Epilepsy and sleep: with special reference to nonconvulsive status epilepticus with continuous diffuse spike-waves during slow-wave sleep

There are numerous important problems concerning relationship between epilepsy and sleep. To clarify the clinical significance and pathophysiology of the nonconvulsive status epilepticus with continuous diffuse spike-waves during slow-wave sleep (CSWS) in EEG, this study was carried out on seven cases each of epilepsies with electrical status epilepticus during slow sleep (ESES) and with peculiar type of nonconvulsive status epilepticus in childhood (PNSE) and four cases of atypical benign partial epilepsy (ABPE). Mental deterioration was most frequently observed in ESES, less in PNSE but none in ABPE. In both ESES and PNSE, mentally deteriorated cases showed suppression of CSWS at significantly later ages than those without deterioration. And spike-wave indices during slow-wave sleep, which were the highest in ESES and lower in PNSE and ABPE, also had a strong relation to mental deterioration. In these three disorders, both clinical seizures and CSWS were suppressed at or before 16 years of age, although they were intractable before adolescence. This finding indicated age dependent evolutions of the three disorders. Coherence and phase analysis of CSWS was undertaken to differentiate primary and secondary bilateral synchrony in seven cases of these three disorders, which have both features of generalized and partial epilepsies. This analysis disclosed secondary bilateral synchrony as the nature of CSWS in six cases. And this analysis method was considered to provide a clue to their pathophysiology. Thus, in these disorders, importance of early diagnosis by EEG including deep sleep and early treatment was recognized.     

Primary and secondary bilateral synchrony in epilepsy: differentiation by estimation of interhemispheric small time differences during short spike-wave activity.

Estimation of interhemispheric small time differences (TDs) during spike-wave bursts in the EEG by coherence and phase analysis is useful for differentiation between primary bilateral synchrony (PBS) and secondary bilateral synchrony (SBS) in epilepsy. Because the previous method via Fast Fourier Transform needed long bursts for reliable analysis, a method using a 2-dimensional autoregressive model was newly developed to enable estimation of TDs even in 1.2 sec bursts, and applied to 19 epileptic patients with apparently bilaterally synchronous spike-wave bursts. At the onsets of bursts, estimated maximal TDs were 5.8 msec or less and inconsistent in leading hemispheres in 10 patients with a clinical diagnosis of idiopathic, cryptogenic or symptomatic generalized epilepsy indicating PBS, while the maximal TDs were 9.3-41.5 msec and consistent in leading in 7 patients with clinically symptomatic partial epilepsy and also in two with idiopathic and symptomatic generalized epilepsy suggesting SBS. Among 8 patients with bursts which suggested SBS and long enough for evaluation of intra-burst TD variation, TDs tended to disappear in the middle to end parts of the bursts in 5 cases, but not in the other 3, suggesting 2 different pathophysiological mechanisms in SBS.     

Primary and secondary bilateral synchrony in epilepsy: differentiation by estimation of interhemispheric small time differences during short spike-wave activity

Estimation of interhemispheric small time differences (TDs) during spike-wave bursts in the EEG by coherence and phase analysis is useful for differentiation between primary bilateral synchrony (PBS) and secondary bilateral synchrony (SBS) in epilepsy. Because the previous method via Fast Fourier Transform needed long bursts for reliable analysis, a method using a 2-dimensional autoregressive model was newly developed to enable estimation of TDs even in 1.2 sec bursts, and applied to 19 epileptic patients with apparently bilaterally synchronous spike-wave bursts.At the onsets of bursts, estimated maximal TDs were 5.8 msec or less and inconsistent in leading hemispheres in 10 patients with a clinical diagnosis of idiopathic, cryptogenic or symptomatic generalized epilepsy indicating PBS, while the maximal TDs were 9.3–41.5 msec and consistent in leading in 7 patients with clinically symptomatic partial epilepsy and also in two with idiopathic and symptomatic generalized epilepsy suggesting SBS.Among 8 patients with bursts which suggested SBS and long enough for evaluation of intra-burst TD variation, TDs tended to disappear in the middle to end parts of the bursts in 5 cases, but not in the other 3, suggesting 2 different pathophysiological mechanisms in SBS.     

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.     

Cognition and Paroxysmal EEG Activities: From a Single Spike to Electrical Status Epilepticus during Sleep

Summary:  Epileptic EEG paroxysms can interfere with cognitive processes producing transitory effects, such as those related to a single spike, as well as long-lasting effects, such as in electrical status epilepticus during slow-wave sleep (ESES). Focal spike-related disruption of cortical functions can produce transitory cognitive impairment, with neuroanatomical specificity between the site of the epileptic focus and the impaired cognitive tasks. ESES represents a model of the long-lasting effects of continuous spike-wave activity on higher cortical functions. The duration of ESES and the localization of interictal foci seem to play a major role in influencing the degree and type of cognitive dysfunction, suggesting that the ESES clinical picture results from a localized disruption of EEG activity caused by focal epileptic activity during sleep. Recently, Giulio Tononi's group reported that a local increase of slow-wave activity (SWA) during sleep after learning is associated with improved performance of the learned task after sleep (Huber et al., Nature 2004;430:78–81). On the basis of these findings, we can speculate that prolonged focal epileptic activity during sleep (as occurring in ESES) interferes with local SWA at the site of the epileptic focus, impairing the neural processes and, possibly, the local plastic changes associated with learning and other cognitive functions.     

