Altered EEG markers of synaptic plasticity in a human model of NMDA receptor deficiency: Anti-NMDA receptor encephalitis.

Plasticity of synaptic strength and density is a vital mechanism enabling memory consolidation, learning, and neurodevelopment. It is strongly dependent on the intact function of N-Methyl-d-Aspartate Receptors (NMDAR). The importance of NMDAR is further evident as their dysfunction is involved in many diseases such as schizophrenia, Alzheimer's disease, neurodevelopmental disorders, and epilepsies. Synaptic plasticity is thought to be reflected by changes of sleep slow wave slopes across the night, namely higher slopes after wakefulness at the beginning of sleep than after a night of sleep. Hence, a functional NMDAR deficiency should theoretically lead to altered overnight changes of slow wave slopes. Here we investigated whether pediatric patients with anti-NMDAR encephalitis, being a very rare but unique human model of NMDAR deficiency due to autoantibodies against receptor subunits, indeed show alterations in this sleep EEG marker for synaptic plasticity. We retrospectively analyzed 12 whole-night EEGs of 9 patients (age 4.3-20.8 years, 7 females) and compared them to a control group of 45 healthy individuals with the same age distribution. Slow wave slopes were calculated for the first and last hour of Non-Rapid Eye Movement (NREM) sleep (factor 'hour') for patients and controls (factor 'group'). There was a significant interaction between 'hour' and 'group' (p = 0.013), with patients showing a smaller overnight decrease of slow wave slopes than controls. Moreover, we found smaller slopes during the first hour in patients (p = 0.022), whereas there was no group difference during the last hour of NREM sleep (p = 0.980). Importantly, the distribution of sleep stages was not different between the groups, and in our main analyses of patients without severe disturbance of sleep architecture, neither was the incidence of slow waves. These possible confounders could therefore not account for the differences in the slow wave slope values, which we also saw in the analysis of the whole sample of EEGs. These results suggest that quantitative EEG analysis of slow wave characteristics may reveal impaired synaptic plasticity in patients with anti-NMDAR encephalitis, a human model of functional NMDAR deficiency. Thus, in the future, the changes of sleep slow wave slopes may contribute to the development of electrophysiological biomarkers of functional NMDAR deficiency and synaptic plasticity in general.

Disparate effects of hormones and vigabatrin on sleep slow waves in patients with West syndrome - An indication of their mode of action?

Synaptic downscaling during sleep, a physiological process to restore synaptic homeostasis and maintain learning efficiency and healthy brain development, has been related to a reduction of the slope of sleep slow waves (SSW). However, such synaptic downscaling seems not to be reflected in high-amplitude SSW. Recently we have shown reduced SSW slopes during hormonal treatment (adrenocorticotrophic hormone, prednisolone) in patients with West syndrome (WS). Yet, whether this reduction was related to successful treatment or reflects a specific effect of hormone therapy is unknown. Thus, we retrospectively analysed nap electroencephalograms of 61 patients with WS successfully treated with hormones, vigabatrin (VGB), or both. The slope of SSW during treatment (T1) and 2-7 months later (T2) when hormonal treatment was tapered off were compared between the treatment groups and healthy, age-matched controls. At T1 hormone treatment reduced the slope of low-amplitude SSW, whereas VGB increased the slope of high-amplitude SSW (linear mixed effect model: FGroup  = 7.04, p < 0.001; FAmplitude  = 1,646.68, p < 0.001; FGroup*Amplitude  = 3.38, p < 0.001). At T2, untreated patients did not differ anymore from healthy controls, whereas those still under VGB showed the same alterations as those with VGB at T1. This result indicates a disparate effect of VGB and hormone on the SSW slope. In particular, hormones seem to reduce the slope of cortical generated low-amplitude SSW, similar to the physiological synaptic downscaling during sleep. Thus, a loss of functional neuronal connectivity might be an alternative explanation of the antiepileptic effect of hormonal treatment.

Sleep-dependent memory consolidation in children with self-limited focal epilepsies.

