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  • 机译 岛状及其癫痫
    摘要: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.
  • 机译 了解抗癫痫药的认知副作用:功能成像会有所帮助吗?
    摘要: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.
  • 机译 连续的脑电图监测-神经学家的水晶球
    摘要:Time to Epileptiform Activity and EEG Background Recovery Are Independent Predictors After Cardiac Arrest Westhall E, Rose I, Rundgren M, Bro-Jeppesen J, Kjaergaard J, Hassager C, Lindehammar H, Horn J, Ullen S, Nielsen N, Friberg H, Cronberg T. Clin Neurophysiol. 2018;129:1660-1668. https://doi.org/10.1016/j.clinph.2018.05.016Objective: To investigate the temporal development of electroencephalogram (EEG) and prognosis. Methods: Prospective observational substudy of the Target Temperature Management trial. Six sites performed simplified continuous EEG monitoring (cEEG) on comatose patients after cardiac arrest, blinded to treating physicians. We determined time points of recovery of a normal-voltage continuous background activity and the appearance of an epileptiform EEG, defined as abundant epileptiform discharges, periodic/rhythmic discharges, or electrographic seizure activity. Results: One hundred thirty-four patients were included, of which 65 had a good outcome. Early recovery of continuous background activity (within 24 hours) occurred in 72 patients and predicted good outcome since 55 (76%) had good outcome, increasing the odds for a good outcome 7 times compared to a late background recovery. Early appearance of an epileptiform EEG occurred in 38 patients and 34 (89%) had a poor outcome, increasing the odds for a poor outcome 6 times compared to a late debut. The time to background recovery and the time to epileptiform activity were highly associated with outcome and levels of neuron-specific enolase. Multiple regression analysis showed that both variables were independent predictors. Conclusions: Time to epileptiform activity and background recovery are independent prognostic indicators. SIGNIFICANCE: Patients with early background recovery combined with late appearance of epileptiform activity may have a good outcome.
  • 机译 抓紧一天没有癫痫发作:已确定可修改的中年危险因素
    摘要:Association Between Midlife Risk Factors and Late-Onset Epilepsy: Results From the Atherosclerosis Risk in Communities Study Johnson EL, Krauss GL, Lee AK, Schneider ALC, Dearborn JL, Kucharska-Newton AM, Huang J, Alonso A, Gottesman RF. JAMA Neurol. 2018 Jul 23 [Epub ahead of print]Importance: The incidence of epilepsy is higher in older age than at any other period of life. Stroke, dementia, and hypertension are associated with late-onset epilepsy; however, the role of other vascular and lifestyle factors remains unclear. Objective: To identify midlife vascular and lifestyle risk factors for late-onset epilepsy. Design, Setting, and Participants: The Atherosclerosis Risk in Communities (ARIC) study is a prospective cohort study of 15 792 participants followed up since 1987 to 1989 with in-person visits, telephone calls, and surveillance of hospitalizations (10 974 invited without completing enrollment). The ARIC is a multicenter study with participants selected from 4 US communities. This study included 10 420 black or white participants from ARIC with at least 2 years of Medicare fee-for-service coverage and without missing baseline data. Data were analyzed between April 2017 and May 2018. Exposures: Demographic, vascular, lifestyle, and other possible epilepsy risk factors measured at baseline (age 45-64 years) were evaluated in multivariable survival models including demographics, vascular risk factors, and lifestyle risk factors. Main Outcomes and Measures: Time to development of late-onset epilepsy (2 or more International Classification of Diseases, Ninth Revision codes for epilepsy or seizures starting at 60 years or older in any claim [hospitalization or outpatient Medicare through 2013]), with first code for seizures after at least 2 years without code for seizures. Results: Of the 10 420 total participants (5878 [56.4%] women and 2794 [26.8%] black participants; median age 55 years at first visit), 596 participants developed late-onset epilepsy (3.33 per 1000 person-years). The incidence was higher in black than in white participants (4.71; 95% confidence interval [CI], 4.12-5.40 vs 2.88; 95% CI, 2.60-3.18 per 1000 person-years). In multivariable analysis, baseline hypertension (hazard ratio [HR], 1.30; 95% CI, 1.09-1.55), diabetes (HR, 1.45; 95% CI, 1.17-1.80), smoking (HR, 1.09; 95% CI, 1.01-1.17), apolipoprotein E ε4 (APOE ε4) genotype (1 allele HR, 1.22; 95% CI, 1.02-1.45; 2 alleles HR, 1.95; 95% CI, 1.35-2.81), incident stroke (HR, 3.38; 95% CI, 2.78-4.10), and dementia (HR, 2.56; 95% CI, 2.11-3.12) were associated with an increased risk of late-onset epilepsy, while higher levels of physical activity (HR, 0.90; 95% CI, 0.83-0.98) and moderate alcohol intake (HR, 0.72; 95% CI, 0.57-0.90) were associated with a lower risk. Results were similar after censoring individuals with stroke or dementia. Conclusions and Relevance: Potentially modifiable risk factors in midlife and the APOE ε4 genotype were positively associated with risk of developing late-onset epilepsy. Although stroke and dementia were both associated with late-onset epilepsy, vascular and lifestyle risk factors were significant even in the absence of stroke or dementia.
