Showing papers in "Epilepsy Currents in 2019"
TL;DR: Intracranial EEG recordings from within the insula, using stereo-EEG or depth electrode techniques, can prove insular seizure origin and lead to interest in the role of the insulas with marked autonomic changes in sudden unexpected death in epilepsy.
Abstract: Insular seizures are great mimickers of seizures originating elsewhere in the brain. The insula is a highly connected brain structure. Seizures may only become clinically evident after ictal activity propagates out of the insula with semiology that reflects the propagation pattern. Insular seizures with perisylvian spread, for example, manifest first as throat constriction, followed next by perioral and hemisensory symptoms, and then by unilateral motor symptoms. On the other hand, insular seizures may spread instead to the temporal and frontal lobes and present like seizures originating from these regions. Due to the location of the insula deep in the brain, interictal and ictal scalp electroencephalogram (EEG) changes can be variable and misleading. Magnetic resonance imaging, magnetic resonance spectroscopy, magnetoencephalography, positron emission tomography, and single-photon computed tomography imaging may assist in establishing a diagnosis of insular epilepsy. Intracranial EEG recordings from within the insula, using stereo-EEG or depth electrode techniques, can prove insular seizure origin. Seizure onset, most commonly seen as low-voltage, fast gamma activity, however, can be highly localized and easily missed if the insula is only sparsely sampled. Moreover, seizure spread to the contralateral insula and other brain regions may occur rapidly. Extensive sampling of the insula with multiple electrode trajectories is necessary to avoid these pitfalls. Understanding the functional organization of the insula is helpful when interpreting the semiology produced by insular seizures. Electrical stimulation mapping around the central sulcus of the insula results in paresthesias, while stimulation of the posterior insula typically produces painful sensations. Visceral sensations are the next most common result of insular stimulation. Treatment of insular epilepsy is evolving, but poses challenges. Surgical resections of the insula are effective but risk significant morbidity if not carefully planned. Neurostimulation is an emerging option for treatment, especially for seizures with onset in the posterior insula. The close association of the insula with marked autonomic changes has led to interest in the role of the insula in sudden unexpected death in epilepsy and warrants additional study with larger patient cohorts.
58 citations
TL;DR: A large body of evidence that has accumulated over the past decade strongly supports the role of both blood–brain barrier (BBB) dysfunction and perivascular inflammation in the pathophysiology of epilepsy and the potential for disease modification in acquired and genetic epilepsies is addressed.
Abstract: A large body of evidence that has accumulated over the past decade strongly supports the role of both blood-brain barrier (BBB) dysfunction and perivascular inflammation in the pathophysiology of epilepsy. Recent preclinical studies indicate that prolonged seizure- or brain injury-induced BBB dysfunction and subsequent perivascular inflammation may play an important role in post-traumatic epileptogenesis. In turn, perivascular inflammation can further sustain BBB dysfunction. In genetic epilepsies, such as tuberous sclerosis complex and other related epileptogenic developmental pathologies, there is an association between the underlying gene mutation, BBB dysfunction, and perivascular inflammation, but evidence for a causal link to epilepsy is lacking. Future neuroimaging studies might shed light on the role of BBB function in different epilepsies and address the potential for disease modification by targeting both the BBB and perivascular inflammation in acquired and genetic epilepsies.
34 citations
TL;DR: This review describes developments in epilepsy research during the last 3 to 4 decades that focused on the dentate gyrus (DG) and its role in temporal lobe epilepsy (TLE).
Abstract: This review describes developments in epilepsy research during the last 3 to 4 decades that focused on the dentate gyrus (DG) and its role in temporal lobe epilepsy (TLE). The emphasis is on basic research in laboratory animals and is chronological, starting with hypotheses that attracted a lot of attention in the 1980s. Then experiments are described that addressed the questions, as well as new methods that often made the experiments possible. In addition, where new questions arose and the implications for clinical epilepsy are discussed.
33 citations
TL;DR: Preclinical studies in rodents now suggest that targeting these new neurons in hippocampal dentate granule cells can have disease-modifying effects in epilepsy.
Abstract: Compelling evidence indicates that hippocampal dentate granule cells are generated throughout human life and into old age. While animal studies demonstrate that these new neurons are important for ...
28 citations
TL;DR: This review focuses on developments through seizure-induced death models and the preventative strategies they may reveal in patients with refractory epilepsy.
Abstract: Sudden unexpected death in epilepsy (SUDEP) is the leading cause of death in patients with refractory epilepsy, accounting for up to 17% of deaths in patients with epilepsy. The pathophysiology of SUDEP has remained unclear, largely because it is unpredictable and commonly unwitnessed. This poses a great challenge to studies in patients. Recently, there has been an increase in animal studies to try to better understand the pathophysiology of SUDEP. In this current review, we focus on developments through seizure-induced death models and the preventative strategies they may reveal.
