Electrical Status Epilepticus During Slow-wave Sleep (ESES): Current Perspectives.

Electrical status epilepticus during slow-wave sleep (ESES) is an epilepsy syndrome with sleep-induced epileptic discharges and acquired impairment of cognition or behavior. Since the disease's original description in 1971, no clear consensus has emerged on diagnostic criteria or optimal treatment. The treatment of ESES can be challenging, often including numerous antiepileptic drugs, immunomodulatory agents, and even surgical interventions. There is little evidence to guide treatment because only retrospective studies and case reports on the efficacy of treatment of ESES are present in literature. In this paper, we aim to analyze the etiopathogenesis of ESES in the new genetic era and to evaluate the treatment modalities in accordance with the genetic data and electroclinic spectrum of ESES. Copyright:

INTRODUCTION

Electrical status epilepticus during slow-wave sleep (ESES) is an age-dependent and self-limited epilepsy syndrome characterized by onset in childhood with a peak around the age of 4–5 years and appearance of cognitive and behavioral disturbances, with or without clinical seizures. ESES was first reported by Patry et al. in 1971 as a subclinical “electrical status epilepticus” induced by sleep in children.[1] The International League Against Epilepsy (ILAE) opted to term the condition “continuous spike and waves during sleep” (CSWS) as a specific epilepsy syndrome characterized by continuous diffuse spike-waves occurring during slow-wave sleep, related to the development of neurocognitive deficits.[2] Today, ESES is the term typically accepted as a unique electrographic pattern covering the term CSWS.[3]

The early diagnosis of this syndrome is essential since there is a significant correlation between permanent cognitive impairment and delayed diagnosis. ESES can last several months or years, but usually resolves before adulthood. However, certain epileptic syndromes such as childhood epilepsy with centrotemporal spikes, atypical childhood epilepsy with centrotemporal spikes, and Landau–Kleffner syndrome may show the ESES pattern. There are some features of more than one of these syndromes or transition from one to another over time.[4] Differential diagnosis of these syndromes is essential with respect to treatment modalities. In this paper, we aim to focus on the current clinical perspectives of the ESES in the new genetic era.

AN ELUSIVE PATHOPHYSIOLOGY

The pathogenesis of ESES is still not fully understood; however, the nature of diffuse epileptiform discharges in ESES during slow-wave sleep seems to be strongly linked to the cortico-thalamic circuitry.[5] The thalamocortical and cortical oscillations operating during non-REM sleep leading to the appearance of the typical physiological graphoelements such as sleep spindles and K complexes and also favor the occurrence of interictal epileptiform discharges.[6] However, in the presence of these epileptogenic areas, connectivity of thalamic structures has a role in the epileptiform synchronization and spread. It has been proposed that desynchronization in the neurotransmission of the thalamic and cortical circuits contributes to potentiation and generalization of epileptiform activity during non-REM sleep.[78]

Cohorts of children with thalamic lesions have shown that approximately a third of these children go on to develop ESES. These findings support that pathologic disruption of the cortico-thalamic circuitry leads to the electroencephalogram (EEG) pattern of ESES.[91011] Functional imaging studies using simultaneous recording of EEG and blood-oxygenation level-dependent (BOLD) and functional magnetic resonance imaging demonstrated that independent of etiology and individual area of initial epileptic activity, patients with ESES were characterized by a consistent specific neuronal network of propagation. The activation in the perisylvian/prefrontal network was associated with both activation in the thalamocortical network and deactivation in the default mode network.[9] These networks activation has a possible influence of epileptic spikes on these networks that may explain neuropsychological deficits and developmental abnormalities in ESES. However, further studies are needed that directly investigate information processing during sleep in relation to epileptic activity and memory consolidation and fluctuations of activity in the default mode network.

ETIOLOGY

A wide variety of etiologic causes of ESES results in unique EEG pattern associated with different seizure types, neuropsychological impairment in the form of global or selective regression of cognitive functions, motor impairment. With the extensive use of genetic analysis in recent decades, the many causes of ESES including structural lesions and increased number of genetic factors, most frequently GRIN2A mutations, have been reported although the etiology of ESES remains undetermined for a significant proportion of patients [Figure 1].[121314151617181920] Mowat–Wilson syndrome, Christianson syndrome, Costeff syndrome, 8p deletion syndrome, CDKL5 disorder, and 9p duplication syndrome have been proposed in the genesis of the ESES syndrome.[1920] A growing number of reports state a possible correlation between different gene mutations and ESES; so, using a dedicated ESES, next-generation sequencing panel can be useful for detecting underlying genetic etiologies. Previously, we reported a case of a girl with a mutation of the SCN1A gene.[21] During follow-up, at 4 years old, she developed ESES. ESES has not been described in the SCN1A mutation. Underlying genetic etiologies in patients with ESES from reported studies were summarized in Table 1.[1920,2223242526272829]

