A pediatrician's guide to epilepsy surgery.

Surgical intervention for epilepsy emerged in the second half of the 20th century as an important option for pediatric patients with medically refractory epilepsy. Both the number of patients undergoing epilepsy surgery and the available surgical procedures for epilepsy have expanded in the last 3 decades, and now range from surgical resection to neuromodulatory device placement1,2 Studies showing that many patients who would be excellent candidates for surgery are still not being offered appropriate interventions have prompted an interest in ensuring that all providers who see patients with epilepsy are aware of the options for epilepsy surgery to facilitate earlier referrals when medications have not been effective3 In this article, we will introduce the pediatrician to the process involved in determining epilepsy surgery candidacy and to surgical outcomes, with the goal of empowering pediatric providers to refer their medically refractory epilepsy patients to a pediatric epilepsy center.

Quantifying trial-by-trial variability during cortico-cortical evoked potential mapping of epileptogenic tissue.

OBJECTIVE: Measuring cortico-cortical evoked potentials (CCEPs) is a promising tool for mapping epileptic networks, but it is not known how variability in brain state and stimulation technique might impact the use of CCEPs for epilepsy localization. We test the hypotheses that (1) CCEPs demonstrate systematic variability across trials and (2) CCEP amplitudes depend on the timing of stimulation with respect to endogenous, low-frequency oscillations. METHODS: We studied 11 patients who underwent CCEP mapping after stereo-electroencephalography electrode implantation for surgical evaluation of drug-resistant epilepsy. Evoked potentials were measured from all electrodes after each pulse of a 30 s, 1 Hz bipolar stimulation train. We quantified monotonic trends, phase dependence, and standard deviation (SD) of N1 (15-50 ms post-stimulation) and N2 (50-300 ms post-stimulation) amplitudes across the 30 stimulation trials for each patient. We used linear regression to quantify the relationship between measures of CCEP variability and the clinical seizure-onset zone (SOZ) or interictal spike rates. RESULTS: We found that N1 and N2 waveforms exhibited both positive and negative monotonic trends in amplitude across trials. SOZ electrodes and electrodes with high interictal spike rates had lower N1 and N2 amplitudes with higher SD across trials. Monotonic trends of N1 and N2 amplitude were more positive when stimulating from an area with higher interictal spike rate. We also found intermittent synchronization of trial-level N1 amplitude with low-frequency phase in the hippocampus, which did not localize the SOZ. SIGNIFICANCE: These findings suggest that standard approaches for CCEP mapping, which involve computing a trial-averaged response over a .2-1 Hz stimulation train, may be masking inter-trial variability that localizes to epileptogenic tissue. We also found that CCEP N1 amplitudes synchronize with ongoing low-frequency oscillations in the hippocampus. Further targeted experiments are needed to determine whether phase-locked stimulation could have a role in localizing epileptogenic tissue.

Mapping Interictal activity in epilepsy using a hidden Markov model: A magnetoencephalography study.

Epilepsy is a highly heterogeneous neurological disorder with variable etiology, manifestation, and response to treatment. It is imperative that new models of epileptiform brain activity account for this variability, to identify individual needs and allow clinicians to curate personalized care. Here, we use a hidden Markov model (HMM) to create a unique statistical model of interictal brain activity for 10 pediatric patients. We use magnetoencephalography (MEG) data acquired as part of standard clinical care for patients at the Children's Hospital of Philadelphia. These data are routinely analyzed using excess kurtosis mapping (EKM); however, as cases become more complex (extreme multifocal and/or polymorphic activity), they become harder to interpret with EKM. We assessed the performance of the HMM against EKM for three patient groups, with increasingly complicated presentation. The difference in localization of epileptogenic foci for the two methods was 7 ± 2 mm (mean ± SD over all 10 patients); and 94% ± 13% of EKM temporal markers were matched by an HMM state visit. The HMM localizes epileptogenic areas (in agreement with EKM) and provides additional information about the relationship between those areas. A key advantage over current methods is that the HMM is a data-driven model, so the output is tuned to each individual. Finally, the model output is intuitive, allowing a user (clinician) to review the result and manually select the HMM epileptiform state, offering multiple advantages over previous methods and allowing for broader implementation of MEG epileptiform analysis in surgical decision-making for patients with intractable epilepsy.

Quantitative electroencephalographic analysis as a potential biomarker of response to treatment with cannabidiol.

