. Ma et al. / Brain & Development 33 (2011) 114–119
(PMA) [3]. The clinical features and prognosis of these epileptic syndromes are different, so it is important to define the syndromic classification for every patient rigorously. The criteria for CAE proposed by ILAE in 1989 are still broadly used. Panayiotopoulos proposed stricter inclusion and exclusion criteria for CAE in 2005 [4]. Whether the new diagnostic criteria for CAE are suitable or not is still controversial. In this study, we analyzed the clinical and EEG features of the CAE patients diagnosed in our hospital meeting the 1989 ILAE criteria and further evaluated these patients using the new criteria with an attempt to explore the feasibility of applying the new criteria for CAE in clinical practice. 2. Subject and methods 2.1. The diagnostic criteria for CAE The criteria proposed by ILAE in 1989 include [5] (1) Onset in children of school age (peak age 5–7 years); (2) Very frequent absence seizures (several to many per day); (3) Ictal EEG reveals bilateral, synchronous and symmetrical spike and waves, usually 3 Hz, on a normal background activity; (4) GTCS often develop during adolescence. The detailed inclusion criteria of this study are as follows: (1) Onset ages range from 3 to12 years; (2) Typical absence seizures as the initial seizure type; (3) Frequent absence seizures per day (=5 times); (4) Absence seizures are associated with bilateral, synchronous and symmetrical 3 Hz GSW discharges in the EEG with normal background; (5) Neurological examinations are normal; (6) Neuroradiological examinations (CT or MRI) are normal. 2.2. The inclusion and exclusion criteria for CAE proposed by Panayiotopoulos in 2005 [4] Inclusion criteria: (1) Age at onset between 4 and 10 years and a peak at 5–7 years; (2) Normal neurological state and development; (3) Brief and frequent absence seizures with abrupt and severe impairment of consciousness; (4) EEG ictal discharges of generalized highamplitude spike and double (maximum occasional 3 spikes are allowed) spike and slow wave complexes. Spike-wave is rhythmic at around 3 Hz with a gradual and regular slowdown from the initial to the terminal phase of the discharge. The duration of the discharges varies from 4 to 20 s. Exclusion criteria: (1) Other than typical absence seizures such as GTCS, or myoclonic jerks before or during the active stage of absences; (2) Eyelid myoclonia, perioral myoclonia, rhythmic massive limb jerking, and single or arrhythmic myoclonic jerks of the head, trunk or limbs; (3) Mild or no impairment of consciousness during the 3–4 Hz discharges; (4) Brief EEG 3–4 Hz spike-wave paroxysms of <4 s, multiple spikes
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(>3) or ictal discharge fragmentations; (5) Visual (photic) and other sensory precipitation of clinical seizures. 2.3. Patients The video-electroencephalogram (VEEG) database between January 1999 and August 2008 in our hospital was searched by using “absence seizures” and “3 Hz GSW” as key-words. The hospital records of all eligible patients were reviewed and other epileptic syndromes with typical absence seizures were excluded. 2.4. VEEG records The total length of the EEG recording was 3–4 h. Hyperventilation (HV) was performed in all patients, and intermittent photic stimulation (IPS) in a part of the patients. All the EEGs were read by two pediatric neurologists and one pediatric specialist in EEG. 2.5. Follow-up The effectiveness of medical treatment on seizures and the prognosis of the patients were followed up through outpatient service. 3. Results A total of 57 patients were searched in the database, and 20 of them were excluded for the following reasons: 15 patients had other epileptic syndromes with typical absence (4 JAE, 6 MAE, 3 EMA, 2 PMA), 3 patients had neck myoclonia with absences, and 2 patients had absence status epilepticus. As a result, 37 patients met the 1989 ILAE criteria. During the EEG examinations, 26 patients were naive to anti-epileptic drugs and 11 had received drug therapy but their seizures were still not well controlled. 3.1. Clinical features Among the whole cohort of 37 patients (15 male and 22 female), the onset age of absence seizures was from 3 to 11 years (medium, 6 years). The onset age of 35 patients ranged from 4 to 10 years, and the other 2 patients were 3 and 11 years, respectively. The absence seizures ranged from 5 to 60 times per day. Two patients (5.4%) had generalized tonic-clonic seizures (GTCS) which occurred after absence seizures. Seven patients (18.9%) had a history of febrile seizures. Family history of epilepsy or (and) febrile seizures in a first or second degree relative was reported in 5 patients (13.5%). All the patients had normal neurological development and brain imaging (CT or MRI). Absence seizures were recorded in all of the children by VEEG. The seizure duration ranged from 3 to 40 s,
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predominantly around 10 s. Seven children (18.9%) had only simple absences, consisting mainly of loss of consciousness, arrest of activity, and staring eyes. Twentyfive children (67.6%) had only complex absences. Five children (13.5%) had both simple and complex absences. Automatisms were seen in 24 children (80%). Six patients (16.2%) had absences with mild myoclonic components which showed jerking of the eyelids. Three patients (8.1%) had absences with atonic components, which showed dropping of the head. One patient (2.7%) had absences with the autonomic components which showed flushing on the face. Three patients (8.1%) had absence with myoclonic components and automatism simultaneously. One patient (2.7%) had absence with atonic components and automatism during one seizure. Absence seizures were provoked by HV in all patients. IPS was performed in 10 patients and no absence seizures were precipitated in any of them.
