childhood epilepsy with centrotemporal spikes
TRANSCRIPT
2019/2020
Patrícia Isabel Ferreira Tuna
Childhood epilepsy with centrotemporal spikes:
electroclinical and neurophysiological characterization
ABRIL, 2020
Mestrado Integrado em Medicina
Área: Ciências Médicas e da Saúde
Tipologia: Dissertação
Trabalho efetuado sob a Orientação de:
Doutora Cláudia Raquel Ferrão de Melo
Trabalho organizado de acordo com as normas da revista:
Clinical Pediatrics
Patrícia Isabel Ferreira Tuna
Childhood epilepsy with centrotemporal spikes:
electroclinical and neurophysiological characterization
ABRIL, 2020
DEDICATÓRIA
Primeiramente à Dra. Cláudia Melo, pela dedicação, disponibilidade e olhar sempre
atento. Sem todo o seu exímio apoio e orientação, certamente este trabalho não seria
possível.
Aos meus amigos, companheiros de caminhada, por tornarem cada obstáculo num motivo
de celebração.
Aos meus pais, eternos merecedores do meu agradecimento, por me elevarem sempre
mais alto, sem nunca deixarem de me amparar.
Ao meu irmão, por tão bem fazer jus ao título, por ser o primeiro e para sempre o melhor
amigo.
Por fim, mas não de todo menos especial, ao Ricardo, quem me faz sorrir e acreditar em
toda e qualquer circunstância.
1
ABSTRACT
Childhood epilepsy with centrotemporal spikes (CECTS) is the most common
pediatric epileptic syndrome. CECTS generally has a benign course and tends to remit in
adolescence. However, it can present as an atypical form, eventually with worse
prognosis. Herein we report the electroclinical features of a sample of children with
CECTS and compare the evolution of typical and atypical CECTS. The clinical records
of patients were retrospectively analyzed. Fifty patients were included, 62.0% were male
and the median age at diagnosis was 7.5 years. The frequency of atypical CECTS was
34.0%. Neuropsychological comorbidities were identified in 36.4% of typical CECTS
and 88.2% of the atypical CECTS group. Atypical CECTS were more frequently treated.
Neuropsychological comorbidities are present in both forms of CECTS, however patients
with atypical CECTS are more affected. Therefore, all these children should benefit from
neuropsychological monitoring and effort should be put on identifying risk factors for
atypical CECTS.
Key Words: Childhood Epilepsy; Centrotemporal Spikes; Rolandic Epilepsy; Atypical;
Electroclinical.
2
GLOSSARY
ADHD Attention Deficit Hyperactivity Disorder
AED Antiepileptic Drug
ASD Autism Spectrum Disorder
CECTS Childhooh Epilepsy Centrotemporl Spikes
CSWS Continuous Spike and Wave During Sleep
CT Centrotemporal
EEG Electroencephalogram
GTCS Generalized Tonic-Clonic Seizure
ILAE International League Against Epilepsy
IQ Intelligence Quotient
MLPA Multiplex Ligation-dependent Probe Amplification
MRI Magnetic Resonance Imaging
NP Neuropediatrics
NREM Non-Rapid Eye Movement
WISC-III Wechsler Intelligence Scale for Children III
3
INTRODUCTION
Childhood epilepsy with centrotemporal spikes (CECTS), also known as rolandic
epilepsy, belongs to the group of childhood idiopathic focal epilepsies.1 CECTS has
generally a benign course, occurring typically in previously healthy children, and tends
to remit in adolescence. Seizures have a focal origin without detectable brain damage.2
CECTS represents approximately 10 to 20% of all childhood epilepsies.1 The prevalence
of this epilepsy in children aged 1 to 15 years is around 15%.3–5 CECTS is characterized
by onset of seizures between 3 and 14 years, with a peak incidence between 7 and 9 years
old.6 Seizures usually resolve by the age of 13 years old, however occasionally occur up
to 18 years old.5 There is a presumed predominance of males, with a ratio of 3:2.1 The
genetic basis of CECTS remains unclear but it is most probably polygenic and complex.7–
9 A high percentage of epilepsy in close relatives has been documented, ranging from
3.5% to 59%.1,8 Although the specific genes responsible for the disease have yet to be
identified, it is thought that chromosomes 11 (11p13) and 15 (15q14) may be
involved.10,11 Mutations in genes like GRIN2A and ELP4 have been found in families
with CECTS.12,13 Other candidate genes include KCNQ2, KCNQ3, BDNF, DEPDC5,
RBFOX1/3 and GABAA-R.1,8
The diagnosis of CECTS is made through clinical history and confirmed with
electroencephalogram (EEG) findings.14 Typical seizures and characteristic
centrotemporal spikes allow the diagnosis. The typical seizures are brief (<5 minutes),
hemifacial seizures that may evolve to a focal to bilateral tonic-clonic seizure.15 Seizures
are usually manifested by unilateral sensory and facial motor changes, oropharyngeal
manifestations, speech disorders and hypersialorrhea.1,5 The characteristic semiology
reflects the origin of the epileptogenic focus in the rolandic or perisilvian sensorimotor
cortex, which represents the face and oropharynx.1 In most patients, seizures are
infrequent and approximately 10% to 21% have only one seizure.16 The number of
seizures is substantially higher during sleep and upon waking.14 10 to 20% of patients
have previous history of febrile seizures.17 The EEG has a characteristic pattern,
composed of high-voltage centrotemporal spikes, often followed by slow waves, which
are activated by sleep and tend to spread from side to side.15 However, the frequency of
centrotemporal spikes, its location and persistence does not determine the clinical
manifestations, the severity or frequency of the seizures, nor the prognosis.1,18,19 It is
known that the centrotemporal spikes are not specific to CECTS.20 Furthermore, the
typical centrotemporal spikes can be found in the EEG of 2-3% of the pediatric
4
population, with less than 10% developing epilepsy.1,21 If the clinical history and the EEG
are consistent with CECTS, there is no indication for further studies to confirm the
diagnosis.1 However, atypical characteristics can lead to the need of additional tests such
as a brain MRI.16 In CECTS, brain imaging is tipically normal, although 15% of patients
with rolandic seizures may have abnormalities on their brain MRI due to other brain
diseases not related to CECTS.22,23
Several studies suggest that children with CECTS may have mild cognitive or behavioral
