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.     

Encephalopathy related to Status Epilepticus during slow Sleep: from concepts to terminology

Five pediatric and adult neurologists with clinical and research interests in Encephalopathy related to Status Epilepticus during slow Sleep (ESES) express their opinions on definition, diagnostic assessment and terminology that may be considered for this condition. The aim of this “debate” is to identify aspects in which there is a shared opinion and areas where there are still controversies in the classification and suggest areas which demand further studies and research.     

EEG features in Encephalopathy related to Status Epilepticus during slow Sleep

Encephalopathy related to Status Epilepticus during slow Sleep (ESES) is a peculiar electro‐clinical condition, with variable etiologies, characterized by an age‐dependent phenomenon of extreme activation of epileptic activity during sleep, i.e. “status epilepticus during sleep”, that is strictly associated with the appearance of cognitive and behavioral disturbances. Even though the peculiar EEG picture is fundamental for the diagnosis of ESES, clear‐cut and shared diagnostic criteria for defining the EEG boundaries of this syndrome are still lacking. The diagnosis of ESES can be further complicated by the variability of the EEG findings, that during the course of the disease can change from diffuse to more or less focal and viceversa, depending both on the spontaneous clinical evolution of this condition and/or on the effects of medications. Given the complexity and the heterogeneity of EEG parameters during the ESES course, it is important to correlate the EEG findings with the concomitant cognitive and behavioral status, possibly taking into account not only the spike‐wave index, but also other parameters, such as for instance the topography of the epileptic abnormalities, their patterns of spread, and their fluctuations over time. Moreover, the epileptiform activity not only during sleep, but also during wakefulness, the presence of focal slowing, the organization of the EEG background and a derangement of the sleep architecture may play a role in determining the clinical picture.     

Medical Management With Diazepam for Electrical Status Epilepticus During Slow Wave Sleep in Children

ObjectiveOral diazepam, administered in varying doses, is among the few proposed treatment options for electrical status epilepticus during slow wave sleep in children. We sought to retrospectively evaluate the long-term efficacy of high-dose oral diazepam in reducing electrographic and clinical evidence of electrical status epilepticus during slow wave sleep in children. Additionally, we surveyed caregivers to assess safety and behavioral outcomes related to ongoing therapy.MethodsWe collected demographic and clinical data on children treated for electrical status epilepticus during slow wave sleep between October 2010 and March 2013. We sought to identify the number of patients who achieved at least a 50% reduction in spike wave index on electroencephalograph after receiving high-dose oral diazepam. We also administered a questionnaire to caregivers to assess for behavioral problems and side effects.ResultsWe identified 42 evaluable patients who received high-dose diazepam (range 0.23-2.02 mg/kg per day) to treat electrical status epilepticus during slow wave sleep. Twenty-six patients had spike reduction data and 18/26 (69.2%) children achieved a greater than 50% reduction in spike wave count from an average of 15.54 to 5.05 (P = 0.001). We received 28 responses to the questionnaire. Some patients experienced new onset of difficulties with problem-solving and speech and writing development. Sleep disturbances (50%) and irritability (57.1%) were the most frequent side effects reported. There did not appear to be a dose-related effect with electroencephalograph changes, behavioral effects, or side effects.ConclusionsHigh-dose oral diazepam significantly reduces the spike wave count on electroencephalograph in children with electrical status epilepticus during slow wave sleep. Although this therapy improves electroencephalograph-related findings, it can be associated with concerning neurological and behavioral side effects in some individuals, so further study is warranted.     

Current treatment options for Encephalopathy related to Status Epilepticus during slow Sleep

The major goal of therapy in patients with Encephalopathy related to Status Epilepticus during slow Sleep (ESES) is to prevent or reduce associated cognitive deficits. Whether or not the EEG pattern of ESES should be completely suppressed to improve cognition is unknown. In clinical practice, there are two major challenges: to establish the optimal treatment strategy in patients with ESES, and to identify the patients who will benefit most from therapy, including atypical cases. Here, we provide a comprehensive overview of the current literature on treatment efficacy in patients with ESES.     

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.     

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

BackgroundEpileptic encephalopathy with electrical status epilepticus during sleep is an age-related and self-limited disorder. The present study analyzed the etiology, demographics, and pathogenesis of patients with electrical status epilepticus during sleep to provide information on the diagnosis and therapy of this syndrome.MethodsThe etiologies of epileptic encephalopathy with electrical status epilepticus during sleep in patients admitted in Chinese People's Liberation Army General Hospital from 2009 to 2014 were retrospectively analyzed. Patients were classified into the genetic, structural-metabolic, and unknown groups according to the etiology. Demographics and clinical characteristics of all the patients were then analyzed and compared among groups.ResultsThe etiologies of epileptic encephalopathy with electrical status epilepticus during sleep 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 of epileptic encephalopathy with electrical status epilepticus during sleep was concentrated at age 6-9 years. The mean age at onset of epilepsy in the genetic group was significantly older than that in the structural-metabolic group (P < 0.05). Age at onset of epileptic encephalopathy with electrical status epilepticus during sleep did not significantly differ between the two groups.ConclusionsElectrical status epilepticus during sleep is an epileptic encephalopathy related to brain development and presents an age-dependent occurrence.     