zures recorded had only one spike per wave. Four patients (10.8%) had double spikes per wave, mainly in occipital area. 3.2.2. Interictal EEG Fragments of GSW (<4 s) were found in 29 patients (78.4%) during sleep (Fig. 1). Among them fragments of GSW occurred when the patients were either drowsy (n = 10) or awaked (n = 9). The GSW could be irregular and asymmetric, and the frequency ranged from 1.5– 4 Hz. Interictal polyspikes (2–3 spikes per wave) were seen in 17 (45.9%) children. Focal epileptiform discharges were seen in 22 (56.8%) children, which predominantly in the anterior areas (Fig. 1). Posterior delta rhythm (2.5–4 Hz) was found in three patients. Interictal EEG was normal in three patients (8.1%). The EEG background was normal in all patients. 3.3. Application of 2005 Panayiotopoulos criteria
3.2. EEG features 3.2.1. Ictal EEG In all 37 patients, the ictal EEG consisted of high amplitude, bilateral, synchronous, symmetrical 3 Hz GSW discharges, with the highest voltage observed in the anterior regions. The duration of the discharges varied from 4 to 20 s in 33 patients (89.2%). 3 Hz GSW discharges shorter than 4 s were recorded in 1 patient (2.7%) and longer than 20 s recorded in 3 patients (5.4%); however, in these 4 patients, most 3 Hz GSW discharges varied from 4 to 20 s. The majority of sei-
We also applied the 2005 Panayiotopoulos criteria for CAE to evaluate these 37 patients. The following findings met the 2005 Panayiotopoulos criteria: All the patients had consciousness loss during absence seizures; and no one had obvious myoclonic features, photosensitivity, or polyspikes more than 3 spikes per wave. However, the following findings showed that not all the patients met the 2005 Panayiotopoulos criteria: the onset age of 2 patients was out of the range of 4 to 10 years; GTCS occurred during absence active stage in 2 patients; the duration of 3 Hz GSW did not range
Fig. 1. GSW fragment and focal discharge in frontal area in CAE patient during sleep.
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from 4 to 20 s in 4 patients; GSW paroxysms fragments shorter than 4 s in 29 patients. As a result, only 7 patients (18.9%) met the 2005 Panayiotopoulos criteria (Table 1). 3.4. Medical treatment and follow-up Totally 29 patients were followed. Although valproic acid (VPA) monotherapy in 28 patients, the seizures were well controlled after 3 days-3 months. In 5 patients who responded poorly to VPA, another drug was added in 4 patients (lamotrigine in 3 and clonazepam in 1 patient) and lamotrigine replaced VPA in 1 patient, and then the seizures were controlled. The following period was from 6 months to 9 year and 6 months. Nineteen patients had withdrawn anti-epileptic drugs and no relapse occurred. Complete remission maintained for more than 1 year in 11 patients. Two children accompanied with GTCS also got their seizures controlled; among them 1 patient had withdrawn anti-epileptic drugs for 1 year. 4. Discussion CAE is a common IGE syndrome with female preponderance. The onset age was not defined clearly in the 1989 ILAE criteria, although it is widely recognized as 3 to 10 years [6–7]. In the 2005 Panayiotopoulos criteria, the onset age was limited to 4–10 years. Some authors argued the children with typical absence seizures before 3 years should be classified as early-onset absence epilepsy, which should be regarded as an independent IGE syndrome [8–9]. Onsets of CAE between 3 to 4 years have been widely reported [10–11]. In our study, we also noted a patient who presented absence seizures when he was 3 years old, while his clinical features met the 2005 CAE criteria. Although most authors classified patients with onset age after 10 years as JAE, the child
Table 1 Re-evaluation of 37 children using the 2005 Panayiotopoulos criteria for CAE. 2005 criteria
Cases met the new criteria
Onset age from 4 to 10 years Normal general physical and neurological examinations Consciousness lost during absence seizures No GTCS or myoclonic jerks prior to or during the active stage of absences No myoclonic features in seizures except mild in eyes, eyebrows and eyelids 53 spikes per wave Duration of 3 Hz GSW 4–20 s No brief 3–4 Hz spike-wave paroxysms of less than 4 s Cases fulfilled the 2005 criteria
35 37 37 35 37 37 33 8 7/37