22 citations
TL;DR: This work discusses current findings, highlights the innovative approaches that have enabled these insights, and provides a unified framework that incorporates these sometimes-conflicting ideas that will be necessary to finally resolve the remaining issues.
Abstract: Absence epilepsy is a disorder of thalamocortical networks. Animal models have provided detailed information regarding the core cellular, synaptic, and network features that contribute to the elect...
21 citations
TL;DR: It is shown that the prevalence of major congenital malformations was significantly higher for all doses of carbamazepine and valproate as well as for phenobarbital at doses of more than 80 mg/d than for lamotrigine at dose of 325mg/d or less, which indicates different antiepileptic drugs and dosages have different teratogenic risks.
Abstract: Teratogenesis of 8 Antiepileptic Drugs in Multinational Experience Tomson T, Battino D, Bonizzoni E, Craig J, Lindhout D, Perucca E, Sabers A, Thomas SV, Vajda F for the EURAP Study Group. Lancet N...
17 citations
TL;DR: The results imply that transient impairment of action potential generation by PVINs may contribute to the initial appearance of epilepsy, but is not the mechanism of ongoing, chronic epilepsy in Dravet syndrome.
Abstract: Selective Nav1.1 Activation Rescues Dravet Syndrome Mice From Seizures and Premature Death Richards KL, Milligan CJ, Richardson RJ, Jancovski N, Grunnet M, Jacobson LH, Undheim EAB, Mobli M, Chow CY, Herzig V, Csoti A, Panyi G, Reid CA, King GF, Petrou S. PNAS. 2018;115:E8077-E8085. Dravet syndrome is a catastrophic, pharmaco-resistant epileptic encephalopathy. Disease onset occurs in the first year of life, followed by developmental delay with cognitive and behavioral dysfunction and substantially elevated risk of premature death. The majority of affected individuals harbor a loss-of-function mutation in one allele of SCN1A, which encodes the voltage-gated sodium channel Nav1.1. Brain Nav1.1 is primarily localized to fast-spiking inhibitory interneurons; thus, the mechanism of epileptogenesis in Dravet syndrome is hypothesized to be reduced inhibitory neurotransmission leading to brain hyperexcitability. We show that selective activation of Nav1.1 by venom peptide Hm1a restores the function of inhibitory interneurons from Dravet syndrome mice without affecting the firing of excitatory neurons. Intracerebroventricular infusion of Hm1a rescues Dravet syndrome mice from seizures and premature death. This precision medicine approach, which specifically targets the molecular deficit in Dravet syndrome, presents an opportunity for treatment of this intractable epilepsy. A Transient Developmental Window of Fast-Spiking Interneuron Dysfunction in a Mouse Model of Dravet Syndrome Favero M, Sotuyo NP, Lopez E, Kearney JA, Goldberg EM. J Neurosci. 2018;38:7912-7927. Dravet syndrome is a severe childhood-onset epilepsy largely due to heterozygous loss-of-function mutation of the gene SCN1A, which encodes the type 1 neuronal voltage-gated sodium (Na+) channel α subunit Nav1.1. Prior studies in mouse models of Dravet syndrome ( Scn1a+/- mice) indicate that, in cerebral cortex, Nav1.1 is predominantly expressed in GABAergic interneurons, in particular in parvalbumin-positive fast-spiking basket cell interneurons (PVINs). This has led to a model of Dravet syndrome pathogenesis in which Nav1.1 mutation leads to preferential dysfunction of interneurons, decreased synaptic inhibition, hyperexcitability, and epilepsy. However, such studies have been implemented at early developmental time points. Here, we performed electrophysiological recordings in acute brain slices prepared from male and female Scn1a+/-mice as well as age-matched wild-type littermate controls and found that, later in development, the excitability of PVINs had normalized. Analysis of action potential waveforms indirectly suggests a reorganization of axonal Na+ channels in PVINs from Scn1a+/- mice, a finding supported by immunohistochemical data showing elongation of the axon initial segment. Our results imply that transient impairment of action potential generation by PVINs may contribute to the initial appearance of epilepsy, but is not the mechanism of ongoing, chronic epilepsy in Dravet syndrome. Significance Statement: Dravet syndrome is characterized by normal early development, temperature-sensitive seizures in infancy, progression to treatment-resistant epilepsy, developmental delay, autism, and sudden unexplained death due to mutation in SCN1A encoding the Na+ channel subunit Nav1.1. Prior work has revealed a preferential impact of Nav1.1 loss on the function of GABAergic inhibitory interneurons. However, such data derive exclusively from recordings of neurons in young Scn1a+/- mice. Here, we show that impaired action potential generation observed in parvalbumin-positive fast-spiking interneurons (PVINs) in Scn1a+/- mice during early development has normalized by postnatal day 35. This work suggests that a transient impairment of PVINs contributes to epilepsy onset, but is not the mechanism of ongoing, chronic epilepsy in Dravet syndrome.
