Functional brain connectivity in electrical status epilepticus in sleep

Aims. Electrical status epilepticus in sleep (ESES) is an age‐related, self‐limited epileptic encephalopathy. The syndrome is characterized by cognitive and behavioral abnormalities and a specific EEG pattern of continuous spikes and waves during slow‐wave sleep. While spikes and sharp waves are known to result in transient cognitive impairment during learning and memory tasks performed during the waking state, the effect of epileptiform discharges during sleep on cognition and behavior is unclear. There is increasing evidence that abnormalities of coherence, a measure of the consistency of the phase difference between two EEG signals when compared over time, is an important feature of brain oscillations and plays a role in cognition and behavior. The objective of this study was to determine whether coherence of EEG activity is altered during slow‐wave sleep in children with ESES when compared to typically developing children. Methods. We examined coherence during epochs of ESES versus epochs when ESES was not present. In addition, we compared coherence during slow‐wave sleep between typically developing children and children with ESES. Results. ESES was associated with remarkably high coherences at all bandwidths and most electrode pairs. While the high coherence was largely attributed to the spikes and spike‐and‐wave discharge, activity between spikes and spike‐and‐wave discharge also demonstrated high coherence. Conclusions. This study indicates that EEG coherence during ESES is relatively high. Whether these increases in coherence correlate with the cognitive and behavioral abnormalities seen in children with this EEG pattern remains to be determined.     

CSWS-related autistic regression versus autistic regression without CSWS

Continuous spike-waves during slow-wave sleep (CSWS) and Landau-Kleffner syndrome (LKS) are two clinical epileptic syndromes that are associated with the electroencephalography (EEG) pattern of electrical status epilepticus during slow wave sleep (ESES). Autistic regression occurs in approximately 30% of children with autism and is associated with an epileptiform EEG in approximately 20%. The behavioral phenotypes of CSWS, LKS, and autistic regression overlap. However, the differences in age of regression, degree and type of regression, and frequency of epilepsy and EEG abnormalities suggest that these are distinct phenotypes. CSWS with autistic regression is rare, as is autistic regression associated with ESES. The pathophysiology and as such the treatment implications for children with CSWS and autistic regression are distinct from those with autistic regression without CSWS.     

Encephalopathy with continuous spike‐waves during slow‐wave sleep: evolution and prognosis

Encephalopathy with continuous spike‐waves during slow‐wave sleep (CSWS) evolves over time, and three stages can be recognized: before the onset of CSWS, during CSWS, and after the CSWS period. Clinical seizures tend to remit spontaneously around puberty. This pattern is independent of the etiological lesion. The CSWS also disappears in all cases. Focal abnormalities instead, may persist for some time after the disappearance of CSWS. The disappearance of the clinical seizures and CSWS may be simultaneous or seizures may disappear before or after disappearance of the CSWS pattern on the EEG. Electroclinical parameters in the pre‐CSWS period that have been proposed to predict a poor outcome are early‐onset seizures, appearance of new seizures, and a significant increase in seizure frequency. From the electrical point of view, an increase in the frequency of the interictal EEG paroxysms while awake and during sleep and bilateral spike‐and‐wave paroxysms may also be predictive of a poor evolution in CSWS. When CSWS disappears, neurocognitive and behavioral status improve, but in most patients, residual moderate to severe neurocognitive impairments remain. In non‐lesional epilepsy, cognitive recovery after cessation of the CSWS depends on the severity and duration of the initial regression. The duration of the CSWS seems to be the most important predictor of cognitive outcome. Early recognition and effective therapy to reduce the seizures and resolve the CSWS may be crucial to improve long‐term prognosis. Cognitive recovery is observed in patients who respond well to AED treatment and outcome depends on the etiology.     

