- Email: [email protected]
Early identification of epileptic encephalopathy with continuous spikes-and-waves during sleep: A case-control study
Accepted Manuscript Early identification of Epileptic Encephalopathy with Continuous Spikes-and-Waves during Sleep: a case-control study Camille Desprairies, Blandine Dozières-Puyravel, Adina Ilea, Vanina Bellavoine, Hala Nasser, Catherine Delanöe, Stéphane Auvin PII:
S1090-3798(17)31708-7
DOI:
10.1016/j.ejpn.2018.04.009
Reference:
YEJPN 2415
To appear in:
European Journal of Paediatric Neurology
Received Date: 8 June 2017 Revised Date:
24 March 2018
Accepted Date: 22 April 2018
Please cite this article as: Desprairies C, Dozières-Puyravel B, Ilea A, Bellavoine V, Nasser H, Delanöe C, Auvin S, Early identification of Epileptic Encephalopathy with Continuous Spikes-and-Waves during Sleep: a case-control study, European Journal of Paediatric Neurology (2018), doi: 10.1016/ j.ejpn.2018.04.009. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Early identification of Epileptic Encephalopathy with Continuous Spikes-andWaves during Sleep: a case-control study Camille Desprairies1,2, Blandine Dozières-Puyravel1, Adina Ilea1, Vanina Bellavoine1,
AP-HP, Hôpital Robert Debré, Service de Neurologie Pédiatrique, 75019 Paris,
SC
1.
RI PT
Hala Nasser3, Catherine Delanöe3, Stéphane Auvin1,2
France
Université Paris Diderot, Sorbonne Paris Cité, INSERM UMR1141, 75019 Paris,
M AN U
2.
France
AP-HP, Hôpital Robert Debré, Service de Physiologie, 75019 Paris, France
Corresponding author:
EP
Stéphane Auvin, MD, PhD
TE D
3.
Service de Neurologie Pédiatrique et des Maladies Métaboliques
AC C
CHU Hôpital Robert Debré 48, boulevard Sérurier
75935 PARIS CEDEX 19 - France Phone: +33 1 40 03 57 24 Fax: +33 1 40 03 47 74 Email: [email protected]
ACCEPTED MANUSCRIPT
ABTRACT: Epileptic encephalopathy with continuous spikes-and-waves during sleep (EE-CSWS) is a rare childhood epilepsy syndrome characterized by a regression in cognitive, behavioral and
RI PT
psychiatric functioning, seizures and a specific electroencephalographic pattern. An early recognition and an appropriate treatment might play a key role in the outcome of this epileptic encephalopathy. We conducted a case-control study to evaluate if there is any clinical or
SC
electroencephalographic sign suggestive of EE-CSWS after the first seizure. We retrospectively identified 10 EE-CSWS patients with available EEG recording at time of the first seizure. We
M AN U
matched them with 10 controls from our first seizure clinics. All EEG recording were analyzed for the study. We did not find any clinical or EEG features that would suggest later development of EE-CSWS. As reported by others, the occurrence of multiple seizures types and a seizure worsening during the follow-up is more frequent in the cases than in the controls. These clinical criteria might be used as a red flag in clinical practice to identify the very few patients with EE-
Keywords:
Case-control
study;
AC C
EP
Encephalopathy; Epilepsy
TE D
CSWS among the frequent patients with BECTS.
Continous
Spikes
and
Waves
in
Sleep;
Epileptic
ACCEPTED MANUSCRIPT
INTRODUCTION Epileptic encephalopathy with continuous spikes-and-waves during sleep (EE-CSWS) is a rare childhood epilepsy syndrome and may represent from 0.2% to 2% of the epilepsies
RI PT
(3). Tassinari et al. first introduced these terms in 1977 as “encephalopathy related to electrical status epilepticus during slow sleep” and “electrical status epilepticus during slow sleep“ (1,2). This syndrome is characterized by a regression in cognitive, behavioral and psychiatric
SC
functioning, seizures and a specific electroencephalographic (EEG) pattern. The core symptom is the cognitive regression that can occur in all subtypes of cognitive functions. The seizure
M AN U
types are not specific (4,5). The EEG pattern at time of diagnosis shows almost continuous slow (typically 1.5-3Hz) (6) spikes-and-wave, seen in slow sleep. Some authors provide percentages of slow wave sleep that must be occupied by continuous spike-and-wave e.g. >50% (7,8) or > 85% (5). The ILAE does not require these criteria (4).
Various terms have been used interchangeably when referring to related but different
TE D
concepts. This results in an increasing of the complexity in communication among clinicians and jeopardizes research in this field (9). This complexity in terminology has been further increased by the various definitions and inclusion criteria in the studies on EE-CSWS (3).
EP
The concept of epileptic encephalopathy (EE) consists of the notion that the epileptic activity itself (seizure and EEG abnormalities) may contribute to severe cognitive and behavioral
AC C
impairments above and beyond what might be expected from the underlying pathology alone (e.g., cortical malformation), and that these can worsen over time (10,11). Suggesting that an early recognition and an appropriate treatment might play a key role in the outcome (11). Our aim was to identify electroclinical elements at the time of the first seizure that might
lead to an early identification of EE-CSWS. We first described their electroclinical characteristics at the first seizure of a group of patients with this orphan pediatric epilepsy syndrome. We then matched them with controls from the first seizure clinics to compare the two groups in order to identify distinctive features that might be helpful for an early recognition of EE-CSWS.
ACCEPTED MANUSCRIPT
PATIENTS AND METHODS We conducted a monocentric study between January 2006 and December 2015. Data were collected on all consecutive cases of EE-CSWS identified by retrieving medical records
The inclusion criteria for the cases were: -
RI PT
from 2 local databases (Pediatric neurology Department and Neurophysiology Department).
Diagnosis of EE-CSWS syndrome based on a clinical history, a cognitive or behavioral
at time of cognitive regression
SC
regression and typical EEG pattern (> 80% of sleep with continuous spike-and-wave)
Children aged from 2 years to 16 years
-
The regression was defined on clinical criteria or on the medical interview.
-
Children who have been followed in our department since the first seizure or at least with
M AN U
-
EEG recording available at time of the first seizure.
We considered the following information for each patient (clinical data were collected
TE D
retrospectively while EEG were reanalyzed for the study): familial and personal antecedents, psychomotor development, epilepsy features (onset, clinical description, treatment, type and frequency of seizures during the follow-up), neurologic examination, the first EEG during
EP
wakefulness and sleep, brain MRI, seizure diary, the regression (cognitive and/or behavioral changes, age of this regression, evolution) and the treatment of EE-CSWS. We describe the
AC C
current condition of patients: all patients had been seen for the study at least in May 2015 or we called for a follow-up at the time of the study. We first described the patients with EE-CSWS. For the second part of the study, the EE-
CSWS patients were matched individually with controls based on the type of the first seizure and the date of the first EEG record (within the same 6-months period). The choice to match cases and controls only on the seizure type allow the evaluation of all the other clinical and electrophysiological characteristics including age at first seizure or any EEG findings. The inclusion criteria for the controls were: same first seizure type than a case
ACCEPTED MANUSCRIPT
within the same 6-month period. The characteristics of the first seizure of each patient were analyzed. We called the controls at time of the study to check the absence of regression or cognitive involvement since the diagnosis. The EEG of each patient (EE-CSWS and matched
RI PT
patients) were re-analyzed for the study (C. Des. & C. Del.). We compared each EE-CSWS patient with a control for clinical description of the first seizure (type, time, age) and the data of the first EEG recording.
SC
Data analysis
All data were recorded anonymously (C. Des.). Percentage were rounded to whole
M AN U
numbers. We reported the mean ± standard error of the mean (SEM) of continuous data. The study was designed to compare the cases and the controls for all studies parameters with non-parametric tests. Mann & Whitney test and Fisher exact tests were performed using the GraphPad Prism 5.01 software. p < 0.05 was considered statistically significant.
TE D
RESULTS
Description of the EE-CSWS patients (Table 1) We included 10 children: 6 girls and 4 boys. 4/10 children had a familial history of
EP
epilepsy. 2/10 children had significant perinatal medical history: one with simple prematurity at 35 weeks of pregnancy and one with cytomegalovirus maternal-fetal infection with deafness and
AC C
periventricular white matter abnormalities. The mean age at the first seizure was 6.1 ± 0.6 years (range 3 to 10 years). The seizure type and the time of occurrence of the first seizure are described in the table 1. 9/10 experienced several seizures before the diagnosis of EE-CSWS. The initial diagnoses were BECTS in 4, Panayiotopoulos syndrome in 2, epilepsy with focal seizures in 3 (multifocal seizures in the patients with CMV infection). Only patient had an abnormal MRI (CMV infection). The details of the electrophysiological data at time of the first seizure are reported in the table 1. Clinical history from the first seizure to the diagnosis of EE-CSWS
ACCEPTED MANUSCRIPT
6/10 exhibited at least 2 types of seizures: generalized seizures (clonic and absence seizures) and focal seizures with focal symptoms including mouth deviation, aphasia or focal clonic seizures. The seizure frequency fluctuated from daily to 1 each 6 weeks. After treatment,
RI PT
all were improved by treatment (7/10 seizure free). The first line of treatment was valproate in 8 patients, levetiracetam in one patient and carbamazepine in one. 5/10 remained on the first monotherapy, while 2/10 needed another monotherapy and 3/10 received combined antiepileptic
SC
drugs (2/10 bitherapy, 1/11 tritherapy).