Magnetoencephalographic Analysis of Secondary Bilateral Synchrony

To assess the clinical value of magnetoencephalography (MEG) in investigating the origin of secondary bilateral synchrony (SBS) in patients with partial epilepsy. MEG and simultaneous electroencephalography (EEG) were recorded with a 204-channel whole-head MEG system in 2 patients. The equivalent current dipoles (ECDs) for epileptic discharges on MEG were calculated according to a single dipole model. In patient 1, the ictal EEG showed bursts of bilateral synchronous 3-Hz spike-and-slow-wave complexes. ECDs obtained from the ictal MEG localized to the right medial frontal lobe. On the second patient's MEG recordings, epileptic discharges corresponding to prolonged EEG bursts of bilateral synchronous spike-and-slow-wave complexes were obtained. ECDs calculated from the prolonged bursts were clustered in the left medial frontal lobe. MEG detected the sources of SBS in the medial frontal lobe. MEG is extremely useful for the identification of the source of SBS.     

Correlation between CSWS and aphasia in Landau-Kleffner syndrome: A study of three cases

We report three typical cases of Landau-Kleffner syndrome with varied courses. The very frequent discharges in sleep EEGs, often showing the patterns of CSWS (continuous spike-waves during slow-wave sleep), either typical (spike-wave complex occupying over 85% of slow-wave sleep duration) or atypical (spike-waves occupying less than 85% of slow-wave sleep), were presented in all our cases. The CSWS seems correlated with aphasia in our cases. Since the disappearance of CSWS might be indicative of a lagged improvement in aphasia, we suggest that sufficiently long-term treatment with anticonvulsants and/or corticosteroids is worthwhile, if the EEG is improved significantly by this treatment.     

Non-linear EEG analysis in children with epilepsy and electrical status epilepticus during slow-wave sleep (ESES)

OBJECTIVE: The objective of this work was to study the non-linear aspects of electroencephalography (EEG) in children with epilepsy and electrical status epilepticus during slow-wave sleep (ESES). METHODS: In this study, we recorded the sleep EEG in 5 subjects with ESES (4 males and one female, aged 6.5-10 years) who were also mentally retarded and affected by cerebral palsy (3 subjects) and hydrocephalus (two subjects). The signals were sampled at 128Hz and stored on hard disk. All the subsequent computational steps were performed on EEG epochs (4096 data points) selected from wakefulness and non-rapid eye movement (non-REM) (with ESES) or REM sleep. The dynamic properties of the EEG were assessed by means of the non-linear cross prediction (NLCP) test which uses 3 different 'model' time series in order to predict non-linearly the original data set (Pred, Ama and Tir). Pred is a measure of the predictability of the time series and Ama and Tir are measures of asymmetry, indicating non-linear structure. Moreover, the correlation dimension (D2) was estimated by means of the algorithm by for the epochs showing non-linear nature. RESULTS: The NLCP test provided evidence of significant non-linear dynamics in all epochs of non-REM sleep, when ESES was evident. Only during this stage, the possible presence of low-dimensional chaos could also be suspected (average D2=4.02; range 3.16-6.21). EEG without ESES could not be distinguished from linearly filtered noise. CONCLUSIONS: The results of the present study seem to indicate that subjects with ESES show a profound modification of their EEG dynamics with the occurrence, during sleep, of long periods characterized by non-linear dynamics and, probably, low-dimensional chaotic structure able to modify in a substantial way their brain functioning during sleep.     

The effect of surgery in encephalopathy with electrical status epilepticus during sleep

Purpose: We analyzed clinical and electroencephalography (EEG) outcomes of 13 patients with pharmacoresistant encephalopathy with electrical status epilepticus during sleep (ESES) following epilepsy surgery. Methods: All patients had symptomatic etiology of ESES and preoperative neuropsychological deterioration. Ten patients had daily atypical absences. Clinical outcome was assessed at 6 months and at 2 years after surgery. Clinical and EEG data were reviewed retrospectively. The spike propagation pattern and area and source strength in source montage were analyzed from preoperative and postoperative EEG studies. Key Findings: Preoperative sleep EEG showed electrical status epilepticus during sleep (SES) with one‐way interhemispheric propagation in nine patients and with two‐way interhemispheric propagation in four. The age of the patients at the time of surgery ranged from 3.6–9.9 years. Focal resection (two patients) or hemispherotomy (one patient with postoperative EEG) either terminated SES or restricted the discharge to one region. Either reduced SES propagation area or source strength was found in four of eight callosotomy patients with postoperative EEG. Of patients who had seizures preoperatively, Engel class I–II seizure outcome was observed in two of three children after focal resection or hemispherotomy and in two of eight children after callosotomy. None of these patients with Engel class I–II outcome had SES with two‐way interhemispheric propagation on preoperative EEG. Cognitive deterioration was halted postoperatively in all except one patient. Cognitive catch‐up of more than 10 IQ points was seen in three patients, all of whom had shown a first measured IQ of >75. Significance: Patients with pharmacoresistant ESES based on symptomatic etiology may benefit from resective surgery or corpus callosotomy regarding both seizure outcome and cognitive prognosis.     

