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.     

Encephalopathy with status epilepticus during slow sleep: "The Penelope syndrome"

ESES (encephalopathy with status epilepticus during sleep) is an epileptic encephalopathy with heterogeneous clinical manifestations (cognitive, motor, and behavioral disturbances in different associations, and various seizure types) related to a peculiar electroencephalography (EEG) pattern characterized by paroxysmal activity significantly activated during slow sleep—that is, a condition of continuous spikes and waves, or status epilepticus, during sleep. The pathophysiologic mechanisms underlying this condition are still incompletely understood; recent data suggest that the abnormal epileptic EEG activity occurring during sleep might cause the typical clinical symptoms by interfering with sleep-related physiologic functions, and possibly neuroplasticity processes mediating higher cortical functions such as learning and memory consolidation. As in the myth of Penelope, the wife of Odysseus, what is weaved during the day will be unraveled during the night.     

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.     

Spatial and temporal dynamics of epileptic activity at sleep onset in the Encephalopathy with Status Epilepticus during slow sleep (ESES) after unilateral thalamic lesions

ObjectiveEncephalopathy with Status Epilepticus during slow Sleep (ESES) is a syndrome where neurocognitive impairment correlates with multifocal Electroencephalography (EEG) spikes increasing abruptly at sleep onset. Demonstration of a focal onset could provide important clues to unravel the mechanisms underlying the condition, but until know it has not been established.MethodsWe studied epileptic dynamics at sleep onset to assess its focal or diffuse features in five patients with perinatal thalamic hemorrhages lateralized to one hemisphere, using high resolution EEG.ResultsDynamical functional connectivity revealed the information flow in the epileptic network and identified primary sources of outflow, equated with cortical spike sources. We found that spikes with important activation originate in restricted cortical areas of the hemisphere with the lesion, spreading widely and quickly at onset of N2 sleep stage.ConclusionsPerinatal thalamic lesions have the potential to induce, years later, a regional onset of epileptic activity with features of ESES in a cortex without apparent structural lesion. Most widespread spike activity in the scalp results from secondary propagation.SignificancePerinatal thalamic lesions produce ESES with focal onset in a restricted cortical area of the hemisphere with the lesion, and prominent secondary propagation.     

Automated quantification of spike-wave activity may be used to predict the development of electrical status epilepticus in sleep (ESES) in children with perinatal stroke

ObjectiveContinuous spike and wave in slow-wave sleep (CSWS), an epileptic encephalopathy, occurs after perinatal stroke where it is associated with cognitive decline. CSWS features a distinct EEG pattern, electrical status epilepticus in sleep (ESES). Biomarkers for the prediction of ESES have not been identified but will facilitate earlier diagnosis and treatment. We hypothesized that spike-frequency and differences in power spectra would be predictive of subsequent ESES.MethodsA cross-sectional study comparing EEG spike-frequency and Power before the development of ESES in patients with perinatal stroke, patients with focal epilepsy, and appropriate controls.Results43 patients met the inclusion criteria; 11 stroke-ESES, 10 stroke controls, 14 epilepsy-ESES, 8 epilepsy controls. ESES patients had higher pre-diagnosis mean spike-frequency (24.0 ± 24 versus 6.6 ± 9.1 SW/min, p = 0.002) than patients that did not develop ESES; these differences present ~ 3 years before ESES diagnosis. Pre-diagnosis, normalized delta power (1–4 Hz) was higher in the stroke-ESES group (105.7 ± 58 dB/Hz) compared to stroke controls (57.4 ± 45 dB/Hz, p = 0.036).ConclusionSpike-frequency and delta power may represent EEG biomarkers of the risk of developing ESES in children with perinatal stroke.SignificanceEEG biomarkers may be used by clinicians to assess which patients are more at-risk for ESES.Using spike-frequency, clinicians may be able to identify patients at risk of developing ESES.     

Encephalopathy with hemi-status epilepticus during sleep or hemi-continuous spikes and waves during slow sleep syndrome: A study of 21 patients

