Slow Sleep Research Articles

DIAGNOSTIC CRITERIA OF SLEEP DISORDERS IN PATIENTS WITH LONG-TERM CHRONIC MERCURY INTOXICATION

Introduction. In the Irkutsk region, chronic mercury intoxication (CRI) occupies a leading place among occupational neurointoxications. An organic personality disorder with insomnia is one of the manifestations of brain damage in CRI. The aim of the study was to establish diagnostic criteria for secondary insomnia in patients with professional CRI for the selection of effective treatment. Material and methods. The study involved 30 people in the long-term CRI and 30 people in the comparison group with sleep disorders that are not in contact with harmful factors. Electroencephalographic, polysomnographic research and questioning were carried out with the assessment of the subjective characteristics of sleep. Information was processed using the Statistika 6.0 application package. Results. It was shown that CRI patients were shown to complain statistically significantly more frequent sleep disturbances than in the comparison group (p = 0.0003), difficulty in maintaining sleep (p = 0.004). As a result of EEG in the group of patients in the long-term CRI, the integral index and the ratio α/β were statistically significantly different from those in the comparison group, and according to the results of polysomnography, more pronounced qualitative and quantitative violations of the night sleep pattern were found in CRI patients; as a decrease in total sleep time (p = 0.0001), increase in sleep time (p = 0.008), number of activations and total wakefulness inside sleep (p = 0.03), decrease in sleep efficiency index (p = 0.006) and increase in an integrative sleep quality index (p = 0.03). According to the discriminant analysis, 4 criteria for diagnosing insomnia in CRI were established: total sleep time (min.), duration of the first stage of slow sleep (%), rhythm ratio α/β, EEG (%) and integral EEG index (%). Conclusion. Considering the data obtained, it is possible to improve approaches to treating insomnia in CRI by prescribing a complex of treatment, including cognitive-behavioral therapy, antidepressants with a sedative effect, as well as alpha training using biofeedback.

Heterogeneous profiles of coupled sleep oscillations in human hippocampus

Cross-frequency coupling of sleep oscillations is thought to mediate memory consolidation. While the hippocampus is deemed central to this process, detailed knowledge of which oscillatory rhythms interact in the sleeping human hippocampus is lacking. Combining intracranial hippocampal and non-invasive electroencephalography from twelve neurosurgical patients, we characterized spectral power and coupling during non-rapid eye movement (NREM) and rapid eye movement (REM) sleep. Hippocampal coupling was extensive, with the majority of channels expressing spectral interactions. NREM consistently showed delta–ripple coupling, but ripples were also modulated by slow oscillations (SOs) and sleep spindles. SO–delta and SO–theta coupling, as well as interactions between delta/theta and spindle/beta frequencies also occurred. During REM, limited interactions between delta/theta and beta frequencies emerged. Moreover, oscillatory organization differed substantially between i) hippocampus and scalp, ii) sites along the anterior-posterior hippocampal axis, and iii) individuals. Overall, these results extend and refine our understanding of hippocampal sleep oscillations.

Continuous spike-waves during slow-wave sleep: Experience during 20 years

Continuous spikes and waves during slow sleep (CSWS) is an EEG pattern that appears during childhood, and is often associated with cognitive impairment. It can appear in the course of epileptic syndromes, as well as in benign epilepsy. The aim of this study is to analyse epidemiological and clinical characteristic of patients with CSWS, in order to describe possible predictive factors in their outcome. A retrospective study was conducted on paediatric patients with CSWS treated in a third-level hospital from November 1997 to November 2017. The study included 25 patients (68% male), of whom 76% had abnormalities in the neuroimaging or suffered from psychomotor development disorder (secondary CSWS). The rest were healthy, or diagnosed with idiopathic epilepsy. The mean age of onset of CSWS was 6.7 years, but earlier in the secondary CSWS cases. Symptoms were present during the CSWS episode in 72% of cases. All of them were treated with antiepileptic drugs, which were effective in 36%. CSWS stopped in 72%, and remission was longer if the CSWS onset occurred at an older age. One-third (33%) presented with sequelae, mostly cognitive and behavioural alterations. Outcome was poorer in those with secondary CSWS and, in those whose CSWS started at an earlier age and lasted longer. The CSWS pattern, although rare, is still a therapeutic challenge. A close follow-up of the patients with epilepsy is important, especially if associated with cognitive impairment, in order to establish an early diagnosis and treatment.