OBJECTIVE: Children with self-limited focal epilepsies of childhood (SLFE) are known to show impaired memory functions, particularly in the verbal domain. Interictal epileptiform discharges (IED) in these epilepsies are more pronounced in nonrapid eye movement (NREM) sleep. Nonrapid eye movement sleep is crucial for consolidation of newly-encoded memories. Therefore, we hypothesize that sleep-dependent memory consolidation is altered in relation to IED in children with SLFE. METHODS: We conducted a prospective case-control study. We applied a verbal (word pair) and a visuospatial (two-dimensional [2D] object location) learning task, both previously shown to benefit from sleep in terms of memory consolidation. Learning took place in the evening, and retrieval was tested in the morning after a night of sleep. Electroencephalogram (EEG) was recorded across night. After sleep-stage scoring, the spike-wave index (SWI) was assessed at the beginning and the end of sleep. Fourteen patients with SLFE (age: 5.5 to 11.6 years) were compared with 15 healthy controls (age: 6.8 to 9.1 years) examined in a previous study. RESULTS: In contrast to healthy controls (mean: +12.9% recalled word pairs, p = .003, standard deviation (SD) = 12.4%), patients did not show overnight performance gains in the verbal memory task (mean: +6.4% recalled word pairs, p > .05, SD = 17.3) Neither patients nor controls showed significant overnight changes in visuospatial task performance. Spike-wave index was negatively correlated with recall performance in the verbal but not in the visuospatial task. SIGNIFICANCE: We found evidence for impaired overnight improvement of performance in children with SLFE in a verbal learning task, with high SWI rates predicting low recall performance. We speculate that spike-waves hamper long-term memory consolidation by interfering with NREM sleep.

Age-Dependency of Location of Epileptic Foci in "Continuous Spike-and-Waves during Sleep": A Parallel to the Posterior-Anterior Trajectory of Slow Wave Activity.

BACKGROUND: Epileptic encephalopathy with continuous spike-and-waves during sleep (CSWS) occurs during childhood and is characterized by an activation of spike wave complexes during slow wave sleep. The location of epileptic foci is variable, as is etiology. A relationship between the epileptic focus and age has been shown in various focal epilepsies following a posterior-anterior trajectory, and a link to brain maturation has been proposed. We hypothesize that in CSWS, maximal spike wave activity, corresponding to the epileptic focus, is related to age and shows a posterior-anterior evolution. FINDINGS: In a retrospective cross-sectional study on CSWS (22 EEGs of 22 patients aged 3.1­13.5 years), the location of the epileptic focus is related to age and follows a posterior-anterior course. Younger patients are more likely to have posterior foci than older ones. CONCLUSIONS: We propose that the posterior-anterior trajectory of maximal spike waves in CSWS might reflect maturational changes of maximal expression of sleep slow waves, which follow a comparable course. Epileptic spike waves, that is, "hyper-synchronized slow waves" may occur at the place where the highest and therefore most synchronized slow waves meet brain tissue with an increased susceptibility to synchronization.

Impaired slow wave sleep downscaling in patients with infantile spasms.

BACKGROUND: West syndrome is a severe epileptic encephalopathy of infancy, characterized by infantile spasms, global retardation, and a severely abnormal electroencephalogram (EEG) pattern known as hypsarrhythmia, which is most prominent during slow waves sleep. The restorative function of slow wave sleep has been linked to downscaling, a neuronal process ensuring a balance of global synaptic strength, which is important for normal cortical functioning and development. A key electrophysiological marker for this downscaling is the reduction of the slope of slow waves across the night. METHODS: We retrospectively compared the slope of slow waves between 14 untreated patients with infantile spasms and healthy age and gender matched controls. Patients were examined in one all-night sleep EEG before treatment, and in two follow-up nap recordings, under and after treatment with corticosteroids. RESULTS: In patients with infantile spasms the overnight reduction in the slope of slow waves was significantly diminished compared to controls (p = 0.009). Moreover, untreated patients revealed overall steeper slopes. During corticosteroid treatment the slope was reduced compared to controls (p = 0.001). After successful treatment the slope was similar between patients and controls. CONCLUSION: Our results provide evidence for reduced downscaling in patients with infantile spasms. Moreover, the marked reduction of the slope during corticosteroid treatment may reflect a loss of synaptic connections due to the effect of glucocorticoids. This altered sleep dependent regulation of synaptic strength in infantile spasms may contribute the underlying pathomechanism of the developmental regression. Furthermore the normalization of synaptic strength due to corticosteroids might provide a potential mechanistic explanation for this treatment strategy.

Spike wave location and density disturb sleep slow waves in patients with CSWS (continuous spike waves during sleep).

OBJECTIVE: In CSWS (continuous spike waves during sleep) activation of spike waves during slow wave sleep has been causally linked to neuropsychological deficits, but the pathophysiologic mechanisms are still unknown. In healthy subjects, the overnight decrease of the slope of slow waves in NREM (non-rapid eye movement) sleep has been linked to brain recovery to regain optimal cognitive performance. Here, we investigated whether the electrophysiologic hallmark of CSWS, the spike waves during sleep, is related to an alteration in the overnight decrease of the slope, and if this alteration is linked to location and density of spike waves. METHODS: In a retrospective study, the slope of slow waves (0.5-2 Hz) in the first hour and last hour of sleep (19 electroencephalography [EEG] electrodes) of 14 patients with CSWS (3.1-13.5 years) was calculated. The spike wave "focus" was determined as the location of highest spike amplitude and the density of spike waves as spike wave index (SWI). RESULTS: There was no overnight change of the slope of slow waves in the "focus." Instead, in "nonfocal" regions, the slope decreased significantly. This difference in the overnight course resulted in a steeper slope in the "focus" compared to "nonfocal" electrodes during the last hour of sleep. Spike wave density was correlated with the impairment of the overnight slope decrease: The higher the SWI, the more hampered the slope decrease. SIGNIFICANCE: Location and density of spike waves are related to an alteration of the physiologic overnight decrease of the slow wave slope. This overnight decrease of the slope was shown to be closely related to the recovery function of sleep. Such recovery is necessary for optimal cognitive performance during wakefulness. Therefore we propose the impairment of this process by spike waves as a potential mechanism leading to neuropsychological deficits in CSWS. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.