Just before the cognitive regression, 5/10 children had an aggravation of the seizure
M AN U
frequency (> 50% compared to the baseline). The seizure was a different seizure type from the start in 3/4. The worsening in seizure frequency happened 2.6 ± 0.5 months in mean before the regression for the four patients.
Diagnosis of the EE-CSWS and evolution
TE D
The mean age at regression was 7.5 ± 0.5 years. The mean time between the first seizure and the diagnosis of EE-CSWS were 18.8 ± 6.6 months. The delay between the regression and the diagnosis was 1.7 ± 0.6 months (Table 1). For one patient, the regression
EP
and the first seizure were observed at the same time. All had a cognitive regression, each child had specific cognitive symptoms: motor that could be gross motor functions (walk, falls) or fine
AC C
motor function (writing, dressing), language (speech, reading, grammar), memory or mathematic reasoning. 7/10 had also a behavioral change with attention disorder, phobia, aggression and opposition. All patients had an EEG at the time of diagnosis. At EE-CSWS diagnosis, all patients have had treatment modification. 10/10 patients received clobazam (5-15mg once a day – Addon in 6/10 and switched in 4/10). All patients were seen 15 to 30 days after the EE-CSWS treatment. All of them exhibit a cognitive improvement (defined as regain of lost cognitive abilities). But for 4 patients, this improvement was considered limited, leading to an additional treatment. One was controlled by adding levetiracetam with clobazam. For 3 of them
ACCEPTED MANUSCRIPT
methylprednisolone pulses followed by oral steroids were used. At 6 months after the diagnosis, all had a cognitive and behavioral improvement but still had some cognitive difficulties. Seizures stopped for 8/10. The EEG became normal for 6/10 while 4/10 showed focal abnormalities
RI PT
without ESES EEG pattern. 4/10 had no relapse based on the follow-up of the intellectual functioning. 2/6 had one relapse and 4/6 had two relapses during the follow-up. The mean delay between the diagnosis of EE-CSWS and the relapse was 9.3 ± 2.9 months. Among patients that
SC
experienced a relapse, 5/6 had seizures at time of the relapse. The relapses were treated by steroid (methylprednisolone pulses followed by oral steroids). One received sulthiam. Treatment
M AN U
of relapse resulted in a cognitive improvement in 5/6 patients, even if the patients still exhibited learning difficulties. Follow-up at the time of the study (mean duration of follow-up was 3.0 ± 0.70 years) showed that 8/10 still had learning/academic difficulties despite the dramatic improvement after EE-CSWS treatment. 2/10 had a full recovery with good academic achievement without any support. 3/10 still experienced seizures. 4/10 had EEG abnormalities consisting in focal
disorders.
TE D
spikes with a moderate increase of the abnormalities during sleep. 8/10 patients had attentional
Description of the control population (Table 2)
EP
We matched 10 controls (epilepsy patients) with our EE-CSWS patients. The control were 5 females and 5 males. The mean age at the first seizure was 6.3 years ± 0.6 (range 3 to
AC C
10). The seizure type and the time of occurrence of the first seizure are described in the table 2. 9/10 were diagnosed BECT and one had Panayiotopoulos syndrome. 2 children received antiepileptic drugs after the first seizure (valproate) without any relapse during the follow-up. Six children started a treatment during the follow-up because of recurrence of seizures (Table 2). All controls were seizure free (two without treatment and five after treatment by valproate or levetiracetam). At the last follow-up (mean duration of follow-up was 1.8 ± 0.3 year), the controls (n=8 (2 were lost to follow-up)) were seizure-free and none of them reported any academic issue. But 2 were diagnosed with ADHD and one had some praxic difficulties that
ACCEPTED MANUSCRIPT
were already observed at diagnosis. The mean duration of treatment was 1.7 ± 0.5 years. The details of the electrophysiological data at time of the first seizure of the controls are
RI PT
reported in the table 2.
Case-Control study: comparison between EE-CSWS and controls (Table 3)
The mean age at first seizure was not different between patients and controls (p=0.79).
SC
At time of first seizure, we did not find any difference comparing the clinical phenotypes of the patients and the controls. The occurrence of multiple seizures types (p=0.014) and the seizures
M AN U
aggravation (p=0.038) were more frequent during the follow-up of the patients that would be diagnosed with EE-CSWS as compared to controls that never had different seizure types or any increase of the seizure frequency. The initiation of treatment during the course of the disease (10/10 before the diagnosis of EE-CSWS and 6/10 in the control group; p=0.09 Fisher exact Test) as well as the type of antiepileptic drugs were not different between
DISCUSSION
TE D
our EE-CSWS group and the controls
EP
Our 10 patients with EE-CSWS have an electroclinical phenotype consistent with the description of this epileptic encephalopathy with an initial diagnosis of epilepsy after few seizures
AC C
mostly BECTS. This was followed by regression that occurred in our patients around 7-year-old. There was a mean delay of 18.8 months between the first seizure and the regression highlighting the existence of a window of time to an early identification of the patients that will developed EE-CSWS. Our case-control study failed to find any electroclinical feature at the first seizure time for an early identification of an evolution to EE-CSWS. However, the occurrence of multiple types of seizures or a seizure aggravation during the follow-up occurred before the cognitive regression.
ACCEPTED MANUSCRIPT
Our 10 patients with EE-CSWS are very closed to the previous publications on this syndrome (12–16). 2 had a significant perinatal history and 4 had a familial history of epilepsy. Some studies reported more frequent perinatal history (3,17). This might be due to the
RI PT
heterogeneity of the inclusion criteria. Among this heterogeneity, some authors used to distinguish “idiopathic” and “symptomatic” EE-CSWS. In the latter, all patients have abnormal MRI with previous neurological disabilities bearing usually a higher risk to have epilepsy (16,18–
SC
22).
The mean age at the first seizure was 6.1 ± 0.6 years (range 3 to 10) while most of the
M AN U
studies reported a younger age at first seizures between 2 years and half and 5 years of age. However, all groups with a first seizure below 4 years of age were reported in symptomatic EECSWS
(16,18,20,21,23).
We
reported
as
several
previous
studies
BECTS
or
Panayiotopoulos syndrome as first diagnosis in children that later develop EE-CSWS. Among 30 patients with EE-CSWS, Kramer et al. described 9 with BECTS and 2 with
TE D
Panayiotopoulos syndrome (23). Comparably, Caraballo et al. reported 21 BECTS, 8 Panayiotopoulos syndrome among described 117 patients (19). N. Frejerman also mentioned that BECTS could be the first diagnose before EE-CSWS with a report of 26 patients (24). This
EP
probably explained why some authors postulate that there is a continuum between BECTS, Landau-Kleffner syndrome and EE-CSWS. The mean age at the regression was 7.1 ± 0.6
AC C
leading to the diagnosis at 7.5 ± 0.5 years of age. This age is comparable with the majorities of the series we already quote, even in symptomatic subgroup (13–15,18,19,25). Looking at distinctive findings with a case-controls study, we cannot find any difference at
time of the first seizure. The age at the first seizure, the type of the seizure, the history of the patients, none of these criteria were statically different. Fejerman et al. drew the same conclusion in a study of 26 patients who have been diagnosed BECTS and then EE-CSWS (24). However, the evolution after the first seizure allow to identify a seizure exacerbation in 4/10 patients (2.6 ± 0.5 months before the regression) and the patients had different types of seizures
ACCEPTED MANUSCRIPT
(6/10) whereas the control patient had only one type of seizure. Most of the patients have at least 2 seizures type. The occurrence of multiple seizure types in EE-CSWS have been already reported: 15/22 patients (68%) (13), 9/10 patients (90%) (14), 13/16 (81%) within the 6 months
RI PT
of the recording of ESES on EEG (12). Several studies have evaluated the differences in the EEG recording between typical BECTS and so call “atypical” BECTS. Mixed results have been reported by analyzing the spike
SC
frequency (26,27), the diffusion of interictal spikes during sleep (28), the occurrence of nondipole spikes (29,30), the abundance of interictal abnormalities in awake or sleep (31), the
M AN U
presence of an intermittent slow wave focus during wakefulness, the presence of multiple asynchronous bilateral spike-wave foci in the first hour of sleep (27). Our analysis cannot find any significant difference between EE-CSWS and controls on the first EEG recording on the spike frequency, the activation during sleep, the abundance of interictal abnormalities (Table 3). Recently, centro-temporal spike source dipole orientation has been reported different between
TE D
typical BECTS and atypical BECTS. Spike dipole was directed anteriorly in patients with good outcome (seizure control) whereas dipole orientation headed posteriorly was observed in patients with poor seizure control or neurocognitive deficits (32). The dipole analysis might be
EP
interesting but might be a barrier for a daily use in clinical practice. There are several limitations in our study. The first limitation is the limited number of
AC C
patients. EE-CSWS is a rare epilepsy syndrome and the patients are mostly referred to tertiary epilepsy center at time of diagnosis further limiting the number of patients with EE-CSWS and available data from the first seizure. The second limitation is linked to our methods. We focused on the clinical history, the characteristics of the first seizure and the data from the first EEG recording while we cannot exclude that some distinctive features might appears on later EEG recordings. This might be particularly the case at the time of seizure worsening. This would be of particular interest since we reported a mean period of 2.6 ± 0.5 months between the seizure
ACCEPTED MANUSCRIPT
worsening when it is observed and the cognitive regression. The last limitations are also based on our methods with the retrospective design. In conclusion, we found, as previously identified, distinctive features allowing to
RI PT
identify an evolution to EE-CSWS such as a seizure worsening or the occurrence of multiple seizure types. These clinical criteria might be used as a red flag in clinical practice to identify the very few patients with EE-CSWS among the frequent patients with
SC
BECTS. For the first time, a work focused on predictive electroclinical characteristics after the first seizure but we did not find any clinical or electrophysiological criteria at time of the first A large prospective cohort study at the European level could be helpful to
M AN U
seizure.
confirm our data and investigate if distinctive EEG features appear during the prodromal
AC C
EP
TE D
phase and if an early treatment might reverse the cognitive consequences of EE-CSWS.
