Modeling seizures in the Human Phenotype Ontology according to contemporary ILAE concepts makes big phenotypic data tractable.

OBJECTIVE: The clinical features of epilepsy determine how it is defined, which in turn guides management. Therefore, consideration of the fundamental clinical entities that comprise an epilepsy is essential in the study of causes, trajectories, and treatment responses. The Human Phenotype Ontology (HPO) is used widely in clinical and research genetics for concise communication and modeling of clinical features, allowing extracted data to be harmonized using logical inference. We sought to redesign the HPO seizure subontology to improve its consistency with current epileptological concepts, supporting the use of large clinical data sets in high-throughput clinical and research genomics. METHODS: We created a new HPO seizure subontology based on the 2017 International League Against Epilepsy (ILAE) Operational Classification of Seizure Types, and integrated concepts of status epilepticus, febrile, reflex, and neonatal seizures at different levels of detail. We compared the HPO seizure subontology prior to, and following, our revision, according to the information that could be inferred about the seizures of 791 individuals from three independent cohorts: 2 previously published and 150 newly recruited individuals. Each cohort's data were provided in a different format and harmonized using the two versions of the HPO. RESULTS: The new seizure subontology increased the number of descriptive concepts for seizures 5-fold. The number of seizure descriptors that could be annotated to the cohort increased by 40% and the total amount of information about individuals' seizures increased by 38%. The most important qualitative difference was the relationship of focal to bilateral tonic-clonic seizure to generalized-onset and focal-onset seizures. SIGNIFICANCE: We have generated a detailed contemporary conceptual map for harmonization of clinical seizure data, implemented in the official 2020-12-07 HPO release and freely available at hpo.jax.org. This will help to overcome the phenotypic bottleneck in genomics, facilitate reuse of valuable data, and ultimately improve diagnostics and precision treatment of the epilepsies.

Cortico-striato-thalamo-cerebellar networks of structural covariance underlying different epilepsy syndromes associated with generalized tonic-clonic seizures.

Generalized tonic-clonic seizures (GTCS) are the severest and most remarkable clinical expressions of human epilepsy. Cortical, subcortical, and cerebellar structures, organized with different network patterns, underlying the pathophysiological substrates of genetic associated epilepsy with GTCS (GE-GTCS) and focal epilepsy associated with focal to bilateral tonic-clonic seizure (FE-FBTS). Structural covariance analysis can delineate the features of epilepsy network related with long-term effects from seizure. Morphometric MRI data of 111 patients with GE-GTCS, 111 patients with FE-FBTS and 111 healthy controls were studied. Cortico-striato-thalao-cerebellar networks of structural covariance within the gray matter were constructed using a Winner-take-all strategy with five cortical parcellations. Comparisons of structural covariance networks were conducted using permutation tests, and module effects of disease duration on networks were conducted using GLM model. Both patient groups showed increased connectivity of structural covariance relative to controls, mainly within the striatum and thalamus, and mostly correlated with the frontal, motor, and somatosensory cortices. Connectivity changes increased as a function of epilepsy durations. FE-FBTS showed more intensive and extensive gray matter changes with volumetric loss and connectivity increment than GE-GTCS. Our findings implicated cortico-striato-thalamo-cerebellar network changes at a large temporal scale in GTCS, with FE-FBTS showing more severe network disruption. The study contributed novel imaging evidence for understanding the different epilepsy syndromes associated with generalized seizures.

Temporal variability profiling of the default mode across epilepsy subtypes.

OBJECTIVE: Epilepsies are a group of neurological disorders sharing certain core features, but also demonstrate remarkable pathogenic and symptomatic heterogeneities. Various subtypes of epilepsy have been identified with abnormal shift in the brain default mode network (DMN). This study aims to evaluate the fine details of shared and distinct alterations in the DMN among epileptic subtypes. METHODS: We collected resting-state functional magnetic resonance imaging (MRI) data from a large epilepsy sample (n = 371) at a single center, including temporal lobe epilepsy (TLE), frontal lobe epilepsy (FLE), and genetic generalized epilepsy with generalized tonic-clonic seizures (GGE-GTCS), as well as healthy controls (HC, n = 150). We analyzed temporal dynamics profiling of the DMN, including edge-wise and node-wise temporal variabilities, and recurrent dynamic states of functional connectivity, to identify abnormalities common to epilepsies as well as those specific to each subtype. RESULTS: The analyses revealed that hypervariable edges within the specific DMN subsystem were shared by all subtypes (all PNBS  < .005), and deficits in node-wise temporal variability were prominent in TLE (all t(243) ≤ 2.51, PFDR  < .05) and FLE (all t(302) ≤ -2.65, PFDR  < .05) but relatively weak in GGE-GTCS. Moreover, dynamic states were generally less stable in patients than controls (all P's < .001). SIGNIFICANCE: Collectively, these findings demonstrated general DMN abnormalities common to different epilepsies as well as distinct dysfunctions to subtypes, and provided insights into understanding the relationship of pathophysiological mechanisms and brain connectivity.

