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.     

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.     

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.     

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.     

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.     

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.     

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.     

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.     

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.     

Epileptic encephalopathy with continuous spikes and waves during sleep in children with shunted hydrocephalus: a study of nine cases

Purpose: We present a series of nine patients with early‐onset hydrocephalus who had seizures and continuous spikes and waves during slow sleep (CSWS) associated with neurocognitive and motor deterioration. Methods: Six boys and three girls aged 9–16 years (mean 11.3 years) were studied. [Correction added after online publication 12‐Apr‐2008: Number of girls and boys has been updated.] All patients underwent clinical examinations, electroencephalographic evaluations, neuroradiological imaging and neuropsychological assessment at first examination. Antiepileptic drugs (AEDs) were given in all cases and changed according to clinical and EEG evolution. Results: Onset of epilepsy occurred from age 8 to 60 months (mean 19.6 months and median 14 months) with focal seizures with or without secondary generalized tonic–clonic seizures. Between ages 6 and 13 years (mean 10.4 years and median 8 years), hyperkinesia, aggressiveness, and poor socialization appeared in all nine cases. Reduced attention span, deterioration of language, and temporospatial disorientation were found in three of them. Negative myoclonus was found in two patients. The EEG showed CSWS. Response to change in treatment was good in all patients. None of the patients had relapses, seven of them have remained seizure free, and two continued having sporadic focal motor seizures during 2–5 years (mean 3 years) of follow‐up. Conclusion: In children with early‐onset hydrocephalus, particularly with behavioral and language disturbances and/or motor deterioration, CSWS should be considered. Periodic EEG recordings during sleep should be done in these children. The early identification of this particular electroclinical picture is crucial to start adequate treatment to avoid progressive cognitive deterioration.     

Cortical visual areas process intestinal information during slow‐wave sleep

Background Previously we have shown that, during sleep, electrical and magnetic stimulation of areas of the stomach and small intestine evoked neuronal and EEG responses in various cortical areas. In this study we wanted to correlate natural myoelectrical activity of the duodenum with cortical neuronal activity, and to investigate whether there is a causal link between them during periods of slow‐wave sleep. Methods We have recorded the myoelectrical activity from the wall of the duodenum and activity of single neurons from three cortical visual areas in naturally sleeping cats and investigated causal interrelationship between these structures during slow‐wave sleep. Key Results About 30% of the cortical neurons studied changed their firing rate dependent on the phases of the peristaltic cycle and demonstrated selectivity to particular pattern of duodenal myoelectrical activity during slow‐wave sleep. This interrelationship was never seen when awake. Conclusions & Inferences This observation supports the hypothesis that, during sleep, the cerebral cortex switches from processing of exteroceptive and proprioceptive information to processing of interoceptive information.     

Jerking during absences: video‐EEG and polygraphy of epileptic myoclonus associated with two paediatric epilepsy syndromes

Objective: Epileptic myoclonus (EM) is reported in many paediatric epilepsies from neonatal period to adolescence. Myoclonus can be the only seizure type or may occur among others, independently or in combination as a single ictal event. We report two children presenting with absences associated with myoclonus, predominating on one side, in a setting of two different types of absence seizures and two different electro‐clinical syndromes. Methods: Patients were explored with long‐duration video‐EEG coupled to surface EMG polygraphy. EEG was visually analysed and complemented by jerk‐locked back‐averaging. Results: Two types of seizure, encompassing myoclonus and absence, were identified: myoclonic absences in the context of epilepsy with myoclonic absences and atypical absences with atonic component (negative myoclonus) in the context of encephalopathy related to status epilepticus during slow sleep (ESES). In the latter case, rhythmic upper limb jerking, mimicking positive myoclonus, corresponded to recovery of muscular tone after each negative myoclonus. Significance: Due to the rhythmic recovery of muscle tone, subsequent rhythmic negative myoclonus may exhibit a similar clinical picture to that of rhythmic positive myoclonus. Video‐EEG recording coupled to EMG polygraphy is essential in order to precisely characterize motor manifestations during seizures with myoclonus [Published with video sequences].     

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.     

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

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