Epileptiform Spikes Research Articles

Silent hippocampal seizures and spikes identified by foramen ovale electrodes in Alzheimer's disease

We directly assessed mesial temporal activity in two Alzheimer’s disease (AD) patients without a history or EEG evidence of seizures, using intracranial foramen ovale electrodes. We detected clinically silent hippocampal seizures and epileptiform spikes during sleep, a period when both were most likely to interfere with memory consolidation. These index cases support a model in which early development of occult hippocampal hyperexcitability may contribute to the pathogenesis of AD.

Electrocorticographic Dynamics as a Novel Biomarker in Five Models of Epileptogenesis.

Postinjury epilepsy (PIE) is a devastating sequela of various brain insults. While recent studies offer novel insights into the mechanisms underlying epileptogenesis and discover potential preventive treatments, the lack of PIE biomarkers hinders the clinical implementation of such treatments. Here we explored the biomarker potential of different electrographic features in five models of PIE. Electrocorticographic or intrahippocampal recordings of epileptogenesis (from the insult to the first spontaneous seizure) from two laboratories were analyzed in three mouse and two rat PIE models. Time, frequency, and fractal and nonlinear properties of the signals were examined, in addition to the daily rate of epileptiform spikes, the relative power of five frequency bands (theta, alpha, beta, low gamma, and high gamma) and the dynamics of these features over time. During the latent pre-seizure period, epileptiform spikes were more frequent in epileptic compared with nonepileptic rodents; however, this feature showed limited predictive power due to high inter- and intra-animal variability. While nondynamic rhythmic representation failed to predict epilepsy, the dynamics of the theta band were found to predict PIE with a sensitivity and specificity of >90%. Moreover, theta dynamics were found to be inversely correlated with the latency period (and thus predict the onset of seizures) and with the power change of the high-gamma rhythm. In addition, changes in theta band power during epileptogenesis were associated with altered locomotor activity and distorted circadian rhythm. These results suggest that changes in theta band during the epileptogenic period may serve as a diagnostic biomarker for epileptogenesis, able to predict the future onset of spontaneous seizures.SIGNIFICANCE STATEMENT Postinjury epilepsy is an unpreventable and devastating disorder that develops following brain injuries, such as traumatic brain injury and stroke, and is often associated with neuropsychiatric comorbidities. As PIE affects as many as 20% of brain-injured patients, reliable biomarkers are imperative before any preclinical therapeutics can find clinical translation. We demonstrate the capacity to predict the epileptic outcome in five different models of PIE, highlighting theta rhythm dynamics as a promising biomarker for epilepsy. Our findings prompt the exploration of theta dynamics (using repeated electroencephalographic recordings) as an epilepsy biomarker in brain injury patients.

A Quantitative Analysis for EEG Signals Based on Modified Permutation-Entropy

PurposeElectroencephalogram (EEG) is a record of brain electrical activities along the scalp which contains precious information related to different brain states. The aim of this study is to investigate the complexity of EEG signals and distinguish the EEG signals with different rhythm. Material and methodsThe EEG time series data used in this study come from single neural mass model. The model with the different parameters produces the EEG signals with different rhythm such as normal EEG signals and epileptiform spikes. The modified permutation-entropy is used to extract the complexity features of the normal EEG signals and epileptiform spikes and is compared with the permutation-entropy algorithm and Rényi permutation-entropy algorithm. The statistical analysis is used to characterize the differences between the signals. ResultsThe signals corresponding to A=3.25 mV and A=3.6 mV are easy to distinguish according to the average values and the standard deviations of the modified permutation-entropy. The statistical results reveal that group differences of the modified permutation-entropy values for the signals corresponding to A=3.25 mV and A=3.4 mV are significant, manifested as F>1 and p<0.05. Compared with the permutation-entropy and Rényi permutation-entropy, F-values of the modified permutation-entropy are the greatest and p-values of the modified permutation-entropy are the smallest. ConclusionThere are significant differences between the complexity features of normal EEG signals and epileptiform spikes signals. The signals can be distinguished under different lengths of time series, embedding dimensions and delay times by using the modified permutation-entropy. The modified permutation-entropy is an effective complexity measure to quantify the EEG signals. Compared with the permutation-entropy and Rényi permutation-entropy, the modified permutation-entropy is more effective to distinguish the EEG signals with different rhythm.