Thalamus and focal to bilateral seizures: A multiscale cognitive imaging study.

OBJECTIVE: To investigate the functional correlates of recurrent secondarily generalized seizures in temporal lobe epilepsy (TLE) using task-based fMRI as a framework to test for epilepsy-specific network rearrangements. Because the thalamus modulates propagation of temporal lobe onset seizures and promotes cortical synchronization during cognition, we hypothesized that occurrence of secondarily generalized seizures, i.e., focal to bilateral tonic-clonic seizures (FBTCS), would relate to thalamic dysfunction, altered connectivity, and whole-brain network centrality. METHODS: FBTCS occur in a third of patients with TLE and are a major determinant of disease severity. In this cross-sectional study, we analyzed 113 patients with drug-resistant TLE (55 left/58 right), who performed a verbal fluency fMRI task that elicited robust thalamic activation. Thirty-three patients (29%) had experienced at least one FBTCS in the year preceding the investigation. We compared patients with TLE-FBTCS to those without FBTCS via a multiscale approach, entailing analysis of statistical parametric mapping (SPM) 12-derived measures of activation, task-modulated thalamic functional connectivity (psychophysiologic interaction), and graph-theoretical metrics of centrality. RESULTS: Individuals with TLE-FBTCS had less task-related activation of bilateral thalamus, with left-sided emphasis, and left hippocampus than those without FBTCS. In TLE-FBTCS, we also found greater task-related thalamotemporal and thalamomotor connectivity, and higher thalamic degree and betweenness centrality. Receiver operating characteristic curves, based on a combined thalamic functional marker, accurately discriminated individuals with and without FBTCS. CONCLUSIONS: In TLE-FBTCS, impaired task-related thalamic recruitment coexists with enhanced thalamotemporal connectivity and whole-brain thalamic network embedding. Altered thalamic functional profiles are proposed as imaging biomarkers of active secondary generalization.

Peri-ictal hypoxia is related to extent of regional brain volume loss accompanying generalized tonic-clonic seizures.

OBJECTIVES: Hypoxia, or abnormally low blood-oxygen levels, often accompanies seizures and may elicit brain structural changes in people with epilepsy which contribute to central processes underlying sudden unexpected death in epilepsy (SUDEP). The extent to which hypoxia may be related to brain structural alterations in this patient group remains unexplored. METHODS: We analyzed high-resolution T1-weighted magnetic resonance imaging (MRI) to determine brain morphometric and volumetric alterations in people with generalized tonic-clonic seizures (GTCS) recorded during long-term video-electroencephalography (VEEG), recruited from two sites (n = 22), together with data from age- and sex-matched healthy controls (n = 43). Subjects were sub-divided into those with mild/moderate (GTCS-hypox-mild/moderate, n = 12) and severe (GTCS-hypox-severe, n = 10) hypoxia, measured by peripheral oxygen saturation (SpO2 ) during VEEG. Whole-brain voxel-based morphometry (VBM) and regional volumetry were used to assess group comparisons and correlations between brain structural measurements as well as the duration and extent of hypoxia during GTCS. RESULTS: Morphometric and volumetric alterations appeared in association with peri-GTCS hypoxia, including volume loss in the periaqueductal gray (PAG), thalamus, hypothalamus, vermis, cerebellum, parabrachial pons, and medulla. Thalamic and PAG volume was significantly reduced in GTCS patients with severe hypoxia compared with GTCS patients with mild/moderate hypoxia. Brainstem volume loss appeared in both hypoxia groups, although it was more extensive in those with severe hypoxia. Significant negative partial correlations emerged between thalamic and hippocampal volume and extent of hypoxia, whereas vermis and accumbens volumes declined with increasing hypoxia duration. SIGNIFICANCE: Brain structural alterations in patients with GTCS are related to the extent of hypoxia in brain sites that serve vital functions. Although the changes are associative only, they provide evidence of injury to regulatory brain sites related to respiratory manifestations of seizures.

Ictal quantitative surface electromyography correlates with postictal EEG suppression.