14 citations
TL;DR: Using next-generation sequencing techniques, pathogenic variants in CACNA1E are established as a cause of DEEs and facilitated R-type calcium currents as a disease mechanism for human epilepsy and developmental disorders.
Abstract: De Novo Pathogenic Variants in CACNA1E Cause Developmental and Epileptic Encephalopathy With Contractures, Macrocephaly, and Dyskinesias Helbig KL, Lauerer RJ, Bahr JC, et al. Am J Hum Genet. 2019;104(3):562. Developmental and epileptic encephalopathies (DEEs) are severe neurodevelopmental disorders often beginning in infancy or early childhood that are characterized by intractable seizures, abundant epileptiform activity on electroencephalogram (EEG), and developmental impairment or regression. CACNA1E is highly expressed in the central nervous system and encodes the α1-subunit of the voltage-gated CaV2.3 channel, which conducts high-voltage-activated R-type calcium currents that initiate synaptic transmission. Using next-generation sequencing techniques, we identified de novo CACNA1E variants in 30 individuals with DEE, characterized by refractory infantile-onset seizures, severe hypotonia, and profound developmental impairment, often with congenital contractures, macrocephaly, hyperkinetic movement disorders, and early death. Most of the 14, partially recurring, variants cluster within the cytoplasmic ends of all 4 S6 segments, which form the presumed CaV2.3 channel activation gate. Functional analysis of several S6 variants revealed consistent gain-of-function effects comprising facilitated voltage-dependent activation and slowed inactivation. Another variant located in the domain II S4-S5 linker results in facilitated activation and increased current density. Five participants achieved seizure freedom on the antiepileptic drug topiramate, which blocks R-type calcium channels. We establish pathogenic variants in CACNA1E as a cause of DEEs and suggest facilitated R-type calcium currents as a disease mechanism for human epilepsy and developmental disorders.
13 citations
TL;DR: A distinct SCN 1A phenotype, early infantile SCN1A encephalopathy is described, which is readily distinguishable from the well-recognized entities of Dravet syndrome and genetic epilepsy with febrile seizures plus.
Abstract: Not All SCN1A Epileptic Encephalopathies Are Dravet Syndrome: Early Profound Thr226Met PhenotypeSadleir LG, Mountier EI, Gill D, et al. Neurology. 2017;89(10):1035-1042.Objective:To define a distin...
9 citations
TL;DR: The need for a broader, multi-stakeholder re-examination of driving regulations for PWE is noted, and the importance of physicians educating patients about local driving laws and about risks of ASD non-adherence is emphasized.
Abstract: This review compiles scientific data about the real dangers faced by people with epilepsy (PWE) who drive. Those include risks of motor vehicle accidents (MVA) in PWE as compared with controls (individuals without epilepsy) and as compared with persons with other medical conditions that impact fitness to drive. Data regarding Accident rates as related to seizure free intervals (SFI), single vs. multiple seizure events, and/or antiseizure drug (ASD) taper and reintroduction are discussed. Variation in state, national, and international laws and guidance for non-commercial and commercial drivers is highlighted, along with some related reasons for driving restrictions. The review concludes by emphasizing the importance of physicians educating patients about local driving laws and about risks of ASD non-adherence. The need for a broader, multi-stakeholder re-examination of driving regulations for PWE is noted.
TL;DR: Recent advancements in the field that provide optimism on the possibility to have first-in-human studies for gene therapy of some forms of epilepsy in the not so distant future are discussed.
Abstract: Gene therapy has recently advanced to the level of standard of care for several diseases. However, its application to neurological disorders is still in the experimental phase. In this review, we d...
TL;DR: This study provides evidence of AED effects on the functional neuroanatomy of language, which might explain subtle language deficits in patients taking otherwise well-tolerated sodium channel–blocking agents.