Estimate the effective connectivity in multi-coupled neural mass model using particle swarm optimization

Abstract Assessment of the effective connectivity among different brain regions during seizure is a crucial problem in neuroscience today. As a consequence, a new model inversion framework of brain function imaging is introduced in this manuscript. This framework is based on approximating brain networks using a multi-coupled neural mass model (NMM). NMM describes the excitatory and inhibitory neural interactions, capturing the mechanisms involved in seizure initiation, evolution and termination. Particle swarm optimization method is used to estimate the effective connectivity variation (the parameters of NMM) and the epileptiform dynamics (the states of NMM) that cannot be directly measured using electrophysiological measurement alone. The estimated effective connectivity includes both the local connectivity parameters within a single region NMM and the remote connectivity parameters between multi-coupled NMMs. When the epileptiform activities are estimated, a proportional–integral controller outputs control signal so that the epileptiform spikes can be inhibited immediately. Numerical simulations are carried out to illustrate the effectiveness of the proposed framework. The framework and the results have a profound impact on the way we detect and treat epilepsy.

Ripples on spikes show increased phase-amplitude coupling in mesial temporal lobe epilepsy seizure-onset zones.

Ripples (80-150 Hz) recorded from clinical macroelectrodes have been shown to be an accurate biomarker of epileptogenic brain tissue. We investigated coupling between epileptiform spike phase and ripple amplitude to better understand the mechanisms that generate this type of pathologic ripple (pRipple) event. We quantified phase amplitude coupling (PAC) between epileptiform electroencephalography (EEG) spike phase and ripple amplitude recorded from intracranial depth macroelectrodes during episodes of sleep in 12 patients with mesial temporal lobe epilepsy. PAC was determined by (1) a phasor transform that corresponds to the strength and rate of ripples coupled with spikes, and a (2) ripple-triggered average to measure the strength, morphology, and spectral frequency of the modulating and modulated signals. Coupling strength was evaluated in relation to recording sites within and outside the seizure-onset zone (SOZ). Both the phasor transform and ripple-triggered averaging methods showed that ripple amplitude was often robustly coupled with epileptiform EEG spike phase. Coupling was found more regularly inside than outside the SOZ, and coupling strength correlated with the likelihood a macroelectrode's location was within the SOZ (p < 0.01). The ratio of the rate of ripples coupled with EEG spikes inside the SOZ to rates of coupled ripples in non-SOZ was greater than the ratio of rates of ripples on spikes detected irrespective of coupling (p < 0.05). Coupling strength correlated with an increase in mean normalized ripple amplitude (p < 0.01), and a decrease in mean ripple spectral frequency (p < 0.05). Generation of low-frequency (80-150 Hz) pRipples in the SOZ involves coupling between epileptiform spike phase and ripple amplitude. The changes in excitability reflected as epileptiform spikes may also cause clusters of pathologically interconnected bursting neurons to grow and synchronize into aberrantly large neuronal assemblies.

Sinusoidal stimulation trains suppress epileptiform spikes induced by 4-AP in the rat hippocampal CA1 region in-vivo.

Deep brain stimulation (DBS) shows promises in the treatment of refractory epilepsy. Due to the complex causes of epilepsy, the mechanisms of DBS are still unclear. Depolarization block caused by the persistent excitation of neurons may be one of the possible mechanisms. To test the hypothesis, 4-aminopyridine (4-AP) was injected in rat hippocampal CA1 region in-vivo to induce epileptiform activity. Sinusoidal stimulation trains were applied to the afferent pathway (Schaffer collaterals) of CA1 region to suppress the epileptiform spikes. Results show that 2-min long trains of sinusoidal stimulation (50 Hz) decreased the firing rate of population spikes (PS) and decreased the PS amplitudes significantly. In addition, small positive sharp waves replaced PS activity during the periods of stimulation. A lower frequency sinusoidal stimulation (10 Hz) failed to decrease the firing rate of PS, but decreased the PS amplitudes significantly. These results suggest that stimulation trains of sinusoidal waves could suppress epileptiform spikes. Presumably, the stimulation with a high enough frequency might excite the downstream neurons persistently and elevate the membrane potentials continuously, thereby cause depolarization blocks in the neurons. The findings of the study provide insights in revealing the mechanisms of DBS, and have important implications to the clinical treatment of epilepsy.