problems, such as attention deficit and hyperactivity disorder (ADHD) or dyslexia24–26,
underperforming their peers.27 One hypothesis is that, these cognitive disorders may be
related to the epileptiform activity that occurs mostly during sleep, interfering with the
mechanisms of learning and memory consolidation.16 The discharges are tipically located
on brain regions essential to the language skills and processing of verbal and auditory
information.28 In addition, several clinical factors related to this epileptic syndrome, such
as the age of the first seizure, hemispheric laterality and the use of antiepileptic drugs
(AED) can also influence the cognitive abilities of this population.26–28
Concerning treatment, antiepileptic drugs are not often recommended in CECTS if the
seizures are only focal and don’t compromise consciousness, and if the child and family
are comfortable with the situation.29 Treatment may be indicated in cases of high
frequency or more severe seizures, especially during wakefulness.16 In these cases, a
single antiepileptic should be attempted. The International League Against Epilepsy
(ILAE) recommends monotherapy with carbamazepine or valproate as the first line
drugs.1,5 Regardless of treatment, this syndrome usually has an excellent prognosis, with
spontaneous remission in most patients 2 to 4 years after the onset of seizures or before
the age of 15.16 The exception to these favorable outcomes are the atypical forms of
CECTS, which seem to be associated with a higher impact on cognitive development and
worser prognosis.27 The atypical forms usually occur at an earlier age and are
characterized by mostly diurnal and prolonged seizures, with the possibility of
progressing to Todd's hemiparesis and status epilepticus.1,27 EEGs also have atypical
characteristics, related to the morphology and location of spikes, with discharges and
waves similar to those found in absence seizures.27 The atypical evolution of CECTS can
result in atypical childhood focal epilepsy, status epilepticus, Landau-Kleffner syndrome
and epileptic encephalopathy with continuous spike-and-wave during sleep.4
5
The aims of this study were to describe the clinical, semiological, scalp EEG, and
neuropsychological features of a group of children with CECTS and to compare the
electroclinical features of the patients with typical and atypical CECTS.
6
METHODS
Study Design
This was a retrospective and cross-sectional study planned in order to review the
electroclinical data of a convenience sample of pediatric patients diagnosed with CECTS.
The research protocol was evaluated and approved by the Ethics Committee of the São
João Hospital Center and access to clinical data was authorized by the Responsible for
Access to Information department.
Participants
Patients were enrolled from the Pediatric Neurology Outpatient Clinic of the São João
Hospital Centre, at Porto (Portugal) from 1st January 2017 to 31th December 2019. To
be included, patients had to meet the clinical and electroencephalographic criteria for the
diagnosis of CECTS, established by the ILAE in 2014. According to ILAE, epilepsy is
defined by one of the following conditions: at least two unprovoked (or reflex) seizures
occurring >24 h apart; one unprovoked (or reflex) seizure and a probability of further
seizures similar to the general recurrence risk (at least 60%) after two unprovoked
seizures, occurring over the next 10 years; diagnosis of an epilepsy syndrome.30 Diagnosis
of CECTS was established in accordance with the international criteria: age of first
afebrile seizure 3-12 years; seizures comprising focal sensorimotor seizures affecting the
vocal tract and face, with or without involvement of the arm; predominant sleep-related
seizures; EEG interictal centro-temporal spikes with normal background.31 Patients with
insufficient data to establish the diagnosis were excluded. Also excluded were patients
with known structural causes of epilepsy (stroke, infection, post-infectious or metabolic);
global learning disability; or focal central neurological deficit on clinical exam. Fifty
patients met the inclusion criteria for diagnosis of CECTS.
Clinical and neurophysiological data
Electronic medical records of outpatient visits between 1st January 2017 and 31th
December 2019 were reviewed. The data collected included: patient’s age, sex,
provenience, follow-up time, age at seizure onset and last seizure, circadian distribution
(awake or asleep), seizures frequency, seizures semiology, episodes duration, treatment
data and family history. Associated comorbidities such as learning deficits, dyslexia,
ADHD, behavior problems and sleep disorders were recorded. EEGs, neuroimaging and
genetic tests findings were also collected.
7
Considering CECTS is an age dependent syndrome, epilepsy was considered resolved
when patients were seizure free, with a normal EEG and passed the age of 15 years
old.29,31 The age of EEG normalization was defined as the time when the disappearance
of the centrotemporal spike was first noted from serial EEG recordings.
Data analysis
Participants were categorized in two groups: typical CECTS and atypical CECTS.
Atypical CECTS was considered if any of the following was present: seizures onset at
early age (≤3 years old); children had developmental delay and/or cognitive impairment;
and atypical EEG findings such as atypical spike morphology and location or abnormal
background.18,27,32 Patients with typical and atypical CECTS were compared according to
age at onset, time of follow-up, number of seizures, age at remission, AED treatment,
comorbidities, age at EEG normalization and family history of epilepsy.
Statistical analysis
Statistical analysis was performed using IBM SPSS Statistics version 26.0. The level
of statistical significance was set at p<0.05. Categorical variables, including sex,
circadian distribution (awake or asleep) and centrotemporal spikes lateralization
(unilateral or bilateral), were presented as absolut and relative frequency and compared
using chi-squared tests. Continuous variables, including age at seizure onset, age at last
seizure and time of follow-up, were presented according to the median and range and
compared using Student’s t-test and the nonparametric Mann-Whitney test.