Electrical status epilepticus in sleep

Electrical status epilepticus in sleep (ESES) describes an electroencephalographic pattern showing significant activation of epileptiform discharges in sleep. The terms continuous spike wave in slow-wave sleep (CSWS) and Landau-Kleffner syndrome (LKS) describe the clinical epileptic syndromes seen with ESES. Although there is an overlap between these 2 syndromes, children with CSWS present with a more global regression have more problematic epilepsy and have EEG foci located predominantly in frontotemporal or frontocentral regions. In contrast, children with LKS present with an acquired auditory agnosia, fewer seizures, and EEG foci in the posterotemporal regions. ESES requires a high degree of clinical suspicion because slow-wave sleep must be recorded to confirm this diagnosis. Treatment of ESES extends beyond just control of the seizures; amelioration of the continuous epileptiform discharge must occur to improve neuropsychological outcome. Although there is little evidence to guide treatment, conventional antiepileptic drugs play only a minimal role. Steroid therapy and high-dose benzodiazepines are most commonly used, but other therapies including intravenous gamma-globulin, the ketogenic diet, and surgical therapy with multiple subpial transaction have shown efficacy in small case series. Although epilepsy resolves with time in most cases, many children are left with significant cognitive or language impairment. Longer duration of ESES appears to be the major predictor of poor outcome; markedly abnormal neuronal activity during a critical period for synaptogenesis may result in aberrant synapse formation, explaining the poorer neuropsychological outcome. Early recognition and effective therapy are necessary to improve long-term prognosis in this condition.     

Scalp‐recorded high‐frequency oscillations in childhood sleep‐induced electrical status epilepticus

Because high‐frequency oscillations (HFOs) may affect normal brain functions, we examined them using electroencephalography (EEG) in epilepsy with continuous spike‐waves during slow‐wave sleep (CSWS), a condition that can cause neuropsychological regression. In 10 children between 6 and 9 years of age with epilepsy with CSWS or related disorders, we investigated HFOs in scalp EEG spikes during slow‐wave sleep through temporal expansion of the EEG traces with a low‐cut frequency filter at 70 Hz as well as through time‐frequency power spectral analysis. HFOs (ripples) concurrent with spikes were detected in the temporally expanded traces, and the frequency of the high‐frequency peak with the greatest power in each patient’s spectra ranged from 97.7 to 140.6 Hz. This is the first report on the detection of HFOs from scalp EEG recordings in epileptic patients. We speculate that epileptic HFOs may interfere with higher brain functions in epilepsy with CSWS.     

Epilepsy with Continuous Spike-Waves During Slow Sleep and Its Treatment

Five children with epilepsy with "continuous spike-waves during slow sleep" (CSWS) are reported. The main clinical features of CSWS include (a) onset between 5 and 7 years of age, (b) the occurrence of several types of seizure (i.e., partial motor, generalized motor, and atypical absence), and (c) the presence of language disturbances and abnormal behavior based on emotional impairment. The EEG findings were characterized by sleep tracings showing almost continuous (greater than 95%), diffuse slow spike and wave activity. After treatment with valproate (VPA) (or ethosuximide, ESM) and clonazepam (CZP), the spike and wave complex status disappeared. Symptoms and signs of the CSWS also decreased. We suggest that combined treatment is an appropriate treatment for CSWS.     

Electrical status epilepticus in sleep (ESES)/continuous spikes and waves during slow sleep (CSWS) syndrome in children: An electroclinical evaluation according to the EEG patterns

ObjectiveThe aim of this study was to describe the electroclinical spectrum in children with electrical status epilepticus in sleep (ESES)/continuous spikes and waves during slow sleep (CSWS) syndrome according to the EEG patterns.MethodsClinical data of 44 patients with ESES/CSWS syndrome who were treated and followed at least two years were analyzed. Records of EEGs of patients were reevaluated to determine two aspects of the ESES pattern: (1) the spike–wave index (SWI) on the NREM sleep EEG (Group I: typical vs. atypical ESES pattern (33/11 patients)) and (2) the area of maximum amplitude of continuous epileptic activity (Group II: anterior vs. posterior ESES pattern (33/11 patients)).ResultsSymptomatic etiology was more defined in patients with the typical ESES pattern (40%) than the group with the atypical ESES pattern (9%) by a factor of four. All patients were receiving at least two antiepileptic drug (AED) treatments. Eighteen patients (41%) received AEDs plus ACTH therapy. Complete disappearance of the ESES pattern on the EEG was observed in 18 patients (41%), more than 50% reduction was observed in five patients (11%), less than 50% reduction was observed in eight patients (18%), and no response was observed in five patients (11%). No significant difference was found when comparing the groups in terms of reduction of seizures and the SWI. Seizure outcome at the two-year follow-up was similar between the group with ESES treated with AEDs plus ACTH and the group with ESES treated with AEDs without ACTH therapy.SignificanceThis study demonstrated that the rate of the SWI (typical vs. atypical ESES) and the maximum amplitude of the ESES pattern (anterior vs. posterior) have no significant correlation with seizure control and reduction of the SWI on the EEG in children with ESES syndrome.     