Particle swarm optimization algorithm based parameters estimation and control of epileptiform spikes in a neural mass model.

This paper proposes an epilepsy detection and closed-loop control strategy based on Particle Swarm Optimization (PSO) algorithm. The proposed strategy can effectively suppress the epileptic spikes in neural mass models, where the epileptiform spikes are recognized as the biomarkers of transitions from the normal (interictal) activity to the seizure (ictal) activity. In addition, the PSO algorithm shows capabilities of accurate estimation for the time evolution of key model parameters and practical detection for all the epileptic spikes. The estimation effects of unmeasurable parameters are improved significantly compared with unscented Kalman filter. When the estimated excitatory-inhibitory ratio exceeds a threshold value, the epileptiform spikes can be inhibited immediately by adopting the proportion-integration controller. Besides, numerical simulations are carried out to illustrate the effectiveness of the proposed method as well as the potential value for the model-based early seizure detection and closed-loop control treatment design.

Magnetoencephalographic signatures of insular epileptic spikes based on functional connectivity.

Failure to recognize insular cortex seizures has recently been identified as a cause of epilepsy surgeries targeting the temporal, parietal, or frontal lobe. Such failures are partly due to the fact that current noninvasive localization techniques fare poorly in recognizing insular epileptic foci. Our group recently demonstrated that magnetoencephalography (MEG) is sensitive to epileptiform spikes generated by the insula. In this study, we assessed the potential of distributed source imaging and functional connectivity analyses to distinguish insular networks underlying the generation of spikes. Nineteen patients with operculo-insular epilepsy were investigated. Each patient underwent MEG as well as T1-weighted magnetic resonance imaging (MRI) as part of their standard presurgical evaluation. Cortical sources of MEG spikes were reconstructed with the maximum entropy on the mean algorithm, and their time courses served to analyze source functional connectivity. The results indicate that the anterior and posterior subregions of the insula have specific patterns of functional connectivity mainly involving frontal and parietal regions, respectively. In addition, while their connectivity patterns are qualitatively similar during rest and during spikes, couplings within these networks are much stronger during spikes. These results show that MEG can establish functional connectivity-based signatures that could help in the diagnosis of different subtypes of insular cortex epilepsy. Hum Brain Mapp 37:3250-3261, 2016. © 2016 Wiley Periodicals, Inc.

1400W, a highly selective inducible nitric oxide synthase inhibitor is a potential disease modifier in the rat kainate model of temporal lobe epilepsy

Status epilepticus (SE) initiates epileptogenesis to transform normal brain to epileptic state which is characterized by spontaneous recurrent seizures (SRS). Prior to SRS, progressive changes occur in the brain soon after SE, for example, loss of blood–brain barrier (BBB) integrity, neuronal hyper-excitability (epileptiform spiking), neuroinflammation [reactive gliosis, high levels of reactive oxygen/nitrogen species (ROS/RNS)], neurodegeneration and synaptic re-organization. Our hypothesis was that modification of early epileptogenic events will alter the course of disease development and its progression. We tested the hypothesis in the rat kainate model of chronic epilepsy using a novel disease modifying drug, 1400W, a highly selective inhibitor of inducible nitric oxide synthase (iNOS/NOS-II). In an in vitro mouse brain slice model, using a multi-electrode array system, co-application of 1400W with kainate significantly suppressed kainate-induced epileptiform spiking. In the rats, in vivo, 4h after the induction of SE with kainate, 1400W (20mg/kg, i.p.) was administered twice daily for three days to target early events of epileptogenesis. The rats were subjected to continuous (24/7) video-EEG monitoring, remotely, for six months from epidurally implanted cortical electrodes. The 1400W treatment significantly reduced the epileptiform spike rate during the first 12–74h post-SE, which resulted in >90% reduction in SRS in long-term during the six month period when compared to the vehicle-treated control group (257±113 versus 19±10 episodes). Immunohistochemistry (IHC) of brain sections at seven days and six months revealed a significant reduction in; reactive astrogliosis and microgliosis (M1 type), extravascular serum albumin (a marker for BBB leakage) and neurodegeneration in the hippocampus, amygdala and entorhinal cortex in the 1400W-treated rats when compared to the vehicle control. In the seven day group, hippocampal Western blots revealed downregulation of inwardly-rectifying potassium (Kir 4.1) channels and glutamate transporter-1 (GLT-1) levels in the vehicle group, and 1400W treatment partially reversed Kir 4.1 levels, however, GLT-1 levels were unaffected. In the six month group, a significant reduction in mossy fiber staining intensity in the inner molecular layer of the dentate gyrus was observed in the 1400W-treated group. Overall these findings demonstrate that 1400W, by reducing the epileptiform spike rate during the first three days of post-insult, potentially modifies epileptogenesis and the severity of chronic epilepsy in the rat kainate model of TLE.