Figure 1

Reported etiologies of ESES

Table 1

Reported monogenic etiologies of ESES

Gene	Location	Associated syndrome	Number of cases
GRIN2A	16p13.2	Epilepsy–aphasia spectrum	22 (31%)
MECP2	Xq28	Rett syndrome	9 (13%)
SLC9A6	Xq26.3	Christianson syndrome	7 (11%)
SCN2A	2q24.3	Early infantile epileptic encephalopathy 11	6 (9%)
ZEB2	2q22.3	Mowat–Wilson syndrome	5 (7%)
KCNB1	20q13.13	Early infantile epileptic encephalopathy 26	5 (7%)
KCNA2	1p13.3	Early infantile epileptic encephalopathy 32	5(7%)
KCNQ2	20q13.33	Early infantile epileptic encephalopathy 7	2 (3%)
SLC6A1	3p25.3	Myoclonic-atonic epilepsy	2 (3%)
NHE6/SLC9A6	Xq26.3	Christianson syndrome	1 (1%)
DRPLA/ ATN1	12p13.31	Dentatorubropallidoluysian atrophy	1(1%)
Neuroserpin	Xq22.1	Familial encephalopathy with neuroserpin inclusion bodies	1(1%)
OPA3	19q13.32	Costeff syndrome	1(1%)
CNKSR2	Xp22.12	The Houge type of X-linked syndromic mental retardation	1(1%)
CDKL5	Xp22.13	CDKL5 disorder	1(1%)
VPS13B	8q22.2	Cohen syndrome	1(1%)
TSC1/TSC2	9q34.13/16p13.3	Tuberous sclerosis complex	1(1%)
WAC	10p12.1	DeSanto–Shinawi syndrome	1(1%)

While there have been a variety of reported structural anomalies associated with ESES, early developmental lesions such as perinatal vascular lesions are commonly reported, in as many as 21–78% of patients; cortical malformations have been reported in up to 1/4 and abnormal myelination has been reported in another 10–15%.[1024,26] Our previous study showed that 70% of patients with ESES had abnormal neuroimaging findings.[10]

CLINICAL SPECTRUM

Various seizure types including focal motor or unilateral clonic/tonic-clonic seizures, atonic seizures, and atypical absence seizures are seen during the clinical course of ESES [Figure 2].[12131415161718] Seizure onset tends to be initially benign and occur daily or more frequently in less than 20% of cases.[5] The majority of cases, up to 70%, will have several seizures per day once the ESES pattern appears. The lack of tonic seizures has been classically considered a major feature of this syndrome.[10] Patients with structural lesions of the brain tend to have seizures earlier (around 2 years of age) than patients with unknown etiology (around 4 years of age). However, the age of onset is variable, ranging from 1 to 14 years, with a mean onset between 4 and 8 years.[30]

Figure 2

Reported type of seizures in patients with ESES

Neurocognitive development is clinically normal in approximately two-thirds of cases; however, a severe neurocognitive regression occurs around 5–6 years of age in most patients. Neurocognitive deterioration affects a wide spectrum of developmental and neurocognitive milestones in varying. Regression domains include language, behavior, learning, memory, attention, social interactions, motor skills, and global intelligence.[31] During follow‐up, the children with epilepsy, clinically and electrophysiologically appearance of the new type of seizures or behavior problems, must alert physicians for the development of ESES.

ELECTRO-CLINICAL CHARACTERISTICS

A typical EEG pattern with continuous epileptic activity occupying a significant proportion of slow-wave sleep is defined by Tassinari.[1] Although the classic electrographic criterion for ESES is an SWI exceeding 85%, the proportion of affected slow sleep required to affect cognition and behavior has been recognized to be lower, with some authors suggesting that ≥50% can be associated with cognitive and behavioral disturbances and thus warrant treatment.[1332] An appropriate electrophysiologic assessment should be performed in wakefulness and afternoon-sleep, maybe sufficient as a first screening, but for a correct diagnosis a full-night EEG recording is recommended.[33]

The SWI is suggested to quantify the frequency of spikes in the EEG record, thought of as the percentage of non-REM sleep occupied by spike waves.[34] It has been reported that the maximum amplitude of the ESES pattern (anterior vs posterior) has no significant correlation with seizure control and reduction of the SWI on the EEG in children with ESES syndrome. There were similar clinical and prognostic features between anterior and posterior ESES pattern.[13]

ESES is often a generalized pattern, but some studies have reported cases with hemi-ESES and focal ESES in children with polymicrogyria, porencephalic cysts, hydrocephalus, and thalamic lesions.[353637] It is an electro-clinical entity whose main EEG characteristic is an extreme activation of paroxysmal activity during sleep, probably subtended by an age-dependent mechanism. Secondary bilateral synchrony contributes to the spread of focal epileptic discharges during sleep.[37] The characteristic EEG patterns during slow-wave sleep ceases around age 11 years, but focal interictal spikes may persist after ESES disappearance.[12]