Cognitive impairment and behavioral disorders in Encephalopathy related to Status Epilepticus during slow Sleep: diagnostic assessment and outcome

Encephalopathy related to Status Epilepticus during slow Sleep (ESES) is an age‐dependent phenomenon, with usual spontaneous resolution during teenage years. However, cognitive outcome is often more disappointing, with permanent cognitive deficits in the large majority of children seen in later life. Presuming this to be an epileptic encephalopathy, current treatment practices are almost exclusively guided by the effect of the AEDs used on the degree of EEG abnormality in sleep. However, the major goal of therapy in ESES syndrome should in fact be to prevent or reduce associated cognitive and neurodevelopmental deficits. Whether or not the EEG pattern of ESES should be completely suppressed to improve cognition is unknown. Discussions on both diagnostic assessment and outcome of cognitive impairment and behavioral disorders should systematically take into account the complexity of the disorder; not only in terms of the evolution or fluctuations of the EEG patterns but also in relation to the underlying etiologies (at least lesional versus non‐lesional) and age at diagnosis. We present a common basic assessment protocol, including the minimum technical requirements for polygraphic recording, and a treatment practice protocol that could both be applied in all centres dealing with this rare form of epilepsy. Such an approach would also allow a comprehensive collection of data prospectively, for a better understanding of the natural evolution of the disorder and an evidence‐based evaluation of our practices.     

Encephalopathy related to Status Epilepticus during slow Sleep: current concepts and future directions

We present some aspects relevant to the definition and diagnosis of Encephalopathy related to Status Epilepticus during slow Sleep (ESES) to further understand the pathophysiological mechanisms in the light of current knowledge and some recent research. Future lines of research in ESES that include investigation of impairment of sleep homeostasis and disruption of age‐related plasticity processes in the developmental age are also discussed.     

Efficacy of Levetiracetam in Electrical Status Epilepticus During Sleep of Children: A Multicenter Experience

BackgroundElectrical status epilepticus during sleep is characterized by epilepsy, a specific electroencephalographic pattern, and neuropsychological impairment. This study aims to evaluate the efficacy and safety of levetiracetam in treating children with electrical status epilepticus during sleep.MethodsA multicenter, retrospective, open-label study enrolled 73 children (mean age: 8 years) affected by electrical status epilepticus during sleep. The efficacy was rated according to the seizure frequency and electroencephalography response.ResultsAfter a mean treatment period of 19 months (range: 6 to 24 months), 33 (63.5%) of 52 patients became seizure-free or had experienced remarkable reduction in seizures. The electrical status epilepticus of 41 (56.2%) of 73 patients disappeared off their electroencephalography. The electroencephalography efficacy of levetiracetam treatment was noted in the monotherapy (61.9%) and add-on (53.9%) groups. The clinical (67.7%) and electroencephalography (64.3%) response rates of the idiopathic group were better than those of the symptomatic group (57.1% and 45.2%, respectively). No patient discontinued the trial because of intolerability of side effects.ConclusionsLevetiracetam is effective in individuals with electrical status epilepticus during sleep with tolerable side effects.     

Focal Status Epilepticus: Clinical Features and Significance of Different EEG Patterns

PURPOSE: Focal status epilepticus is typically diagnosed by the observation of continuous jerking motor activity, but many other manifestations have been described. EEG evidence of focal status may take several forms, and their interpretation is controversial. We detailed the clinical spectrum of focal status in patients diagnosed by both clinical deficit and EEG criteria and contrasted clinical manifestations in patients with different EEG patterns. METHODS: Patients were diagnosed with a neurologic deficit and discrete recurrent focal electrographic seizures or rapid, continuous focal epileptiform discharges on EEG. Clinical findings were determined by chart review. RESULTS: Of 41 patients with focal status, acute vascular disease was the cause in 21; 10 of 41 had exacerbations of prior epilepsy. A variety of clinical seizure types occurred, both before and after the EEG diagnosis, but the diagnosis was not expected in 28 patients before the EEG. Three had no obvious clinical seizures. Focal motor seizures and an abnormal mental status were the most common manifestations at the time of the EEG. With antiepileptic drugs, almost all had control of clinical seizures, and most improved in mental status. Patients with rapid continuous focal epileptiform discharges were nearly identical in presentation, likelihood of diagnosis, subsequent seizures, response to medication, and outcome to those with discrete seizures on EEG. CONCLUSIONS: Focal status epilepticus may be seen with a wide variety of clinical seizure types or without obvious clinical seizures. The diagnosis is often delayed or missed and should be considered after strokes or clinical seizures when patients do not stabilize or improve as expected. The diagnosis should be made equally whether patients have discrete electrographic seizures or continuous rapid focal epileptiform discharges on the EEG, and the same response to medications and outcome should be anticipated for the two groups.     