EPILEPTIFORM SPIKE DETECTION VIA CONVOLUTIONAL NEURAL NETWORKS.

The EEG of epileptic patients often contains sharp waveforms called "spikes", occurring between seizures. Detecting such spikes is crucial for diagnosing epilepsy. In this paper, we develop a convolutional neural network (CNN) for detecting spikes in EEG of epileptic patients in an automated fashion. The CNN has a convolutional architecture with filters of various sizes applied to the input layer, leaky ReLUs as activation functions, and a sigmoid output layer. Balanced mini-batches were applied to handle the imbalance in the data set. Leave-one-patient-out cross-validation was carried out to test the CNN and benchmark models on EEG data of five epilepsy patients. We achieved 0.947 AUC for the CNN, while the best performing benchmark model, Support Vector Machines with Gaussian kernel, achieved an AUC of 0.912.

Millimeter-scale epileptiform spike propagation patterns and their relationship to seizures

Objective. Current mapping of epileptic networks in patients prior to epilepsy surgery utilizes electrode arrays with sparse spatial sampling (∼1.0 cm inter-electrode spacing). Recent research demonstrates that sub-millimeter, cortical-column-scale domains have a role in seizure generation that may be clinically significant. We use high-resolution, active, flexible surface electrode arrays with 500 μm inter-electrode spacing to explore epileptiform local field potential (LFP) spike propagation patterns in two dimensions recorded from subdural micro-electrocorticographic signals in vivo in cat. In this study, we aimed to develop methods to quantitatively characterize the spatiotemporal dynamics of epileptiform activity at high-resolution. Approach. We topically administered a GABA-antagonist, picrotoxin, to induce acute neocortical epileptiform activity leading up to discrete electrographic seizures. We extracted features from LFP spikes to characterize spatiotemporal patterns in these events. We then tested the hypothesis that two-dimensional spike patterns during seizures were different from those between seizures. Main results. We showed that spatially correlated events can be used to distinguish ictal versus interictal spikes. Significance. We conclude that sub-millimeter-scale spatiotemporal spike patterns reveal network dynamics that are invisible to standard clinical recordings and contain information related to seizure-state.

Immediate epileptogenesis: Impact on brain in C57BL/6J mouse kainate model.

We have recently demonstrated immediate epileptogenesis in the C57BL/6J mouse, the strain that is resistant to kainate-induced neurotoxicity. By using a repeated low dose of kainate, we produced mild and severe status epilepticus (SE) models. In the present study, we demonstrate the impact of mild and severe SE, and spontaneous convulsive/nonconvulsive seizures (CS/NCS) on structure and function of the hippocampus, entorhinal cortex, and amygdala at 7, 14 and 28 day post-SE. Immunohistochemistry (IHC) of brain sections confirmed reactive astrogliosis and microgliosis, neurodegeneration, and increased neurogenesis in both groups. The epileptiform spike rate was higher in the severe group during first 12 days, but they decreased thereafter. Morris water maze test confirmed cognitive deficit in both mild and severe groups at 12d post-SE. However, MRI and IHC at 18 weeks did not reveal any changes in the hippocampus. These findings suggest that in C57BL/6J mice, immediate spontaneous CS could be responsible for early brain pathology or vice versa, however, the persistent spontaneous NCS for a long-term had no impact on the brain structure in both groups.