The spectrum of neuropsychiatric abnormalities associated with electrical status epilepticus in sleep

Electrical status epilepticus in sleep (ESES) is an electrographic pattern consisting of an almost continuous presence of spike-wave discharges in slow wave sleep. ESES is frequently encountered in pediatric syndromes associated with epilepsy or cognitive and language dysfunction. It can be present in various evolutionary stages of a spectrum of diseases, the prototypes of which are the 'continuous spikes and waves during slow wave sleep' syndrome (CSWS), the Landau-Kleffner syndrome (LKS), as well as in patients initially presenting as benign childhood epilepsy with centrotemporal spikes (BECTS). The purpose of this article is to review the literature data on the semiology, electrographic findings, prognosis, therapeutic options, as well as the current theories on the pathophysiology of these disorders. The frequent overlap of CSWS, LKS, and BECTS urges an increased level of awareness for the occasional transition from benign conditions such as BECTS to more devastating syndromes such as LKS and CSWS. Identification of atypical signs and symptoms, such as high discharge rates, prolonged duration of ESES, neuropsychiatric and cognitive dysfunction, lack of responsiveness to medications, and pre-existing neurologic conditions is of paramount importance in order to initiate the appropriate diagnostic measures. Prolonged and if needed repetitive sleep electroencephalographs (EEGs) are warranted for proper diagnosis.     

Sulthiame add-on therapy in children with focal epilepsies associated with encephalopathy related to electrical status epilepticus during slow sleep (ESES)

Purpose: In children with symptomatic or idiopathic focal epilepsies, their disease may evolve into an epileptic encephalopathy related to continuous spike and wave during slow sleep (CSWS) or electrical status epilepticus during slow sleep (ESES). ESES syndrome implies serious risks of neuropsychologic impairment, and its treatment has frequently been disappointing. The aim of this study is to present our experience using sulthiame as add‐on treatment in 53 patients with ESES syndrome that was refractory to other antiepileptic drugs (AEDs). Methods: Neurologic examinations, cerebral magnetic resonance imaging (MRI), and repeated prolonged sleep electroencephalography (EEG) studies were performed in all cases. Data about school achievements and or neuropsychological evaluations were obtained repeatedly during the follow‐up of 1.5–16 years. Sulthiame was added in doses ranging between 5 and 30 mg/kg/day. Key Findings: Since add‐on of sulthiame, 10 of 28 patients in the symptomatic group became seizure free: 4 patients with normal EEG studies and 6 with residual spikes. Nine of 28 patients showed a significant reduction in number of seizures and presented spikes but no ESES on EEG. The other nine cases showed neither clinical nor EEG improvement. A striking result was that 3 of 11 children with unilateral polymicrogyria and ESES syndrome became seizure free, and in another six a significant improvement in frequency of seizures and in EEG abnormalities seemed to be related to the add‐on of sulthiame. Twenty‐one of the 25 patients in the idiopathic group became seizure free and without ESES in <3 months after add on of sulthiame. In two of the patients the changes were seen in a few days. Significance: We understand that sulthiame may be effective as add‐on treatment in children with ESES syndrome.     

A review of the relationships between Landau-Kleffner syndrome, electrical status epilepticus during sleep, and continuous spike-waves during sleep

The goal of this report is to review the relationships between Landau-Kleffner syndrome (LKS), electrical status epilepticus during sleep (ESES), and continuous spike-waves during sleep (CSWS). LKS is a clinical syndrome involving mainly acquired aphasia and sometimes seizures. Other clinical findings include cognitive impairments and global regression of behavior. The EEG may evolve from more benign conditions into ESES (or CSWS), seen in 50% of patients with LKS, or may also show focal findings. Seizures include atypical absence, generalized tonic-clonic, atonic, and partial motor attacks. Effective medications are discussed. The EEG patterns CSWS and ESES are likely equivalent terms. CSWS is used by some authors, and ESES by others. Patients with these patterns usually show mental retardation, seizures, and global regression. More benign EEG patterns, like focal discharges, may develop into these more severe generalized patterns, which are associated with atypical absences, negative myoclonus, and cognitive disturbances. Memory disorders are common, because the nearly continuous generalized discharges in sleep do not allow for the memory consolidation that also occurs during sleep. Medications and possible etiologies are discussed.     