8
RESULTS
The final sample included 50 individuals with diagnosis of CECTS, 62.0% were male
and the median age at the time of data collection was 11.8 (range: 4.3-18.3) years old.
The median time of follow-up was 2.2 (range: 0.4-9.7) years. Patients were mainly
referred from the emergency department (72.0%). Three patients had history of febrile
seizures before the diagnosis of CECTS. Family history was positive for epilepsy in 12
cases (24.0%), 6 of them concerning first degree relatives. Family history of febrile
seizures was reported in four cases. The demographic characteristics are summarized in
Table 1.
Electroclinical features
Age at seizure onset ranged from 1.2 to 13.7 years, with a median age of 7.5 years old.
The number of reported seizures per patient, since the beginning of epilepsy, varied from
1 seizure (16.0%) to more than 10 seizures (18.0%) (Table 2). The approximate episode
duration was reported by parents, with 72.0% of seizures lasting less than 5 minutes. Only
2 children had seizures longer than 15 minutes. The semiology of the reported seizures in
which parents were able to give enough information to describe them is presented in Table
2. Regarding the circadian pattern, 37 patients had seizures only during sleep (74.0%); 10
during wakefulness (20.0%); and 3 had seizures during sleep and wakefulness (6.0%).
Epilepsy remission was documented on 5 patients (10.0%). In this group, with epilepsy
remission, the median age at last reported seizure was 11.1 (range: 6.0-14.2) years.
A total of 114 interictal EEGs were recorded (with a median of 2 EEGs per patient).
Centrotemporal spikes and activation by drowsiness and/or NREM sleep were
documented in at least one of their EEGs (Table 3). Five patients exhibited continuous
spike-wave during sleep (CSWS), three of whom were treated with prednisolone. One of
these patients had an autism spectrum disorder. Overall, 66.0% of children showed EEG
normalization at the time of our assessment. The median age at the time of EEG
normalization was 11.4 (range: 7.2-15.2) years; of these 33 children, 42.4% experienced
EEG resolution before the age of 13 years old. The median time between the last seizure
and EEG normalization was 2.0 (range: 0.3-6.9) years. There was no reported recurrence
of seizures after the EEG normalization. Table 3 summarizes the main
electrophysiological features.
9
Treatment history
One AED was prescribed to 42 patients (84.0%). The most common AED was valproic
acid, which was used in 83.3% of children, followed by levetiracetam on 28.6% and
carbamazepine on 4.8%. Lamotrigine was used on one child. Clobazam was used as add-
on treatment for seizures in one patient. One patient has been treated with valproic acid
and levetiracetam for a short period. The median time between the first seizure and the
start of AED was 0.2 (range: 0.0-7.5) years. Of the 42 children who received treatment,
50.0% continued to present seizures while on AEDs. In the 14 patients who had already
stopped the medication at the time of our evaluation, the median treatment duration was
5.0 (range: 1.4-9.4) years. Individuals under treatment with AED showed a higher number
of seizures (57.5% vs. 25.0% with more than 5 seizures, p=0.017). Table 4 shows the
differences in demographic data between treated and untreated patients.
Neuropsychological profile
A neuropsychological comorbidity was reported in 54.0% of cases, namely: ADHD
(26.0%), learning problems (40.0%) and dyslexia (6.0%). In addition, three children were
diagnosed with autism spectrum disorder prior to CECTS diagnosis. Data regarding the
Intelligence Quotient (IQ) was available for 17 of these 29 children, using the Wechsler
Intelligence Scale for Children III (WISC-III). The median verbal IQ was 86.0 (range: 60
–105) and median non-verbal IQ was 88.5 (range: 70-121). The median global IQ was
87.0 (range: 62-114). Sleep problems were reported by parents in 28.0% of cases
(examples: restless sleep, sleepwalking, initial insomnia). Age at first seizure (p=0.050),
treatment (p=0.444) and number of seizures (p=0.284) were not associated with the
presence of comorbidities.
Other auxiliary examinations
Brain MRI was performed in 34 individuals due to the persistence of seizures after
antiepileptic treatment or due to the early age of seizure onset. While 79.4% were reported
as normal, 7 cases had minor and unrelated abnormalities on MRI. GRIN2A gene
sequencing and MLPA was performed in seven individuals who presented CSWS EEG
pattern or neuropsychological comorbidities. Polymorphic variants with unknown
significance were identified in only one patient who had a CSWS syndrome.
10
Sub-group analysis: Typical and atypical CECTS
Considering previously described criteria, 34.0% of the patients were classified as
atypical CECTS. This group showed seizures onset at a yonger age (p=0.042), had higher
frequency of febrile seizures history (p=0.035), a higher percentage of treated patients
(p=0.039) and fewer EEG with only unilateral spikes (p=0.001). These children showed
more comorbidities (p<0.001): 41.0% had ADHD, 11.8% had dyslexia and 88.3% had
learning problems. Neither the age at EEG normalization (p=0.892) nor the total number
of seizures (p=0.358) were significantly different between the two groups. The family
history of epilepsy (p=0.728) was also not different between the two groups. Table 5
shows the differences between patients with typical and atypical CECTS.
Table 1: Demographic data of the 50 patients with diagnosis of CECTS.
N (%)
Male gender 31 (62.0%)
Age at time of data collection: years, median
(range)
11.8 (4.3-18.3)
Referral to NP clinic
Emergency department
Other pediatric clinics
Primary health care
36 (72.0%)
11 (22.0%)
3 (6.0%)
Febrile seizures 3 (6.0%)
Family history of epilepsy 12 (24.0%)
Table 2: Clinical data and seizures semiology of the 50 patients with diagnosis of
CECTS.