Synchronization and Propagation of Electrical Potentials in Neural Networks in the Cerebral Cortex

On the basis of the published data the scheme is proposed which explains the spread and synhronization of oscillatory activity in cortex. The main property of the neocortex is the existence of vertically oriented functional columns. Within and between the neuronal columns exist a feedforward and feedback morphological and functional connections. At the certain conditions inside the single module temporal windows are created using inhibitory process, and a synchronized activity can be generated of variable frequency (oscillations). The activity in the columns is enhanced by the synchronous involvement of great amount of neurons which is expressed in the form of local field potentials of high amplitude. Further the information about arisen in a single generator activity is transmitted through direct links to the nearby generator or to the group of such generators. In the nearby generator the activity increases and is transferred to the next generator. At the same time the signal is transmitted through feedback to the primary generator, and the activity is terminated until the next cycle will be initiated and so on along the cortex. The most important notion is that in the transfer of activity from one generator to another is involved a small number of elements. The major part of recorded oscillations of different frequency or epileptiform discharges, is not transmitted via the brain, but is generated in each module according to the characteristics transferred to it. The generation of epileptiform spikes occurs in cases when balance of inhibition determined by GABA A and GABA B receptors is disturbed.

Maternal Stress Combined with Terbutaline Leads to Comorbid Autistic-Like Behavior and Epilepsy in a Rat Model.

Human autism is comorbid with epilepsy, yet, little is known about the causes or risk factors leading to this combined neurological syndrome. Although genetic predisposition can play a substantial role, our objective was to investigate whether maternal environmental factors alone could be sufficient. We examined the independent and combined effects of maternal stress and terbutaline (used to arrest preterm labor), autism risk factors in humans, on measures of both autistic-like behavior and epilepsy in Sprague-Dawley rats. Pregnant dams were exposed to mild stress (foot shocks at 1 week intervals) throughout pregnancy. Pups were injected with terbutaline on postnatal days 2-5. Either maternal stress or terbutaline resulted in autistic-like behaviors in offspring (stereotyped/repetitive behaviors and deficits in social interaction or communication), but neither resulted in epilepsy. However, their combination resulted in severe behavioral symptoms, as well as spontaneous recurrent convulsive seizures in 45% and epileptiform spikes in 100%, of the rats. Hippocampal gliosis (GFAP reactivity) was correlated with both abnormal behavior and spontaneous seizures. We conclude that prenatal insults alone can cause comorbid autism and epilepsy but it requires a combination of teratogens to achieve this; testing single teratogens independently and not examining combinatorial effects may fail to reveal key risk factors in humans. Moreover, astrogliosis may be common to both teratogens. This new animal model of combined autism and epilepsy permits the experimental investigation of both the cellular mechanisms and potential intervention strategies for this debilitating comorbid syndrome.

Immediate Epileptogenesis after Kainate-Induced Status Epilepticus in C57BL/6J Mice: Evidence from Long Term Continuous Video-EEG Telemetry.