ACCEPTED MANUSCRIPT
Drowsy sleep
#2 M
0
7Y4
End by Bilat involvement Sleep
#3 F
0
5Y8M
Aphasia followed by Bilat involvement Awaking
#4 F
FS
4Y1M
Focal Sz
#5 M
Perinatal cyanosis
3Y
#6 F
Migraine
8Y6M
End by Bilat involvement Sleep Focal Sz (Occipital) Awaking
Motor/Praxis Memory
7Y5M
Delay between first seizure and regression/ Diagnosis 17M/21M
7Y10M
Motor/Writing Attention
7Y11M
7M/7M
5Y10M
Language
5Y10M
3M/3M
Unclassified
5Y4M
Motor/falls Motor/Writing Language
5Y5M
6M/7M
Epilepsy with focal Sz
8Y10M
Motor/Writing Language
8Y11M
71M/72M
Reading Spelling Maths
9Y10M
12M/16M
Awake: Normal Sleep: 2 foci Right T; Left CT Diffusion to right
BECTS
Awake: 1 focus Right CT Sleep: Generalization Activation >80%
BECTS
Awake: 2 foci Right CT and left T Sleep: occipitall diffusion Activation >80%
Single Sz
Awake: 2 foci Right C Right T Sleep: Diffusion Activation >80%
Awake: 1 focus Left C Sleep: No sleep Awake: 2 foci Left Occ; Right Occ. Asynchrony Sleep: Synchronization
AC C
Awaking
Initial diagnosis
Age at regression
RI PT
End by bilat involvement
EEG Awake Sleep
7Y2M
SC
Simple 5Y9M Prematurity
1st Sz type / daytime occurence
M AN U
1st Sz (Age)
Type of regression
Age at the diagnosis of EECSWS
TE D
#1 M
Personal history
EP
Patient Sex
Panayiotopoulos 9Y6M Syndrome
ACCEPTED MANUSCRIPT
Activation >50%
Awaking
#8 F
Migraine
4Y3M
Focal Sz Awaking
#9 M
Twin pregnancy
5Y2M
Focal Sz Awaking
9Y6M
End by bilateral involment Sleep
7Y7M
Language
7Y10M
7M/9M
Motor Language
7Y1M
35M/35M
6Y3M
Motor/Writing Spelling
6Y3M
13M/13M
9Y5M
Global Behavior
9Y11M
0/5M
Panayiotopoulos 7Y1M Syndrome
BECTS
Awake: 1 focus Right T Controlat diffusion Sleep: Generalization Activation >80%
BECTS
EP
0
Epilepsy with focal Sz CMV infection
Awake: 2 foci Right CT Left CT Sleep: Generalization Activation >80%
AC C
#10 F
No slow sleep Awake: 2 foci Right CT Left C Generalization Sleep: Generalization Activation >80% Awake: 1 focus Left F Bilat diffusion Sleep: Bilat diffusion Activation >50%
RI PT
Focal Sz
SC
7Y2M
M AN U
CMV MF infection
TE D
#7 F
Table 1: Electroclinical characteristics of EE-CSWS patients at the first seizure BECTS: Benign Epilepsy with Centro-Temporal Spikes; Bilat: bilateral; C: central; CT: centrotemporal; F: Frontal; FS: febrile seizure; Sz: seizure; GTC Sz : generalized tonic-clonic seizure; M: months; MF: maternofoetal; Occ: Occipital; T: temporal; Y: years
ACCEPTED MANUSCRIPT
Familial history Father : epilepsy with recovery at puberty
MRI No MRI
1st Sz (Age) 6Y6M
1st Sz type / daytime Focal Sz secondary generalized Awaking
#E F
#F F
Graphic difficulties and anxiety
None
None
Normal
7Y6M
End by Bilat involvement
Initial diagnosis BECTS
Sz Recurrence / Treatment No / none
Normal
BECTS
Yes / VPA
Awake: 2 foci Right FT, Left CT Sleep: Activation <50%
BECTS
Yes / VPA, LEV, OXC
Awake: 1 focus Left CT Occ and T diffusion Sleep: Activation >80%
BECTS
None
Awake: 1 focus Left T Controlat diffusion Sleep: 2 foci Left T Right CT Activation >80%
BECTS
NA
Awake: 2 foci Left CT Right CT Diffusion Sleep: Synchronization Generalization
BECTS
Yes / LEV
Awake: 1 focus Right T Controlat diffusion Sleep: Activation >80%
SC
10Y
Sleep Focal Sz secondary generalized
M AN U
Normal
Falling asleep
TE D
#D M
Motor skills impairment None
Peters syndrome (one uncle and one cousin)
Father: JAE
None
No MRI
6Y7M
EP
#C F
Initial middle language delay Peters syndrome Gestational diabetes and hypertension during pregnancy
NA
AC C
#B M
EEG
RI PT
Controls Personal Sex history #A Hyperactivity M
One aunt: 2 Sz One sister: 1 Sz
Normal
7Y3M
Focal Sz secondary generalization Sleep End by Bilat involvement Sleep
5Y3M
Focal Sz Awake
ACCEPTED MANUSCRIPT
None
One sister : 1 FS
Normal
6Y10M
Focal Sz
Activation >80% Normal
Panayiotopoulos No
#H F
Preeclampsia and premature birth at 33 SA None
Grandfather: epilepsy Sister: FS None
No MRI
4Y10M
Unknown Focal Sz
Normal
BECTS
NA
No MRI
3Y2M
Awake: 2 foci Left CT Right T Diffusion Sleep: Activation >80% of Right focus
BECTS
Yes / LEV
Awake: 2 foci Right CT Right C Sleep: Activation >80% of Right CT
BECTS
Yes / LEV
Awake Focal Sz secondary generalization
None
None
No MRI
5Y2M
End by Bilat involvement Sleep
TE D
Table 2. Electroclinical characteristics of controls at the first seizure BECTS: Benign Epilepsy with Centro-Temporal Spikes; Bilat: bilateral; C: central; CT: centrotemporal; LEV: levetiracetam; F: Frontal; FS: febrile seizure; Sz: seizure; GTC Sz : generalized tonic-clonic seizure; M: months; MF: maternofoetal; NA: Not Available; Occ:
EP
Occipital; OXC: oxcarbazepine; T: temporal; VPA: valproate; Y: years
AC C
#J F
M AN U
Sleep
SC
#I M
RI PT
#G M
ACCEPTED MANUSCRIPT
0 3
0 5
0.65
3
2
1
2
1
1
6 4
7 3
4 1 6.1 ± 0.6
SC
M AN U
3 1
9 5 6
0.61 1 -
0.64 0/64
5 1
0.65 -
2
0.63
2
1
6.3 ± 0.6
0.79
Comparison during the evolution EE-CSWS Controls 65 ± 28 193 ± 85
7 0 0
EEG comparison during the awake (one control under treatment) EE-CSWS Controls 1.4 ± 0.2 (n=10) 1.1 ± 0.3 (n=10)
AC C
Mean number of foyer 1 or more foci Bilateral focus if multiple foci Diffusion of the focus Mean amplitude (µV) Normal EEG
RI PT
P value 0.61
EP
Treatments introduction delay (days) Repetitive seizures Seizures aggravation Multiple types of seizure
Controls (n=10) 2
TE D
Pregnancy and delivery issues Epilepsy Familial history of epilepsy Familial neurological history Scholar difficulties after the first seizure Psychiatric or comportemental issues after the first seizure Partial first seizure Generalized first seizure Nocturnal first seizure First seizure at the drowsiness First seizure at the awake First seizure during the day Age at the first seizure
EE-CSWS (n=10) 3
P value 0.13
0.9 0,038* 0.014*
P value 0.46
9 (n= 10) 4 (n=5)
7 (n=10) 3(n=4)
0.58 1
4 (n=9) 242.4 ± 78.8 (n=5) 1 (n=10)
5 (n=7) 186.7 ± 17.5 (n=6) 3 (n=10)
0.57 0.64 0.57
EEG comparison during the asleep or sleep
ACCEPTED MANUSCRIPT
EE-CSWS (n=9) 1.9 ± 0.4
Controls (n=10) 1.2 ± 0.3
P value 0.36
AC C
EP
TE D
M AN U
SC
RI PT
Mean number of focus 1 or more foci 9 7 0.21 Bilateral focus if 5 4 0.29 multiple foci Diffusion of the focus 6 4 0.37 Synchronization of 5 1 0.06 the foci Bilateral 4 (4/8) 1 0.11 generalization during sleep Abnormalities > 80 % 6 (6/8) 6 0.63 sleep Physiological figures 9 10 1 of sleep Mean amplitude (µV) 324.6 ± 115.7 267.1 ± 74.5 0.5 Table 3. Comparaison in the electroclinical phenotype of EE-CSWS patients vs controls
ACCEPTED MANUSCRIPT
REFERENCES 1.