N (%) or median (range)
Age at seizure onset: years, median (range) 7.5 (1.2-13.7)
Age at last seizure: years, median (range) 11.3 (6.0-14.9)
Number of reported seizures per patient
1 seizure
[2;5[ seizures
[5;10[seizures
>10 seizures
8 (16.0%)
17 (34.0%)
14 (28.0%)
9 (18.0%)
11
Seizures semiology1
Focal
Hemifacial Seizures
Oropharingolaryngeal ictal manifestations
Arrest of speech
Hypersalivation
Progression to hemyconvulsion
Focal with bilateralization
Presumed primarly GTCS
Todd’s hemiparesis
Status Epileticus
32 (64.0%)
19 (59.4%)
16 (50.0%)
12 (37.5%)
16 (50.0%)
11 (34.4%)
7 (14.0%)
23 (46.0%)
1 (2.0%)
0 (0.0%)
AED treatment 42 (84.0%)
Neuropsychological comorbidity
ADHD
Learning problems
Dyslexia
Intellectual disability
ASD
13 (26.0%)
21 (42.0%)
3 (6.0%)
9 (18.0%)
3 (6.0%)
GTCS: Generalized Tonic-Clonic Seizure; ASD: Autism Spectrum Disorder
1 – This item refers to the semiology of the reported seizures in which parents were able to give enough
information to describe them.
Table 3: Electrophysiological data from the 114 interictal EEGs performed by the 50
patients with diagnosis of CECTS.
N (%)
With CT spikes 80 (70.2%)
Bilateral CT spikes 43 (37.8%)
Activation by drowsiness and
NREM sleep
81 (71.1%)
Not activated by
overbreathing
111 (97.4%)
Normal sleep organization 109 (95.6%)
Continuous spike wave
during sleep
8 (7.0%)
12
Other patterns of discharges 10 (8.8%)
CT: centrotemporal; NREM: non-rapid eye movement.
Table 4: Differences in demographic data between treated and untreated patients.
Treated
patients
n=42
Untreated
patients
n=8
p value
Number of reported seizures
per patient
1 seizure
[2;5[ seizures
[5;10[seizures
>10 seizures
6 (15.0%)
11(27.5%)
14(35.0%)
9 (22.5%)
2 (25.0%)
6 (75.0%)
0 (0.0%)
0 (0.0%)
<0.05
Age at seizure onset: years,
median (range)
7.2
(1.2-13.7)
8.2
(7.1-8.6) 0.204
Time of follow-up: years,
median (range)
2.8
(0.4-9.7)
1.0
(0.0-2.8) <0.05
Neuropsychological
comorbidities
24
(57.1%)
3
(37.5%) 0.444
Table 5: Differences in demographic data between patients with typical CECTS and
those with atypical CECTS.
Typical
CECTS
n=33
Atypical
CECTS
n=17
p value
Gender (M/F) 20/13 11/6 0.777
Age at seizure onset: years,
median (range)
8.0
(4.0-11.0)
6.1
(1.2-13.7)
<0.05
Age at last seizure of patients
with remission: years,
median (range)
9.8
(6.0-11.3)
12.7
(11.1-14.2)
0.400
Age at EEG normalization:
years, median (range)
11.4
(7.2-14.3)
11.0
(8.9-15.4)
0.892
13
Number of seizures: N (%)
1 seizure
[2;5[ seizures
[5;10[seizures
>10 seizures
7 (21.2%)
13(39.4%)
8 (24.2%)
5 (15.2%)
1 (6.7%)
4 (26.7%)
6 (40.0%)
4 (26.7%)
0.358
Treated patients: N (%) 25
(75.8%)
17
(100.0%)
<0.05
Treatment duration: years,
median (range)
4.2
(1.4-7.8)
7.7
(5.9-9.4)
0.132
EEG w/ unilateral spikes:
N (%)
23
(69.7%)
4
(23.5%)
0.001
Febrile seizures: N (%) 0
(0.0%)
3
(17.6%)
<0.05
Family history of epilepsy:
N (%)
7
(21.2%)
5
(29.4%)
0.728
Neuropsychological
comorbidities: N (%)
12
(36.4%)
15
(88.2%)
<0.001
14
DISCUSSION
In this study we were able to describe the main electroclinical features of a
retrospective cohort of children with CECTS, their comorbidities and evolution through
their follow-up period. Typical and atypical groups were compared, allowing to identify
differences between these groups. A lower age at seizure onset, previous febrile seizures
history and a higher prevalence of neuropsychological comorbidities seem to be the most
distinctive features of the atypical group.
A predominance of CECTS in males has been described by several studies6,19,25,27 and
was also identified in our sample. There is no clear explanation for this finding. Likewise,
median age at seizure onset around 7 years-old and epilepsy remission around 10 years-
old were in agreement with the literature.6,16,18 The reasons behind the typical age of
seizures onset and epilepsy remission seem to be related to cerebral maturation.6,28 The
greater neuroplasticity in children in combination with functionally less specialized
neural networks can lead to the development of pathological processes.28 Recent studies
have shown that systemic brain disorganization on CECTS reduces functional
connectivity in the rolandic area and influences large-scale brain networks.28 Given the
age-related brain maturation, Lee et al. (2018) suggested that a certain fixed period may
be necessary to allow this maturation for recovery.6
The typical circadian pattern of seizures in CECTS is the occurrence during sleep,
however seizures during wakefulness are often reported.6,27,33 In our study, there is a
significant percentage of patients with reported seizures only during wakefulness. We
must note that probably these children may present underreported seizures during sleep.
The occurrence of seizures exclusively during wakefulness has been pointed as a risk
factor for atypical CECTS, nonetheless this question remains under research.4,27 Seizures
semiology in CECTS has been extensively described trough literature, namely: unilateral
facial sensory-motor symptoms, hypersalivation, speech arrest and oro-pharyngo-
laryngeal symptoms.1,5,14 Our cohort presented the typical seizures, although they also
showed a high frequency of presumed primarily generalized seizures. Tovia E. et al.
(2011) reported that 39.7% of individuals with CECTS experienced GTCS during the
follow-up time.34 These findings may be explained by eyewitness testimony or memory
bias from family, or by the timing in which the seizure was witnessed.
