Syndrome of Electrical Status Epilepticus During Sleep: Epileptic Encephalopathy Related to Brain Development

Accepted Manuscript Syndrome of Electrical Status Epilepticus during Sleep: Epileptic Encephalopathy Related to Brain Development Xiao-Qiao Chen, MD, Wei-Na Zhang, MD, Lin-Yan Hu, MD, Meng-Jia Liu, MD, LiPing Zou, MD, PhD PII:

S0887-8994(15)30038-2

DOI:

10.1016/j.pediatrneurol.2015.12.006

Reference:

PNU 8801

To appear in:

Pediatric Neurology

Received Date: 7 July 2015 Revised Date:

9 December 2015

Accepted Date: 13 December 2015

Please cite this article as: Chen X-Q, Zhang W-N, Hu L-Y, Liu M-J, Zou L-P, Syndrome of Electrical Status Epilepticus during Sleep: Epileptic Encephalopathy Related to Brain Development, Pediatric Neurology (2016), doi: 10.1016/j.pediatrneurol.2015.12.006. 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.

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The title of article: Syndrome of Electrical Status Epilepticus during Sleep: Epileptic Encephalopathy Related to

Running title:ESES, encephalopathy related to brain development. Author’s name:

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Brain Development

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Xiao-Qiao Chen, MD1, Wei-Na Zhang, MD1, Lin-Yan Hu, MD1, Meng-Jia Liu, MD1, Li-Ping Zou, MD, PhD1,2*

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Affiliation of the authors:

1. Department of Pediatrics, Chinese PLA General Hospital, Beijing 100583, China; 2. Center of Epilepsy, Beijing Institute for Brain Disorders, Beijing 100069, China. Gant numbers and sources of support:

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This work was supported by grants from the Major State Basic Research Development Program (973; No. 2012CB517903), the National Natural Science Foundation of China (nos. 81471329) and Public health program of Capital (Z141100002114001).

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*Correspondence:

Li-Ping Zou, MD, PhD,

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Department of Pediatrics, Chinese PLA General Hospital, Beijing100853, China; Center of Epilepsy, Beijing Institute for Brain Disorders, Beijing 100069, China. Tel: +86-10-55499016; Fax: +86-10-66939770; E-mail: [email protected]

Word count (the body of the manuscript): 2939.

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Syndrome of Electrical Status Epilepticus during Sleep: Epileptic Encephalopathy Related to Brain Development

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Abstract BACKGROUND: Epileptic encephalopathy with electrical status epilepticus during sleep is

an age-related and self-limited disorder.The present study analyzed the etiology,

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demographics, and pathogenesis of patients with electrical status epilepticus during sleep to

provide information on the diagnosis and therapy of this syndrome. METHODS: The

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etiologies of ESES in patients administered in Chinese People’s Liberation Army General Hospitalfrom 2009 to 2014 were retrospectively analyzed. Patients were classified into the genetic, structural–metabolic and unknown groupsaccording to the etiology. Demographics and clinical characteristics of all patients with ESES were then analyzed and compared among

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groups. RESULTS: The etiologies of ESES in 75 patients mainly included benign childhood epilepsy with centrotemporal spikes, Landau–Kleffner syndrome, polymicrogyria, and migration disorders. Age at onset of epilepsy did not show a specific pattern, but age at onset

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of ESES was concentrated at 6 to 9 years of age. The mean age at onset of epilepsy in the genetic group was significantly older than that in the structural-metabolic group (P < 0.05).

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Age at onset of ESES did not significantly differ between the two groups. CONCLUSIONS:

Electrical status epilepticus during sleep is an epileptic encephalopathy related to brain development and presents an age-dependent occurrence.

Key words:

Electrical Status Epilepticus during Sleep; Etiology; Children; Genetic;

Structural–metabolic.

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Introduction Epileptic encephalopathy with electrical status epilepticus during sleep (ESES) is an

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age-related and self-limited disorder. ESES is characterized by epilepsy with a specific electroencephalography (EEG) pattern during nonrapid eye movement (NREM) sleep, different seizure types, and neuropsychological impairment

[1]

. The distinctive EEG pattern [2]

, consists of continuous

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associated with ESES, which was first described by Patry in 1971

and diffused spike waves mainly at 1.5 Hz to 2.5 Hz during slow sleep

[3]

. Spike wave index

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(SWI) plays a central role in the diagnostic criteria of ESES. Various criteria include SWI of at least 90%, 85%, 60%, 50%, and 25% [4]. The International League against Epilepsy (ILAE) did not establish an exact cutoff value and merely reported strong activation of epileptiform activity during sleep. The long-term outcome of ESES has shown to be favorable, with

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seizures and epileptiform discharge disappearing in all cases. However, impairment of the cortical network caused by epileptic disturbances during network maturation may be permanent.