Abstract: Effects of Carbamazepine and Lamotrigine on Functional Magnetic Resonance Imaging Cognitive Networks Xiao F, Caciagli L, Wandschneider B, Sander JW, Sidhu M, Winston G, Burdett J, Trimmel K, Hill A, Vollmar C, Vos SB, Ourselin S, Thompson PJ, Zhou D, Duncan JS, Koepp MJ. Epilepsia. 2018;59:1362-1371. Objective To investigate the effects of sodium channel-blocking antiepileptic drugs (AEDs) on functional magnetic resonance imaging (fMRI) language network activations in patients with focal epilepsy. Methods In a retrospective study, we identified patients who were treated at the time of language fMRI scanning with either carbamazepine (CBZ; n = 42) or lamotrigine (LTG; n = 42), but not another sodium channel-blocking AED. We propensity-matched 42 patients taking levetiracetam (LEV) as "patient-controls" and included further 42 age- and gender-matched healthy controls. After controlling for age, age at onset of epilepsy, gender, and antiepileptic comedications, we compared verbal fluency fMRI activations between groups and out-of-scanner psychometric measures of verbal fluency. Results Patients on CBZ performed less well on a verbal fluency tests than those taking LTG or LEV. Compared to either LEV-treated patients or controls, patients taking CBZ showed decreased activations in left inferior frontal gyrus and patients on LTG showed abnormal deactivations in frontal and parietal default mode areas. All patient groups showed fewer activations in the putamen bilaterally compared to controls. In a post hoc analysis, out-of-scanner fluency scores correlated positively with left putamen activation. Significance Our study provides evidence of AED effects on the functional neuroanatomy of language, which might explain subtle language deficits in patients taking otherwise well-tolerated sodium channel-blocking agents. Patients on CBZ showed dysfunctional frontal activation and more pronounced impairment of performance than patients taking LTG, which was associated only with failure to deactivate task-negative networks. As previously shown for working memory, LEV treatment did not affect functional language networks.
TL;DR: This study illustrates the clinical diagnostic relevance of WES for patients with both epilepsy and ID and demonstrates that implementing WES diagnostics might have impact on the (antiepileptic) treatment strategy in this population.
Abstract: Diagnostic Exome Sequencing in 100 Consecutive Patients With Both Epilepsy and Intellectual Disability Snoeijen-Schouwenaars FM, van Ool JS, Verhoeven JS, et al. Epilepsia. 2019;60(1):155-164. doi:...
TL;DR: A field study demonstrates the applicability and usability of the wearable accelerometer device (Epi-Care) that has previously been validated in EMUs for detecting bilateral tonic-clonic seizures (BTCS) and proposes actions that can facilitate development of novel methods and devices.
Abstract: Standards for testing and clinical validation of seizure detection Beniczky S, Ryvlin P. Epilepsia. 2018;59(S1):9-13. https://doi.org/10.1111/epi.14049 To increase the quality of studies on seizure detection devices, we propose standards for testing and clinical validation of such devices. We identified 4 key features that are important for studies on seizure detection devices: subjects, recordings, data analysis and alarms, and reference standard. For each of these features, we list the specific aspects that need to be addressed in the studies, and depending on these, studies are classified into 5 phases (0-4). We propose a set of outcome measures that need to be reported, and we propose standards for reporting the results. These standards will help in designing and reporting studies on seizure detection devices, they will give readers clear information on the level of evidence provided by the studies, and they will help regulatory bodies in assessing the quality of the validation studies. These standards are flexible, allowing classification of the studies into one of the 5 phases. We propose actions that can facilitate development of novel methods and devices. User-based evaluation of applicability and usability of a wearable accelerometer device for detecting bilateral tonic-clonic seizures: a field study Meritam P, Ryvlin P, Beniczky S. Epilepsia. 2018;59(S1):48-52. https://doi.org/10.1111/epi.14051 Clinical validation studies of seizure detection devices conducted in epilepsy monitoring units (EMUs) can be biased by the artificial environment. We report a field (phase 4) study of a wearable accelerometer device (Epi-Care) that has previously been validated in EMUs for detecting bilateral tonic-clonic seizures (BTCS). Seventy-one patients using the device (or their caregivers) completed the modified Post-Study System Usability Questionnaire. Median time patients had been using the device was 15 months (range = 24 days to 6 years). In 10% of cases, patients stopped using the device due to reasons related to the device. The median sensitivity (90%) and false alarm rate (0.1/day) were similar to what had been determined in EMUs. Patients and caregivers were overall satisfied with the device (median = 5.5 on the 7-point Likert scale), considered the technical aspects satisfactory, and considered the device comfortable and efficient. Adverse effects occurred in 11% but were only mild: skin irritation at the wrist and interference with home electronic appliances. In 55%, the device influenced the number of seizures logged into the seizure diary, and in 40%, it contributed to fewer seizure-related injuries. This field study demonstrates the applicability and usability of the wearable accelerometer device for detecting BTCS. Wearable devices for sudden unexpected death in epilepsy prevention Ryvlin P, Ciumas C, Wisniewski I, Beniczky S. Epilepsia. 2018;59(S1):61-66. https://doi.org/10.1111/epi.14054 Sudden unexpected death in epilepsy (SUDEP) is most often associated with the occurrence of generalized tonic-clonic seizures (GTCS), a seizure type that can now be detected with high sensitivity and specificity by wearable or bed devices. The recent development in such devices and their performance offer multiple opportunities to tackle SUDEP and its prevention. Reliable GTCS detection might help physicians optimize antiepileptic treatment, which could in turn reduce the risk of SUDEP. Generalized tonic-clonic seizures-triggered alarms can lead to immediate intervention by caregivers that are also likely to decrease the odd of SUDEP. The biosignals used to detect GTCS might provide novel SUDEP biomarkers, in particular, by informing on several important characteristics of the ictal and postictal periods (type of GTCS, duration of tonic phase, rotation in the prone position, presence and duration of postictal immobility and bradycardia, rise in electrodermal activity). Other biosensors not yet used for detecting GTCS might provide complementary information, such as the presence and intensity of ictal/postictal hypoxemia. The above biomarkers, if strongly predictive, could help identify patients at very high risk of SUDEP, enabling better assessment of individual risk, as well as selection of appropriate patients for clinical studies aiming at preventing SUDEP. The same biosignals could also be used as ancillary biomarkers to test the impact of various interventions before moving to highly challenging randomized controlled trials with SUDEP as a primary outcome.