The definition of atypical CECTS varies considerably between authors. In our study we
chose to classify as atypical CECTS children with an atypical age of seizure onset, history
of developmental delay, intellectual disability diagnosis or atypical interictal EEG.18,27,32
15
It may be debatable if patients with exclusively wakefulness seizures, a high number of
seizures or a worse response to AED, could be classified as atypical cases. However, we
found that these factors could be biased and were not consistent throughout literature. In
this study, a high frequency of atypical cases was found, comparing to the reported range
from 9.0% to 52.0%.34,35 Children with atypical CECTS showed seizures onset at a
younger age, had higher frequency of febrile seizures history and a higher frequency of
neuropsychological comorbidities.
The presence of intermittent slow-wave focus, multiple asynchronous spike-wave foci,
long spike-wave clusters, generalized “absence-like” spike wave discharges, conjunction
of interictal paroxysms with negative or positive myoclonia, and abundance of interictal
abnormalities during wakefulness and sleep have been identified as criteria predictive of
atypical evolution.4,27 Wirrell et al. (1995) found atypical spike location in 17.0% of their
group, with spikes shifting into the frontal and parietal areas and also presenting in the
occipital regions.35 In our study, around 8.8% of the performed EEGs had a non-rolandic
location. In our sample, 5 patients had an EEG pattern compatible with CSWS, yet only
3 of them were symptomatic and treated in accordance. CECTS, Landau-Kleffner
syndrome and the CSWS are different entitities considered as a part of a continuous
spectrum of disorders.4 A common genetic predisposition has been proposed and is
currently under research. Filipini et al. (2015) showed that the CSWS pattern on the EEG
can have a long-term impact on cognitive functions.27 Language delay, neurocognitive
deficit and neuropsychiatric comorbidities, such as autism, are commonly associated with
this condition.4 The development of these characteristics is largely dependent on the EEG
pattern, including the location and abundance of epiletiform discharges. However, the
pathophysiological mechanism is still unclear.4 CSWS EEG pattern has been documented
in children with CECTS.4,27 Some of these children present with aphasia, cognitive
deterioration or behavioral problems, however sometimes the EEG pattern is not
combined with clinical findings. None of our patients evolved to Landau-Kleffner
syndrome.
Usually, children's EEG normalizes after remission of seizures but the time lag between
the last seizure and normalization of the EEG is not unanimous.36 In our sample, 18
patients had normalized EEG and the median age at EEG normalization was 11.4 years.
In another retrospective study of 69 patients with CECTS, the mean age at EEG
normalization was 11.6 years6, which is in line with our results.
16
ILAE recommends that children with CECTS may be surveilled without AED treatment
or, if treatment is necessary, ideally with only one AED.1,5 A high percentage of children
was under treatment in the present study. Furthermore, all patients with atypical CECTS
were treated, requiring a tighter control of the disease. The prevalence of AED treatment
in CECTS is highly variable, ranging from 29.0% to 86.0%.19,29 Recent studies suggest a
trend that favors treatment.19 A high percentage of our patients experienced recurrence of
seizures while on medication, higher than the prevalence of seizure recurrence reported
in other studies (6-18%).27,33 Ross et al. (2019) showed that the convulsive burden and
poor response to treatment in CECTS is higher than previously assumed.19 This hinders
the question if CECTS is not as pharmacoresponsive as presumed or if treatment
approaches need to be optimized.19 ILAE recommend valproic acid or carbamazepine as
the first-line monotherapy options.1 Several studies showed that children with bilateral
interictal EEG findings respond well to both valproate and carbamazepine, but children
with unilateral findings may respond better to carbamazepine.1,37,38 In our study, patients
were not treated based on this hypothesis, but it may be an interesting point to consider.
In keeping with the findings of previous studies27,34,39, patients with atypical CECTS
showed higher neuropsychological impairment. Moreover, 36.4% of patients with typical
CECTS also had neuropsychological comorbidities, which suggest the need for
neuropsychological monitoring of all children with CECTS. Wickens et al. (2017)
demonstrated that children with CECTS present a profile of pervasive cognitive
difficulties.28 Growing and recent literature data exploring cognitive and behavioral
outcomes, suggest that children with CECTS perform below the level of their peers.24,28,38
In our study, we found a high frequency of learning problems, not only in association
with intellectual disability. Ross et al. (2019), in a prospective study of 60 children with
CECTS, showed that neuropsychologic comorbidities are common at diagnosis and
during the course of the disease.19 Miziara et al. (2012) in a recent study assessed the
performance of 40 children with CECTS and concluded that they showed lower scores
on cognitive assessment tests, comparing to controls.27 Currie et al. (2017), described that
children with CECTS had poorer word reading, reading comprehension and non-verbal
IQ skills than children without this epileptic syndrome.24 In our study, although there
were few patients with an IQ rating, the averages of verbal and non-verbal IQ were lower
than the average of the general population. Furthermore, it was found that 16.0% of
patients had language disorders. This is consistent with the fact that the discharges that
occur at CECTS are focused on brain regions (rolandic area) essential to the functioning
17
of language skills.26 In addition, studies have shown that other clinical factors associated
with CECTS can influence normal language development, such as age at onset,
hemispheric laterality and administration of AED.24,33,38 It is thought that abnormalities
in learning and cognitive development may be related to the epileptic discharges present
in CECTS.27 We found no association between the number of seizures and the presence
of comorbidities. Several factors could account for the learning impairment in children
with epilepsy. Electroencephalogram discharges may affect cognition and sleep. Sleep
disruption affects not only the neurophysiological and neurochemical mechanisms
important for the memory-learning process, but also influences the expression of EEG
discharges and seizures.27 Epilepsy and EEG paroxysms may affect sleep structure,
interfering with these physiological functions.27 In our study, 28.0% of patients had sleep
disorders, which can also justify the high percentage of learning problems. Accordingly
to the Center for Diseases Control and Prevention, during 2014-2016, the prevalence of
children aged 3-17 years who had ever been diagnosed with a developmental disability
increased to 6.99%.40 Therefore, it seems quite reasonable to establish that children with
CECTS (typical or atypical) have a higher prevalence of developmental disabilities.
