Patients with epileptic encephalopathy with spike wave activation in sleep (EE-SWAS) often display drug-resistant epilepsy. The activation of epileptic activity during sleep is associated temporally with neurocognitive impairment and causes a spectrum of disorders within the epilepsy-aphasia syndrome. The prognosis is dependent on promptness of treatment and etiology. However, there is no clear consensus with regards to the optimal management for patients with EE-SWAS. We queried our Pediatric Epilepsy Outcome-Informatics Project (PEOIP) database for all patients treated with anakinra in our centre. We herein report a case of a female with EE-SWAS, who demonstrated remarkable neurocognitive improvement with anakinra. We suggest that a trial of anakinra may be an option for patients with EE-SWAS due to non-structural and possibly inflammatory etiology.

In the context of childhood epilepsy, the concept of continuous spike-waves during slow sleep (CSWS) includes several childhood-onset heterogeneous conditions that share electroencephalograms (EEGs) characterized by a high frequency of paroxysmal abnormalities during sleep, which have negative effects on the cognitive development and behavior of the child. These negative effects may have the characteristics of a clear regression or of a slowdown in development. Seizures are very often present, but not constantly. The above makes it clear why CSWS have been included in epileptic encephalopathies, in which, by definition, frequent EEG paroxysmal abnormalities have an unfavorable impact on cognitive functions, including socio-communicative skills, causing autistic features, even regardless of the presence of clinically overt seizures. Although several decades have passed since the original descriptions of the electroclinical condition of CSWS, there are still many areas that are little-known and deserve to be further studied, including the EEG diagnostic criteria, the most effective electrophysiological parameter for monitoring the role of the thalamus in CSWS pathogenesis, its long-term evolution, the nosographic location of Landau-Kleffner syndrome, standardized neuropsychological and behavioral assessments, and pharmacological and non-pharmacological therapies.

Objective  Electrical status epilepticus in sleep (ESES) is defined by near-continuous epileptiform discharges during sleep along with cognitive, behavioral, and/or imaging abnormalities. We studied the neurocognitive profile and their correlation with 18 F fluorodeoxyglucose positron emission tomography (FDG PET) brain abnormalities in children with ESES. Methods  Fourteen children with ESES with normal magnetic resonance imaging (MRI) from March to December 2019 were included. The intelligence quotient (IQ) and child behavior checklist (CBCL) scores were estimated using validated scales, and FDG PET brain was done at the same point of time to look for cerebral metabolic defects which was compared with a control group. Results  Fourteen patients with a mean age of 8.2 ± 2.7 years were analyzed. The average duration of epilepsy was 6 ± 2.8 years. The mean IQ was 72.4 ± 18.2 and mean CBCL score was 37.3 ± 11.8. There was negative correlation between IQ and CBCL ( r  = -0.55, p  < 0.001). The duration of epilepsy also showed negative correlation with IQ ( r  = -4.75, p  < 0.001). FDG PET scan showed predominant thalamic hypometabolism in 12 of 14 patients (85.7%) on visual analysis with multiple other hypometabolic cortical and subcortical regions in the brain. The quantitative analysis showed significant difference in metabolism of basal ganglion when compared with control group. The total number of hypometabolic regions seen in the brain showed moderate positive correlation with CBCL score but no significant correlation with the IQ of cases. Conclusion  This study demonstrates functional impairment of cerebral cortical, basal ganglia, and thalamic hypometabolism in a cohort of ESES patients with normal structural MRI brain study. There was a moderate correlation of extent and pattern of cerebral hypometabolism with the neuropsychological status of the child and duration of epilepsy.

Electrical status epilepticus of slow-wave sleep (ESES) is characterized by excessive interictal spike-wave discharges on EEG during sleep and can occur in the absence of overt clinical seizures. Continuous spike-wave during slow wave sleep (CSWS), an epilepsy syndrome associated with ESES, is associated with a plateau/decline in cognitive development and increases in behavioral and emotional dysregulation. Here we present a case in which neuropsychological (NP) evaluation initially ordered based on memory and attention concerns led to the identification of subclinical seizure activity and an evolving epileptic encephalopathy in an 11-year-old child with a history of remote neurological insult. The patient was referred for an initial NP evaluation at age 8 which revealed weaknesses in functions typically mediated by the dominant (usually left) hemisphere juxtaposed with her left hemiparesis. EEG was recommended which showed independent, multifocal spike and sharp wave discharges exacerbated by sleep. Follow-up NP evaluations over the following 26 months, during which time aggressive treatment was initiated, coincided with EEG findings of an evolving epileptic encephalopathy in the patient who continued to remain free from clinical seizures. This case highlights the importance of comprehensive epilepsy care and routine involvement of neuropsychology in the management of complex epilepsy patients.