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The etiology of ESES remains unknown. Several clinical syndromes, particularly encephalopathy with continuous spikes and waves during slow sleep (CSWS)

[2]

,

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Landau–Kleffner syndrome (LKS), and atypical benign childhood epilepsy with centrotemporal spikes (BECTS) [5], may exhibit the EEG pattern of ESES. ESES is associated

with structural abnormalities in brain, such as polymicrogyria[6], migration disorders

[5]

,

hydrocephalus [7], porencephalic lesions [8], thalamic lesions [9], and schizencephaly[10]. Recent studies have found that immune disorders may play a pathogenic role in ESES [11, 12]. Specific types of chromosome aberration were also reported to be related to ESES [5]. 3

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Neuropsychological impairment is not only an important clinical feature of ESES but also a primary factor that influences its poor long-term prognosis. A large number of studies

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demonstrated that ESES encephalopathy is an epileptic encephalopathy, and persistent continuous spike-and-wave discharges over years are responsible for the development of complex and severe neurologic impairments in the patients

. Age at onset of ESES in

[16]

. Lasting for months or years,

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majority of ESES cases ranges from 3 to 12 years old

[13-15]

particularly after adolescence, clinical manifestations and epileptiform discharges of patients [17]

. However, residual neuropsychological impairment will

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with ESES may remit in all cases

persists in more than 50% of ESES cases

[18]

. This specific age-dependent phenomenon of

ESES is similar to that of another epileptic encephalopathy called infantile spasms, which occur in infancy and early childhood. Infantile spasms typically begin at around 6 months of

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age, are infrequent before 4 months, and rarely occur after 1 year. A number of studies proposed that the occurrence of infantile spasms is closely related to a critical period of brain development in infancy

[19]

. Similarly, we infer that ESES may be related to brain

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development in childhood. ESES begins during the time of cortical synaptogenesis, when the elemental functional circuitry is being established in the brain particularly between 1 and 8

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years of age. A paroxysmal disturbance of high magnitude that develops during high axonal sprouting synapse formation would destroy the cortical network in the brain and subsequently manifests as neuropsychological impairment in patients with ESES [20]. In the current research, the etiologies and clinicalcharacteristics of patients with ESES from Chinese People’s Liberation Army (PLA) General Hospital were retrospectively studied. The pathogenesis of ESES was also preliminarily discussed to provide information for the diagnosis and therapy 4

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of this syndrome.

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Materials and Methods Study design

This research was designed as a retrospective study. Patients diagnosed with ESES were

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recruited from Chinese PLA General Hospital between 2009 and 2014. The demographics,

clinical characteristics, and etiologies of patients with ESES were retrospectively analyzed.

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The trial was conducted in accordance with the international rules of good clinical practice and approved by the Ethical Committee of the Chinese PLA General Hospital. Informed consent was obtained from parents of each patient prior to the initiation of trial-related procedures.

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Medical history was obtained from each patient. All patients underwent complete blood count, biochemical tests, video EEG, and cerebral magnetic resonance imaging (MRI). All-night video EEG was performed for at least 12 hours in each patient. The international

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10/20 electrode placement system was also used. Open–closed eye test and hyperventilation were included in every video EEG test. Data on school achievements and neuropsychological

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evaluations were obtained according to clinical judgment by experienced physicians on the basis of the Denver Developmental Screening Test for patients aged lower than 6 years and Raven’s Standard Progressive Matrices for patients aged higher than 6 years. Data analysis was performed based on the following procedure. (1) All patients were divided based on etiology into three groups, namely, genetic, structural–metabolic, and unknown groups. The etiologies of patients from different groups were further analyzed. Age 5

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at onset of epilepsy and ESES, as well time interval between the onset of first seizures and the onset of ESES, were analyzed and compared in all patients from different groups. (2) Age at

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onset of epilepsy and ESES of all patients were compared with the developmental graph reported by Insel et al [21].

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Patients

All patients were selected based on the following inclusion criteria: (1) onset of focal

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seizures or focal EEG discharge; (2) further occurrence of new clinical manifestations, such as atypical absences, atonic, myoclonic, and negative myoclonic seizures; (3) characterized epileptic activity of ESES particularly during NREM according to video EEG and continuous focal or diffuse spikes and waves with SWI ≥ 50%. SWI was confirmed by two physicians

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trained in electrophysiological imaging; (4) cognitive impairment or behavioral disturbances related to the ESES period; and (5) Epilepsy patients regularly visited our clinic since the first seizure onset.