The prevalence of ADHD in our sample was high (26.0%), comparing to the earlier
reported prevalence ranging from 5 to 31%.34,41 These values of ADHD prevalence are
clearly higher that those reported on general population, ranging from 2 to 18%.42–44 A
previous study of 74 children with CECTS showed that 65.6% of patients had ADHD.41
ADHD was even more prevalent in our group of atypical CECTS, illustrating, once more,
the association of atypical CECTS with a higher frequency of neuropsychological
comorbidities.
It should be noted that this study had some limitations, mainly due to its retrospective
nature and to the fact that the information was collected through analysis of clinical
records. Additionally, most of the information available was obtained from the
testimonies of parents or caregivers, which can alter the accuracy of data. The small
sample size is another limitation to underline. Nevertheless, we gathered an extensively
characterized sample, with a significant group of atypical CECTS cases, allowing to
identify electroclinical features that should be considered on their follow-up. We added
information to the electroclinical profile of patients with atypical CECTS and their
evolution. A prospective longitudinal cohort study would help to better understand the
electroclinical determinant features of atypical CECTS and their natural history and
18
prognosis. We also suggest, for future studies, the use of internationally accepted criteria
for atypical CECTS and to explore the risk-benefit of AED use in this epilepsy syndrome.
19
CONCLUSION
Regardless CECTS is an age dependent and limited epileptic syndrome, we identified
a significant frequency of learning and behavior problems in these patients and also a
high recurrence of seizures among treated patients. Our observations support that patients
with lower age at seizure onset, developmental delay and/or atypical EEG patterns should
be closely monitored due to the higher occurrence of learning problems and other
neuropsychological comorbidities. Early in the follow-up of children with CECTS we
should put effort on clearly distinguishing the atypical cases. Patients with risk factors for
atypical CECTS should benefit from an early and planned neuropsychological evaluation
program and cognitive intervention. It would be also determinant to understand if patients
with CECTS really benefit from treatment with AED, considering the potential drug
cognitive impact adding to the frequent learning problems of this population.
20
DECLARATION OF CONFLICTING INTERESTS
Authors declare that there is no conflict of interest.
21
REFERENCES
1. Dryżałowski P, Jóźwiak S, Franckiewicz M, Strzelecka J. Benign epilepsy with
centrotemporal spikes – Current concepts of diagnosis and treatment. Neurol
Neurochir Pol. 2018;52(6):677-689. doi:10.1016/j.pjnns.2018.08.010
2. Panayiotopoulos C. Benign childhood focal seizures and related epileptic
syndromes. A Clin Guid to Epileptic Syndr Their Treat. 2007:285.
3. Kramer U, Zelnik N, Lerman-Sagie T, Shahar E. Benign childhood epilepsy with
centrotemporal spikes: Clinical characteristics and identification of patients at
risk for multiple seizures. J Child Neurol. 2002;17(1):17-19.
doi:10.1177/088307380201700104
4. Lee YJ, Hwang SK, Kwon S. The Clinical Spectrum of Benign Epilepsy with
Centro-Temporal Spikes: a Challenge in Categorization and Predictability. J
Epilepsy Res. 2017;7(1):1-6. doi:10.14581/jer.17001
5. Vikash Katewa MP. A Review of the Not So Benign- Benign Childhood
Epilepsy with Centrotemporal Spikes. J Neurol Neurophysiol. 2015;06(04):4-7.
doi:10.4172/2155-9562.1000314
6. Lee EH, You SJ. Factors associated with electroencephalographic and clinical
remission of benign childhood epilepsy with centrotemporal spikes. Brain Dev.
2019;41(2):158-162. doi:10.1016/j.braindev.2018.08.011
7. Mohandas N, Loke YJ, Mackenzie L, et al. Deciphering the role of epigenetics in
self-limited epilepsy with centrotemporal spikes. Epilepsy Res.
2019;156(July):106163. doi:10.1016/j.eplepsyres.2019.106163
8. Xiong W, Zhou D. Progress in unraveling the genetic etiology of rolandic
epilepsy. Seizure. 2017;47:99-104. doi:10.1016/j.seizure.2017.02.012
9. Vears DF, Tsai MH, Sadleir LG, et al. Clinical genetic studies in benign
childhood epilepsy with centrotemporal spikes. Epilepsia. 2012;53(2):319-324.
doi:10.1111/j.1528-1167.2011.03368.x
10. Strug L, Clarke T, Chiang T. Centrotemporal sharp wave EEG trait in rolandic
epilepsy maps to elongator protein complex 4 (ELP4). Eur J Hum Genet.
2009;17:1171–1181.
11. Neubauer B, Fiedler B, Himmelein B. Centrotemporal spikes in families with
rolandic epilepsy: linkage to chromosome 15q14. Neurology. 1998;51:1608–
1612.
12. Neubauer B, Waldegger S, Heinzinger J. KCNQ2 and KCNQ3 mutations
contribute to different idiopathic epilepsy syndromes. Neurology. 2008;71:177.
13. Lesca G, Rudolf G, Bruneau N, et al. GRIN2A mutations in acquired epileptic
aphasia and related childhood focal epilepsies and encephalopathies with speech
and language dysfunction. Nat Genet. 2013;45(9):1061-1066.
doi:10.1038/ng.2726
14. LOISEAU P, BEAUSSART M. The Seizures of Benign Childhood Epilepsy with
Rolandic Paroxysmal Discharges. Epilepsia. 1973;14(4):381-389.
doi:10.1111/j.1528-1157.1973.tb03977.x
22
15. Panayiotopoulos C, Michael M, Sanders S, Valeta T. Benign childhood focal
epilepsies: assessment of established and newly recognized syndromes. Brain.