  • 机译 癫痫发作,非癫痫事件,创伤,焦虑或以上所有
    • 作者:Jay Salpekar
    • 刊名:Epilepsy Currents
    • 2019年第1期
    摘要:Psychiatric Comorbidity and Traumatic Brain Injury Attribution in Patients With Psychogenic Nonepileptic or Epileptic Seizures: A Multicenter Study of US Veterans Salinsky M, Rutecki P, Parko K, Goy E, Storzbach D, O’Neil M, Binder L, Joos S. Epilepsia. 2018. Epub ahead of print. Objective: To determine the frequency and severity of psychiatric disorders and attribution of seizures to traumatic brain injury (TBI) in veterans with verified psychogenic nonepileptic seizures (PNES) versus epileptic seizures (ES). Methods: We studied 333 consecutive admissions to the monitoring units of 3 Veterans Administration epilepsy centers. All patients underwent continuous video-electroencephalographic recording to define definite PNES or ES. Evaluations included the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, 4th edition, posttraumatic stress disorder (PTSD) Checklist, Beck Depression Inventory II, and Patient Seizure Etiology Questionnaire. Interviews and questionnaires were completed prior to final seizure type diagnosis and patient debriefing. The primary outcome measure was a comparison of Axis I psychiatric diagnoses in patients diagnosed with PNES versus ES. Results: A total of 81 patients were diagnosed with PNES and 70 with ES. Posttraumatic stress disorder was the most frequent Axis I diagnosis in veterans with PNES (64% vs 13% of those with ES; P < .001). Posttraumatic stress disorder was common regardless of deployment to a war theater or combat exposure. Mood, substance abuse, and anxiety disorders were also more common in the PNES group. Traumatic brain injury was cited as a likely cause of seizures by 47% of veterans with PNES versus 25% of those with ES (P = .01). Posttraumatic stress disorder and attribution of seizures to TBI were found in 30% of veterans with PNES versus 3% of those with ES (P < .001). Significance: In veterans referred for inpatient seizure evaluation, PTSD was strongly associated with a diagnosis of PNES versus ES. The association of PNES with PTSD, attribution of seizures to TBI, or both, may prompt early consideration of PNES.
  • 机译 PNES中的感知:双向问题
    摘要:Health Care Practitioners’ Perceptions of Psychogenic Nonepileptic Seizures: A Systematic Review of Qualitative and Quantitative Studies Rawlings GH, Reuber M. Epilepsia. 2018;59(6):1109-1123. doi:10.1111/epi.14189. Epub 2018 May 11.A recent systematic synthesis of qualitative research demonstrated that patients with psychogenic nonepileptic seizures (PNES) often experience unsatisfactory encounters with health-care practitioners (HCPs). It is important to understand such interactions from the perspective of those responsible for delivering care. This systematic review aimed to examine the attitudes and perceptions of HCPs toward PNES. A systematic search of 3 databases (Web of Science, PubMed, and CINAHL) was conducted in November 2017. Studies from around the world published after 1997 using qualitative or quantitative methodologies were reviewed. An interpretative stance was taken to analyze the data utilizing a grounded theory approach. The quality of studies included was assessed using the Mixed Methods Appraisal Tool. Overall, 30 separate studies capturing the views of at least 3900 professionals were included. Five concepts emerged from the analysis: (1) HCPs’ responses demonstrated uncertainty about many aspects of PNES, including diagnosis and treatment; (2) HCPs understood PNES in dualistic terms, perceiving the condition as largely associated with psychological factors; (3) patients with PNES were considered challenging and frustrating; (4) HCPs held mixed or contested views about who is responsible for treating patients with PNES; and (5) PNES was viewed as less severe or disabling than epilepsy and associated with a greater degree of volition. Although some HCPs have an excellent understanding of PNES, the views of many give rise to concern. The number of qualitative studies that directly ask HCPs about their perceptions of PNES is limited. Moreover, some professional groups (ie, mental health specialists) are underrepresented in current research. This study reveals a demand for additional training. However, effort is needed also to change the attitudes of some practitioners toward PNES.