Local Sleep Oscillations: Implications for Memory Consolidation.

Accumulating evidence suggests that sleep is important for plasticity and memory consolidation (Maquet, 2001; Walker and Stickgold, 2004; Datta and Maclean, 2007; Diekelmann and Born, 2010; Tononi and Cirelli, 2014; Dudai et al., 2015)—the transformation of new labile memories encoded in wakefulness into stable representations that integrate into long-term memory networks. A central model accounting for memory consolidation during sleep is that of coupling between hippocampal (HC) and neocortical networks (Buzsaki, 1996). According to this two-stage model of memory formation [also termed the hippocampal—neocortical dialogue model (Buzsaki, 1989)], the dominant direction of information flow across the brain differs between wake and sleep periods. During wakefulness, acquisition of sensory information mainly drives signal propagation from cortex to hippocampus (HC) (Buzsaki, 1998; Mormann et al., 2008). By contrast, during subsequent non-rapid eye movement (NREM) sleep, this model suggests a central role for information flow from HC to cortex especially around sharp-wave ripples (SWRs) events (Buzsaki, 1998). Accordingly, slow waves that originate in the neocortex repeatedly reactivate the newly encoded HC information when SWRs occur, driving subsequent activity in select cortical circuits (Siapas and Wilson, 1998). However, it is clear that information flow is not strictly unidirectional (Wagner et al., 2010) and may involve complex loops (Rothschild et al., 2017). HC reactivation tends to co-occur with sleep spindles that optimize plasticity (Seibt et al., 2017), resulting in long-term modification of synaptic efficacy. Thus, hippocampal–neocortical coupling requires interregional cross-frequency coordination between sleep oscillations, including slow waves and sleep spindles in thalamo-cortical circuits as well as HC ripples. The underlying prevalent assumption is that sleep oscillations (slow waves in particular) are global events that co-occur nearly simultaneously across different brain regions. But in fact, they have been described as traveling waves propagating from anterior-to-posterior cortex (Massimini et al., 2004), and they typically occur out of phase across different cortical sites (Nir et al., 2011; Vyazovskiy et al., 2011; Malerba et al., 2019). How can we reconcile models requiring co-occurrence of sleep oscillations with accumulating evidence of non-uniform timing of oscillations across the brain? In this article, we first review the current data that sheds light on this question, and highlight recent studies that link regional coupling of sleep oscillations with consolidation of specific memories. Then, we highlight the gap between sleep and memory theory and experimental evidence. Based on studies that monitor and manipulate specific cortical circuits, we propose that coupling can occur between sleep oscillations in general, and between HC and cortex specifically, but that such coupling likely involves different brain regions at each point in time, contributing to memory consolidation in select circuits.

Continuous spike-waves during slow–wave sleep: Experience during 20 years

IntroductionContinuous spikes and waves during slow sleep (CSWS) is an EEG pattern that appears during childhood, and is often associated with cognitive impairment. It can appear in the course of epileptic syndromes, as well as in benign epilepsy. The aim of this study is to analyse epidemiological and clinical characteristics of patients with CSWS, in order to describe possible predictive factors in their outcome. MethodsA retrospective study was conducted on paediatric patients with CSWS treated in a third-level hospital from November 1997 to November 2017. ResultsThe study included 25 patients (68% male), of whom 76% had abnormalities in the neuroimaging or suffered from psychomotor development disorder (secondary CSWS). The rest were healthy, or diagnosed with idiopathic epilepsy. The mean age of onset of CSWS was 6.7 years, but earlier in the secondary CSWS cases. Symptoms were present during the CSWS episode in 72% of cases. All of them were treated with antiepileptic drugs, which were effective in 36%. CSWS stopped in 72%, and remission was longer if the CSWS onset occurred at an older age. One-third (33%) presented with sequelae, mostly cognitive and behavioural alterations. Outcome was poorer in those with secondary CSWS and, in those whose CSWS started at an earlier age and lasted longer. ConclusionThe CSWS pattern, although rare, is still a therapeutic challenge. A close follow-up of the patients with epilepsy is important, especially if associated with cognitive impairment, in order to establish an early diagnosis and treatment.