OBJECTIVE: To test the hypothesis that neurophysiologic biomarkers of muscle activation during convulsive seizures reveal seizure severity and to determine whether automatically computed surface EMG parameters during seizures can predict postictal generalized EEG suppression (PGES), indicating increased risk for sudden unexpected death in epilepsy. Wearable EMG devices have been clinically validated for automated detection of generalized tonic-clonic seizures. Our goal was to use quantitative EMG measurements for seizure characterization and risk assessment. METHODS: Quantitative parameters were computed from surface EMGs recorded during convulsive seizures from deltoid and brachial biceps muscles in patients admitted to long-term video-EEG monitoring. Parameters evaluated were the durations of the seizure phases (tonic, clonic), durations of the clonic bursts and silent periods, and the dynamics of their evolution (slope). We compared them with the duration of the PGES. RESULTS: We found significant correlations between quantitative surface EMG parameters and the duration of PGES (p < 0.001). Stepwise multiple regression analysis identified as independent predictors in deltoid muscle the duration of the clonic phase and in biceps muscle the duration of the tonic-clonic phases, the average silent period, and the slopes of the silent period and clonic bursts. The surface EMG-based algorithm identified seizures at increased risk (PGES ≥20 seconds) with an accuracy of 85%. CONCLUSIONS: Ictal quantitative surface EMG parameters correlate with PGES and may identify seizures at high risk. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that during convulsive seizures, surface EMG parameters are associated with prolonged postictal generalized EEG suppression.

Morphological and molecular correlates of altered hearing sensitivity in the genetically audiogenic seizure-prone hamster GASH/Sal.

Rodent models of audiogenic seizures, in which seizures are precipitated by an abnormal response of the brain to auditory stimuli, are crucial to investigate the neural bases underlying ictogenesis. Despite significant advances in understanding seizure generation in the inferior colliculus, namely the epileptogenic nucleus, little is known about the contribution of lower auditory stations to the seizure-prone network. Here, we examined the cochlea and cochlear nucleus of the genetic audiogenic seizure hamster from Salamanca (GASH/Sal), a model of reflex epilepsy that exhibits generalized tonic-clonic seizures in response to loud sound. GASH/Sal animals under seizure-free conditions were compared with matched control hamsters in a multi-technical approach that includes auditory brainstem responses (ABR) testing, histology, scanning electron microscopy analysis, immunohistochemistry, quantitative morphometry and gene expression analysis (RT-qPCR). The cochlear histopathology of the GASH/Sal showed preservation of the sensory hair cells, but a significant loss of spiral ganglion neurons and mild atrophy of the stria vascularis. At the electron microscopy level, the reticular lamina exhibited disarray of stereociliary tufts with blebs, loss or elongated stereocilia as well as non-parallel rows of outer hair cells due to protrusions of Deiters' cells. At the molecular level, the abnormal gene expression patterns of prestin, cadherin 23, protocadherin 15, vesicular glutamate transporters 1 (Vglut1) and -2 (Vglut2) indicated that the hair-cell mechanotransduction and cochlear amplification were markedly altered. These were manifestations of a cochlear neuropathy that correlated to ABR waveform I alterations and elevated auditory thresholds. In the cochlear nucleus, the distribution of VGLUT2-immunolabeled puncta was differently affected in each subdivision, showing significant increases in magnocellular regions of the ventral cochlear nucleus and drastic reductions in the granule cell domain. This modified inputs lead to disruption of Vglut1 and Vglut2 gene expression in the cochlear nucleus. In sum, our study provides insight into the morphological and molecular traits associated with audiogenic seizure susceptibility in the GASH/Sal, suggesting an upward spread of abnormal glutamatergic transmission throughout the primary acoustic pathway to the epileptogenic region.

Electropositive seizures and non-convulsive status epilepticus in a critically ill patient with prior skull defect.

Epileptiform discharges captured on routine scalp EEG typically carry a surface negative dipole. We present a patient whose continuous EEG recording in the intensive care setting captured frequent electropositive non-convulsive seizures. Epileptiform discharges with positive polarity are common in the pediatric population but have rarely been reported in adult patients. When reported in adults, such patients usually have skull defects. As surface positive discharges are scarce, adult electroencephalographers should be prudent to differentiate such discharges from artifact, particularly in an intensive care setting where EEG artifact is common.

SUDEP in Spain: An Epilepsy Monitoring Unit based case series.

PURPOSE: SUDEP is the first cause of mortality related to epilepsy. However, in Spain there are no published cases or series from Epilepsy Monitoring Units that could expose the characteristics of SUDEP in our population. METHOD: We reviewed all patients treated at our Spanish Epilepsy Reference Centre who died between 2010-2018. SUDEP cases were classified as definite, probable, possible or near-SUDEP. Epilepsy type, demographics and case detection issues were described. RESULTS: From 1250 evaluated patients, 102 died during the study period. Seven patients were diagnosed with SUDEP or near-SUDEP: two definite SUDEP, one definite SUDEP plus, two probable SUDEP and two near-SUDEP. Specific problems for detection and registration of SUDEP inherent to the Spanish healthcare system and the legal framework were defined. Only 43% of cases were known by the referral neurologist. SUDEP incidence was 1.3 per 1000 patient/year, comprising 0.56% of all deaths in our cohort. Two cases were female, the average age was 36 years (18-61). All patients had focal epilepsy and suffered from generalized tonic-clonic seizures. All witnessed cases occurred after a focal to bilateral tonic-clonic seizure. Four cases occurred during sleep and all non-witnessed cases were found in prone position. One case occurred during video-EEG monitoring. CONCLUSIONS: Our casuistic represents the first Epilepsy Monitoring Unit based case series of SUDEP conducted in Spain. The incidence in our population agrees with the reported in other countries. However, in our population, SUDEP is probably underdiagnosed due to administrative and legal issues.