Tassinari C, Terzano G, Capocchi G, Bernardina Dalla B, Vigevano F, Daniele O, et al. Epileptic seizures during sleep in children. Penry JK, editor Epilepsy, The 8th International
2.
RI PT
SymposiumNew York: Raven Press. 1977. p. 345–54. Tassinari CA, Dravet C R. Encephalopathy related to electrical status epilepticus during slow sleep. Electroenceph clin Neurophysiol. 1977;(43):529–30.
Sánchez Fernández I, Loddenkemper T, Peters JM, Kothare S V. Electrical status
SC
3.
epilepticus in sleep: Clinical presentation and pathophysiology. Pediatr Neurol. Elsevier
4.
M AN U
Inc.; 2012;47(6):390–410.
Commission on Classification and Terminology of the International League Against Epilepsy. Proposal for Revised Classification of Epilepsies and Epileptic Syndromes. Epilepsia. 1989;30(4):389–99.
5.
Tassinari CA, Rubboli G, Volpi L, Meletti S, D’Orsi G, Franca M, et al. Encephalopathy
TE D
with electrical status epilepticus during slow sleep or ESES syndrome including the acquired aphasia. Clin Neurophysiol. 2000;111(SUPPL. 2):94–102. 6.
Sanchez Fernández I, Peters JM, Hadjiloizou S, Prabhu SP, Zarowski M, Stannard KM, et
EP
al. Clinical staging and electroencephalographic evolution of continuous spikes and waves during sleep. Epilepsia. 2012;53(7):1185–95. Beaumanoir A. EEG data. In: Beaumanoir A, Bureau M, Deonna T, Mira L, Tassinari CA,
AC C
7.
editors Continuous spikes and waves during slow sleep, London: John Libbey,. 1995. p. 217–23. 8.
Scheltens-De Boer M. Guidelines for EEG in encephalopathy related to ESES/CSWS in children. Epilepsia. 2009;50(SUPPL. 7):13–7.
9.
Galanopoulou AS, Bojko A, Lado F, Moshé SL. The spectrum of neuropsychiatric abnormalities associated with electrical status epilepticus in sleep. Brain Dev. 2000;22(5):279–95.
ACCEPTED MANUSCRIPT
10.
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.
11.
Auvin S, Roberta M, Vezzani A. Current understanding and neurobiology of epileptic encephalopathies. Neurobiol Dis. Elsevier Inc.; 2016;
Saltik S, Uluduz D, Cokar O, Demirbilek V, Dervent A. A clinical and EEG study on
SC
12.
RI PT
2010;51(4):676–85.
idiopathic partial epilepsies with evolution into ESES spectrum disorders. Epilepsia.
13.
M AN U
2005;46(4):524–33.
Değerliyurt A, Yalnizoğlu D, Bakar EE, Topçu M, Turanli G. Electrical status epilepticus during sleep: A study of 22 patients. Brain Dev. 2015;37(2):250–64.
14.
Seegmüller C, Deonna T, Mayor Dubois C, Valenti-Hirsch MP, Hirsch E, Metz-Lutz MN, et al. Long-term outcome after cognitive and behavioral regression in nonlesional epilepsy
15.
TE D
with continuous spike-waves during slow-wave sleep. Epilepsia. 2012;53(6):1067–76. Kramer U, Nevo Y, Neufeld MY, Fatal A, Leitner Y, Harel S. Epidemiology of epilepsy in childhood: A cohort of 440 consecutive patients. Pediatr Neurol. 1998;18(1):46–50. Arhan E, Serdaroglu A, Aydin K, Hirfanoglu T, Soysal AS. Epileptic encephalopathy with
EP
16.
electrical status epilepticus: An electroclinical study of 59 patients. Seizure. BEA Trading
17.
AC C
Ltd; 2015;26:86–93.
Scholtes FBJ, Hendriks MPH, Renier WO. Cognitive deterioration and electrical status epilepticus during slow sleep. Epilepsy Behav. 2005;6(2):167–73.
18.
Caraballo RH, Fortini S, Flesler S, Pasteris MC, Caramuta L, Portuondo E. Encephalopathy with status epilepticus during sleep: Unusual EEG patterns. Seizure. 2015;25:117–25.
19.
Caraballo RH, Veggiotti P, Kaltenmeier MC, Piazza E, Gamboni B, Avaria MFL, et al. Encephalopathy with status epilepticus during sleep or continuous spikes and waves
ACCEPTED MANUSCRIPT
during slow sleep syndrome: A multicenter, long-term follow-up study of 117 patients. Epilepsy Res. Elsevier B.V.; 2013;105(1–2):164–73. 20.
Chen J, Cai F, Jiang L, Hu Y, Feng C. A prospective study of dexamethasone therapy in
RI PT
refractory epileptic encephalopathy with continuous spike-and-wave during sleep. Epilepsy Behav. Elsevier Inc.; 2016;55:1–5. 21.
Chen XQ, Zhang WN, Hu LY, Liu MJ, Zou LP. Syndrome of Electrical Status Epilepticus
SC
during Sleep: Epileptic Encephalopathy Related to Brain Development. Pediatr Neurol [Internet]. Elsevier Inc; 2016;56:35–41. Available from: h
Liukkonen E, Kantola-Sorsa E, Paetau R, Gaily E, Peltola M, Granström ML. Long-term
M AN U
22.
outcome of 32 children with encephalopathy with status epilepticus during sleep, or ESES syndrome. Epilepsia. 2010;51(10):2023–32. 23.
Kramer U, Sagi L, Goldberg-Stern H, Zelnik N, Nissenkorn A, Ben-Zeev B. Clinical spectrum and medical treatment of children with electrical status epilepticus in sleep
24.
TE D
(ESES). Epilepsia. 2009;50(6):1517–24.
Fejerman N, Caraballo R, Tenembaum SN. Atypical evolutions of benign localizationrelated epilepsies in children: are they predictable? Epilepsia. 2000;41(4):380–90. Sinclair DB, Snyder TJ. Corticosteroids for the treatment of Landau-Kleffner syndrome
EP
25.
and continuous spike-wave discharge during sleep. Pediatr Neurol. 2005;32(5):300–6. Weglage J, Demsky A, Pietsch M, Kurlemann G. Neuropsychological, intellectual, and
AC C
26.
behavioral findings in patients with centrotemporal spikes with and without seizures. Developmental Medicine & Child Neurology. 1997. p. 646–651. 27.
Nicolai J, Van Der Linden I, Arends JBAM, Van Mil SGM, Weber JW, Vles JSH, et al. EEG characteristics related to educational impairments in children with benign childhood epilepsy with centrotemporal spikes. Epilepsia. 2007;48(11):2093–100.
28.
De Saint-Martin A, Carcangiu R, Arzimanoglou A, Massa R, Thomas P, Motte J, et al. Semiology of typical and atypical rolandic epilepsy: A video-EEG analysis. Epileptic
ACCEPTED MANUSCRIPT
Disord. 2001;3(4):173–81. 29.
Gregory DL, Wong PK. Clinical relevance of a dipole field in rolandic spikes. Epilepsia. 1992;33(1):36–44. Vinayan
KP,
Biji
V,
Thomas
S
V.
Educational
problems
with
underlying
RI PT
30.
neuropsychological impairment are common in children with Benign Epilepsy of Childhood with Centrotemporal Spikes (BECTS). Seizure. 2005;14(3):207–12.
Massa R, de Saint-Martin A, Carcangiu R, Rudolf G, Seegmuller C, Kleitz C, et al. EEG
SC
31.
criteria predictive of complicated evolution in idiopathic rolandic epilepsy. Neurology.
Kim H, Yoo IH, Lim BC, Hwang H, Chae JH, Choi J, et al. Averaged EEG spike dipole analysis may predict atypical outcome in Benign Childhood Epilepsy with Centrotemporal Spikes
(BCECTS).
Brain
Dev.
The
EP
TE D
2016;38(10):903–8.
AC C
32.
M AN U
2001;57(6):1071–9.
Japanese
Society
of
Child
Neurology;
ACCEPTED MANUSCRIPT Highlights:
-
An early recognition might play a key role in the outcome of EE-CSWS
-
Using
a
Case-control
study,
we
did
not
identify
any
clinical
or
CSWS.