Long-term outcome after cognitive and behavioral regression in nonlesional epilepsy with continuous spike-waves during slow-wave sleep

Purpose: To present the long‐term follow‐up of 10 adolescents and young adults with documented cognitive and behavioral regression as children due to nonlesional focal, mainly frontal, epilepsy with continuous spike‐waves during slow wave sleep (CSWS). Methods: Past medical and electroencephalography (EEG) data were reviewed and neuropsychological tests exploring main cognitive functions were administered. Key Findings: After a mean duration of follow‐up of 15.6 years (range, 8–23 years), none of the 10 patients had recovered fully, but four regained borderline to normal intelligence and were almost independent. Patients with prolonged global intellectual regression had the worst outcome, whereas those with more specific and short‐lived deficits recovered best. The marked behavioral disorders resolved in all but one patient. Executive functions were neither severely nor homogenously affected. Three patients with a frontal syndrome during the active phase (AP) disclosed only mild residual executive and social cognition deficits. The main cognitive gains occurred shortly after the AP, but qualitative improvements continued to occur. Long‐term outcome correlated best with duration of CSWS. Significance: Our findings emphasize that cognitive recovery after cessation of CSWS depends on the severity and duration of the initial regression. None of our patients had major executive and social cognition deficits with preserved intelligence, as reported in adults with early destructive lesions of the frontal lobes. Early recognition of epilepsy with CSWS and rapid introduction of effective therapy are crucial for a best possible outcome.     

Cognitive deterioration and electrical status epilepticus during slow sleep

The results of long-term follow-up of 10 children with global or specific cognitive deterioration and, on the electroencephalogram, electrical status epilepticus during sleep (ESES) are described. They were referred because of cognitive deterioration and underwent repeated neurological and neuropsychological examinations and all-night electroencephalography. A previous cognitive level was known or could be estimated in all. Seven children had a continuous spikes and waves during sleep (CSWS) syndrome, with global cognitive deterioration in four and more specific cognitive decline in three, and another three children had Landau-Kleffner syndrome (LKS). Of the last three, two children never had seizures, while the other had localization-related epilepsy. No children experienced aggravation of clinical seizures. However, therapy was disappointing. Cognitive dysfunction did not respond to valproate and/or benzodiazepines in 9 of the 10 children. A frontal epileptic focus was found in 5 of 7 children with CSWS, and a left temporal focus in 2 of 3 children with LKS. The ESES persisted in CSWS for 5-9 years and in LKS for 1-5 years, and disappeared at puberty. Good cognitive recovery after disappearance of ESES occurred in only one child, and partial recovery in four. An unfavorable prognosis of cognitive deterioration seems to be related to long-duration ESES and/or early onset epileptic activity. The authors are of the opinion that cognitive deterioration in children, with or without manifest epileptic seizures, should mandate electroencephalographic investigation during sleep.     

Encephalopathy related to Status Epilepticus during slow Sleep: a link with sleep homeostasis?

Encephalopathy related to Status Epilepticus during slow Sleep (ESES) is a childhood epilepsy syndrome characterized by appearance of cognitive and behavioural disturbances in conjunction with a striking activation of EEG epileptic abnormalities during sleep. The link between the extreme amount of epileptic discharges during sleep and the deterioration of cognitive functions and behavior is poorly understood. We hypothesize that the negative effects of ESES may depend on the impairment of the synaptic homeostasis processes occurring during normal sleep and that are particularly important in the developmental age. Sleep ensures synaptic homeostasis by promoting synaptic weakening/elimination after the increase of synaptic strength that occurs during wakefulness. Changes in synaptic strength are reflected in the EEG by changes of sleep slow wave activity (SWA). Recent studies in ESES have failed to show changes of sleep SWA, particularly at the site of the epileptic focus, suggesting a spike‐related impairment of the homeostatic recovery of sleep. This impaired synaptic homeostasis in the critical period of development may alter cortical wiring and thereby disrupt, often irreversibly, cognitive functions and behavior, leading to the neuropsychological compromise typical of ESES.     