PurposeTo retrospectively analyze the electroclinical features, etiology, treatment, and prognosis of 21 patients with encephalopathy with hemi-status epilepticus during sleep (ESES) or hemi-continuous spikes and waves during slow sleep (CSWSS) syndrome.MethodsCharts of 21 patients with hemi-ESES/CSWSS syndrome followed between 1997 and 2012 were analyzed. Inclusion criteria were: (1) Focal seizures or apparently generalized seizures and focal EEG epileptiform discharges; (2) Further occurrence of atypical absences, and myoclonic, atonic, and/or generalized seizures; (3) Cognitive impairment and/or behavioral disturbances; (4) Hemi-continuous spike-and-wave discharges during slow sleep in more than 85% of non-REM sleep at onset and throughout the ESES/CSWSS period.ResultsMean follow-up from onset of hemi-ESES/CSWSS was 8 years (range, 2–15 years). Idiopathic cases were not identified. Unilateral polymicrogyria was found in 11, shunted hydrocephalus in four, a porencephalic cyst associated with polymicrogyria in three, and a thalamic lesion in three children. All started with focal seizures with or without secondary generalization. During the hemi-ESES/CSWSS period, all children developed new types of seizure, such as negative and positive myoclonus, absences, motor deterioration, cognitive impairment, and behavioral disturbances. All AED responders returned to baseline cognitive development. Seven patients were refractory to AEDs.ConclusionOur study suggests that the hemi-ESES/CSWSS syndrome has electroclinical features compatible with an epileptic encephalopathy. The most commonly used treatments were clobazam, ethosuximide, and sulthiame, alone or in combination. In refractory cases, high-dose corticosteroids were administered. Although the number of patients in this study is too low to draw definite conclusions, we consider that in children with hemi-ESES/CSWSS secondary to a unilateral lesion, surgery should be considered.     

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.     

The contribution of the EEG technologists in the diagnosis of Panayiotopoulos syndrome (susceptibility to early onset benign childhood autonomic seizures)

PURPOSE: To assess the contribution of the EEG technologists in the diagnosis of children with epileptic seizures. METHODS: We analysed the clinical information obtained by the EEG technologists from children with epileptic seizures and their parents, and assessed its value for the generation of a clinically useful EEG report and a plausible electroclinical diagnosis. Interviews were based on a qualitative questionnaire, and were videotaped. We focused on Panayiotopoulos syndrome (PS) because it has a high rate of misdiagnosis, usually for encephalitis or other severe cerebral insults. RESULTS: Between 1998 and 2001, 424 EEG were performed in 308 children aged 1-14 years, of whom 228 (74%) had one or more epileptic seizures. We diagnosed PS in 14 children (6.1%), mainly based on clinical information. Three other had symptomatic ictal vomiting. In 9 of the 14 children with PS, diagnosis was achieved by the information collected by the EEG technologist. Five of these children were being treated for encephalitis, and management was altered accordingly. In a further three children the diagnosis of PS was confirmed. CONCLUSION: These findings demonstrate that the contribution of the EEG technologists to the diagnosis of people with epilepsies can expand well beyond their established role of recording and describing an EEG. We propose that technologists should be actively involved in prospective electroclinical studies if carefully designed protocols are used.     

Panayiotopoulos syndrome and symptomatic occipital lobe epilepsy of childhood: a clinical and EEG study

Aim. Panayiotopoulos syndrome (PS) is an age‐related seizure susceptibility syndrome that affects the central autonomic system. Although the majority of the few ictal recordings obtained so far suggest an occipital origin, semiological and interictal EEG data appear to favour more extensive involvement. In this study, the characteristics (including those based on semiology and EEG) of children with Panayiotopoulos syndrome (n=24) and those with lesion‐related, symptomatic occipital lobe epilepsy (SOLE) (n=23) were compared. Methods. Detailed semiological information and EEG parameters including the localisation, distribution, density (n/sec), reactivity, and morphological characteristics of spike‐wave foci and their relationship with different states of vigilance were compared between the two groups. Results. The age at seizure onset was significantly younger in patients with symptomatic occipital lobe epilepsy than in those with PS (mean age at onset: 3.4 versus 5.6 years, respectively; p=0.044). Autonomic seizures (p=0.001) and ictal syncope (p=0.055) were more frequent in PS than in symptomatic occipital lobe epilepsy (87.5% and 37.5% versus 43.5% and 13%, respectively). The interictal spike‐wave activity increased significantly during non‐rapid eye movement (non‐REM) sleep in both groups. The spike waves in non‐REM seen in PS tended to spread mainly to central and centro‐temporal regions. Conclusions. The results indicate that although common features do exist, Panayiotopoulos syndrome differs from symptomatic occipital lobe epilepsy and has a unique low epileptogenic threshold related to particular brain circuits.     

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.     

Expanding the clinical and EEG spectrum of CNKSR2-related encephalopathy with status epilepticus during slow sleep (ESES)