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whose onset age was 11 years in this cohort had many absence seizures (>10 times) per day, and her clinical features met CAE rather than JAE; therefore, it is inappropriate to classify her to other epileptic syndromes. Impairment of consciousness is severe in CAE, but may be mild or inconspicuous in other syndromes with typical absences such as EMA or MAE. All the patients in this cohort showed consciousness loss, demonstrating that consciousness impairment is severe in CAE patients. Mild or no impairment of consciousness during 3–4 Hz discharges is an exclusion criterion in 2005 Panayiotopoulos criteria. Complex absences are much more common than simple absences, especially absences with automatisms. A single patient may have both simple and complex absences [12]. That is also true in our study: the complex absences were all absences with automatisms in the patients who had both simple and complex absences. Absence with automatisms and absence with mild myoclonic components occurred at the same time in 3 patients and with atonic components occurred in 1 patient, suggesting that several components may occur during a given complex absence seizure. Mild myoclonic elements of the eyes, eyelids and eyebrows are common during absence. However, severe eyelid or perioral myoclonus, rhythmic limb jerking and single or arrhythmic myoclonic jerks of the head, trunk or limbs during absence ictus may indicate other IGE syndromes with absences. In 3 patients who showed neck myoclonia with absence and excluded from this cohort, their absence seizures were not frequent and the duration of absences was short, consciousness impairment was mild, the duration of 3 Hz GSW was 3–5 s; therefore, they can not be classified as CAE. In CAE, the absence seizures generally occur many times each day (up to 200 per day) [4], while the absence seizures are fewer than 5 times per day in JAE. Duration of the absences varies from 4 to 20 s, mainly around 10 s in CAE [13]. Typical absence seizures of CAE are easy to precipitate by HV. HV is very important in the diagnosis of CAE. A diagnosis of CAE should be questioned in an untreated child whose typical absence seizures can not be provoked by HV [14]. In our study, absence seizures were provoked by HV in all 37 patients, which further highlighted the importance oh HV in the diagnosis of CAE. The 1989 ILAE criteria states that GTCSs often develop during adolescence in CAE patients. Many authors still believe GTCS is a risk factor of worse prognosis in CAE [6,15]. However, also some studies found that the occurrence of GTCS had no obvious relationship with final outcome [10,11,16]. According to Panayiotopoulos, about 10% of patients may develop a few solitary or infrequency GTCS in adolescence or adult life [12]. In our cohort, GTCS occurred during the active stage of absences in 2 children, but their initial seizures were all absences and GTCS were few. The 2 children were fol-
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lowed up for 3–4 years, and they were all seizure-free. One patient had withdrawn anti-epileptic drugs for 1 year, and the other patient was still using drugs but remained clinical seizure-free. Therefore, these 2 patients can not be classified to other epileptic syndromes. Photosensitivity was not mentioned in 1989 ILAE criteria, although it was considered as a risk factor of poor prognosis in some studies [17–18]. Clinical photosensitivity or consistent provocation of typical absence by IPS was considered as an exclusion criterion for CAE in 2005 Panayiotopoulos criteria. Photosensitivity was far fewer in CAE than that in other epileptic syndromes with typical absences such as EMA and MAE [17]. In our study, IPS was performed in 10 patients and there was no photic induction of seizures, indicating that photosensitivity is seldom in CAE. The diagnosis of CAE should be questioned in a child whose absence seizures are photosensitive. Ictal EEG consists of high amplitude 3 Hz GSW discharges, which are of higher voltage in the anterior regions. There are rhythmic at around 3 Hz (2.5–4 Hz) with a regular slowing down of the frequency by 0.5– 1 Hz from the initial to the terminal phase of the discharge [11]. The children in our cohort completely met the above features. The number of polyspikes was not mentioned in the 1989 ILAE criteria, but was mentioned in the 2005 Panayiotopoulos criteria, which states that EEG ictal discharges of generalized high-amplitude