The occurrence of multiple seizure types and a seizure worsening during the
EP
TE D
M AN U
SC
follow-up was more frequent in EE-CSWS
AC C
-
RI PT
electrophysiological features at the first seizure to identify the evolution to EE-
S1090-3798(17)31708-7
DOI:
10.1016/j.ejpn.2018.04.009
Reference:
YEJPN 2415
To appear in:
European Journal of Paediatric Neurology
Received Date: 8 June 2017 Revised Date:
24 March 2018
Accepted Date: 22 April 2018
Please cite this article as: Desprairies C, Dozières-Puyravel B, Ilea A, Bellavoine V, Nasser H, Delanöe C, Auvin S, Early identification of Epileptic Encephalopathy with Continuous Spikes-and-Waves during Sleep: a case-control study, European Journal of Paediatric Neurology (2018), doi: 10.1016/ j.ejpn.2018.04.009. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Early identification of Epileptic Encephalopathy with Continuous Spikes-andWaves during Sleep: a case-control study Camille Desprairies1,2, Blandine Dozières-Puyravel1, Adina Ilea1, Vanina Bellavoine1,
AP-HP, Hôpital Robert Debré, Service de Neurologie Pédiatrique, 75019 Paris,
SC
1.
RI PT
Hala Nasser3, Catherine Delanöe3, Stéphane Auvin1,2
France
Université Paris Diderot, Sorbonne Paris Cité, INSERM UMR1141, 75019 Paris,
M AN U
2.
France
AP-HP, Hôpital Robert Debré, Service de Physiologie, 75019 Paris, France
Corresponding author:
EP
Stéphane Auvin, MD, PhD
TE D
3.
Service de Neurologie Pédiatrique et des Maladies Métaboliques
AC C
CHU Hôpital Robert Debré 48, boulevard Sérurier
75935 PARIS CEDEX 19 - France Phone: +33 1 40 03 57 24 Fax: +33 1 40 03 47 74 Email: [email protected]
ACCEPTED MANUSCRIPT
ABTRACT: Epileptic encephalopathy with continuous spikes-and-waves during sleep (EE-CSWS) is a rare childhood epilepsy syndrome characterized by a regression in cognitive, behavioral and
RI PT
psychiatric functioning, seizures and a specific electroencephalographic pattern. An early recognition and an appropriate treatment might play a key role in the outcome of this epileptic encephalopathy. We conducted a case-control study to evaluate if there is any clinical or
SC
electroencephalographic sign suggestive of EE-CSWS after the first seizure. We retrospectively identified 10 EE-CSWS patients with available EEG recording at time of the first seizure. We
M AN U
matched them with 10 controls from our first seizure clinics. All EEG recording were analyzed for the study. We did not find any clinical or EEG features that would suggest later development of EE-CSWS. As reported by others, the occurrence of multiple seizures types and a seizure worsening during the follow-up is more frequent in the cases than in the controls. These clinical criteria might be used as a red flag in clinical practice to identify the very few patients with EE-
Keywords:
Case-control
study;
AC C
EP
Encephalopathy; Epilepsy
TE D
CSWS among the frequent patients with BECTS.
Continous
Spikes
and
Waves
in
Sleep;
Epileptic
ACCEPTED MANUSCRIPT
INTRODUCTION Epileptic encephalopathy with continuous spikes-and-waves during sleep (EE-CSWS) is a rare childhood epilepsy syndrome and may represent from 0.2% to 2% of the epilepsies
RI PT
(3). Tassinari et al. first introduced these terms in 1977 as “encephalopathy related to electrical status epilepticus during slow sleep” and “electrical status epilepticus during slow sleep“ (1,2). This syndrome is characterized by a regression in cognitive, behavioral and psychiatric
SC
functioning, seizures and a specific electroencephalographic (EEG) pattern. The core symptom is the cognitive regression that can occur in all subtypes of cognitive functions. The seizure
M AN U
types are not specific (4,5). The EEG pattern at time of diagnosis shows almost continuous slow (typically 1.5-3Hz) (6) spikes-and-wave, seen in slow sleep. Some authors provide percentages of slow wave sleep that must be occupied by continuous spike-and-wave e.g. >50% (7,8) or > 85% (5). The ILAE does not require these criteria (4).
Various terms have been used interchangeably when referring to related but different
TE D
concepts. This results in an increasing of the complexity in communication among clinicians and jeopardizes research in this field (9). This complexity in terminology has been further increased by the various definitions and inclusion criteria in the studies on EE-CSWS (3).
EP
The concept of epileptic encephalopathy (EE) consists of the notion that the epileptic activity itself (seizure and EEG abnormalities) may contribute to severe cognitive and behavioral
AC C
impairments above and beyond what might be expected from the underlying pathology alone (e.g., cortical malformation), and that these can worsen over time (10,11). Suggesting that an early recognition and an appropriate treatment might play a key role in the outcome (11). Our aim was to identify electroclinical elements at the time of the first seizure that might
lead to an early identification of EE-CSWS. We first described their electroclinical characteristics at the first seizure of a group of patients with this orphan pediatric epilepsy syndrome. We then matched them with controls from the first seizure clinics to compare the two groups in order to identify distinctive features that might be helpful for an early recognition of EE-CSWS.
ACCEPTED MANUSCRIPT
PATIENTS AND METHODS We conducted a monocentric study between January 2006 and December 2015. Data were collected on all consecutive cases of EE-CSWS identified by retrieving medical records
The inclusion criteria for the cases were: -
RI PT
from 2 local databases (Pediatric neurology Department and Neurophysiology Department).
Diagnosis of EE-CSWS syndrome based on a clinical history, a cognitive or behavioral
at time of cognitive regression
SC
regression and typical EEG pattern (> 80% of sleep with continuous spike-and-wave)
Children aged from 2 years to 16 years
-
The regression was defined on clinical criteria or on the medical interview.
-
Children who have been followed in our department since the first seizure or at least with
M AN U
-
EEG recording available at time of the first seizure.
We considered the following information for each patient (clinical data were collected
TE D
retrospectively while EEG were reanalyzed for the study): familial and personal antecedents, psychomotor development, epilepsy features (onset, clinical description, treatment, type and frequency of seizures during the follow-up), neurologic examination, the first EEG during
EP
wakefulness and sleep, brain MRI, seizure diary, the regression (cognitive and/or behavioral changes, age of this regression, evolution) and the treatment of EE-CSWS. We describe the
AC C
current condition of patients: all patients had been seen for the study at least in May 2015 or we called for a follow-up at the time of the study. We first described the patients with EE-CSWS. For the second part of the study, the EE-
CSWS patients were matched individually with controls based on the type of the first seizure and the date of the first EEG record (within the same 6-months period). The choice to match cases and controls only on the seizure type allow the evaluation of all the other clinical and electrophysiological characteristics including age at first seizure or any EEG findings. The inclusion criteria for the controls were: same first seizure type than a case
ACCEPTED MANUSCRIPT
within the same 6-month period. The characteristics of the first seizure of each patient were analyzed. We called the controls at time of the study to check the absence of regression or cognitive involvement since the diagnosis. The EEG of each patient (EE-CSWS and matched
RI PT
patients) were re-analyzed for the study (C. Des. & C. Del.). We compared each EE-CSWS patient with a control for clinical description of the first seizure (type, time, age) and the data of the first EEG recording.
SC
Data analysis
All data were recorded anonymously (C. Des.). Percentage were rounded to whole
M AN U
numbers. We reported the mean ± standard error of the mean (SEM) of continuous data. The study was designed to compare the cases and the controls for all studies parameters with non-parametric tests. Mann & Whitney test and Fisher exact tests were performed using the GraphPad Prism 5.01 software. p < 0.05 was considered statistically significant.
TE D
RESULTS
Description of the EE-CSWS patients (Table 1) We included 10 children: 6 girls and 4 boys. 4/10 children had a familial history of
EP
epilepsy. 2/10 children had significant perinatal medical history: one with simple prematurity at 35 weeks of pregnancy and one with cytomegalovirus maternal-fetal infection with deafness and
AC C
periventricular white matter abnormalities. The mean age at the first seizure was 6.1 ± 0.6 years (range 3 to 10 years). The seizure type and the time of occurrence of the first seizure are described in the table 1. 9/10 experienced several seizures before the diagnosis of EE-CSWS. The initial diagnoses were BECTS in 4, Panayiotopoulos syndrome in 2, epilepsy with focal seizures in 3 (multifocal seizures in the patients with CMV infection). Only patient had an abnormal MRI (CMV infection). The details of the electrophysiological data at time of the first seizure are reported in the table 1. Clinical history from the first seizure to the diagnosis of EE-CSWS
ACCEPTED MANUSCRIPT
6/10 exhibited at least 2 types of seizures: generalized seizures (clonic and absence seizures) and focal seizures with focal symptoms including mouth deviation, aphasia or focal clonic seizures. The seizure frequency fluctuated from daily to 1 each 6 weeks. After treatment,
RI PT
all were improved by treatment (7/10 seizure free). The first line of treatment was valproate in 8 patients, levetiracetam in one patient and carbamazepine in one. 5/10 remained on the first monotherapy, while 2/10 needed another monotherapy and 3/10 received combined antiepileptic
SC
drugs (2/10 bitherapy, 1/11 tritherapy).