  • 机译 早期癫痫病的药物:证据与经验?
    摘要:Comparative Effectiveness of Levetiracetam vs Phenobarbital for Infantile Epilepsy Grinspan ZM, Shellhaas RA, Coryell J, Sullivan JE, Wirrell EC, Mytinger JR, Gaillard WD, Kossoff EH, Valencia I, Knupp KG, Wusthoff C, Keator C, Ryan N, Loddenkemper T, Chu CJ, Novotny EJ Jr, Millichap J, Berg AT. JAMA Pediatr. 2018 Apr 1;172(4):352-360. doi: 10.1001/jamapediatrics.2017.5211.Importance: More than half of infants with new-onset epilepsy have electroencephalographic and clinical features that do not conform to known electroclinical syndromes (ie, nonsyndromic epilepsy). Levetiracetam and phenobarbital are the most commonly prescribed medications for epilepsy in infants, but their comparative effectiveness is unknown. Objective: To compare the effectiveness of levetiracetam versus phenobarbital for nonsyndromic infantile epilepsy. Design, Setting, and Participants: The Early Life Epilepsy Study—a prospective, multicenter, observational cohort study conducted from March 1, 2012, to April 30, 2015, in 17 US medical centers—enrolled infants with nonsyndromic epilepsy and a first afebrile seizure between 1 month and 1 year of age. Exposures: Use of levetiracetam or phenobarbital as initial monotherapy within 1 year of the first seizure. Main Outcomes and Measures: The binary outcome was freedom from monotherapy failure at 6 months, defined as no second prescribed antiepileptic medication and freedom from seizures beginning within 3 months of initiation of treatment. Outcomes were adjusted for demographics, epilepsy characteristics, and neurologic history, as well as for observable selection bias using propensity score weighting and for within-center correlation using generalized estimating equations. Results: Of the 155 infants in the study (81 girls and 74 boys; median age, 4.7 months [interquartile range, 3.0-7.1 months]), those treated with levetiracetam (n = 117) were older at the time of the first seizure than those treated with phenobarbital (n = 38; median age, 5.2 months [interquartile range, 3.5-8.2 months] vs 3.0 months [interquartile range, 2.0-4.4 months]; P < .001). There were no other significant bivariate differences. Infants treated with levetiracetam were free from monotherapy failure more often than those treated with phenobarbital (47 [40.2%] vs 6 [15.8%]; P = .01). The superiority of levetiracetam over phenobarbital persisted after adjusting for covariates, observable selection bias, and within-center correlation (odds ratio, 4.2; 95% confidence interval [CI], 1.1-16; number needed to treat, 3.5 [95% CI, 1.7-60]). Conclusions and Relevance: Levetiracetam may have superior effectiveness compared to phenobarbital for initial monotherapy of nonsyndromic epilepsy in infants. If 100 infants who received phenobarbital were instead treated with levetiracetam, 44 would be free from monotherapy failure instead of 16 by the estimates in this study. Randomized clinical trials are necessary to confirm these findings.
  • 机译 癫痫发作检测设备准备好进行黄金时间了吗?
    摘要:Standards for testing and clinical validation of seizure detection Beniczky S, Ryvlin P. Epilepsia. 2018;59(S1):9-13. 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. 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. 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.
  • 机译 基因问题:癫痫基因治疗的障碍
    摘要: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 discuss 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.