PURPOSE: Pharmaceutical grade cannabidiol (CBD) is one of the newest anti-seizure medications for refractory epilepsy, and the effects of CBD on EEG have not been fully described. METHODS: Patients enrolled in a CBD expanded access study had EEGs prior to and 12 weeks after initiation of CBD treatment for their refractory epilepsy. In addition to evaluating the clinical EEG reports, a nonbiased quantitative EEG (qEEG) analysis of background EEG was performed to determine whether consistent changes occur in the EEG in response to administration of CBD. RESULTS: No significant qualitative changes were seen, nor changes in quantitative markers of EEG amplitude (RMS amplitude, standard deviation of the amplitude, skewness, or kurtosis), frequency (relative delta, theta, or alpha power), Spearman correlation, or coherence between brain regions. However, relative beta power and 1/f slope, a measure of signal noise increased with the addition of CBD. When patients were separated into responders and nonresponders based on seizure reduction with CBD, responders also had decreased Spearman correlation between the frontopolar and occipital regions after addition of CBD, suggesting that responders may have quantitatively improved EEG background organization after CBD initiation. The differences in beta and 1/f slope were also seen more robustly in CBD responders compared with nonresponders after CBD initiation. These differences disappeared when analyzing only patients not taking benzodiazepines, suggesting that the effect of CBD on seizures was related to the ability of the brain to further increase beta in response to CBD in patients already taking benzodiazepines. We noted that even before initiation of CBD, 1/f slope was also significantly different in responders compared to nonresponders. Therefore, to explore the baseline EEG in responders and nonresponders, we utilized a variable selection procedure to identify baseline EEG features that could predict whether a patient's seizures would improve with CBD. In the optimal multivariable logistic model, baseline coherence, Spearman correlation, and patient sex jointly predicted whether a patient in this cohort would respond to CBD (defined as a seizure reduction of 40% or greater) with 74% accuracy. This model performed less well on a data set of reduced duration and variability, highlighting the importance of real-world testing of any clinically relevant model. CONCLUSION: These results suggest that there are subtle changes in certain metrics detected by qEEG even at baseline that may not be perceived during qualitative EEG analysis and that could be used in the future as a biomarker to predict a patient's clinical response to CBD administration. Development of such a predictive EEG biomarker, especially before the initiation of a medication trial, could reduce unnecessary ASM exposure and improve outcomes for patients with epilepsy facing new medication selection.

Stereoelectroencephalography in the very young: Case report.

Stereoelectroencephalography (SEEG) is an increasingly popular invasive monitoring approach to epilepsy surgery in patients with drug-resistant epilepsies. The technique allows a three-dimensional definition of the epileptogenic zones (EZ) in the brain. It has been shown to be safe and effective in adults and older children but has been used sparingly in children less than two years old due to concerns about pin fixation in thin bone, registration accuracy, and bolt security. As such, most current series of pediatric invasive EEG explorations do not include young participants, and, when they do, SEEG is often not utilized for these patients. Recent national survey data further suggests SEEG is infrequently utilized in very young patients. We present a novel case of SEEG used to localize the EZ in a 17-month-old patient with thin cranial bone, an open fontanelle, and severe drug-resistant epilepsy due to tuberous sclerosis complex (TSC), with excellent accuracy, surgical results, and seizure remission.

Electrophysiological Biomarkers in Genetic Epilepsies.

Precision treatments for epilepsy targeting the underlying genetic diagnoses are becoming a reality. Historically, the goal of epilepsy treatments was to reduce seizure frequency. In the era of precision medicine, however, outcomes such as prevention of epilepsy progression or even improvements in cognitive functions are both aspirational targets for any intervention. Developing methods, both in clinical trial design and in novel endpoints, will be necessary for measuring, not only seizures, but also the other neurodevelopmental outcomes that are predicted to be targeted by precision treatments. Biomarkers that quantitatively measure disease progression or network level changes are needed to allow for unbiased measurements of the effects of any gene-level treatments. Here, we discuss some of the promising electrophysiological biomarkers that may be of use in clinical trials of precision therapies, as well as the difficulties in implementing them.

Correction to: Neurological complications of pediatric cancer.

The authors have noticed a typographical error in the published article.

Neurological complications of pediatric cancer.

Both the onset of various malignancies as well as the treatment of cancer can lead to neurologic symptoms which can be difficult to diagnose. In this review, we highlight the varied ways in which neurologic sequelae of cancer and its treatment manifest in children. Initial neurologic presentation may be secondary to mass effect or to immune-mediated paraneoplastic syndromes. Treatment effects on the nervous system may arise from surgery, chemotherapy, radiation, or bone marrow transplantation. In addition, the rapidly expanding field of immunotherapies for cancer has generated numerous new approaches to eradicating cancer including monoclonal antibodies, checkpoint inhibitors, and chimeric antigen receptor T cells (CAR-T cells), which have neurologic side effects mediated by immune responses that are also being recognized. Here we review common consult questions to the neurologist and our general approach to these scenarios including altered mental status, headaches, seizures, and sensorimotor complaints, considering the multifactorial nature of each.