The C57BL/6J mouse as a model of seizure/epilepsy is challenging due to high mortality and huge variability in response to kainate. We have recently demonstrated that repeated administration of a low dose of kainate by intraperitoneal route can induce severe status epilepticus (SE) with 94% survival rate. In the present study, based on continuous video-EEG recording for 4-18 weeks from epidurally implanted electrodes on the cortex, we demonstrate that this method also induces immediate epileptogenesis (<1-5 days post-SE). This finding was based on identification of two types of spontaneous recurrent seizures; behavioral convulsive seizures (CS) and electrographic nonconvulsive seizures (NCS). The identification of the spontaneous CS, stage 3-5 types, was based on the behaviors (video) that were associated with the EEG characteristics (stage 3-5 epileptiform spikes), the power spectrum, and the activity counts. The electrographic NCS identification was based on the stage 1-2 epileptiform spike clusters on the EEG and their associated power spectrum. Severe SE induced immediate epileptogenesis in all the mice. The maximum numbers of spontaneous CS were observed during the first 4-6 weeks of the SE and they decreased thereafter. Mild SE also induced immediate epileptogenesis in some mice but the CS were less frequent. In both the severe and the mild SE groups, the spontaneous electrographic NCS persisted throughout the 18 weeks observation period, and therefore this could serve as a chronic model for complex seizures. However, unlike rat kainate models, the C57BL/6J mouse kainate model is a unique regressive CS model of epilepsy. Further studies are required to understand the mechanism of recovery from spontaneous CS in this model, which could reveal novel therapeutic targets for epilepsy.

P89. Differential diagnosis between epilepsy and parasomnia may be difficult even on 10–20 video-EEG

Sleep related attacks of bizarre complex movements may be due to either epilepsy or non-REM parasomnia. Differential diagnosis can be especially difficult in mentally retarded patients due to lack of detailed medical history and presence of epilepsy risk factors such as brain lesions. We present the case of a 19 year-old male with history of preterm birth, perinatal intracerebral hemorrhage, and post-hemorrhagic hydrocephalus. His parents reported up to 20 attacks per night characterized by startle from sleep, fearful expression in his eyes, grabbing hold of the bedframe, body rocking, and groaning, each episode lasting between 10 and 30 s. Several standard EEGs were normal. Cranial computed tomography (CT) scan showed a ventriculo-peritoneal shunt catheter in place. He was diagnosed with parasomnia following standard polysomnography in an external sleep laboratory. In our institution, polysomnography and 10–20 video EEG monitoring were performed for four nights, and 13 of the habitual attacks were recorded. All attacks occurred out of sleep with six attacks occurring from slow-wave sleep (N3) and seven occurring out of light sleep (N2). All but one attack were lacking an ictal EEG change, only one event was associated with rhythmic evolving theta in the left frontal region lasting for a few seconds. Tachykardia of up to 170 beats per minute was seen in all events. Video review revealed that the sequence of clinical features was extremely stereotypical and monomorphic across all 13 events. Interictal EEG was completely normal during the awake stage as well as during sleep in the first and second nights. Only in nights three and four, interictal sleep EEG revealed several spikes in the left frontal region. We diagnosed left frontal lobe epilepsy with exclusively sleep-related hypermotor seizures and stared the patient on anticonvulsant medication. This case demonstrates that the differential diagnosis of epilepsy versus Non-REM parasomnia may be difficult even with 10–20 video EEG. The vast majority of seizures (or all) may lack an ictal EEG pattern, and interictal epileptiform spikes or sharp waves may be very infrequent or absent. Short events with a very stereotypic sequence of clinical features as well as attacks arising from light sleep (N2) support the diagnosis of epilepsy. One or two nights of polysomnography – even with an extended 10–20 EEG montage – may not be sufficient to differentiate parasomnia from epileptic seizures.

Cariprazine delays ouabain-evoked epileptiform spikes and loss of activity in rat hippocampal slices

In the only bipolar cycling in vitro model, rat hippocampal slices are treated with the sodium pump inhibitor ouabain, which induces epileptiform activity, followed by refractory activity loss that recovers and cycles back to epileptiform activity. Thus, clinical cycling seen in patients with bipolar disorder is modeled on a cellular level as alternating hyperactivity and hypoactivity interspersed with normal activity. In this study, we tested the ability of cariprazine a new antipsychotic candidate to block ouabain-induced changes in rat hippocampal slices. Cycling of population spikes and epileptiform bursts was evoked using an extracellular stimulation electrode located in the Schaeffer collaterals of 400-µm-thick rat hippocampal slices treated with ouabain (3.3μM) alone or in combination with cariprazine (1, 5, 25, and 50µM). Responses were recorded using an extracellular electrode placed in the cell body layer of the CA1 region. Cariprazine 25 and 50µM delayed ouabain-induced epileptiform burst onset and subsequent activity loss. Lower cariprazine concentrations were ineffective. Cariprazine delays the onset of ouabain-induced epileptiform bursts and the loss of spiking activity similarly to that previously demonstrated with the mood stabilizer lithium. These results suggest that cariprazine may have therapeutic potential for treatment of bipolar disorder.