Parasagittal hemispherotomy in hemispheric polymicrogyria with electrical status epilepticus during slow sleep: Indications, results and follow-up

PurposePolymicrogyria (PMG), although the most common brain malformation, represents a low percentage among patients operated on for epilepsy. In cases of hemispheric PMG, electrical status epilepticus during slow sleep (ESESS) may occur leading to an aggravation of the neurological condition and a risk of drug resistance. In such cases, surgical treatment can be offered. MethodsFrom a population of 230 children who underwent hemispherotomy for epilepsy, we retrospectively reviewed the patients with unilateral PMG and drug-resistant ESESS focusing on clinical charts, electrophysiological data and post-surgical outcome. ResultsEighteen patients were operated on at a mean age of 7.2 years. The average age was 2 years at seizure onset and 4.4 years at diagnosis of ESESS. All the patients preoperatively had some degree of developmental delay associated with a hemiparesis. During ESESS all of them evidenced a cognitive decline and eight experienced a worsening of the hemiparesis; ESESS was resistant to at least three antiepileptic drugs.The outcome of epilepsy, with a mean follow-up of 12.8 years showed that ESESS disappeared in all patients while 16 of 18 became seizure-free. An improvement of behavior and cognitive condition was observed in all. ConclusionHemispherotomy can be helpful in patients with drug-resistant ESESS and hemispheric PMG while keeping in mind that more often an accurate medical treatment can be sufficient. The main benefit of surgery is to definitively stop the seizures and to withdraw the medical treatment while keeping in mind the risk of motor aggravation.

Idiopathic encephalopathy related to status epilepticus during slow sleep (ESES) as a “pure” model of epileptic encephalopathy. An electroclinical, genetic, and follow-up study

ObjectiveThe objective of the study was to investigate electroclinical and neuropsychological features, genetic background, and evolution of children with idiopathic encephalopathy with status epilepticus during slow sleep (ESES), including Landau–Kleffner syndrome (LKS). Material and methodsAll children diagnosed with idiopathic ESES at the Danish Epilepsy Centre between March 2003 and December 2014 were retrospectively reviewed. Repeated 24-hour electroencephalography (24-h EEG) recordings, neuropsychological assessments, and clinical–neurological evaluation were performed throughout the follow-up in all patients. In 13 children, genetic investigations were performed. ResultsWe collected 24 children (14 males and 10 females). Mean age at ESES diagnosis was 6 years, and mean ESES duration was 2 years and 7 months. Twenty-one children had epileptic seizures. Three children had LKS. Topography of sleep-related EEG epileptic abnormalities was diffuse in 3 subjects, hemispheric in 6, multifocal in 9, and focal in 6. During the active phase of ESES, all children presented with a heterogeneous combination of behavioral and cognitive disturbances. In 14 children, a parallel between severity of the clinical picture and spike–wave index (SWI) was observed. We could not find a strict correlation between the type and severity of neurobehavioral impairment and the side/topography of sleep-related EEG discharges during the active phase of ESES. At the last follow-up, 21 children were in remission from ESES. Complete recovery from neurobehavioral disorders was observed in 5 children. Genetic assessment, performed in 13 children, showed GRIN2A variant in two (15.4%). SignificanceOur patients with idiopathic ESES showed a heterogeneous pattern of epileptic seizures, neurobehavioral disorders, and sleep EEG features. Only one-fourth of children completely recovered from the neuropsychological disturbances after ESES remission. Lack of correlation between severity/type of cognitive derangement and SWI and/or topography of sleep EEG epileptic abnormalities may suggest the contribution of additional factors (including impaired sleep homeostasis due to epileptic activity) in the neurobehavioral derangement that characterize ESES.