TL;DR: While administrative claims analysis supports the utility of cEEG for critically ill patients, the findings suggest variable benefit by diagnosis, and investigation with greater clinical detail is warranted.
Abstract: Continuous EEG Is Associated With Favorable Hospitalization Outcomes for Critically Ill Patients. Hill CE, Blank LJ, Thibault D, et al. Willis Neurology. 2018. doi:https://doi.org/10.1212/WNL.00000...
TL;DR: It is shown that repetitive Diffuse Mild Traumatic Brain Injury is sufficient for the development of spontaneous recurrent seizures in a subset of mice, and an atypical response of astrocytes induced by diffuse TBI is identified, characterized by the rapid loss of homeostatic proteins and lack ofAstrocyte coupling while reactive astrogliosis markers or glial scar formation was absent.
Abstract: Repetitive Diffuse Mild Traumatic Brain Injury Causes An Atypical Astrocyte Response and Spontaneous Recurrent Seizures Shandra O, Winemiller AR, Heithoff BP, et al. J Neurosci. 2019;39(10):1944-1963. doi:10.1523/JNEUROSCI.1067-18.2018. Epub 2019 Jan 21. PMID: 30665946 . Focal traumatic brain injury (TBI) induces astrogliosis, a process essential to protecting uninjured brain areas from secondary damage. However, astrogliosis can cause loss of astrocyte homeostatic functions and possibly contributes to comorbidities such as posttraumatic epilepsy (PTE). Scar-forming astrocytes seal focal injuries off from healthy brain tissue. It is these glial scars that are associated with epilepsy originating in the cerebral cortex and hippocampus. However, the vast majority of human TBIs also present with diffuse brain injury caused by acceleration-deceleration forces leading to tissue shearing. The resulting diffuse tissue damage may be intrinsically different from focal lesions that would trigger glial scar formation. Here, we used mice of both sexes in a model of repetitive mild/concussive closed-head TBI, which only induced diffuse injury, to test the hypothesis that astrocytes respond uniquely to diffuse TBI and that diffuse TBI is sufficient to cause PTE. Astrocytes did not form scars and classic astrogliosis characterized by upregulation of glial fibrillary acidic protein was limited. Surprisingly, an unrelated population of atypical reactive astrocytes was characterized by the lack of glial fibrillary acidic protein expression, rapid and sustained downregulation of homeostatic proteins, and impaired astrocyte coupling. After a latency period, a subset of mice developed spontaneous recurrent seizures reminiscent of PTE in human patients with TBI. Seizing mice had larger areas of atypical astrocytes compared with nonseizing mice, suggesting that these atypical astrocytes might contribute to epileptogenesis after diffuse TBI. Traumatic brain injury is a leading cause of acquired epilepsies. Reactive astrocytes have long been associated with seizures and epilepsy in patients, particularly after focal/lesional brain injury. However, most TBIs also include nonfocal, diffuse injuries. Here, we showed that repetitive diffuse TBI is sufficient for the development of spontaneous recurrent seizures in a subset of mice. We identified an atypical response of astrocytes induced by diffuse TBI characterized by the rapid loss of homeostatic proteins and lack of astrocyte coupling while reactive astrocyte markers or glial scar formation was absent. Areas with atypical astrocytes were larger in animals that later developed seizures suggesting that this response may be one root cause of epileptogenesis after diffuse TBI.
TL;DR: Activation of the p.Arg1872Trp mutation in adult mice was sufficient to generate seizures and death, indicating that successful therapy will require lifelong treatment, and insight is provided into the pathogenic mechanism of this gain-of-function mutation of SCN8A.