BACKGROUND: Continuous spike and wave of sleep with encephalopathy (CSWS) is a rare and severe developmental electroclinical epileptic encephalopathy characterized by seizures, abundant sleep activated interictal epileptiform discharges, and cognitive regression or deceleration of expected cognitive growth. The cause of the cognitive symptoms is unknown, and efforts to link epileptiform activity to cognitive function have been unrevealing. Converging lines of evidence implicate thalamocortical circuits in these disorders. Sleep spindles are generated and propagated by the same thalamocortical circuits that can generate spikes and, in healthy sleep, support memory consolidation. As such, sleep spindle deficits may provide a physiologically relevant mechanistic biomarker for cognitive dysfunction in epileptic encephalopathies.
METHODS: We describe the longitudinal course of a child with CSWS with initial cognitive regression followed by dramatic cognitive improvement after treatment. Using validated automated detection algorithms, we analyzed electroencephalograms for epileptiform discharges and sleep spindles alongside contemporaneous neuropsychological evaluations over the course of the patient\'s disease. We found that sleep spindles increased dramatically with high-dose diazepam treatment, corresponding with marked improvements in cognitive performance. We also found that the sleep spindle rate was anticorrelated to spike rate, consistent with a competitively shared underlying thalamocortical circuitry.
CONCLUSIONS: Epileptic encephalopathies are challenging electroclinical syndromes characterized by combined seizures and a deceleration or regression in cognitive skills over childhood. This report identifies thalamocortical circuit dysfunction in a case of epileptic encephalopathy and motivates future investigations of sleep spindles as a biomarker of cognitive function and a potential therapeutic target in this challenging disease.

Pathogenic variants in connector enhancer of kinase suppressor of Ras-2 (CNKSR2) located on the X chromosome (Xp22.12) lead to a disorder characterized by developmental delay and a characteristic seizure phenotype. To date, 20 affected males representing 13 different pathogenic variants have been published.
We identified an 8-year-old male with seizures, abnormal electroencephalogram (EEG) with epileptiform abnormalities in the right hemisphere, and developmental delay with notable loss of speech following seizure onset. Additional concerns include multiple nighttime awakenings, hyperactivity, and autism spectrum disorder. Genetic testing identified a de novo pathogenic nonsense variant in CNKSR2. Through an active family support group, an additional 12 males are described, each harboring a different CNKSR2 variant. The clinical presentation and natural history consistently show early developmental delay, sleep disturbances, and seizure onset in childhood that is initially intractable but later becomes better controlled. Virtually all of the pathogenic variants are predicted to be loss of function, including genomic deletions, nonsense variants, splice site mutations, and small insertions or deletions.
This expanded knowledge, combined with functional studies and work with animal models currently underway, will enable a better understanding and improved ability to care for individuals with CNKSR2-related neurodevelopmental and epilepsy disorder.

Investigators from the Hospital Dona Estefânia, Escola Superior de Tecnologias e Saúde de Lisboa and Centro Hospitalar Psiquiátrico de Lisboa investigated 38 patients with continuous spike-wave of sleep (CSWS) syndrome.

Continuous 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.
A 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.
43 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).
Spike-frequency and delta power may represent EEG biomarkers of the risk of developing ESES in children with perinatal stroke.
EEG 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 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.
We 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.
Dynamical 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.
Perinatal 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.
Perinatal thalamic lesions produce ESES with focal onset in a restricted cortical area of the hemisphere with the lesion, and prominent secondary propagation.

BACKGROUND: Epileptic encephalopathy with electrical status epilepticus in sleep (ESES) is an epilepsy syndrome occurring almost exclusively in children, usually at an age between 4 and 12 years. It is characterised by abundant sleep-induced epileptic activity in the electroencephalogram (EEG) and by acquired cognitive and behavioural deficits. The goal of treatment is to prevent further decline or even improve cognitive functioning. Based on mostly small and retrospective studies, corticosteroids and clobazam are regarded by many clinicians as the most effective pharmacological treatments. This European multicentre randomised controlled trial is designed to compare the effects of corticosteroids and clobazam on cognitive functioning after 6 months. Secondary outcomes include cognitive functioning after 18 months, EEG abnormalities in sleep, safety and tolerability, and seizure frequency. We also aimed at investigating whether treatment response in epileptic encephalopathy with ESES can be predicted by measurement of inflammatory mediators and autoantibodies in serum.
METHODS: The pragmatic study will be performed in centres with expertise in the treatment of rare paediatric epilepsy syndromes across Europe. A total of 130 patients, 2 to 12 years of age, with epileptic encephalopathy with ESES will be enrolled and randomised in a 1:1 ratio to receive either corticosteroids (monthly intravenous methylprednisolone pulses or daily oral prednisolone) or oral clobazam for 6 months according to an open-label parallel-group design. Follow-up visits with clinical assessment, EEGs, and neuropsychological testing are scheduled for up to 18 months. Blood samples for cytokine and autoantibody testing are obtained before treatment and 8 months after treatment initiation.
CONCLUSIONS: The treatment of epileptic encephalopathy with ESES aims at improving cognitive outcome. This randomised controlled study will compare the most frequently used treatments, i.e. corticosteroids and clobazam. If the study proves superiority of one treatment over the other or identifies biomarkers of treatment response, results will guide clinicians in the early treatment of this severe epilepsy syndrome.
BACKGROUND: ISRCTN, ISRCTN42686094 . Registered on 24 May 2013.