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Patients with other epileptic encephalopathies (e.g., Lennox–Gastaut syndrome and West syndrome) and other focal epilepsies with secondary bilateral synchronies that did not fulfill

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the criteria for ESES were excluded.

Statistical analysis

Mean and standard deviation (x ± s) was used to describe statistics for normally distributed continuous variables. Statistics following a skewed distribution were expressed as medians (M), and One–Way ANOVA was performed to compare differences among groups. 6

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Regarding to multiple comparisons, Least Significant Difference (LSD)test was used to compare

means

between

groups.

When

statistics

followed

a

skewed

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distributionKruskal-Wallis H test was used to compare differences among groups (≥3),

Results were considered significant at P < 0.05.

Results

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Demographics, clinical characteristics, and etiology

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whereas Mann–Whitney U test was performed to compare differences between two groups.

Seventy-five patients with ESES, which comprised 45 males and 30 females, with a mean age of 6 years and 2 months, were included in the study. The age at onset of epilepsy was 4 months to 12 years and 4 months, with a mean age of 4 years and 8 months ± 2 years

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and 7 months. The age at onset of ESES was 1 year to 14 years and 4 months, with a mean age of 7 years and 7 months ± 2 years and 10 months. All the patients included were detected with some cognitive impairment. Thirty-eight of 75 patients were classified into the genetic

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group; of these patients, BECTS (including atypical BECTS)was diagnosed in 34 children and LKS was diagnosed in four children. ESES was detected in two patients with BECTS

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during treatment with oxcarbazepine and lamotrigine, and ESES disappeared upon withdrawal of these drugs. Thirty-two patients were classified into the structural–metabolic group. The etiologies of these patients included polymicrogyria, migration disorders, hydrocephalus,perinatal

hypoxic-ischemic

encephalopathy(Figure

1),schizencephaly,

encephalitis, porencephalic lesions, intracranial hemorrhage, autism, and autoimmune disorders. ESES in one patient was caused by autoimmune disorder. An 8-year-old boy was 7

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diagnosed with neuroblastoma at 5 months of age. He had suffered from mental retardation and epilepsy refractory to antiepileptic drugs for 6 years. The age at onset of ESES in this

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case was 7 years and 8 months. Onconeuronal antibody test showed positive detection of anti-Ma2 and anti-CV2/CRMP5 antibodies. ESES disappeared and clinical manifestations

improved after the patient was treated with glucocorticoids, and onconeuronal antibody test [22]

. Meanwhile, etiology was undetermined in five patients, who

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showed negative results

showed normal MRI scans and no definite signs of lesions in neurological examinations.

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These patients were then classified in the “unknown” group (Table 1).

Characteristics of ages at onset of ESES

An interesting phenomenon was observed in this study. Although age at onset of epilepsy

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did not present any central tendency or regularity, age at onset of ESES evidently concentrated in the group with patients aged 6 to 9 years, with the associated curve shaped like a Mexican hat. Insel et al

[21]

demonstrated that changes in grey matter density persisted

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until mid-twenties, with the prefrontal cortex being the last to mature and both synaptic elimination and increased myelination continued into early adulthood. The prefrontal

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excitatory synapse density peaked at around 5 years of age and declined late in the development. In the present study, age at onset of 75 patients with ESES concentrated in the age group of 6 to 9 years, which closely coincides with the time at which the prefrontal excitatory synapse density reached its maximum (Figure 2).

Comparison of demographics and clinical characteristics among groups 8

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Seventy-five patients with ESES were divided into three groups according to etiology. Thirty-eight patients (20 males and 18 females) were included in the genetic group.

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Thirty-two patients (23 males and 9 females) were included in the structural–metabolic group. In addition, 5 patients were classified into the unknown group. In the genetic group, the age at

onset of epilepsy ranged from 2 years to 10 years, with a mean age of 5 years and 6 months ±

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2 years and 4 months, whereas the age at onset of ESES ranged from 3 years and 2 months to

13 years and 2 months, with a mean age of 7 years and 11 months ± 2 years and 4 months.