  • 机译 双重代理mTOR
    摘要:Remodeled Cortical Inhibition Prevents Motor Seizures in Generalized Epilepsy Jiang X, Lupien-Meilleur A, Tazerart S, Lachance M, Samarova E, Araya R, Lacaille JC, Rossignol E. Ann Neurol. 2018 Sep;84(3):436-451.Objective: Deletions of CACNA1A, encoding the α1 subunit of CaV 2.1 channels, cause epilepsy with ataxia in humans. Whereas the deletion of Cacna1a in γ-aminobutyric acidergic (GABAergic) interneurons (INs) derived from the medial ganglionic eminence (MGE) impairs cortical inhibition and causes generalized seizures in Nkx2.1Cre;Cacna1ac/c mice, the targeted deletion of Cacna1a in somatostatin-expressing INs (SOM-INs), a subset of MGE-derived INs, does not result in seizures, indicating a crucial role of parvalbumin-expressing (PV) INs. Here, we identify the cellular and network consequences of Cacna1a deletion specifically in PV-INs. Methods: We generated PVCre;Cacna1ac/c mutant mice carrying a conditional Cacna1a deletion in PV neurons and evaluated the cortical cellular and network outcomes of this mutation by combining immunohistochemical assays, in vitro electrophysiology, 2-photon imaging, and in vivo video-electroencephalographic recordings. Results: PVCre;Cacna1ac/c mice display reduced cortical perisomatic inhibition and frequent absences, but only rare motor seizures. Compared to Nkx2.1Cre;Cacna1ac/c mice, PVCre;Cacna1ac/c mice have a net increase in cortical inhibition, with a gain of dendritic inhibition through sprouting of SOM-IN axons, largely preventing motor seizures. This beneficial compensatory remodeling of cortical GABAergic innervation is mechanistic target of rapamycin complex 1 (mTORC1)-dependent, and its inhibition with rapamycin leads to a striking increase in motor seizures. Furthermore, we show that a direct chemogenic activation of cortical SOM-INs prevents motor seizures in a model of kainate-induced seizures. Interpretation: Our findings provide novel evidence suggesting that the remodeling of cortical inhibition, with an mTOR-dependent gain of dendritic inhibition, determines the seizure phenotype in generalized epilepsy and that mTOR inhibition can be detrimental in epilepsies not primarily due to mTOR hyperactivation.
  • 机译 从恐惧到颞叶癫痫的治疗
    摘要:Pharmaco-Genetic Therapeutics Targeting Parvalbumin Neurons Attenuate Temporal Lobe Epilepsy Wang Y, Liang J, Chen L, Shen Y, Zhao J, Xu C, Wu X, Cheng H, Ying X, Guo Y, Wang S, Zhou Y, Wang Y, Chen Z. Neurobiol Dis. 2018;117:149-60. Epub 2018/06/13. doi: 10.1016/j.nbd.2018.06.006. PubMed PMID: 29894753.Temporal lobe epilepsy (TLE) is the most common type of epilepsy and is often medically refractory. Previous studies suggest that selective pharmaco-genetic inhibition of pyramidal neurons has therapeutic value for the treatment of epilepsy; however, there is a risk of disrupting normal physical functions. Here, we test whether pharmaco-genetic activation of parvalbumin neurons, which are transgenetically transduced with the modified muscarinic receptor hM3Dq, can attenuate TLE. We found that pharmaco-genetic activation of hippocampal parvalbumin neurons in epileptogenic zone not only significantly extends the latency to different seizure stages and attenuates seizure activities in acute seizure model but also greatly alleviates the severity of seizure onsets in 2 chronic epilepsy models. This manipulation did not affect the normal physical function evaluated in various cognitive tasks. Further, the activation of parvalbumin neurons produced an inhibition on parts of surrounding pyramidal neurons, and the direct inactivation of pyramidal neurons via the viral expression of a modified muscarinic receptor hM4Di produced a similar anti-ictogenic effect. Interestingly, pharmacogenetic inactivation of pyramidal neurons was more sensitive to impair cognitive function. Those data demonstrated that pharmaco-genetic seizure attenuation through targeting parvalbumin neurons rather than pyramidal neurons may be a novel and relatively safe approach for treating refractory TLE.
  • 机译 一击奇观和二击块茎:对TSC2的第二击导致球体内的块茎样细胞
    摘要: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.
  • 机译 Dravet综合征:发展性和癫痫性脑病
    摘要: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 ofSCN1A, 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.
  • 机译 皮质发育异常的时空连续体
    摘要:Somatic Mutations Activating the mTOR Pathway in Dorsal Telencephalic Progenitors Cause a Continuum of Cortical Dysplasias D’Gama AM, Woodworth MB, Hossain AA, Bizzotto S, Hatem NE, LaCoursiere CM, Najm I, Ying Z, Yang E, Barkovich AJ, Kwiatkowski DJ, Vinters HV, Madsen JR, Mathern GW, Blümcke I, Poduri A, Walsh CA. Cell Rep. 2017;21:3754-3766.Focal cortical dysplasia (FCD) and hemimegalencephaly (HME) are epileptogenic neurodevelopmental malformations caused by mutations in mTOR pathway genes. Deep sequencing of these genes in FCD/HME brain tissue identified an etiology in 27 (41%) of 66 cases. Radiographically indistinguishable lesions are caused by somatic activating mutations in AKT3, MTOR, and PIK3CA and germline loss-of-function mutations in DEPDC5, NPRL2, and TSC1/2, including TSC2 mutations in isolated HME demonstrating a “two-hit” model. Mutations in the same gene cause a disease continuum from FCD to HME to bilateral brain overgrowth, reflecting the progenitor cell and developmental time when the mutation occurred. Single-cell sequencing demonstrated mTOR activation in neurons in all lesions. Conditional Pik3ca activation in the mouse cortex showed that mTOR activation in excitatory neurons and glia, but not interneurons, is sufficient for abnormal cortical overgrowth. These data suggest that mTOR activation in dorsal telencephalic progenitors, in some cases specifically the excitatory neuron lineage, causes cortical dysplasia.