Abstract: Prominent role of forebrain excitatory neurons in SCN8A encephalopathy. Bunton-Stasyshyn RKA, Wagnon JL, Wengert ER, Barker BS, Faulkner A, Wagley PK, Bhatia K, Jones JM, Maniaci MR, Parent JM, Goodkin HP, Patel MK, Meisler MH. Brain. 2019;142(2):362-375. doi:10.1093/brain/awy324. De novo mutations of the sodium channel gene SCN8A result in an epileptic encephalopathy with refractory seizures, developmental delay, and elevated risk of sudden death. p.Arg1872Trp is a recurrent de novo SCN8A mutation reported in 14 unrelated individuals with epileptic encephalopathy that included seizure onset in the prenatal or infantile period and severe verbal and ambulatory comorbidities. The major biophysical effect of the mutation was previously shown to be impaired channel inactivation accompanied by increased current density. We have generated a conditional mouse mutation in which expression of this severe gain-of-function mutation is dependent upon Cre recombinase. Global activation of p.Arg1872Trp by EIIa-Cre resulted in convulsive seizures and lethality at 2 weeks of age. Neural activation of the p.Arg1872Trp mutation by Nestin-Cre also resulted in early-onset seizures and death. Restriction of p.Arg1872Trp expression to excitatory neurons using Emx1-Cre recapitulated seizures and juvenile lethality between 1 and 2 months of age. In contrast, activation of p.Arg1872Trp in inhibitory neurons by Gad2-Cre or Dlx5/6-Cre did not induce seizures or overt neurological dysfunction. The sodium channel modulator GS967/Prax330 prolonged survival of mice with global expression of R1872W and also modulated the activity of the mutant channel in transfected cells. Activation of the p.Arg1872Trp mutation in adult mice was sufficient to generate seizures and death, indicating that successful therapy will require lifelong treatment. These findings provide insight into the pathogenic mechanism of this gain-of-function mutation of SCN8A and identify excitatory neurons as critical targets for therapeutic intervention.
TL;DR: This work suggests that, even during the interictal state, functional connectivity is reinforced within epileptic cortices (EZ and PZ) with a gradual organization, consistent with computational studies suggesting that connectivity is crucial in order to model the spatiotemporal dynamics of seizures.
Abstract: Interictal stereotactic-EEG functional connectivity in refractory focal epilepsies Lagarde S, Roehri N, Lambert I, et al. Brain. 2018;141(10):2966-2980. Drug-refractory focal epilepsies are network diseases associated with functional connectivity alterations both during ictal and interictal periods. A large majority of studies on the interictal/resting state have focused on functional magnetic resonance imaging (MRI)-based functional connectivity. Few studies have used electrophysiology, despite its high-temporal capacities. In particular, stereotactic-electroencephalogram (EEG) is highly suitable to study functional connectivity because it permits direct intracranial electrophysiological recordings with relative large-scale sampling. Most previous studies in stereotactic-EEG have been directed toward temporal lobe epilepsy, which does not represent the whole spectrum of drug-refractory epilepsies. The present study aims at filling this gap, investigating interictal functional connectivity alterations behind cortical epileptic organization and its association with postsurgical prognosis. To this purpose, we studied a large cohort of 59 patients with malformation of cortical development explored by stereotactic-EEG with a wide spatial sampling (76 distinct brain areas were recorded, median of 13.2 per patient). We computed functional connectivity using nonlinear correlation. We focused on 3 zones defined by stereotactic-EEG ictal activity: the epileptogenic zone (EZ), the propagation zone (PZ), and the noninvolved zone. First, we compared within-zone and between-zones functional connectivity. Second, we analyzed the directionality of functional connectivity between these zones. Third, we measured the associations between functional connectivity measures and clinical variables, especially postsurgical prognosis. Our study confirms that functional connectivity differs according to the zone under investigation. We found: (1) a gradual decrease in the within-zone functional connectivity with higher values for EZ and PZ, and lower for noninvolved zones; (2) preferential coupling between structures of the EZ; (3) preferential coupling between EZ and PZ; and (4) poorer postsurgical outcome in patients with higher functional connectivity of non-involved zone (within-noninvolved zone, between noninvolved zone, and PZ functional connectivity). Our work suggests that, even during the interictal state, functional connectivity is reinforced within epileptic cortices (EZ and PZ) with a gradual organization. Moreover, larger functional connectivity alterations, suggesting more diffuse disease, are associated with poorer postsurgical prognosis. This is consistent with computational studies suggesting that connectivity is crucial in order to model the spatiotemporal dynamics of seizures. Dynamic brain network states in human generalized spike-wave discharges Tangwiriyasakul C, Perani S, Centeno M, et al. Brain. 