TREATMENT STRATEGIES

ESES is a particularly difficult-to-treat childhood epileptic syndrome. There is currently no consensus on the treatment of ESES. There is also no methodological consensus on EEG abnormality quantification and treatment efficacy evaluation.[36] Whether to treat epileptiform activity without a direct clinical correlate and, especially, to what extent to treat EEG findings is still unclear. Although the treatment of ESES is not supported by any large-scale, randomized, controlled trials with blinded and standardized cognitive outcome assessment, benzodiazepines and corticosteroids are the mainstay of recommended treatment except for a small minority of patients whose ESES occurs in the setting of focal structural abnormalities and are favorable candidates for surgical resection.[1415,3940] A randomized, controlled, European, multicenter trial is still ongoing and may provide further directions (RESCUE ESES, Randomized European trial of Steroids versus Clobazam Usage for Encephalopathy with Electrical Status Epilepticus in Sleep) (ISRCTN42686094).

Still, a large proportion of patients have seizures that are refractory to initial therapies, and the effectiveness of these agents is often compromised by poor tolerability, especially with regard to long courses of corticosteroids and benzodiazepines. Some retrospective studies suggest that sodium valproate, ethosuximide, levetiracetam, sulthiame, topiramate, amantadine, and immunomodulatory agents may be effective in the treatment of ESES.[1641424344] The ketogenic diet (KD) is an additional treatment option which may add to the more commonly used high-dose benzodiazepines, other anti-seizure medications and steroids.[45] Jeong et al. reported that the patients with structural lesion and drug-resistant ESES should be evaluated for hemispherectomy as they may experience the cessation of seizures, termination of ESES, and improvement in neuropsychological status.[46]

We conducted a MEDLINE literature search using PubMed to identify articles published. If information on cognitive and EEG improvement was available, treatment effects on EEG and cognition in patients with ESES from reported studies were summarized in Table 2.[121314151617181920] Antiepileptic drugs (n = 375) were associated with improvement cognition in 42% of patients, steroids (n = 161) in 66%, benzodiazepines (n = 146) in 35%, and surgery (n = 32) in 76%. Elektroensefalografi improvement was seen in 34% of patients treated with conventional antiepileptic drugs, in 63% of patients treated with steroids, in 42% of patients treated with benzodiazepines, and in 84% of patients after surgery.

Table 2

Reported treatment effects on EEG and cognition in patients with ESES

Treatment	Number of patients	EEG improvement	Cognitive improvement
Conventional antiepileptic drugs	375	32%	34%
Steroids	161	66%	63%
Benzodiazepines	146	35%	42%
Surgery	32	76%	84%
Others	63	35%	59%
Total	777	42%	46%

OUTCOME AND PREDICTORS OF OUTCOME

Following resolution of ESES, improvement in language development, learning disabilities, and behavioral disturbances are generally observed; however, this is variable and individualized. The majority of cognitive and behavioral deficits often remain, especially in verbal and attention abilities. Only 10–40% of children's cognition and language becomes normal after the ESES pattern has resolved.[1847484950]

The negative effects of ESES may depend on the lack or decrement of physiological sleep features occurring in the critical period of brain maturation. Physiological graphoelements of sleep have been shown to play a role in the consolidation of recently learned information and maintenance of cognitive function.[51] In ESES, disruption of normal sleep architecture might be an additional factor impairing the remodeling of neuronal networks subserving cognitive performance, normally occurs during sleep.

Longer duration of ESES, abnormal development before the onset of ESES, and severity of initial regression are the most important risk factors of cognitive impairment in the long term.[3852] Like Landau–Kleffner syndrome, older age at onset is correlated with a better cognitive outcome although this does not appear to be absolute.[535455] Severity is correlated with an SWI in some studies. The epileptic activity is believed to contribute to neuropsychiatric impairments.[5657]

CONCLUSION

Despite the favorable long-term prognosis of epilepsy and of the normalization of the EEG, cognitive deficits and behavioral disorders may persist for life. Developmental lesions, especially those affecting the thalamus, can play a role in the development of ESES. There is little evidence to guide treatment since only retrospective studies and case reports on the efficacy of treatment of ESES are present in literature. The clinicians’ approaches to the treatment of ESES syndrome differ a lot and there is no agreement on the best treatment. Wide use of the genetic investigation including epilepsy gene panels, array-cGH, whole-exome sequencing, and whole-genome sequencing may be capable of diagnosing etiologically well-known cases with ESES whom might be treated with personalized medicine. Taken together, randomized controlled trials are needed to provide an improved evidence basis for a rational approach for the treatment of ESES.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.