  • 机译 “我们到了吗?”寻求治疗难治性癫痫
    摘要:Biochemical Autoregulatory Gene Therapy for Focal Epilepsy Lieb A, Qiu Y, Dixon CL, Heller JP, Walker MC, Schorge S, Kullmann DM. Nat Med. 2018;24:1324-1329.Despite the introduction of more than one dozen new antiepileptic drugs in the past 20 years, approximately one-third of people who develop epilepsy continue to have seizures on mono- or polytherapy. Viral-vector-mediated gene transfer offers the opportunity to design a rational treatment that builds on mechanistic understanding of seizure generation and that can be targeted to specific neuronal populations in epileptogenic foci. Several such strategies have shown encouraging results in different animal models, although clinical translation is limited by possible effects on circuits underlying cognitive, mnemonic, sensory, or motor function. Here, we describe an autoregulatory antiepileptic gene therapy, which relies on neuronal inhibition in response to elevations in extracellular glutamate. It is effective in a rodent model of focal epilepsy and is well tolerated, thus lowering the barrier to clinical translation.
  • 机译 塔尔她吹了!寻找对卡马西平具有抗药性的大鲸鱼
    摘要:Polyamine Modulation of Anticonvulsant Drug Response: A Potential Mechanism Contributing to Pharmacoresistance in Chronic Epilepsy Beckonert NM, Opitz T, Pitsch J, Soares da Silva P, Beck H. J Neurosci. 2018;38(24):5596-5605. .Despite the development of numerous novel anticonvulsant drugs, ∼30% of patients with epilepsy remain refractory to antiepileptic drugs (AEDs). Many established and novel AEDs reduce hyperexcitability via voltage- and use-dependent inhibition of voltage-gated Na+ channels. For the widely used anticonvulsant carbamazepine (CBZ), use-dependent block of Na+ channels is significantly reduced both in experimental and human epilepsies. However, the molecular underpinnings of this potential cellular mechanism for pharmacoresistance have remained enigmatic. Here, we describe the mechanism that leads to the emergence of CBZ-resistant Na+ channels. We focused on the endogenous polyamine system, which powerfully modulates Na+ channels in a use-dependent manner. We had shown previously that the intracellular polyamine spermine is reduced in chronic epilepsy, resulting in increased persistent Na+ currents. Because both spermine and CBZ bind use-dependently in spatial proximity within the Na+ channel pore, we hypothesized that spermine loss might also be related to diminished CBZ response. Using the pilocarpine model of refractory epilepsy in male rats and whole-cell patch-clamp recordings, we first replicated the reduction of use-dependent block by CBZ in chronically epileptic animals. We then substituted intracellular spermine via the patch pipette in different concentrations. Under these conditions, we found that exogenous spermine significantly rescues use-dependent block of Na+ channels by CBZ. These findings indicate that an unexpected modulatory mechanism, depletion of intracellular polyamines, leads both to increased persistent Na+ currents and to diminished CBZ sensitivity of Na+ channels. These findings could lead to novel strategies for overcoming pharmacoresistant epilepsy that target the polyamine system. Significance Statement: Pharmacoresistant epilepsy affects ∼18 million people worldwide, and intense efforts have therefore been undertaken to uncover the underlying molecular and cellular mechanisms. One of the key known candidate mechanisms of pharmacoresistance has been a loss of use-dependent Na+ channel block by the anticonvulsant CBZ, both in human and experimental epilepsies. Despite intense scrutiny, the molecular mechanisms underlying this phenomenon have not been elucidated. We now show that a loss of intracellular spermine in chronic epilepsy is a major causative factor leading to the development of CBZ-resistant Na+ currents. This finding can be exploited both for the screening of anticonvulsants in expression systems and for novel strategies to overcome pharmacoresistance that target the polyamine system.