2018;141(10):2981-2994. Generalized spike-wave discharges in idiopathic generalized epilepsy are conventionally assumed to have abrupt onset and offset. However, in rodent models, discharges emerge during a dynamic evolution of brain network states, extending several seconds before and after the discharge. In human idiopathic generalized epilepsy, simultaneous EEG and functional MRI shows cortical regions may be active before discharges, and network connectivity around discharges may not be normal. Here, in human idiopathic generalized epilepsy, we investigated whether generalized spike-wave discharges emerge during a dynamic evolution of brain network states. Using EEG-functional MRI, we studied 43 patients and 34 healthy control subjects. We obtained 95 discharges from 20 patients. We compared data from patients with discharges with data from patients without discharges and healthy controls. Changes in MRI (blood oxygenation level dependent) signal amplitude in discharge epochs were observed only at and after EEG onset, involving a sequence of parietal and frontal cortical regions then thalamus ( P < .01, across all regions and measurement time points). Examining MRI signal phase synchrony as a measure of functional connectivity between each pair of 90 brain regions, we found significant connections ( P < .01, across all connections and measurement time points) involving frontal, parietal and occipital cortex during discharges, and for 20 seconds after EEG offset. This network prominent during discharges showed significantly low synchrony (below 99% confidence interval for synchrony in this network in nondischarge epochs in patients) from 16 seconds to 10 seconds before discharges, then ramped up steeply to a significantly high level of synchrony 2 seconds before discharge onset. Significant connections were seen in a sensorimotor network in the minute before discharge onset. This network also showed elevated synchrony in patients without discharges compared to healthy controls ( P = .004). During 6 seconds prior to discharges, additional significant connections to this sensorimotor network were observed, involving prefrontal, and precuneus regions. In healthy subjects, significant connections involved a posterior cortical network. In patients with discharges, this posterior network showed significantly low synchrony during the minute prior to discharge onset. In patients without discharges, this network showed the same level of synchrony as in healthy controls. Our findings suggest persistently high sensorimotor network synchrony, coupled with transiently (at least 1 minute) low posterior network synchrony, may be a state predisposing to generalized spike-wave discharge onset. Our findings also show that EEG onset and associated MRI signal amplitude change is embedded in a considerably longer period of evolving brain network states before and after discharge events.
TL;DR: Investigation of the therapeutic potential of the interleukin-6 receptor inhibitor tocilizumab in patients with new-onset refractory status epilepticus found no recurrence of SE and 2 patients experienced severe adverse events related to infection during the tocilIZumab therapy.
Abstract: Tocilizumab Treatment for New Onset Refractory Status Epilepticus Jun JS, Lee ST, Kim R, Chu K, Lee SK. Ann Neurol. 2018;84(6):940-945. doi:10.1002/ana.25374. We investigated the therapeutic potential of the interleukin-6 receptor inhibitor tocilizumab in 7 patients with new-onset refractory status epilepticus (NORSE) who remained refractory to conventional immunotherapy with rituximab (n = 5) or without rituximab (n = 2). Status epilepticus (SE) was terminated after 1 or 2 doses of tocilizumab in 6 patients with a median interval of 3 days from the initiation. They had no recurrence of SE during the observation. However, 2 patients experienced severe adverse events related to infection during the tocilizumab therapy. Further prospective controlled studies are warranted to validate the efficacy and safety of tocilizumab in patients with NORSE.
TL;DR: It is shown that mosaic biallelic inactivation during neural progenitor expansion is necessary for the formation of dysplastic cells and increased glia production in 3-dimensional cortical spheroids and suggest that variable developmental timing of somatic mutations could contribute to the heterogeneity in the neurological presentation of TSC.
Abstract: Genetically Engineered Human Cortical Spheroid Models of Tuberous Sclerosis Blair JD, Hockemeyer D, Bateup HS. Nat Med. 2018;24(10):1568-1578. doi:10.1038/s41591-018-0139-y. Epub 2018 Aug 20. PubMed PMID: 30127391; PubMed Central PMCID: PMC6261470. Tuberous sclerosis complex (TSC) is a multisystem developmental disorder caused by mutations in the TSC1 or TSC2 genes, whose protein products are negative regulators of mechanistic target of rapamycin complex 1 signaling. Hallmark pathologies of TSC are cortical tubers-regions of dysmorphic, disorganized neurons, and glia in the cortex that are linked to epileptogenesis. To determine the developmental origin of tuber cells, we established human cellular models of TSC by CRISPR-Cas9-mediated gene editing of TSC1 or TSC2 in human pluripotent stem cells (hPSCs). Using heterozygous TSC2 hPSCs with a conditional mutation in the functional allele, we show that mosaic biallelic inactivation during neural progenitor expansion is necessary for the formation of dysplastic cells and increased glia production in 3-dimensional cortical spheroids. Our findings provide support for the second-hit model of cortical tuber formation and suggest that variable developmental timing of somatic mutations could contribute to the heterogeneity in the neurological presentation of TSC.
TL;DR: This work identified the phenotypic signature of huMG, which was distinct from peripheral myeloid cells but was comparable to fresh hu MG, and detected microglia regional heterogeneity using a hybrid workflow combining Cytobank and R/Bioconductor for multidimensional data analysis.