A Child With Pancytopenia and Optic Disc Swelling.

A previously healthy 16-year-old adolescent boy presented with pallor, blurry vision, fatigue, and dyspnea on exertion. Physical examination demonstrated hypertension and bilateral optic nerve swelling. Laboratory testing revealed pancytopenia. Pediatric hematology, ophthalmology and neurology were consulted and a life-threatening diagnosis was made.

Target-selectivity of parvalbumin-positive interneurons in layer II of medial entorhinal cortex in normal and epileptic animals.

The medial entorhinal cortex layer II (MEClayerII ) is a brain region critical for spatial navigation and memory, and it also demonstrates a number of changes in patients with, and animal models of, temporal lobe epilepsy (TLE). Prior studies of GABAergic microcircuitry in MEClayerII revealed that cholecystokinin-containing basket cells (CCKBCs) select their targets on the basis of the long-range projection pattern of the postsynaptic principal cell. Specifically, CCKBCs largely avoid reelin-containing principal cells that form the perforant path to the ipsilateral dentate gyrus and preferentially innervate non-perforant path forming calbindin-containing principal cells. We investigated whether parvalbumin containing basket cells (PVBCs), the other major perisomatic targeting GABAergic cell population, demonstrate similar postsynaptic target selectivity as well. In addition, we tested the hypothesis that the functional or anatomic arrangement of circuit selectivity is disrupted in MEClayerII in chronic TLE, using the repeated low-dose kainate model in rats. In control animals, we found that PVBCs innervated both principal cell populations, but also had significant selectivity for calbindin-containing principal cells in MEClayerII . However, the magnitude of this preference was smaller than for CCKBCs. In addition, axonal tracing and paired recordings showed that individual PVBCs were capable of contacting both calbindin and reelin-containing principal cells. In chronically epileptic animals, we found that the intrinsic properties of the two principal cell populations, the GABAergic perisomatic bouton numbers, and selectivity of the CCKBCs and PVBCs remained remarkably constant in MEClayerII . However, miniature IPSC frequency was decreased in epilepsy, and paired recordings revealed the presence of direct excitatory connections between principal cells in the MEClayerII in epilepsy, which is unusual in normal adult MEClayerII . Taken together, these findings advance our knowledge about the organization of perisomatic inhibition both in control and in epileptic animals. © 2015 Wiley Periodicals, Inc.

Brain State Is a Major Factor in Preseizure Hippocampal Network Activity and Influences Success of Seizure Intervention.

Neural dynamics preceding seizures are of interest because they may shed light on mechanisms of seizure generation and could be predictive. In healthy animals, hippocampal network activity is shaped by behavioral brain state and, in epilepsy, seizures selectively emerge during specific brain states. To determine the degree to which changes in network dynamics before seizure are pathological or reflect ongoing fluctuations in brain state, dorsal hippocampal neurons were recorded during spontaneous seizures in a rat model of temporal lobe epilepsy. Seizures emerged from all brain states, but with a greater likelihood after REM sleep, potentially due to an observed increase in baseline excitability during periods of REM compared with other brains states also characterized by sustained theta oscillations. When comparing the firing patterns of the same neurons across brain states associated with and without seizures, activity dynamics before seizures followed patterns typical of the ongoing brain state, or brain state transitions, and did not differ until the onset of the electrographic seizure. Next, we tested whether disparate activity patterns during distinct brain states would influence the effectiveness of optogenetic curtailment of hippocampal seizures in a mouse model of temporal lobe epilepsy. Optogenetic curtailment was significantly more effective for seizures preceded by non-theta states compared with seizures that emerged from theta states. Our results indicate that consideration of behavioral brain state preceding a seizure is important for the appropriate interpretation of network dynamics leading up to a seizure and for designing effective seizure intervention. SIGNIFICANCE STATEMENT: Hippocampal single-unit activity is strongly shaped by behavioral brain state, yet this relationship has been largely ignored when studying activity dynamics before spontaneous seizures in medial temporal lobe epilepsy. In light of the increased attention on using single-unit activity for the prediction of seizure onset and closed-loop seizure intervention, we show a need for monitoring brain state to interpret correctly whether changes in neural activity before seizure onset is pathological or normal. Moreover, we also find that the brain state preceding a seizure determines the success of therapeutic interventions to curtail seizure duration. Together, these findings suggest that seizure prediction and intervention will be more successful if tailored for the specific brain states from which seizures emerge.