Grand mal seizure induced by low-dose fentanyl and lidocaine in a young child

Surgical procedures require general anesthesia using combinations of drugs including fentanyl and/or lidocaine. Because many of these drugs have bimodal anticonvulsant/proconvulsant effects, they must be administered carefully. We herein report a case of seizure attack during anesthesia induction with low-dose fentanyl and lidocaine in a young child with no history of seizures. A 10-year-old girl was scheduled to receive an elective tenectomy. After a few seconds of fentanyl and lidocaine administration for anesthesia induction, she developed generalized tonic–clonic seizures. Seizures subsided spontaneously after 3 minutes. The patient's blood sugar, serum electrolytes, and arterial blood gas analysis were normal immediately after the event. She remained hemodynamically stable; however, the surgery was postponed after communication and discussion with the surgeon. Postoperatively, there was no evidence of postictal phase, and serum electrolytes and magnetic resonance imaging of the brain were normal. The patient had an uneventful recovery. However, electroencephalogram showed that hyperventilation stimulation test induced isolated epileptiform spikes over O1, suggesting a potential paroxysmal disorder over the left occipital area. This report is on a rare complication likely caused by fentanyl or lidocaine, which suggests that these drugs should be used cautiously in children whose clinical epileptic activities have been verified or are strongly suspected.

Spotlight on the February 10 Issue

#### Notable in Neurology This issue features articles on 3-tesla functional MR language mapping compared to direct cortical stimulation in gliomas and on GRIN2A , an aptly named gene for speech dysfunction. Other featured articles focus on gamma frequency oscillations preceding interictal epileptiform spikes in seizure onset zones and on colonic mucosal α-synuclein lacking specificity as a biomarker for Parkinson disease. ### Peripheral nerve ultrasound in pediatric Charcot-Marie-Tooth disease type 1A![Graphic][1]</img> Nerve ultrasound is a noninvasive and well-tolerated peripheral nerve imaging modality. This study of 29 children with Charcot-Marie-Tooth disease type 1A (CMT1A) and 29 controls demonstrated a marked increase in … [1]: /embed/inline-graphic-1.gif

Melatonin improves sleep in children with epilepsy: a randomized, double-blind, crossover study

ObjectiveInsomnia, especially maintenance insomnia, is widely prevalent in epilepsy. Although melatonin is commonly used, limited data address its efficacy. We performed a randomized, double-blind, placebo-controlled, crossover study to identify the effects of melatonin on sleep and seizure control in children with epilepsy. MethodsEleven prepubertal, developmentally normal children aged 6–11 years with epilepsy were randomized by a software algorithm to receive placebo or a 9-mg sustained release (SR) melatonin formulation for four weeks, followed by a one-week washout and a four-week crossover condition. The pharmacy performed blinding; patients, parents, and study staff other than a statistician were blinded. The primary outcomes were sleep onset latency and wakefulness after sleep onset (WASO) measured on polysomnography. The secondary outcomes included seizure frequency, epileptiform spike density per hour of sleep on electroencephalogram (EEG), and reaction time (RT) measures on psychomotor vigilance task (PVT). Statistical tests appropriate for crossover designs were used for the analysis. ResultsData were analyzed from 10 subjects who completed the study. Melatonin decreased sleep latency (mean difference, MD, of 11.4 min and p = 0.02) and WASO (MD of 22 min and p = 0.04) as compared to placebo. No worsening of spike density or seizure frequency was seen. Additionally, slow-wave sleep duration and rapid eye movement (REM) latency were increased with melatonin and REM sleep duration was decreased. These changes were statistically significant. Worsening of headache was noted in one subject with migraine on melatonin. ConclusionSR melatonin resulted in statistically significant decreases in sleep latency and WASO. No clear effects on seizures were observed, but the study was too small to allow any conclusions to be drawn in this regard.