Ketogenic diet in the treatment of refractory continuous spikes and waves during slow sleep

Purpose: To evaluate the effect of the ketogenic diet on electroclinical characteristics and cognitive function in children with continuous spikes and waves during slow sleep (CSWS). Methods: Five children (four boys, one girl) aged between 8 and 13 years with CSWS refractory to conventional antiepileptic drugs (AEDs), including levetiracetam, and steroids were included. The prospective electroclinical assessment was performed prior to the ketogenic diet and once every 6 months post initiation during the 2‐year period. All children underwent neuropsychological testing prior to the ketogenic diet and four of the children again 12 months after the diet’s introduction. In case 4 the testing has been performed after 7 months and the diet was withdrawn after 9 months because of the lack of efficacy and the parent’s wishes. In two patients the cognitive functions were also evaluated after 24 months since the diet’s initiation. During the period on the ketogenic diet the concomitant AED treatment was unchanged. Results: Electrographic evaluation after 24 months on the ketogenic diet showed CSWS resolution in one patient, mild decrease of the spike–wave index in one, and lack of response in three patients. The ketogenic diet did not influence the neuropsychological outcome, and intelligence quotient (IQ) scores remained low at the end of the follow‐up period. However, in two patients an improvement in attention and behavior was demonstrated. Discussion: This is the first study evaluating the efficacy of the ketogenic diet in children with CSWS. Five presented cases were refractory to AEDs and steroids. Only one case responded with complete CSWS disappearance; in one the effect of the ketogenic diet was partial and intermittent, whereas in three patients no response has been observed. These results show that the ketogenic diet did not appear to influence the neuropsychological outcome; however, the absence of a control group makes it impossible to conclude with certainty.     

Encephalopathy related to status epilepticus during slow sleep (ESES) as atypical evolution of Panayiotopoulos syndrome: an EEG and neuropsychological study

Aim: We report two patients with Panayiotopoulos syndrome (PS) who developed encephalopathy related to status epilepticus during slow sleep (ESES) at the peak of their clinical course. Methods: Clinical charts and EEG data were reviewed. Results: The patients exhibited nocturnal autonomic seizures and occipital EEG foci, the latter of which later evolved into multifocal EEG foci with synchronous frontopolar and occipital spikes (Fp‐O EEG foci), and finally into continuous spikes‐waves during sleep (CSWS; spike‐wave index >85% based on whole‐night sleep recording) at eight years and seven years of age, respectively. The occipital spikes always preceded frontopolar spikes by 30～50 mseconds based on the analysis of CSWS. Neuropsychological ability, including IQ, deteriorated during the CSWS period in both patients. The autonomic seizures and focal to bilateral tonic‐clonic seizures were initially resistant to antiepileptic drugs (AEDs), and occurred more than 10 times in both patients. However, the seizures and EEG findings gradually resolved, and AEDs were successfully terminated in both patients. Conclusion: PS can progress to ESES if the clinical course exhibits atypical evolution. The initial autonomic symptom of the seizures and interictal Fp‐O EEG foci should be carefully monitored in patients with CSWS or ESES.     

Epilepsy with Electrical Status Epilepticus During Slow Sleep and Secondary Bilateral Synchrony

Summary: In 3 children with "epilepsy with electrical status epilepticus during slow sleep" (ESES), we estimated interhemispheric small time differences (TDs) during spike-wave activity in EEG by coherence and phase analysis by the two-dimensional autoregressive model to differentiate their continuous diffuse spike-waves during slow-wave sleep (CSWS) between primary bilateral synchrony and secondary bilateral synchrony (SBS). Maximal TDs at onset of apparently bilateral synchronous spike-wave bursts (BSSWs) during slow-wave sleep were 12·0–26·5 ms (mean 20·3 ms) with consistent leading hemispheres in eight bursts of the 3 patients, indicating SBS as pathophysiology of their CSWS. This suggestion was supported by their clinico-EEG findings, including the effect of a single oral dose of clobazam (CLB) on EEG. Three ictal BSSWs of atypical absence seizures in 2 patients were also analyzed to obtain maximal TDs of 17·9–41·7 ms (mean 26·3 ms) at onset, with the same leading sides as in sleep, also indicating SBS. Examination of intraburst TD variations showed no consistent disappearance of TDs during the latter part of the bursts, in either sleep or the ictal EEGs of atypical absences, and a role of the corpus callosum was suggested in the generation of SBS in ESES.     