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 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.     

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.     

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.     

Acetazolamide for electrical status epilepticus in slow‐wave sleep

Electrical status epilepticus in slow‐wave sleep (ESES) is characterized by nearly continuous spike–wave discharges during non–rapid eye movement (REM) sleep. ESES is present in Landau‐Kleffner syndrome (LKS) and continuous spike and wave in slow‐wave sleep (CSWS). Sulthiame has demonstrated reduction in spike–wave index (SWI) in ESES, but is not available in the United States. Acetazolamide (AZM) is readily available and has similar pharmacologic properties. Our aims were to assess the effect of AZM on SWI and clinical response in children with LKS and CSWS. Children with LKS or CSWS treated with AZM at our institution were identified retrospectively. Pre‐ and posttherapy electroencephalography (EEG) studies were evaluated for SWI. Parental and teacher report of clinical improvement was recorded. Six children met criteria for inclusion. Three children (50%) demonstrated complete resolution or SWI <5% after AZM. All children had improvement in clinical seizures and subjective improvement in communication skills and school performance. Five of six children had subjective improvement in hyperactivity and attention. AZM is a potentially effective therapy for children with LKS and CSWS. This study lends to the knowledge of potential therapies that can be used for these disorders, which can be challenging for families and providers.     

Acquired cognitive dysfunction with focal sleep spiking activity

The syndrome of continuous spike-waves during slow sleep (CSWS) is considered an epileptic encephalopathy in which the epileptiform abnormalities may contribute to progressive cognitive dysfunction. The characteristic electroencephalographic feature of the syndrome occurs during non-REM sleep, and takes the form of continuous bilateral and diffuse slow spike-waves that persist through all slow sleep stages. Using a case study design including clinical, neuropsychological, electroencephalographic, and positron emission tomography with 18F-fluorodeoxyglucose (PET-FDG) investigations, we describe the clinical and electroencephalographic findings in two patients who presented with nonsymptomatic epilepsy with unilateral spike-waves during sleep. Both patients presented with a left unilateral motor neglect of the upper limb that was associated with unilateral CSWS activity over the right hemisphere, predominantly in the centrotemporal region. PET-FDG studies during the active phase of CSWS showed right centrotemporal hypermetabolism in both cases. After treatment, a regression of the CSWS activity and an improvement of the cerebral FDG pattern were paralleled by a remission of the motor neglect. These cases demonstrate that the electroencephalographic pattern of CSWS in nonsymptomatic epilepsies is not necessarily diffuse and bilateral, and that focal unilateral CSWS activity can be associated with focal neuropsychological deficits. These findings add further evidence that the spectrum of clinical conditions associated with the electroencephalographic pattern of CSWS can include different forms of acquired cognitive disturbances that may be focal in nature.     

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.     

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.     

Coexistence of idiopathic rolandic epilepsy and CSWS in two families

PURPOSE: To report two families combining benign childhood epilepsy with centrotemporal spikes (BCECS) and cryptogenic epilepsy with continuous spike-waves during sleep (CSWS) in first-degree relatives. METHODS: Clinical, EEG, and cerebral imaging data are described. RESULTS: FAMILY 1: The proband was 3 years old at epilepsy onset. First seizures were convulsive, with centrotemporal spikes on EEG. At age 5 years, he had complex partial seizures, psychomotor regression, and centrotemporal CSWS. [(18)F]fluorodeoxyglucose (FDG) positron emission tomography (PET) showed left parietal hypermetabolism. After several antiepileptic drug (AED) trials, valproate (VPA) and ethosuximide (ESM) induced seizure remission, CSWS disappearance, and psychomotor improvement. Learning disabilities, however, persisted. Family history was remarkable for BCECS in his father. FAMILY 2: The proband was 2 years old at epilepsy onset. First seizures were convulsive, with centrotemporal CSWS on EEG. Despite several AED trials including corticosteroids, focal negative myoclonia, atypical absences, and psychomotor regression occurred, leading to severe mental retardation. FDG-PET showed bilateral parietal hypermetabolism. Vagus nerve stimulator was implanted. Her family history was remarkable for BCECS in her father and febrile convulsions in infancy in her mother. CONCLUSIONS: These data suggest the existence of a common genetic basis between BCECS and cryptogenic epilepsies with CSWS. The higher expression in patients with CSWS could be related to other genetic or acquired factors. These data suggest that these epileptic syndromes constitute edges of a continuum.     

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.