ObjectiveTo investigate the clinical and EEG features of Encephalopathy with Status Epilepticus during slow Sleep (ESES) related to CNKSR2 pathogenic variants.MethodsDetailed clinical history, repeated wakefulness/overnight sleep EEGs, brain MRI were collected in five patients, including one female, with CNKSR2-related ESES.ResultsNeurodevelopment in infancy was normal in two patients, delayed in three. Epilepsy onset (age range: 2–6 years) was associated with appearance or aggravation of cognitive impairment, language regression and/or behavioral disorders. Worsening of epilepsy and of cognitive/behavioral disturbances paralleled by enhancement of non-rapid eye movement (NREM) sleep-related, frontally predominant, EEG epileptic discharges [spike-wave-index (SWI): range 60–96%] was consistent with ESES. In three patients, episodes of absence status epilepticus or aggravation of atypical absences occurred, in this latter case associated with striking increment of awake SWI. Speech/oro-motor dyspraxia was diagnosed in four patients. In two patients, long-term follow-up showed epilepsy remission and persistence of mild/moderate cognitive disorders and behavioral disturbances into adulthood.ConclusionsNovel findings of our study are occurrence also in females, normal neurodevelopment before epilepsy onset, epilepsy aggravation associated with enhanced awake SWI, mild/moderate evolution in adulthood and language disorder due to speech/oro-motor dyspraxia.SignificanceOur findings expand the phenotypic spectrum of CNKSR2-related ESES.     

Surgical management of pediatric patients with encephalopathy due to electrical status epilepticus during sleep (ESES)

Aims: ESES is a developmental epileptic disorder directly responsible for progressive encephalopathy and neurocognitive regression. The natural history, indications for surgical intervention, and predictors for favorable seizure and neuropsychological outcome remain unclear. Methods: We performed a retrospective review of children who underwent resective or disconnective surgery for ESES between January 2009 and July 2016 at a large tertiary pediatric center. Information on the patients’ demographics, seizure semiology, radiographic and electrographic findings, and surgical management was collected. The primary outcome was seizure freedom at last follow‐up visit, and secondary outcomes were neuropsychological improvement and electrographic ESES resolution. Results: We identified 11 children who underwent surgery for ESES. The mean ages were 3.2 years for seizure onset, 7.1 years for formal ESES diagnosis, and 9.4 years for surgery. Seizure etiologies included cortical malformations (four patients), encephalomalacia and gliosis from prior hemorrhage or tumor resections (three patients), developmental porencephaly (one patient), and Rasmussen's encephalitis (one patient); the etiology was unknown in two children. Preoperatively, nine children had motor deficits, seven had speech and language delay, and three had visual field defects. All children had seizures and neuropsychological regression prior to surgical consideration. Focal cortical resections were performed in seven children, and hemispherectomies in four. Post‐operatively, nine children experienced decreased seizure frequency, eight had neuropsychological improvement, and nine had resolution of electrographic ESES. Patients with poor surgical outcomes had more significant pre‐operative comorbidities, in addition to bilateral ESES activity. Conclusion: In this case series, surgery for a carefully selected group of children with ESES is safe and feasible, yielding rates of seizure freedom and neuropsychological improvement that compare favorably with previous reports for antiepileptic drugs, benzodiazepines, and steroids. As we gain greater understanding into the management of ESES, surgery is an increasingly useful tool for patients with mild or moderate neurodevelopmental delay, focal epileptogenic foci, and hemi‐ESES electrographic findings.     

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.     

Panayiotopoulos syndrome and diffuse paroxysms as the first EEG manifestation at clinical onset: a study of nine patients

Aim. To present a retrospective study of nine children with Panayiotopoulos syndrome associated with diffuse spikes and waves as the sole EEG manifestation at onset. Methods. Charts of children with typical clinical criteria of Panayiotopoulos syndrome, electroclinically followed between February 2000 and February 2012, were reviewed. Results. Among 150 patients who met the electroclinical criteria of Panayiotopoulos syndrome, we identified nine children who presented with the typical clinical manifestations but who, on EEG, only had diffuse paroxysms at onset that continued along the course of the syndrome. In three, in addition to the diffuse paroxysms, focal spikes appeared later. From a clinical point of view, other features were otherwise unremarkable. Diffuse spike‐and‐wave discharges were observed in all patients when awake and during sleep (100%). Later, three children also had focal spikes during sleep, which were occipital in one, frontal in one, and temporo‐occipital in the remaining patient. Spikes were activated by sleep in all three cases. During disease evolution, no particular electroclinical pattern was observed. Two patients who received clobazam and carbamazepine, respectively, did not respond well to the drugs and valproic acid was added with excellent seizure control. Outcome was good. Conclusions. We present evidence that patients with Panayiotopoulos syndrome may have diffuse discharges at onset as the sole EEG manifestation, which last throughout the course of the syndrome. In some, focal paroxysms developed later. The course was benign. In our group of patients, clinical features and evolution were similar to those of typical cases of Panayiotopoulos syndrome.     

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.     

RFT1‐congenital disorder of glycosylation (CDG) syndrome: a cause of early‐onset severe epilepsy

RFT1‐congenital disorder of glycosylation (CDG) syndrome, a recessive N‐glycosylation disorder caused by mutation in the RFT1 gene, is a very rare subtype of CDG syndrome associated with deafness, developmental delay, and non‐specific epilepsy. The aim of this report is to describe the electroclinical presentation of epilepsy associated with this condition. [Published with video sequences online]