Association of inattention with slow-spindle density in sleep EEG of children with attention deficit-hyperactivity disorder

ObjectiveWe evaluated the power of slow sleep spindles during sleep stage 2 to clarify their relationship with executive function, especially with attention, in children with attention deficit-hyperactivity disorder (ADHD). MethodsSubjects were 21 children with ADHD and 18 aged-matched, typically developing children (TDC). ADHD subjects were divided into groups of only ADHD and ADHD + autism spectrum disorder (ASD). We employed the Continuous Performance Test (CPT) to measure attention. We focused on sleep spindle frequencies (12–14 Hz) in sleep stage 2 and performed a power spectral analysis using fast Fourier transform techniques and compared sleep spindles with the variability of reaction time in CPT. ResultsIn the CPT, reaction variabilities in ADHD and ADHD + ASD significantly differed from those in TDC. Twelve-hertz spindles were mainly distributed in the frontal pole and frontal area and 14-Hz spindles in the central area. The ratio of 12-Hz frontal spindle power was higher in ADHD than in TDC, especially in ADHD + ASD. Significant correlation between the ratio of 12-Hz spindles and reaction time variability was observed. ConclusionsTwelve-hertz frontal spindle EEG activity may have positive associations with sustained attention function. Slow frontal spindles may be useful as a biomarker of inattention in children with ADHD.

Quantitative EEG analysis in Encephalopathy related to Status Epilepticus during slow Sleep.

Since its first description, quantifying the burden of epileptiform abnormalities in sleep EEG has played a fundamental role in the diagnosis of Encephalopathy related to Status Epilepticus during slow Sleep (ESES). In fact, in the 1971 seminal paper by Tassinari's group and in the following studies on this syndrome, the amount of epileptiform discharges (EDs) was calculated as the percentage of slow sleep occupied by spike-and-waves and referred to as "spike and wave index" (SWI). However, nowadays it is becoming increasingly clear that the SWI alone does not explain the whole clinical course of patients affected by ESES. In this paper, we aim to provide a state-of-the-art summary of the quantitative EEG methods currently used in the ESES/CSWS literature, highlighting the possible pitfalls and discrepancies explaining the unsatisfactory correlation between SWI and clinical course. Furthermore; we illustrate a number of methodological refinements - taking into account inter-individual, intra-individual, and temporal variability of EDs - alongside "new" quantitative variables -including ED-related and sleep-related features - potentially useful to reach a reliable electro-clinical correlation 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.

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.

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.

Progressive intellectual impairment in children with Encephalopathy related to Status Epilepticus during slow Sleep.

We investigated whether Encephalopathy related to Status Epilepticus during slow Sleep (ESES) in childhood was associated with progressive intellectual decline. Participants were identified from the caseload of a single paediatric neurosciences centre and EEG department. A retrospective review of overnight sleep EEG reports (n=2200) over a five-year period identified twenty-two children as having the neurophysiological characteristics of ESES. All had repeat neuropsychological assessment using the WISC-III (UK) and/or WPPSI-R (UK). There was a statistically significant reduction in Full-Scale IQ and Performance IQ across a mean and median time interval of two years. Around a third of the participants showed a clinically significant regression in intellectual functioning evidenced by =>12-point reduction in IQ. These patients were not distinguishable from the rest of the cohort in terms of clinical history, imaging or duration of ESES. The reduction in IQ reflected reduced processing speed, working memory and overall cognitive efficiency. Children with a history of ESES require close monitoring in order to support educational planning and provide families with accurate information about prognosis.

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.

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.

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.

A commentary on Encephalopathy related to Status Epilepticus during slow Sleep: from concepts to terminology.

A commentary on Encephalopathy related to Status Epilepticus during slow Sleep: from concepts to terminology.

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.

Linking epilepsy, sleep disruption and cognitive impairment in Encephalopathy related to Status Epilepticus during slow Sleep (ESES)

Linking epilepsy, sleep disruption and cognitive impairment in Encephalopathy related to Status Epilepticus during slow Sleep (ESES)