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.     

Pathophysiology of encephalopathy related to continuous spike and waves during sleep: the contribution of neuroimaging

In the last three decades, studies on functional neuroimaging have helped us to understand pathophysiological mechanisms responsible for electro‐clinical patterns associated with epileptic encephalopathies with continuous spikes and waves during slow sleep (ECSWS). MEG and EEG source reconstruction have revealed sources of pathological brain activity associated with epileptiform discharges in the perisylvian region pointing to the significance of this brain area for ECSWS. PET studies have revealed areas of focal hypermetabolism in perisylvian, superior temporal and inferior parietal regions as well as central cortices which were related to epileptic activity. The widespread hypometabolism in regions that belong to the default network (prefrontal and posterior cingulate cortices, parahippocampal gyrus and precuneus) was interpreted as remote inhibition following epileptic activity, which could contribute to cognitive deficits in affected individuals. Note that the described metabolic changes were functional and disappeared after successful treatment and recovery of ECSWS and were found in both sleep and wakefulness which may account for cognitive deficits in patients during the day. EEG‐fMRI studies have revealed a functional fingerprint of epileptic encephalopathy: significant positive BOLD signal changes were identified in the perisylvian regions, prefrontal cortex and anterior cingulate as well as thalamus and negative BOLD signal changes in the regions of the default mode network. The pattern of activation represents a propagation of epileptic activity specific to encephalopathy, which is independent of etiology and type of seizure associated with ECSWS. In summary, methods of neuroimaging have shed light on pathogenic mechanisms of ECSWS which may account for a number of clinical phenomena associated with this condition.     

A novel de novo TET3 loss-of-function variant in a Turkish boy presenting with neurodevelopmental delay and electrical status epilepticus during slow-wave sleep

BackgroundBeck-Fahrner syndrome is caused by homozygous or heterozygous mutations in TET3 on chromosome 2p13. The general characteristics of this syndrome include behavioral abnormalities such as autistic features, attention-deficit hyperactivity disorder, learning disabilities, and epilepsy.Case presentationSix years old male patient was found to have a de novo TET3 loss-of-function variant by whole-exome sequencing (WES) analysis and was diagnosed with electrical status epilepticus during slow-wave sleep (ESES) based on clinical and electroencephalogram (EEG) characteristics. The patient had a neurodevelopmental delay from the age of 3 months and started experiencing generalized tonic–clonic seizures and regression at the age of 5 years. EEG findings were consistent with ESES, and WES analysis revealed a novel heterozygous nonsense NM_001366022.1:c.1594C > T (p.Arg532*) variant in TET3. Valproic acid and immunotherapy were administered for the first 6 months, and clobazam was administered orally in addition to oral valproic acid therapy for the next 6 months. Clinical improvement was noted regardless of EEG improvement for the first 6 months. EEG improvement was achieved with clobazam. No regression was observed following the discontinuation of immunotherapy.ConclusionDecreased TET3 enzyme activity may be one of the new genetic etiologies of ESES.     

Measuring spike strength in patients with continuous spikes and waves during sleep: Comparison of methods for prospective use as a clinical index

ObjectiveTo compare methods of estimating spike strength as a potential index in the assessment of continuous spikes and waves during sleep (CSWS).MethodsSpikes were searched and averaged automatically from pre- and postoperative EEGs of ten patients with CSWS who underwent corpus callosotomy (eight) or resective epilepsy surgery (two). From the most prominent spike, we measured peak amplitude and root mean square (RMS) over ±150 ms window around the peak. In order to compensate for spatiotemporal instability of spikes, the cumulative amplitude and RMS were computed from the highest quartile of electrodes (Ampl-Q and RMS-Q, respectively). The stability of parameters was studied by comparing two ten minute epochs during the first hour of NREM sleep, as well as by analyzing overnight variation of indices in further ten patients with CSWS. The Ampl-Q and RMS-Q were compared between pre- and postoperative recordings.ResultsAll four measures, amplitude, RMS, Ampl-Q and RMS-Q, were correlated with each other and highly dependent on NREM/REM-sleep stage and arousals. Expectedly, Ampl-Q and RMS-Q had the greatest intra-individual stability. The amplitude had up to 71% intra-individual variation making it unhelpful for clinical use. Ampl-Q and RMS-Q were comparable in assessing change following surgical treatment.ConclusionsComputing an integrated RMS over multiple electrodes during steady NREM sleep offers a stable and reliable parameter for evaluating the strength of spikes in CSWS.SignificanceAnalyzing spike strength with RMS-Q may offer a clinically useful, supplementary index for EEG monitoring of CSWS where spike index has been of limited value.