spike and double (maximum occasional three spikes are allowed) spike and slow wave complexes is an inclusion criterion. In this study, 4 patients had double spikes and waves in ictal EEG and no one had polyspikes (3 or more than 3 spikes per wave), indicating that polyspikes more than 3 spikes per wave are rare in ictal EEG. The duration of the discharges varies from 4 to 20 s was considered as an inclusion criterion in the 2005 Panayiotopoulos criteria. In this cohort, the duration of 3 Hz GSW shorter than 4 s was noted in 1 patient and longer than 20 s in 3 patients in ictal EEG; however, the majority of their duration of 3 Hz GSW was 4–20 s. These 4 children still fit the clinical features of CAE. It seemed more reasonable to make “the majority duration of 3 Hz GSW is 4–20 s ” as an inclusion criterion. The interictal discharges are found in almost all children with active CAE, especially GSW fragments during sleep and drowsiness. The GSW may be irregular and asymmetric [14]. Sadlier et al. [13] found that fragments of GSW were seen in all but 4 of the 47 children, among which 97% in sleep and 70% in drowsiness. In our study, fragments of GSW occurred in 29 patients during sleep, including fragments of GSW during drowsiness in 10 patients, demonstrating that fragments of GSW are common during sleep and drowsiness in CAE patients. In the 2005 Panayiotopoulos criteria, brief 3–4 Hz spike-wave paroxysms of less than 4 s is regarded as an exclusion criterion. Our study showed it would be
more reasonable if the sleep and drowsiness stages were excluded when using this exclusion criterion. Focal discharges were seen in 22 patients (56.8%) and consisted mainly of anterior areas in this study, which was consistent with the previous report [19]. Polyspikes often occurred in the interictal EEG of CAE patients. Interictal polyspikes (2 to 5 spikes per wave) were seen in 40% of children in Sadleir’s report [13]. Multiple spikes (>3) was an exclusion criterion in the 2005 Panayiotopoulos criteria. In our study, multiple spikes (2–3 per wave) were found in the interictal EEG in 17 patients; however, no one had more than 3 spikes per wave, which provided supportive evidence to the 2005 Panayiotopoulos criteria. According to Sadleir et al. [13], only 5 of 47 (11%) patients classified as 1989 CAE criteria met the 2005 Panayiotopoulos criteria. According to Grosso et al. [15], the 2005 Panayiotopoulos criteria applied to 62/ 118 (52.1%) CAE patients. In our study, among 37 patients meeting 1989 ILAE criteria, only 7 (18.9%) met the 2005 Panayiotopoulos criteria. The other 30 patients did not meet these criteria due to: 3–4 Hz GSW paroxysms lasting less than 4 s (n = 29); onset before 4 years (n = 1) or after 10 years (n = 1); GTCS occurred during the active stage of absences (n = 2); and 3–4 Hz GSW < 4 s (n = 1) or >20 s (n = 3). Our study demonstrates basically the new inclusion and exclusion criteria of the 2005 Panayiotopoulos criteria are suitable for diagnosis of CAE; however, the exclusion criterion “brief EEG 3–4 Hz paroxysms lasting less than 4 s” does not properly interpret the patients’ status (awaking, drowsiness or sleep), which may rule out many patients, making the diagnosis even more difficult. In conclusion, more efforts should be made to further optimize the 2005 Panayiotopoulos criteria. Acknowledgment This study was supported by a Grant from the Research Foundation of Peking University First Hospital. References [1] Callenbach P, Geerts A, Arts W, et al. Familial occurrence of epilepsy in children with newly diagnosed multiple seizures: dutch study of epilepsy in childhood. Epilepsia 1998;39:331–6. [2] Engel J. A proposed diagnostic scheme for people with epileptic seizures and with epilepsy: report of the ILAE task force on classification and terminology. Epilepsia 2001;42:796–803. [3] Panayiotopoulos CP. Syndromes of idiopathic generalized epilepsies not recognized by the International League Against Epilepsy. Epilepsia 2005;46:57–66. [4] Loiseau P, Panayiotopoulos CP. Childhood Absence Epilepsy. Available at www.ilae-epilepsy.org/Visitors/Centre/ctf. Ret Type: Internet Communication. [5] Commission on classification and terminology of the International League Against Epilepsy. Proposal for revised classification of epilepsies and epileptic syndromes. Epilepsia 1989;30:389–99.
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