In vivo evaluation of the dentate gate theory in epilepsy.

The dentate gyrus is a region subject to intense study in epilepsy because of its posited role as a 'gate', acting to inhibit overexcitation in the hippocampal circuitry through its unique synaptic, cellular and network properties that result in relatively low excitability. Numerous changes predicted to produce dentate hyperexcitability are seen in epileptic patients and animal models. However, recent findings question whether changes are causative or reactive, as well as the pathophysiological relevance of the dentate in epilepsy. Critically, direct in vivo modulation of dentate 'gate' function during spontaneous seizure activity has not been explored. Therefore, using a mouse model of temporal lobe epilepsy with hippocampal sclerosis, a closed-loop system and selective optogenetic manipulation of granule cells during seizures, we directly tested the dentate 'gate' hypothesis in vivo. Consistent with the dentate gate theory, optogenetic gate restoration through granule cell hyperpolarization efficiently stopped spontaneous seizures. By contrast, optogenetic activation of granule cells exacerbated spontaneous seizures. Furthermore, activating granule cells in non-epileptic animals evoked acute seizures of increasing severity. These data indicate that the dentate gyrus is a critical node in the temporal lobe seizure network, and provide the first in vivo support for the dentate 'gate' hypothesis.

Cerebellar Directed Optogenetic Intervention Inhibits Spontaneous Hippocampal Seizures in a Mouse Model of Temporal Lobe Epilepsy.

Temporal lobe epilepsy is often medically refractory and new targets for intervention are needed. We used a mouse model of temporal lobe epilepsy, on-line seizure detection, and responsive optogenetic intervention to investigate the potential for cerebellar control of spontaneous temporal lobe seizures. Cerebellar targeted intervention inhibited spontaneous temporal lobe seizures during the chronic phase of the disorder. We further report that the direction of modulation as well as the location of intervention within the cerebellum can affect the outcome of intervention. Specifically, on-demand optogenetic excitation or inhibition of parvalbumin-expressing neurons, including Purkinje cells, in the lateral or midline cerebellum results in a decrease in seizure duration. In contrast, a consistent reduction in spontaneous seizure frequency occurs uniquely with on-demand optogenetic excitation of the midline cerebellum, and was not seen with intervention directly targeting the hippocampal formation. These findings demonstrate that the cerebellum is a powerful modulator of temporal lobe epilepsy, and that intervention targeting the cerebellum as a potential therapy for epilepsy should be revisited.

Closed-loop optogenetic intervention in mice.

Optogenetic interventions offer novel ways of probing, in a temporally specific manner, the roles of specific cell types in neuronal network functions of awake, behaving animals. Despite the unique potential for temporally specific optogenetic intervention in disease states, a major hurdle in its broad application to unpredictable brain states in a laboratory setting is constructing a real-time responsive system. We recently created a closed-loop system for stopping spontaneous seizures in chronically epileptic mice by using optogenetic intervention. This system performs with a very high sensitivity and specificity, and the strategy is not only relevant to epilepsy but also can also be used to react to diverse brain states in real time, with optogenetic or other interventions. The protocol presented here is highly modular and requires variable amounts of time to perform. We describe the basic construction of a complete system, and we include our downloadable custom closed-loop detection software, which can be used for this purpose.

On-demand optogenetic control of spontaneous seizures in temporal lobe epilepsy.

Temporal lobe epilepsy is the most common type of epilepsy in adults, is often medically refractory, and due to broad actions and long-time scales, current systemic treatments have major negative side-effects. However, temporal lobe seizures tend to arise from discrete regions before overt clinical behaviour, making temporally and spatially specific treatment theoretically possible. Here we report the arrest of spontaneous seizures using a real-time, closed-loop, response system and in vivo optogenetics in a mouse model of temporal lobe epilepsy. Either optogenetic inhibition of excitatory principal cells, or activation of a subpopulation of GABAergic cells representing <5% of hippocampal neurons, stops seizures rapidly upon light application. These results demonstrate that spontaneous temporal lobe seizures can be detected and terminated by modulating specific cell populations in a spatially restricted manner. A clinical approach built on these principles may overcome many of the side-effects of currently available treatment options.

Neurogliaform and Ivy Cells: A Major Family of nNOS Expressing GABAergic Neurons.