Just before the cognitive regression, 5/10 children had an aggravation of the seizure
M AN U
frequency (> 50% compared to the baseline). The seizure was a different seizure type from the start in 3/4. The worsening in seizure frequency happened 2.6 ± 0.5 months in mean before the regression for the four patients.
Diagnosis of the EE-CSWS and evolution
TE D
The mean age at regression was 7.5 ± 0.5 years. The mean time between the first seizure and the diagnosis of EE-CSWS were 18.8 ± 6.6 months. The delay between the regression and the diagnosis was 1.7 ± 0.6 months (Table 1). For one patient, the regression
EP
and the first seizure were observed at the same time. All had a cognitive regression, each child had specific cognitive symptoms: motor that could be gross motor functions (walk, falls) or fine
AC C
motor function (writing, dressing), language (speech, reading, grammar), memory or mathematic reasoning. 7/10 had also a behavioral change with attention disorder, phobia, aggression and opposition. All patients had an EEG at the time of diagnosis. At EE-CSWS diagnosis, all patients have had treatment modification. 10/10 patients received clobazam (5-15mg once a day – Addon in 6/10 and switched in 4/10). All patients were seen 15 to 30 days after the EE-CSWS treatment. All of them exhibit a cognitive improvement (defined as regain of lost cognitive abilities). But for 4 patients, this improvement was considered limited, leading to an additional treatment. One was controlled by adding levetiracetam with clobazam. For 3 of them
ACCEPTED MANUSCRIPT
methylprednisolone pulses followed by oral steroids were used. At 6 months after the diagnosis, all had a cognitive and behavioral improvement but still had some cognitive difficulties. Seizures stopped for 8/10. The EEG became normal for 6/10 while 4/10 showed focal abnormalities
RI PT
without ESES EEG pattern. 4/10 had no relapse based on the follow-up of the intellectual functioning. 2/6 had one relapse and 4/6 had two relapses during the follow-up. The mean delay between the diagnosis of EE-CSWS and the relapse was 9.3 ± 2.9 months. Among patients that
SC
experienced a relapse, 5/6 had seizures at time of the relapse. The relapses were treated by steroid (methylprednisolone pulses followed by oral steroids). One received sulthiam. Treatment
M AN U
of relapse resulted in a cognitive improvement in 5/6 patients, even if the patients still exhibited learning difficulties. Follow-up at the time of the study (mean duration of follow-up was 3.0 ± 0.70 years) showed that 8/10 still had learning/academic difficulties despite the dramatic improvement after EE-CSWS treatment. 2/10 had a full recovery with good academic achievement without any support. 3/10 still experienced seizures. 4/10 had EEG abnormalities consisting in focal
disorders.
TE D
spikes with a moderate increase of the abnormalities during sleep. 8/10 patients had attentional
Description of the control population (Table 2)
EP
We matched 10 controls (epilepsy patients) with our EE-CSWS patients. The control were 5 females and 5 males. The mean age at the first seizure was 6.3 years ± 0.6 (range 3 to
AC C
10). The seizure type and the time of occurrence of the first seizure are described in the table 2. 9/10 were diagnosed BECT and one had Panayiotopoulos syndrome. 2 children received antiepileptic drugs after the first seizure (valproate) without any relapse during the follow-up. Six children started a treatment during the follow-up because of recurrence of seizures (Table 2). All controls were seizure free (two without treatment and five after treatment by valproate or levetiracetam). At the last follow-up (mean duration of follow-up was 1.8 ± 0.3 year), the controls (n=8 (2 were lost to follow-up)) were seizure-free and none of them reported any academic issue. But 2 were diagnosed with ADHD and one had some praxic difficulties that
ACCEPTED MANUSCRIPT
were already observed at diagnosis. The mean duration of treatment was 1.7 ± 0.5 years. The details of the electrophysiological data at time of the first seizure of the controls are
RI PT
reported in the table 2.
Case-Control study: comparison between EE-CSWS and controls (Table 3)
The mean age at first seizure was not different between patients and controls (p=0.79).
SC
At time of first seizure, we did not find any difference comparing the clinical phenotypes of the patients and the controls. The occurrence of multiple seizures types (p=0.014) and the seizures
M AN U
aggravation (p=0.038) were more frequent during the follow-up of the patients that would be diagnosed with EE-CSWS as compared to controls that never had different seizure types or any increase of the seizure frequency. The initiation of treatment during the course of the disease (10/10 before the diagnosis of EE-CSWS and 6/10 in the control group; p=0.09 Fisher exact Test) as well as the type of antiepileptic drugs were not different between
DISCUSSION
TE D
our EE-CSWS group and the controls
EP
Our 10 patients with EE-CSWS have an electroclinical phenotype consistent with the description of this epileptic encephalopathy with an initial diagnosis of epilepsy after few seizures
AC C
mostly BECTS. This was followed by regression that occurred in our patients around 7-year-old. There was a mean delay of 18.8 months between the first seizure and the regression highlighting the existence of a window of time to an early identification of the patients that will developed EE-CSWS. Our case-control study failed to find any electroclinical feature at the first seizure time for an early identification of an evolution to EE-CSWS. However, the occurrence of multiple types of seizures or a seizure aggravation during the follow-up occurred before the cognitive regression.
ACCEPTED MANUSCRIPT
Our 10 patients with EE-CSWS are very closed to the previous publications on this syndrome (12–16). 2 had a significant perinatal history and 4 had a familial history of epilepsy. Some studies reported more frequent perinatal history (3,17). This might be due to the
RI PT
heterogeneity of the inclusion criteria. Among this heterogeneity, some authors used to distinguish “idiopathic” and “symptomatic” EE-CSWS. In the latter, all patients have abnormal MRI with previous neurological disabilities bearing usually a higher risk to have epilepsy (16,18–
SC
22).
The mean age at the first seizure was 6.1 ± 0.6 years (range 3 to 10) while most of the
M AN U
studies reported a younger age at first seizures between 2 years and half and 5 years of age. However, all groups with a first seizure below 4 years of age were reported in symptomatic EECSWS
(16,18,20,21,23).
We
reported
as
several
previous
studies
BECTS
or
Panayiotopoulos syndrome as first diagnosis in children that later develop EE-CSWS. Among 30 patients with EE-CSWS, Kramer et al. described 9 with BECTS and 2 with
TE D
Panayiotopoulos syndrome (23). Comparably, Caraballo et al. reported 21 BECTS, 8 Panayiotopoulos syndrome among described 117 patients (19). N. Frejerman also mentioned that BECTS could be the first diagnose before EE-CSWS with a report of 26 patients (24). This
EP
probably explained why some authors postulate that there is a continuum between BECTS, Landau-Kleffner syndrome and EE-CSWS. The mean age at the regression was 7.1 ± 0.6
AC C
leading to the diagnosis at 7.5 ± 0.5 years of age. This age is comparable with the majorities of the series we already quote, even in symptomatic subgroup (13–15,18,19,25). Looking at distinctive findings with a case-controls study, we cannot find any difference at
time of the first seizure. The age at the first seizure, the type of the seizure, the history of the patients, none of these criteria were statically different. Fejerman et al. drew the same conclusion in a study of 26 patients who have been diagnosed BECTS and then EE-CSWS (24). However, the evolution after the first seizure allow to identify a seizure exacerbation in 4/10 patients (2.6 ± 0.5 months before the regression) and the patients had different types of seizures
ACCEPTED MANUSCRIPT
(6/10) whereas the control patient had only one type of seizure. Most of the patients have at least 2 seizures type. The occurrence of multiple seizure types in EE-CSWS have been already reported: 15/22 patients (68%) (13), 9/10 patients (90%) (14), 13/16 (81%) within the 6 months
RI PT
of the recording of ESES on EEG (12). Several studies have evaluated the differences in the EEG recording between typical BECTS and so call “atypical” BECTS. Mixed results have been reported by analyzing the spike
SC
frequency (26,27), the diffusion of interictal spikes during sleep (28), the occurrence of nondipole spikes (29,30), the abundance of interictal abnormalities in awake or sleep (31), the
M AN U
presence of an intermittent slow wave focus during wakefulness, the presence of multiple asynchronous bilateral spike-wave foci in the first hour of sleep (27). Our analysis cannot find any significant difference between EE-CSWS and controls on the first EEG recording on the spike frequency, the activation during sleep, the abundance of interictal abnormalities (Table 3). Recently, centro-temporal spike source dipole orientation has been reported different between
TE D
typical BECTS and atypical BECTS. Spike dipole was directed anteriorly in patients with good outcome (seizure control) whereas dipole orientation headed posteriorly was observed in patients with poor seizure control or neurocognitive deficits (32). The dipole analysis might be
EP
interesting but might be a barrier for a daily use in clinical practice. There are several limitations in our study. The first limitation is the limited number of
AC C
patients. EE-CSWS is a rare epilepsy syndrome and the patients are mostly referred to tertiary epilepsy center at time of diagnosis further limiting the number of patients with EE-CSWS and available data from the first seizure. The second limitation is linked to our methods. We focused on the clinical history, the characteristics of the first seizure and the data from the first EEG recording while we cannot exclude that some distinctive features might appears on later EEG recordings. This might be particularly the case at the time of seizure worsening. This would be of particular interest since we reported a mean period of 2.6 ± 0.5 months between the seizure
ACCEPTED MANUSCRIPT
worsening when it is observed and the cognitive regression. The last limitations are also based on our methods with the retrospective design. In conclusion, we found, as previously identified, distinctive features allowing to
RI PT
identify an evolution to EE-CSWS such as a seizure worsening or the occurrence of multiple seizure types. These clinical criteria might be used as a red flag in clinical practice to identify the very few patients with EE-CSWS among the frequent patients with
SC
BECTS. For the first time, a work focused on predictive electroclinical characteristics after the first seizure but we did not find any clinical or electrophysiological criteria at time of the first A large prospective cohort study at the European level could be helpful to
M AN U
seizure.
confirm our data and investigate if distinctive EEG features appear during the prodromal
AC C
EP
TE D
phase and if an early treatment might reverse the cognitive consequences of EE-CSWS.