Treatment with flunitrazepam of continuous spikes and waves during slow wave sleep (CSWS) in children.

We describe our treatment of two boys with continuous spikes and waves during slow wave sleep (CSWS). One of the boys was suffering from non-convulsive status epilepticus and the other from conscious disturbance with automatism. Their ictal EEG readings showed continuous diffuse spike and wave complexes, which were considered to show electrical status. The boys were diagnosed as having CSWS, and were later diagnosed with Landau-Kleffner syndrome (LKS). EEG readings returned to normal on intravenous injection of flunitazepam (FZP) at a dose of 0.02 mg/kg, suggesting that FZP is an effective treatment for CSWS.     

Epileptic encephalopathies of the Landau-Kleffner and continuous spike and waves during slow-wave sleep types: Genomic dissection makes the link with autism

Purpose: The continuous spike and waves during slow‐wave sleep syndrome (CSWSS) and the Landau‐Kleffner (LKS) syndrome are two rare epileptic encephalopathies sharing common clinical features including seizures and regression. Both CSWSS and LKS can be associated with the electroencephalography pattern of electrical status epilepticus during slow‐wave sleep and are part of a clinical continuum that at its benign end also includes rolandic epilepsy (RE) with centrotemporal spikes. The CSWSS and LKS patients can also have behavioral manifestations that overlap the spectrum of autism disorders (ASD). An impairment of brain development and/or maturation with complex interplay between genetic predisposition and nongenetic factors has been suspected. A role for autoimmunity has been proposed but the pathophysiology of CSWSS and of LKS remains uncharacterized. Methods: In recent years, the participation of rare genomic alterations in the susceptibility to epileptic and autistic disorders has been demonstrated. The involvement of copy number variations (CNVs) in 61 CSWSS and LKS patients was questioned using comparative genomic hybridization assays coupled with validation by quantitative polymerase chain reaction (PCR). Key Findings: Whereas the patients showed highly heterogeneous in genomic architecture, several potentially pathogenic alterations were detected. A large number of these corresponded to genomic regions or genes (ATP13A4, CDH9, CDH13, CNTNAP2, CTNNA3, DIAPH3, GRIN2A, MDGA2, SHANK3) that have been either associated with ASD for most of them, or involved in speech or language impairment, or in RE. Particularly, CNVs encoding cell adhesion proteins (cadherins, protocadherins, contactins, catenins) were detected with high frequency (≈20% of the patients) and significant enrichment (cell adhesion: p = 0.027; cell adhesion molecule binding: p = 9.27 × 10^?7). Significance: Overall our data bring the first insights into the possible molecular pathophysiology of CSWSS and LKS. The overrepresentation of cell adhesion genes and the strong overlap with the genetic, genomic and molecular ASD networks, provide an exciting and unifying view on the clinical links among CSWSS, LKS, and ASD.     

Interictal epileptiform discharges in sleep and the role of the thalamus in Encephalopathy related to Status Epilepticus during slow Sleep

EEG activation of interictal epileptiform discharges (IEDs) during NREM sleep is a well‐described phenomenon that occurs in the majority of epileptic syndromes. In drug‐resistant focal epilepsy, IED activation seems to be related to slow wave activity (SWA), especially during arousal fluctuations, namely phase A of the cyclic alternating pattern (CAP). Conversely, in childhood focal epileptic syndromes, including Encephalopathy related to Status Epilepticus during slow Sleep (ESES), IED activation seems primarily modulated by sleep‐inducing and maintaining mechanisms as reflected by the dynamics of spindle frequency activity (SFA) rather than SWA. In this article, we will review the effect of sleep on IEDs with a particular attention on the activation and modulation of IEDs in ESES. Finally, we will discuss the role of the thalamus and cortico‐thalamic circuitry in this syndrome.