Impaired slow wave sleep downscaling in encephalopathy with status epilepticus during sleep (ESES).

OBJECTIVE: "Encephalopathy related to electrical status epilepticus during slow wave sleep" (ESES) is characterised by the electroencephalographic pattern of continuous spike waves during slow wave sleep (CSWS) and variable neuropsychological impairments. The synaptic homeostasis hypothesis predicts that the strength of synapses is decreased during sleep. The slope of slow waves during NREM sleep best reflects this "downscaling". METHODS: In a retrospective case control study, we analysed the time course of the slope of EEG slow waves of nine patients with ESES. The patients showed continuous spike waves (>85%) associated with regression or stagnation of cognitive functions. The data of the patient group were compared to nine healthy age and gender matched controls. RESULTS: In control subjects we found the expected decrease of the slope of slow waves from the first to the last hour of sleep (17.2% decrease, p<0.001). In contrast, patients showed no significant change in slope across the night. CONCLUSIONS: This finding may reflect a disruption of the downscaling process during sleep, which may contribute to the developmental regression in these children. SIGNIFICANCE: Thus, our findings contribute to the understanding of the pathomechanisms leading to the regression observed in children with ESES and support the view that the goal of the treatment in children with ESES should not only be to reduce seizures, but also to resolve the continuous spike wave activity.

Effects of valproic acid on sleep in children with epilepsy.

PURPOSE: Parents frequently report increased sleep duration in their children during treatment with valproic acid (VPA). We assessed sleep duration and sleep behavior before and after tapering VPA in children treated for more than 6 months. METHODS: Sleep variables were assessed by questionnaire, diary, and actigraphy (for 7 consecutive days and nights) before and 8-12 weeks after termination of VPA. RESULTS: Forty-six children (age range 1.7-17.4 years) completed the study. The questionnaire data showed no significant difference in bed and wake time, duration of sleep, and time to fall asleep before and after ending VPA treatment, although some qualitative measures on daytime sleepiness improved after tapering VPA. The actigraphy data revealed that the average sleep amount without VPA was reduced in 33 children (9 of them >30 min) and longer in 13 children (1 of them >30 min). The mean Assumed Sleep Time per Day decreased by 15.2 min or 9.5 min when the physiologic decrease of sleep duration within 0.3 years was considered. Also mean Actual Sleep Time per Day was significantly reduced after VPA termination (-15.2 min; after correction -10.7 min). The reduction was only significant in children older than age 6 years. DISCUSSION: Termination of VPA after long-term treatment leads to a significant reduction of sleep duration in children older than 6 years of age. The change was small in the majority, but considerable in a subgroup of children.

Electroencephalographic changes after pediatric cardiac surgery with cardiopulmonary bypass: is slow wave activity unfavorable?

Pediatric cardiac surgery with cardiopulmonary bypass (CPB) is frequently associated with neurologic deficits. We describe the postoperative EEG changes, assess their possible causes, and evaluate their relevance to neurologic outcome. Thirty-one children and five neonates with congenital heart disease were included. EEG recording started after intubation and continued until 22-96 h after CPB. In addition to conventional analysis, spectral analysis was performed for occipital and frontal electrodes, and differences between pre- and postoperative delta power (delta-deltaP) were calculated. Maximum values of occipital delta-deltaP that occurred within 48 h after CPB were correlated with clinical variables and with perioperative markers of oxidative stress and inflammation. Occipital delta-deltaP correlated with frontal delta-deltaP, and maximum delta-deltaP correlated with conventional rating. Distinct rise of deltaP was detected in 18 of 21 children without any acute or long-term neurologic deficits but only in five of 10 children with temporary or permanent neurologic deficits. Furthermore, maximally registered delta-deltaP was inversely associated with duration of CPB and postoperative ventilation. Maximal delta-deltaP was also inversely associated with the loss of plasma ascorbate (as an index of oxidative stress) and plasma levels of IL-6 and IL-8. Slow wave activity frequently occurs within 48 h after CPB. However, our data do not support the notion that EEG slowing is associated with adverse neurologic outcome. This is supported by the fact that EEG slowing was associated with less oxido-inflammatory stress.