ACCEPTED MANUSCRIPT
Drowsy sleep
#2 M
0
7Y4
End by Bilat involvement Sleep
#3 F
0
5Y8M
Aphasia followed by Bilat involvement Awaking
#4 F
FS
4Y1M
Focal Sz
#5 M
Perinatal cyanosis
3Y
#6 F
Migraine
8Y6M
End by Bilat involvement Sleep Focal Sz (Occipital) Awaking
Motor/Praxis Memory
7Y5M
Delay between first seizure and regression/ Diagnosis 17M/21M
7Y10M
Motor/Writing Attention
7Y11M
7M/7M
5Y10M
Language
5Y10M
3M/3M
Unclassified
5Y4M
Motor/falls Motor/Writing Language
5Y5M
6M/7M
Epilepsy with focal Sz
8Y10M
Motor/Writing Language
8Y11M
71M/72M
Reading Spelling Maths
9Y10M
12M/16M
Awake: Normal Sleep: 2 foci Right T; Left CT Diffusion to right
BECTS
Awake: 1 focus Right CT Sleep: Generalization Activation >80%
BECTS
Awake: 2 foci Right CT and left T Sleep: occipitall diffusion Activation >80%
Single Sz
Awake: 2 foci Right C Right T Sleep: Diffusion Activation >80%
Awake: 1 focus Left C Sleep: No sleep Awake: 2 foci Left Occ; Right Occ. Asynchrony Sleep: Synchronization
AC C
Awaking
Initial diagnosis
Age at regression
RI PT
End by bilat involvement
EEG Awake Sleep
7Y2M
SC
Simple 5Y9M Prematurity
1st Sz type / daytime occurence
M AN U
1st Sz (Age)
Type of regression
Age at the diagnosis of EECSWS
TE D
#1 M
Personal history
EP
Patient Sex
Panayiotopoulos 9Y6M Syndrome
ACCEPTED MANUSCRIPT
Activation >50%
Awaking
#8 F
Migraine
4Y3M
Focal Sz Awaking
#9 M
Twin pregnancy
5Y2M
Focal Sz Awaking
9Y6M
End by bilateral involment Sleep
7Y7M
Language
7Y10M
7M/9M
Motor Language
7Y1M
35M/35M
6Y3M
Motor/Writing Spelling
6Y3M
13M/13M
9Y5M
Global Behavior
9Y11M
0/5M
Panayiotopoulos 7Y1M Syndrome
BECTS
Awake: 1 focus Right T Controlat diffusion Sleep: Generalization Activation >80%
BECTS
EP
0
Epilepsy with focal Sz CMV infection
Awake: 2 foci Right CT Left CT Sleep: Generalization Activation >80%
AC C
#10 F
No slow sleep Awake: 2 foci Right CT Left C Generalization Sleep: Generalization Activation >80% Awake: 1 focus Left F Bilat diffusion Sleep: Bilat diffusion Activation >50%
RI PT
Focal Sz
SC
7Y2M
M AN U
CMV MF infection
TE D
#7 F
Table 1: Electroclinical characteristics of EE-CSWS patients at the first seizure BECTS: Benign Epilepsy with Centro-Temporal Spikes; Bilat: bilateral; C: central; CT: centrotemporal; F: Frontal; FS: febrile seizure; Sz: seizure; GTC Sz : generalized tonic-clonic seizure; M: months; MF: maternofoetal; Occ: Occipital; T: temporal; Y: years
ACCEPTED MANUSCRIPT
Familial history Father : epilepsy with recovery at puberty
MRI No MRI
1st Sz (Age) 6Y6M
1st Sz type / daytime Focal Sz secondary generalized Awaking
#E F
#F F
Graphic difficulties and anxiety
None
None
Normal
7Y6M
End by Bilat involvement
Initial diagnosis BECTS
Sz Recurrence / Treatment No / none
Normal
BECTS
Yes / VPA
Awake: 2 foci Right FT, Left CT Sleep: Activation <50%
BECTS
Yes / VPA, LEV, OXC
Awake: 1 focus Left CT Occ and T diffusion Sleep: Activation >80%
BECTS
None
Awake: 1 focus Left T Controlat diffusion Sleep: 2 foci Left T Right CT Activation >80%
BECTS
NA
Awake: 2 foci Left CT Right CT Diffusion Sleep: Synchronization Generalization
BECTS
Yes / LEV
Awake: 1 focus Right T Controlat diffusion Sleep: Activation >80%
SC
10Y
Sleep Focal Sz secondary generalized
M AN U
Normal
Falling asleep
TE D
#D M
Motor skills impairment None
Peters syndrome (one uncle and one cousin)
Father: JAE
None
No MRI
6Y7M
EP
#C F
Initial middle language delay Peters syndrome Gestational diabetes and hypertension during pregnancy
NA
AC C
#B M
EEG
RI PT
Controls Personal Sex history #A Hyperactivity M
One aunt: 2 Sz One sister: 1 Sz
Normal
7Y3M
Focal Sz secondary generalization Sleep End by Bilat involvement Sleep
5Y3M
Focal Sz Awake
ACCEPTED MANUSCRIPT
None
One sister : 1 FS
Normal
6Y10M
Focal Sz
Activation >80% Normal
Panayiotopoulos No
#H F
Preeclampsia and premature birth at 33 SA None
Grandfather: epilepsy Sister: FS None
No MRI
4Y10M
Unknown Focal Sz
Normal
BECTS
NA
No MRI
3Y2M
Awake: 2 foci Left CT Right T Diffusion Sleep: Activation >80% of Right focus
BECTS
Yes / LEV
Awake: 2 foci Right CT Right C Sleep: Activation >80% of Right CT
BECTS
Yes / LEV
Awake Focal Sz secondary generalization
None
None
No MRI
5Y2M
End by Bilat involvement Sleep
TE D
Table 2. Electroclinical characteristics of controls at the first seizure BECTS: Benign Epilepsy with Centro-Temporal Spikes; Bilat: bilateral; C: central; CT: centrotemporal; LEV: levetiracetam; F: Frontal; FS: febrile seizure; Sz: seizure; GTC Sz : generalized tonic-clonic seizure; M: months; MF: maternofoetal; NA: Not Available; Occ:
EP
Occipital; OXC: oxcarbazepine; T: temporal; VPA: valproate; Y: years
AC C
#J F
M AN U
Sleep
SC
#I M
RI PT
#G M
ACCEPTED MANUSCRIPT
0 3
0 5
0.65
3
2
1
2
1
1
6 4
7 3
4 1 6.1 ± 0.6
SC
M AN U
3 1
9 5 6
0.61 1 -
0.64 0/64
5 1
0.65 -
2
0.63
2
1
6.3 ± 0.6
0.79
Comparison during the evolution EE-CSWS Controls 65 ± 28 193 ± 85
7 0 0
EEG comparison during the awake (one control under treatment) EE-CSWS Controls 1.4 ± 0.2 (n=10) 1.1 ± 0.3 (n=10)
AC C
Mean number of foyer 1 or more foci Bilateral focus if multiple foci Diffusion of the focus Mean amplitude (µV) Normal EEG
RI PT
P value 0.61
EP
Treatments introduction delay (days) Repetitive seizures Seizures aggravation Multiple types of seizure
Controls (n=10) 2
TE D
Pregnancy and delivery issues Epilepsy Familial history of epilepsy Familial neurological history Scholar difficulties after the first seizure Psychiatric or comportemental issues after the first seizure Partial first seizure Generalized first seizure Nocturnal first seizure First seizure at the drowsiness First seizure at the awake First seizure during the day Age at the first seizure
EE-CSWS (n=10) 3
P value 0.13
0.9 0,038* 0.014*
P value 0.46
9 (n= 10) 4 (n=5)
7 (n=10) 3(n=4)
0.58 1
4 (n=9) 242.4 ± 78.8 (n=5) 1 (n=10)
5 (n=7) 186.7 ± 17.5 (n=6) 3 (n=10)
0.57 0.64 0.57
EEG comparison during the asleep or sleep
ACCEPTED MANUSCRIPT
EE-CSWS (n=9) 1.9 ± 0.4
Controls (n=10) 1.2 ± 0.3
P value 0.36
AC C
EP
TE D
M AN U
SC
RI PT
Mean number of focus 1 or more foci 9 7 0.21 Bilateral focus if 5 4 0.29 multiple foci Diffusion of the focus 6 4 0.37 Synchronization of 5 1 0.06 the foci Bilateral 4 (4/8) 1 0.11 generalization during sleep Abnormalities > 80 % 6 (6/8) 6 0.63 sleep Physiological figures 9 10 1 of sleep Mean amplitude (µV) 324.6 ± 115.7 267.1 ± 74.5 0.5 Table 3. Comparaison in the electroclinical phenotype of EE-CSWS patients vs controls
ACCEPTED MANUSCRIPT
REFERENCES 1.