Neurogliaform and Ivy cells are members of an abundant family of neuronal nitric oxide synthase (nNOS) expressing GABAergic interneurons found in diverse brain regions. These cells have a defining dense local axonal plexus, and display unique synaptic properties including a biphasic postsynaptic response with both a slow GABA(A) component and a GABA(B) component following even a single action potential. The type of transmission displayed by these cells has been termed "volume transmission," distinct from both tonic and classical synaptic transmission. Electrical connections are also notable in that, unlike other GABAergic cell types, neurogliaform family cells will form gap junctions not only with other neurogliaform cells, but also with non-neurogliaform family GABAergic cells. In this review, we focus on neurogliaform and Ivy cells throughout the hippocampal formation, where recent studies highlight their role in feedforward inhibition, uncover their ability to display a phenomenon called persistent firing, and reveal their modulation by opioids. The unique properties of this family of cells, their abundance, rich connectivity, and modulation by clinically relevant drugs make them an attractive target for future studies in vivo during different behavioral and pharmacological conditions.

Basket cell dichotomy in microcircuit function.

A diversity of GABAergic cell types exist within each brain area, and each cell type is thought to play a unique role in the modulation of principal cell output. Basket cells, whose axon terminals surround principal cell somata and proximal dendrites, have a privileged and influential position for regulating the firing of principal cells. This review explores the dichotomy of the two basket cell classes, cholecystokinin- (CCK) and parvalbumin (PV)-containing basket cells, beginning with differences at the level of the individual cell and subsequently focusing on two ways in which this intrinsic dichotomy is enhanced by extrinsic factors. Neuromodulatory influences, exemplified by the effects of the peptide CCK, dynamically enhance the differential functions of the two cell types. Specifications at the level of the postsynaptic principal cell, including input-specific differences in chloride handling and differences in long-range projection patterns of the principal cell targets, also enhance the distinct network function of basket cells. In this review, new findings will be highlighted concerning the roles of neuromodulatory control and postsynaptic long-range projection pattern in the definition of basket cell function.

Neurogliaform cells in the molecular layer of the dentate gyrus as feed-forward γ-aminobutyric acidergic modulators of entorhinal-hippocampal interplay.

Feed-forward inhibition from molecular layer interneurons onto granule cells (GCs) in the dentate gyrus is thought to have major effects regulating entorhinal-hippocampal interactions, but the precise identity, properties, and functional connectivity of the GABAergic cells in the molecular layer are not well understood. We used single and paired intracellular patch clamp recordings from post-hoc-identified cells in acute rat hippocampal slices and identified a subpopulation of molecular layer interneurons that expressed immunocytochemical markers present in members of the neurogliaform cell (NGFC) class. Single NGFCs displayed small dendritic trees, and their characteristically dense axonal arborizations covered significant portions of the outer and middle one-thirds of the molecular layer, with frequent axonal projections across the fissure into the CA1 and subicular regions. Typical NGFCs exhibited a late firing pattern with a ramp in membrane potential prior to firing action potentials, and single spikes in NGFCs evoked biphasic, prolonged GABA(A) and GABA(B) postsynaptic responses in GCs. In addition to providing dendritic GABAergic inputs to GCs, NGFCs also formed chemical synapses and gap junctions with various molecular layer interneurons, including other NGFCs. NGFCs received low-frequency spontaneous synaptic events, and stimulation of perforant path fibers revealed direct, facilitating synaptic inputs from the entorhinal cortex. Taken together, these results indicate that NGFCs form an integral part of the local molecular layer microcircuitry generating feed-forward inhibition and provide a direct GABAergic pathway linking the dentate gyrus to the CA1 and subicular regions through the hippocampal fissure.

Pursuing paradoxical proconvulsant prophylaxis for epileptogenesis.

There are essentially two potential treatment options for any acquired disorder: symptomatic or prophylactic. For acquired epilepsies that follow a variety of different brain insults, there remains a complete lack of prophylactic treatment options, whereas at the same time these epilepsies are notoriously resistant, once they have emerged, to symptomatic treatments with antiepileptic drugs. The development of prophylactic strategies is logistically challenging, both for basic researchers and clinicians. Nevertheless, cannabinoid-targeting drugs provide a very interesting example of a system within the central nervous system (CNS) that can have very different acute and long-term effects on hyperexcitability and seizures. In this review, we outline research on cannabinoids suggesting that although cannabinoid antagonists are acutely proconvulsant, they may have beneficial effects on long-term hyperexcitability following brain insults of multiple etiologies, making them promising candidates for further investigation as prophylactics against acquired epilepsy. We then discuss some of the implications of this finding on future attempts at prophylactic treatments, specifically, the very short window within which prevention may be possible, the possibility that traditional anticonvulsants may interfere with prophylactic strategies, and the importance of moving beyond anticonvulsants-even to proconvulsants-to find the ideal preventative strategy for acquired epilepsy.