  • 机译 2018年美国癫痫学会年会的要点
    摘要:The American Epilepsy Society Meeting in New Orleans attracted more than 5900 attendees. There was a lively exchange of new science, innovation, education, clinical practice, and many other items related to epilepsy. Educational symposia were a major part of the meeting and explored varying topics of interest for all types of epilepsy professionals. This article reviews highlights of the meeting presented in major symposia. Topics ranged from how to treat varying aspects of epilepsy as a consultant in the hospital to finding the scientific underpinning of the interaction between sleep and epilepsy. Pros and cons of novel antiseizure medications, dietary, and stimulation treatments were discussed. Epilepsy may impair memory and we need to learn what is the pathophysiologic relationship. Febrile status epilepticus may have severe consequences for a later life with seizures. Epilepsy professionals should be very well aware of the ethical implications of devasting seizures and their associated disability. These are just a few select topics of the many that we need to study further to archive the final goal to improve the lives of patients with epilepsy.
  • 机译 治疗有效,那么谁会害怕PNES?
    摘要:Adherence With Psychotherapy and Treatment Outcomes for Psychogenic Nonepileptic Seizures Tolchin B, Dworetzky BA, Martino S, et al. Neurology. 2019;92(7):e675-e679. doi:10.1212/WNL.0000000000006848.Objective:We conducted a prospective cohort study of patients with psychogenic nonepileptic seizures (PNES) to examine the association between adherence to psychotherapy and outcomes, including significant (≥50%) reduction in PNES frequency, PNES freedom, improvement in quality of life, and reduction in emergency department (ED) utilization.
  • 机译 抗抑郁药对癫痫孕妇是否安全?迹象表明是
    • 作者:Katherine Noe
    • 刊名:Epilepsy Currents
    • 2019年第3期
    摘要:The Use of Antidepressant Drugs in Pregnant Women With Epilepsy: A Study From the Australian Pregnancy Register Sivathamboo N, Hitchcock A, Graham J, et al. Epilepsia. 2018;59(9):1696-1704.Objective: To study interactions between first-trimester exposure to antidepressant drugs (ADDs) and antiepileptic drugs (AEDs) and a history of clinical depression and/or anxiety on pregnancy outcomes and seizure control in pregnant women with epilepsy (WWE). Methods: We examined data from the Australian Pregnancy Register of Antiepileptic Drugs in Pregnancy, collected from 1999 to 2016. The register is an observational, prospective database, from which this study retrospectively analyzed a cohort. Among the AED-exposed outcomes, comparisons were made among 3 exposure groups: (1) pregnancy outcomes with first-trimester exposure to ADDs, (2) outcomes with mothers diagnosed with depression and/or anxiety but who were not medicated with an ADD, and (3) those with mothers who were not diagnosed with depression and/or anxiety and were not medicating with ADD. Prevalence data were analyzed using Fisher exact test. Results: A total of 2124 pregnancy outcomes were included in the analysis; 1954 outcomes were exposed to AEDs in utero, whereas 170 were unexposed. Within the group of WWE taking AEDs, there was no significant difference in the prevalence of malformations in infants who were additionally exposed to ADDs (10.2%; 95% confidence interval [CI]: 3.9-16.6), compared to individuals in the non-ADD-medicated depression and/or anxiety group (7.7%, 95% CI: 1.2-14.2), or those without depression or anxiety (6.9%, 95% CI: 5.7-8.1; P = .45). The malformation rates in pregnancy outcomes unexposed to AEDs were also similar in the above groups (P = .27). In WWE medicated with AEDs and ADDs, the frequency of convulsive seizures (P = .78), or nonconvulsive seizures (P = .45) throughout pregnancy, did not differ across comparative groups. Significance: Comedicating with ADDs in WWE taking AEDs does not appear to confer a significant added teratogenic risk, and it does not affect seizure control.
  • 机译 不要只站在那儿:做点什么!介入治疗
    摘要:Hypoxemia Following Generalized Convulsive Seizures: Risk Factors and Effect of Oxygen Therapy Rheims S, Alvarez BM, Alexandre V, Curot J, Maillard L, Bartolomei F, et al; the REPO2MSE Study Group. Hypoxemia following generalized convulsive seizures: risk factors and effect of oxygen therapy. Neurology. 2019;92(3):e183-e193Objective:To analyze the factors that determine the occurrence or severity of postictal hypoxemia in the immediate aftermath of a generalized convulsive seizure (GCS).

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