2008;131:2264–2286.
16. Sánchez Fernández I, Loddenkemper T. Pediatric focal epilepsy syndromes. J
Clin Neurophysiol. 2012;29(5):425-440. doi:10.1097/WNP.0b013e31826bd943
17. Kajitani, Kimura, Sumita, Kaneko. Relationship between benign epilepsy of
children with centrotemporal EEG foci and febrile convulsions. Brain Dev.
1992;14:230-234.
18. Callenbach PMC, Bouma PAD, Geerts AT, et al. Long term outcome of benign
childhood epilepsy with centrotemporal spikes: Dutch Study of Epilepsy in
Childhood. Seizure. 2010;19(8):501-506. doi:10.1016/j.seizure.2010.07.007
19. Ross EE, Stoyell SM, Kramer MA, Berg AT, Chu CJ. The natural history of
seizures and neuropsychiatric symptoms in childhood epilepsy with
centrotemporal spikes (CECTS). Epilepsy Behav. 2020;103(xxxx):106437.
doi:10.1016/j.yebeh.2019.07.038
20. Panayiotopoulos C. Benign childhood partial seizures and related epileptic
syndromes. Curr Probl Epilepsy. 15.
21. Cavazzuti, Cappella, Nalin. Longitudinal study of epileptiform EEG patterns in
normal Children. Epilepsia. 1980;21:43-55.
22. Santanelli, Bureau, Magaudda, Cobi, Roger. Benign partial epilepsy with
centrotemporal (or Rolandic) spikes and brain lesion. Epilepsia. 1989;30:182-
188.
23. Lundberg, Weis, Eeg-Olofsson, Raininko. Hippocampal region asymmetry
assessed by 1H-MRS in Rolandic epilepsy. Epilepsia. 2003;44:205-2010.
24. Currie NK, Lew AR, Palmer TM, et al. Reading comprehension difficulties in
children with rolandic epilepsy. Dev Med Child Neurol. 2018;60(3):275-282.
doi:10.1111/dmcn.13628
25. Lima EM, Rzezak P, dos Santos B, et al. The relevance of attention deficit
hyperactivity disorder in self-limited childhood epilepsy with centrotemporal
spikes. Epilepsy Behav. 2018;82:164-169. doi:10.1016/j.yebeh.2018.03.017
26. Teixeira J, Santos ME. Language skills in children with benign childhood
epilepsy with centrotemporal spikes: A systematic review. Epilepsy Behav.
2018;84:15-21. doi:10.1016/j.yebeh.2018.04.002
27. Parisi P, Paolino MC, Raucci U, Ferretti A, Villa MP, Trenite DKN. “Atypical
forms” of benign epilepsy with centrotemporal spikes (BECTS): How to
diagnose and guide these children. A practical/scientific approach. Epilepsy
Behav. 2017;75:165-169. doi:10.1016/j.yebeh.2017.08.001
28. Wickens S, Bowden SC, D’Souza W. Cognitive functioning in children with self-
limited epilepsy with centrotemporal spikes: A systematic review and meta-
analysis. Epilepsia. 2017;58(10):1673-1685. doi:10.1111/epi.13865
29. Verrotti A, Latini G, Trotta D, Giannuzzi R, Salladini C, Chiarelli F. Population
study of benign rolandic epilepsy: Is treatment needed? [6] (multiple letters).
23
Neurology. 2002;59(3):476. doi:10.1212/WNL.59.3.476
30. Fisher RS, Acevedo C, Arzimanoglou A, et al. ILAE Official Report: A practical
clinical definition of epilepsy. Epilepsia. 2014;55(4):475-482.
doi:10.1111/epi.12550
31. Loiseau P, Duché B, Cordova S, Dartigues JF, Cohadon S. Prognosis of Benign
Childhood Epilepsy with Centrotemporal Spikes: A Foliow‐Up Study of 168
Patients. Epilepsia. 1988;29(3):229-235. doi:10.1111/j.1528-
1157.1988.tb03711.x
32. Fejerman N. Atypical rolandic epilepsy. Epilepsia. 2009;50:9-12.
33. Verrotti A, D’Alonzo R, Rinaldi VE, Casciato S, D’Aniello A, Di Gennaro G.
Childhood absence epilepsy and benign epilepsy with centro-temporal spikes: a
narrative review analysis. World J Pediatr. 2017;13(2):106-111.
doi:10.1007/s12519-017-0006-9
34. Tovia E, Goldberg-Stern H, Ben Zeev B, et al. The prevalence of atypical
presentations and comorbidities of benign childhood epilepsy with
centrotemporal spikes. Epilepsia. 2011;52(8):1483-1488. doi:10.1111/j.1528-
1167.2011.03136.x
35. Wirrell EC, Camfield PR, Gordon KE, Dooley JM, Camfield CS. Benign
Rolandic Epilepsy: Atypical Features Are Very Common. J Child Neurol.
1995;10(6):455-458. doi:10.1177/088307389501000606
36. Han JY, Choi SA, Chung YG, et al. Change of centrotemporal spikes from onset
to remission in self-limited epilepsy with centrotemporal spikes (SLECTS).
Brain Dev. 2019. doi:10.1016/j.braindev.2019.11.005
37. Pavlou E, Gkampeta A, Evangeliou A, Athanasiadou-Piperopoulou F. Benign
epilepsy with centro-temporal spikes (BECTS): Relationship between unilateral
or bilateral localization of interictal stereotyped focal spikes on EEG and the
effectiveness of anti-epileptic medication. Hippokratia. 2012;16(3):221-224.
38. Datta AN, Oser N, Bauder F, et al. Cognitive impairment and cortical
reorganization in children with benign epilepsy with centrotemporal spikes.