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Moreover, the time between the onset of first seizures and the onset of ESES was 0 to 6 years and 6 months, with a median time of 2 years and 2 months. In the structural-metabolic group, the age at onset of epilepsy ranged from 4 months to 10 years and 4 months, with a mean age of 3 years and 11 months ± 2 years and 9 months, whereas the age at onset of ESES ranged

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from 1 year and 8 months to 14 years and 4 months, with a mean age of 7 years and 6 months ± 3 years and 2 months. Furthermore, the time between the onset of first seizures and the onset of ESES was 0 to 12 years, with a median time of 3 years. Age at onset of epilepsy

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significantly differed among the genetic, structural–metabolic and unknown groups (F = 4.086, P = 0.021). Regarding to multiple comparisons, age at onset of epilepsy significantly

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differed between the genetic and structural–metabolic groups (P = 0.010). It did not significantly differ between unknown group and genetic group (P = 0.107), neither between unknown group and structural–metabolic group (P = 0.774). However, age at onset of ESES (F = 1.391, P = 0.256) and the time between the onset of first seizures and the onset of ESES (χ2= 3.752, P = 0.153) did not significantly differ among the three groups.Regarding to

multiple comparisons, age at onset of ESES (P=0.565) and the time between the onset of first 9

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seizures and the onset of ESES (Z = −1.787, P = 0.074) did not significantly differ between

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genetic and structural-metabolic groups.(Table 2)

Discussion

Seventy-five patients with ESES obtained from Chinese People’s Liberation Army

into

genetic,

structural–metabolic,

and

unknown

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General Hospital were retrospectively analyzed. The patients were divided based on etiology groups.

Demographics,

clinical

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characteristics, and etiologies were analyzed and compared among the groups.

In the present study, ESES manifests in the syndromes of BECTS and LKS, which is consistent with previous reports

[17]

. ESES was induced by oxcarbazepine and lamotrigine in

two patients. Similarly, several studies have demonstrated that antiepileptic drugs, such as

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carbamazepine, phenobarbital, and oxcarbazepine, may induce or worsen ESES [23-25]. As such, caution must be exerted while using antiepileptic drugs in treating BECTS and some specific syndromes of epilepsy to avoid iatrogenic EEG deterioration. With regard to

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structural–metabolic factors, ESES was detected in patients with polymicrogyria, migration disorders, porencephalic lesions, encephalitis, schizencephaly, hydrocephalus, autism, and

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immune factors. Polymicrogyria was the most common etiology in the structural–metabolic group; hence, the results of this study are consistent with previous reports [5, 14]. Interestingly,

one ESES case was induced by autoimmune disorder. Recently, detection of autoantibodies in unexplained epilepsy cases reinforced the causal factor of immunity and inflammation in epilepsy cases with unknown etiology

[26]

. Underlying immune disorder has also been

proposed as the etiology for certain cases of CSWS/ESES 10

[12]

. Hence, immune disorders

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should be considered when devising treatment plans for ESES refractory to many antiepileptic drugs. Moreover, five patients in this study were classified under the unknown

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group because of undetermined etiology. Structural–metabolic or genetic abnormalities in these uncharacterized cases may be identified through improved detection methods.

An interesting phenomenon was reported in this study. Although age at onset of epilepsy

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did not present any central tendency or regularity, age at onset of ESES evidently concentrated at 6 to 9 years. The specific pattern of EEG is self-limited, and ESES

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disappeared in almost all patients by adolescence. In addition, age at onset of epilepsy in the genetic group was significantly older than that in the structural–metabolic group. However, age at onset of ESES did not significantly differ between the genetic and structural–metabolic groups. The mean age at onset of ESES was around 7 years in both groups. A similar result

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was found in another multicenter, long-term follow-up study of 117 patients with ESES by Caraballo et al [14]. According to reports by ILEA in 2001, ESES syndrome was regarded as an epileptic encephalopathy [1], in which neurological deterioration is attributed entirely or partly

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to epileptic activity [27]. Classical anatomical post-mortem studies indicated that both synaptic elimination and increased myelination continue into early adulthood [21]. A decline in synaptic

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counts was also found since 5 years of age, when maximum synaptic counts were detected, to adolescence [28]. Functional disorders or neuropsychological impairment usually begin during

cortical synaptogenesis, when the elemental functional circuitry is being established in the brain particularly between ages of 1 and 8 years. In the process of synaptogenesis, neurons and synaptic contacts are initially overproduced in early life stage. Neuronal activity and synaptic contacts are used to determine the strength or elimination of these synapses. Aside 11

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from genetic programming, the environment plays a crucial role in the establishment of permanent synaptic contacts. When epileptiform discharge persists during synaptic formation,

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epileptic activity can act to strengthen synaptic contacts, which would normally be eliminated [20]

. The major role of NREM in learning and memory has been widely accepted. Epileptiform

activity disturbs majority of NREM cases in ESES and thus interferes with learning and [27]

. In this study, the onset of ESES was detected concentrated during 6 years to 9

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memory

years of age, which is the critical time of synaptogenesis. We inferred that continuous

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epileptiform activity during NREM of patients with ESES may disturb the time of cortical synaptogenesis, during which elemental functional circuitry is being established in the brain. The specific age-dependent phenomenon of ESES suggests that its occurrence may be related to brain development, particularly synaptic formation (Figure 2). The results of the present

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study confirm that ESES is an age-dependent disorder and possibly related to brain development. However, lack of basic researches to study the pathogenesis of ESES and Lack of genetic evidence of patients in the genetic group are problems of our study. However, we

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had collected all the blood samples of patients in the genetic group. Genetic analysis will be included in our further studies. In addition, basic researches are needed to investigate the

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pathophysiologic mechanism of ESES..