Abstract: Human microglia regional heterogeneity and phenotypes determined by multiplexed single-cell mass cytometryBottcher C, Schlickeiser S, Sneeboer MAM, et al. Nat Neurosci. 2019;22(1):78-90.Microglia, ...
TL;DR: Gene-based analysis identifies exome-wide significant enrichment of damaging de novo mutations in NF1, a gene primarily linked to neurofibromatosis, in infantile spasm and indicates that EE/DEE is not an aggregate of simple Mendelian disorders.
Abstract: Comprehensive Analysis of Coding Variants Highlights Genetic Complexity in Developmental and Epileptic EncephalopathyTakata A, Nakashima M, Saitsu H, et al. Nat Commun. 2019;10(1):2506. doi:10.1038...
TL;DR: Among children and adults with the Lennox-Gastaut syndrome, the addition of cannabidiol at a dose of 10 or 20 mg/kg/d to a conventional antiepileptic regimen resulted in greater reductions in the frequency of drop seizures than placebo.
Abstract: Effect of Cannabidiol on Drop Seizures in the Lennox-Gastaut Syndrome Devinsky O, Patel AD, Cross JH, et al; GWPCARE3 Study Group. N Engl J Med. 2018;378:1888-1897.Background:Cannabidiol has been u...
TL;DR: In veterans referred for inpatient seizure evaluation, PTSD was strongly associated with a diagnosis of PNES versus ES, and the association of P NES with PTSD, attribution of seizures to TBI, or both, may prompt early consideration of PES.
Abstract: Psychiatric Comorbidity and Traumatic Brain Injury Attribution in Patients With Psychogenic Nonepileptic or Epileptic Seizures: A Multicenter Study of US VeteransSalinsky M, Rutecki P, Parko K, Goy...
TL;DR: The majority of patients with ANT DBS for retractable epilepsy did not experience psychiatric adverse effects, and certain DBS parameters might predispose to sudden depressive or slowly manifesting paranoid symptoms that are reversible via programming changes.
Abstract: Reversible Psychiatric Adverse Effects Related to Deep Brain Stimulation of the Anterior Thalamus in Patients With Refractory EpilepsyJarvenpaa S, Peltola J, Rainesalo S, et al. Epilepsy Behav. 201...
TL;DR: The prevalence and burden of ictal–interictal patterns, including electrographic seizures after moderate to severe traumatic brain injury, and to correlate continuous electroencephalography features with functional outcome were described.
Abstract: Lateralized Periodic Discharges Frequency Correlates With Glucose MetabolismSubramaniam T, Jain A, Hall LT, Cole AJ, Westover MB, Rosenthal ES, Struck AF. Neurology. 2019;92(7):e670-e674.Objective:...
TL;DR: One-third of newly diagnosed persons remain untreated up to 3 years after epilepsy diagnosis, which highlights the consequences of delayed treatment after epilepsy diagnosed, which might be preventable.
Abstract: Assessment and Effect of a Gap Between New-Onset Epilepsy Diagnosis and Treatment in the USKalilani L, Faught E, Kim H, Burudpakdee C, Seetasith A, Laranjo S, Friesen D, Haeffs K, Kiri V, Thurman D...
TL;DR: This study demonstrates the presence of focal and distributed inflammation in neocortical epilepsy, and there may be a role for TSPO PET for the evaluation of patients with suspected neocorticals seizure foci, particularly when other imaging modalities are unrevealing.
Abstract: Neuroinflammation in Neocortical Epilepsy Measured by PET Imaging of Translocator ProteinDickstein LP, Liow JS, Austermuehle A, et al. Epilepsia. 2019. doi:10.1111/epi.15967. Epub ahead of print. P...
TL;DR: The characteristics of subacute encephalopathy with seizures in alcoholics syndrome, a subtype of focal NCSE occurring in chronic alcoholism with specific features, including encephalitis, lateralized periodic discharges on the EEG, chronic microvascular ischemia on neuroimaging studies, and possible recurrence when chronic antiseizure treatment is stopped are reviewed.
Abstract: A recent assessment of the classification of nonconvulsive status epilepticus (NCSE) has incorporated the specific electroencephalographic (EEG) patterns on a syndromic basis. Such a clinical EEG syndromic approach may enable more accurate and expedited diagnosis of particular subtypes of NCSE so as to improve therapy. Herein, we review the characteristics of subacute encephalopathy with seizures in alcoholics syndrome, a subtype of focal NCSE occurring in chronic alcoholism with specific features, including encephalopathy, lateralized periodic discharges on the EEG, chronic microvascular ischemia on neuroimaging studies, and possible recurrence when chronic antiseizure treatment is stopped.