Tassinari C, Terzano G, Capocchi G, Bernardina Dalla B, Vigevano F, Daniele O, et al. Epileptic seizures during sleep in children. Penry JK, editor Epilepsy, The 8th International
2.
RI PT
SymposiumNew York: Raven Press. 1977. p. 345–54. Tassinari CA, Dravet C R. Encephalopathy related to electrical status epilepticus during slow sleep. Electroenceph clin Neurophysiol. 1977;(43):529–30.
Sánchez Fernández I, Loddenkemper T, Peters JM, Kothare S V. Electrical status
SC
3.
epilepticus in sleep: Clinical presentation and pathophysiology. Pediatr Neurol. Elsevier
4.
M AN U
Inc.; 2012;47(6):390–410.
Commission on Classification and Terminology of the International League Against Epilepsy. Proposal for Revised Classification of Epilepsies and Epileptic Syndromes. Epilepsia. 1989;30(4):389–99.
5.
Tassinari CA, Rubboli G, Volpi L, Meletti S, D’Orsi G, Franca M, et al. Encephalopathy
TE D
with electrical status epilepticus during slow sleep or ESES syndrome including the acquired aphasia. Clin Neurophysiol. 2000;111(SUPPL. 2):94–102. 6.
Sanchez Fernández I, Peters JM, Hadjiloizou S, Prabhu SP, Zarowski M, Stannard KM, et
EP
al. Clinical staging and electroencephalographic evolution of continuous spikes and waves during sleep. Epilepsia. 2012;53(7):1185–95. Beaumanoir A. EEG data. In: Beaumanoir A, Bureau M, Deonna T, Mira L, Tassinari CA,
AC C
7.
editors Continuous spikes and waves during slow sleep, London: John Libbey,. 1995. p. 217–23. 8.
Scheltens-De Boer M. Guidelines for EEG in encephalopathy related to ESES/CSWS in children. Epilepsia. 2009;50(SUPPL. 7):13–7.
9.
Galanopoulou AS, Bojko A, Lado F, Moshé SL. The spectrum of neuropsychiatric abnormalities associated with electrical status epilepticus in sleep. Brain Dev. 2000;22(5):279–95.
ACCEPTED MANUSCRIPT
10.
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.
11.
Auvin S, Roberta M, Vezzani A. Current understanding and neurobiology of epileptic encephalopathies. Neurobiol Dis. Elsevier Inc.; 2016;
Saltik S, Uluduz D, Cokar O, Demirbilek V, Dervent A. A clinical and EEG study on
SC
12.
RI PT
2010;51(4):676–85.
idiopathic partial epilepsies with evolution into ESES spectrum disorders. Epilepsia.
13.
M AN U
2005;46(4):524–33.
Değerliyurt A, Yalnizoğlu D, Bakar EE, Topçu M, Turanli G. Electrical status epilepticus during sleep: A study of 22 patients. Brain Dev. 2015;37(2):250–64.
14.
Seegmüller C, Deonna T, Mayor Dubois C, Valenti-Hirsch MP, Hirsch E, Metz-Lutz MN, et al. Long-term outcome after cognitive and behavioral regression in nonlesional epilepsy
15.
TE D
with continuous spike-waves during slow-wave sleep. Epilepsia. 2012;53(6):1067–76. Kramer U, Nevo Y, Neufeld MY, Fatal A, Leitner Y, Harel S. Epidemiology of epilepsy in childhood: A cohort of 440 consecutive patients. Pediatr Neurol. 1998;18(1):46–50. Arhan E, Serdaroglu A, Aydin K, Hirfanoglu T, Soysal AS. Epileptic encephalopathy with
EP
16.
electrical status epilepticus: An electroclinical study of 59 patients. Seizure. BEA Trading
17.
AC C
Ltd; 2015;26:86–93.
Scholtes FBJ, Hendriks MPH, Renier WO. Cognitive deterioration and electrical status epilepticus during slow sleep. Epilepsy Behav. 2005;6(2):167–73.
18.
Caraballo RH, Fortini S, Flesler S, Pasteris MC, Caramuta L, Portuondo E. Encephalopathy with status epilepticus during sleep: Unusual EEG patterns. Seizure. 2015;25:117–25.
19.
Caraballo RH, Veggiotti P, Kaltenmeier MC, Piazza E, Gamboni B, Avaria MFL, et al. Encephalopathy with status epilepticus during sleep or continuous spikes and waves
ACCEPTED MANUSCRIPT
during slow sleep syndrome: A multicenter, long-term follow-up study of 117 patients. Epilepsy Res. Elsevier B.V.; 2013;105(1–2):164–73. 20.
Chen J, Cai F, Jiang L, Hu Y, Feng C. A prospective study of dexamethasone therapy in
RI PT
refractory epileptic encephalopathy with continuous spike-and-wave during sleep. Epilepsy Behav. Elsevier Inc.; 2016;55:1–5. 21.
Chen XQ, Zhang WN, Hu LY, Liu MJ, Zou LP. Syndrome of Electrical Status Epilepticus
SC
during Sleep: Epileptic Encephalopathy Related to Brain Development. Pediatr Neurol [Internet]. Elsevier Inc; 2016;56:35–41. Available from: h
Liukkonen E, Kantola-Sorsa E, Paetau R, Gaily E, Peltola M, Granström ML. Long-term
M AN U
22.
outcome of 32 children with encephalopathy with status epilepticus during sleep, or ESES syndrome. Epilepsia. 2010;51(10):2023–32. 23.
Kramer U, Sagi L, Goldberg-Stern H, Zelnik N, Nissenkorn A, Ben-Zeev B. Clinical spectrum and medical treatment of children with electrical status epilepticus in sleep
24.
TE D
(ESES). Epilepsia. 2009;50(6):1517–24.
Fejerman N, Caraballo R, Tenembaum SN. Atypical evolutions of benign localizationrelated epilepsies in children: are they predictable? Epilepsia. 2000;41(4):380–90. Sinclair DB, Snyder TJ. Corticosteroids for the treatment of Landau-Kleffner syndrome
EP
25.
and continuous spike-wave discharge during sleep. Pediatr Neurol. 2005;32(5):300–6. Weglage J, Demsky A, Pietsch M, Kurlemann G. Neuropsychological, intellectual, and
AC C
26.
behavioral findings in patients with centrotemporal spikes with and without seizures. Developmental Medicine & Child Neurology. 1997. p. 646–651. 27.
Nicolai J, Van Der Linden I, Arends JBAM, Van Mil SGM, Weber JW, Vles JSH, et al. EEG characteristics related to educational impairments in children with benign childhood epilepsy with centrotemporal spikes. Epilepsia. 2007;48(11):2093–100.
28.
De Saint-Martin A, Carcangiu R, Arzimanoglou A, Massa R, Thomas P, Motte J, et al. Semiology of typical and atypical rolandic epilepsy: A video-EEG analysis. Epileptic
ACCEPTED MANUSCRIPT
Disord. 2001;3(4):173–81. 29.
Gregory DL, Wong PK. Clinical relevance of a dipole field in rolandic spikes. Epilepsia. 1992;33(1):36–44. Vinayan
KP,
Biji
V,
Thomas
S
V.
Educational
problems
with
underlying
RI PT
30.
neuropsychological impairment are common in children with Benign Epilepsy of Childhood with Centrotemporal Spikes (BECTS). Seizure. 2005;14(3):207–12.
Massa R, de Saint-Martin A, Carcangiu R, Rudolf G, Seegmuller C, Kleitz C, et al. EEG
SC
31.
criteria predictive of complicated evolution in idiopathic rolandic epilepsy. Neurology.
Kim H, Yoo IH, Lim BC, Hwang H, Chae JH, Choi J, et al. Averaged EEG spike dipole analysis may predict atypical outcome in Benign Childhood Epilepsy with Centrotemporal Spikes
(BCECTS).
Brain
Dev.
The
EP
TE D
2016;38(10):903–8.
AC C
32.
M AN U
2001;57(6):1071–9.
Japanese
Society
of
Child
Neurology;
ACCEPTED MANUSCRIPT Highlights:
-
An early recognition might play a key role in the outcome of EE-CSWS
-
Using
a
Case-control
study,
we
did
not
identify
any
clinical
or
CSWS.
The occurrence of multiple seizure types and a seizure worsening during the
EP
TE D
M AN U
SC
follow-up was more frequent in EE-CSWS
AC C
-
RI PT
electrophysiological features at the first seizure to identify the evolution to EE-