Conclusion

ESES syndrome is a specific age-dependent encephalopathy with distinct EEG pattern and possibly originates from multiple etiologies, particularly genetic and structural–metabolic causes. In this study, ESES was induced by antiepileptic drugs and autoimmune disorder in 12

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three cases. Age at onset of epilepsy significantly differed in different etiological groups. However, age at onset of ESES, with a mean age of around 7 years, did not significantly

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differ between the groups. This study reveals that ESES is an epileptic encephalopathy

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possibly related to brain development.

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and effects of aging. Brain Res, 1979. 163(2): p. 195-205.

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28. Huttenlocher, P.R., Synaptic density in human frontal cortex - developmental changes

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Figure legends: Figure 1.EEGs of anESES patient experiencingperinatal hypoxic-ischemic encephalopathy at

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birth.The EEG above (A) was recorded in 2008 when the patient was 1 year old. It shows focal discharges mainly in the anterior regions.The EEG below (B) was recorded in 2014

when the patient was 7 years old, showingcontinuous spike-and-wave activity in more than 50%

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of NREM sleep.

Figure 2.Relationship between age at onset of ESES and brain development. Abscissa

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corresponds to ages of patients with ESES. The ordinate on the left represents the percentage of the maximum number of synapses. The ordinate on the right represents the number of patients. Changes in the percentages of prefrontal excitatory and inhibitory synapses are shown by the upper and lower curves, respectively, with increasing age. (A) Blue spots

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represent the numbers of patients at their corresponding ages of onset of epilepsy. (B) Red spots represent the numbers of patients at their corresponding ages of onset of ESES. Age at onset of ESES was concentrated at 6 to 9 years. The curves and statistics about brain

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development were adapted from the study of Insel et al [21].

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Table 1. Etiologies and group distribution of 75 ESES patients Groups

Number of Patients (%)

Genetic group

38 (50.7)

BECTS*

34 (45.3)

Drug induced

2 (2.7)

LKS†

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4 (5.3)

Structural-metabolic group

32 (42.7)

9 (12.0)

Migrational disorders

6 (8.0)

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Polymicrogyria

Hydrocephalus

4 (5.3)

perinatal hypoxic-ischemic encephalopathy

3 (4.0)

Schizencephaly

2 (2.7)

Encephalitis

3 (4.0) 2 (2.7)

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Porencephalic lesions Intracranial hemorrhage

1 (1.3)

Autism

1 (1.3)

Autoimmune disorders

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Unknown group

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n=75

1 (1.3) 5 (6.7)

Abbreviation:

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*BECTS = Benign childhood epilepsy with centrotemporal spikes; †LKS = Landau Kleffner syndrome;

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Table 2.

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Comparison of Demographics and Clinical Characteristics among genetic, structural-metabolic and unknown groups Age at onset of epilepsy

Age at onset of ESES

Time*

（x±s）

（x±s）

（M）

7 yr. 11 mo. ±2 yr. 4 mo.

2 yr.2 mo.

Gender Patients

Genetic group

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Nmuber of Group Name

38

20M/18F

5 yr. 6 mo. ±2 yr. 4 mo.

32

23M/9F

3 yr. 11 mo. ±2 yr. 9 mo.

5

2M/3F

3 yr. 6 mo. ±3 yr. 1 mo.

5 yr. 8 mo. ±4 yr.

1 yr. 10mo.

Statistical Value

F=4.086

F=1.391

χ2=3.752

P value

P=0.021＜0.05

P=0.256＞0.05

P=0.153＞0.05

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Structural-

Unknown group

AC C

EP

* Time between the Onset of First Seizures and Onset of ESES

TE D

metabolic group

20

7 yr. 6 mo. ±3 yr. 2 mo.

3 yr.

AC C

EP

TE D

M AN U

SC

RI PT

ACCEPTED MANUSCRIPT

AC C

EP

TE D

M AN U

SC

RI PT

ACCEPTED MANUSCRIPT