Epilepsia. 2013;54(3):487-494. doi:10.1111/epi.12067
39. Verrotti A, Latini G, Trotta D, et al. Typical and atypical rolandic epilepsy in
childhood: A follow-up study. Pediatr Neurol. 2002;26(1):26-29.
doi:10.1016/S0887-8994(01)00353-8
40. Zablotsky B, Black LI, Blumberg SJ. Estimated Prevalence of Children With
Diagnosed Developmental Disabilities in the United States, 2014-2016. NCHS
Data Brief. 2017;(291):1-8.
41. Danhofer P, Pejčochová J, Dušek L, Rektor I, Ošlejšková H. The influence of
EEG-detected nocturnal centrotemporal discharges on the expression of core
symptoms of ADHD in children with benign childhood epilepsy with
centrotemporal spikes (BCECTS): A prospective study in a tertiary referral
center. Epilepsy Behav. 2018;79:75-81. doi:10.1016/j.yebeh.2017.11.007
42. Danielson ML, Bitsko RH, Ghandour RM, Holbrook JR, Kogan MD, Blumberg
SJ. Prevalence of Parent-Reported ADHD Diagnosis and Associated Treatment
24
Among U.S. Children and Adolescents, 2016. J Clin Child Adolesc Psychol.
2018;47(2):199-212. doi:10.1080/15374416.2017.1417860
43. Wolraich ML, Hagan JF, Allan C, et al. Clinical practice guideline for the
diagnosis, evaluation, and treatment of attention-deficit/hyperactivity disorder in
children and adolescents. Pediatrics. 2019;144(4). doi:10.1542/peds.2019-2528
44. Merikangas KR, He JP, Brody D, Fisher PW, Bourdon K, Koretz DS. Prevalence
and treatment of mental disorders among US children in the 2001-2004
NHANES. Pediatrics. 2010;125(1):75-81. doi:10.1542/peds.2008-2598
25
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26
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31
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should be listed there.
Appendices should be lettered to distinguish from numbered tables and figures. Include
a descriptive title for each appendix (e.g., “Appendix A. Variable Names and
Definitions”). Cross-check text for accuracy against appendices. Avoid using
abbreviations in the title and subtitle, unless space considerations require an exception or
unless the title or subtitle includes the name of a group that is best known by its acronym.
In both cases the abbreviation should be expanded in the abstract and at first appearance
in the text.
Footnotes should be avoided in text, but are allowed on the title page. They are placed in
the following order: author affiliations, death of an author, information about members
of a group, corresponding author contact information.
4.5 English language editing services
Authors seeking assistance with English language editing, translation, or figure and
manuscript formatting to fit the journal’s specifications should consider using SAGE
Language Services. Visit SAGE Language Services on our Journal Author Gateway for
further information.
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5. Submitting your manuscript
CLP is hosted on SAGE Track, a web based online submission and peer review system
powered by ScholarOne™ Manuscripts. Visit https://mc.manuscriptcentral.com/clp to
login and submit your article online.
IMPORTANT NOTE: Please check whether you already have an account in the system
before trying to create a new one. If you have reviewed or authored for the journal in the
past year it is likely that you will have had an account created. For further guidance on
submitting your manuscript online please visit ScholarOne Online Help.
5.1 ORCID
As part of our commitment to ensuring an ethical, transparent and fair peer review process
SAGE is a supporting member of ORCID, the Open Researcher and Contributor ID.
ORCID provides a unique and persistent digital identifier that distinguishes researchers
from every other researcher, even those who share the same name, and, through
integration in key research workflows such as manuscript and grant submission, supports
automated linkages between researchers and their professional activities, ensuring that
their work is recognized.
The collection of ORCID iDs from corresponding authors is now part of the submission
process of this journal. If you already have an ORCID iD you will be asked to associate
that to your submission during the online submission process. We also strongly encourage
all co-authors to link their ORCID ID to their accounts in our online peer review
platforms. It takes seconds to do: click the link when prompted, sign into your ORCID
account and our systems are automatically updated. Your ORCID iD will become part of
your accepted publication’s metadata, making your work attributable to you and only you.
Your ORCID iD is published with your article so that fellow researchers Reading your
work can link to your ORCID profile and from there link to your other publications. If
you do not already have an ORCID iD please follow this link to create one or visit our
ORCID homepage to learn more.
5.2 Information required for completing your submission
You will be asked to provide contact details and academic affiliations for all co-authors
via the submission system and identify who is to be the corresponding author. These
details must match what appears on your manuscript. At this stage, please ensure you
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have included all the required statements and declarations and uploaded any additional
supplementary files (including reporting guidelines where relevant).
5.3 Permissions
Please also ensure that you have obtained any necessary permission from copyright
holders for reproducing any illustrations, tables, figures or lengthy quotations previously
published elsewhere. For further information including guidance on fair dealing for
criticism and review, please see the Copyright and Permissions page on the SAGE Author
Gateway.
6. On acceptance and publication
6.1 SAGE Production
Your SAGE Production Editor will keep you informed as to your article’s progresso
throughout the production process. Proofs will be sent by PDF to the corresponding
author and should be returned promptly. Authors are reminded to check their proofs
carefully to confirm that all author information, including names, affiliations, sequence
and contact details are correct, and that Funding and Conflict of Interest statements, if
any, are accurate. Please note that if there are any changes to the author list at thi stage,
all authors will be required to complete and sign a form authorising the change.
6.2 Online First publication
Online First allows final articles (completed and approved articles awaiting assignment
to a future issue) to be published online prior to their inclusion in a journal issue, which
significantly reduces the lead time between submission and publication. Visit the SAGE
Journals help page for more details, including how to cite Online First articles.
6.3. Access to your published article
SAGE provides authors with online access to their final article.
6.4. Promoting your article
Publication is not the end of the process! You can help disseminate your paper and ensure
it is as widely read and cited as possible. The SAGE Author Gateway has numerous
resources to help you promote your work. Visit the Promote Your Article page on the
Gateway for tips and advice.