Seizure characteristics, treatment, and outcome in autoimmune synaptic encephalitis: A long-term study.

OBJECTIVES: The objective of this study was to report seizure characteristics, long-term outcome, and potential factors associated with persistent seizures in patients with autoimmune synaptic encephalitis (ASE). METHOD: Clinical data and courses of 52 patients with ASE who presented with seizures at the Department of Neurology of the First Hospital of Jilin University from January 2015 to August 2017 were reviewed. Seizure outcomes were assessed with a median follow-up duration of 30 months (8-40 months). RESULTS: Most patients (71.2%) presented with seizure at initial consultation; focal to bilateral tonic-clonic seizures (50.0%) were the most common type. The temporal lobe (73.5%) was the prominent region of seizure origin, which was incident with hippocampal lesions on magnetic resonance imaging (MRI) in 62.1% of the patients. Status epilepticus, subclinical seizures, and nonepileptic events were observed in 28.9%, 36.8%, and 28.9% of the patients, respectively. Twenty-seven out of the 43 followed-up patients (62.8%) exhibited seizure remission after initial immunotherapy. Others (37.2%) developed persistent seizures to different extents. Six out of 9 patients experienced additional seizure freedom because of antiepileptic drugs (AEDs); however, the seizures of the other three patients, with serious conditions, showed poor response. Patients with anti-N-methyl-d-aspartate receptor antibodies had a lower risk of developing persistent seizures than those with anti-leucine-rich glioma-inactivated 1 (LGI1) or anti-γ-aminobutyric acid receptor type B receptor (GABABR) antibodies (P = 0.001). CONCLUSIONS: A complex of clinical and subclinical seizures, and nonepileptic events characterize ASE. Patients with anti-LGI1 or anti-GABABR antibodies have a higher risk of developing persistent seizures; AEDs are suitable for achieving additional seizure freedom, but not for patients with serious conditions. A few patients present with super-refractory epilepsy despite multiple treatments.

[Postictal pulmonary oedema: a review of the literature]. / Edema pulmonar postictal: revision de la bibliografia.

INTRODUCTION: Postictal neurogenic pulmonary oedema is an infrequent condition of varying severity, probably related to sudden unexpected death in epilepsy (SUDEP). It is more frequent in patients with generalised tonic-clonic seizures of long duration or with status epilepticus. AIM: Based on a review of the literature, the aim is to describe the clinical characteristics, pathophysiology, radiological findings, treatment and prognosis of patients with postictal pulmonary oedema. DEVELOPMENT: A search of the literature was performed in the PubMed, Embase, Cochrane Database of Systematic Reviews and BVS databases using a combination of free terms. The limits of the search applied were: papers published between 1 January 2000 and 26 April 2018, and papers for which the abstract was available. Altogether 23 papers were found, most of which were clinical cases, and used to extract the information needed to carry out the review. CONCLUSIONS: In postictal pulmonary oedema, generalised tonic-clonic seizures are the most frequently reported type. The most common clinical manifestations were dyspnoea and tachycardia appearing within a few minutes after the seizure. Among the paraclinical findings the most frequent was leukocytosis. In general terms, a good prognosis was found in most cases, with improvement of the oedema within a period of between 12 and 96 hours. Only two of the 21 patients reported died. In addition, in a clinical pathology study in patients with SUDEP, pulmonary oedema appeared in most cases.

TITLE: Edema pulmonar postictal: revision de la bibliografia.Introduccion. El edema pulmonar neurogeno postictal es una patologia poco frecuente con gravedad variable, probablemente en relacion con la muerte subita asociada a la epilepsia (SUDEP). La frecuencia es mayor en pacientes con crisis tonicoclonicas generalizadas de larga duracion o con estado epileptico. Objetivo. Por medio de una revision de la bibliografia se pretende describir las caracteristicas clinicas, la fisiopatologia, los hallazgos radiologicos, el tratamiento y el pronostico de los pacientes con edema pulmonar postictal. Desarrollo. Se realizo una busqueda de la bibliografia en las bases de datos PubMed, Embase, Cochrane y BVS empleando una combinacion de terminos libres. Se aplicaron como limites de busqueda: articulos publicados desde el 1 de enero de 2000 hasta el 26 de abril de 2018 y articulos que contaran con el resumen disponible. En total se revisaron 23 articulos, en su mayoria casos clinicos, de los cuales se obtuvo la informacion para desarrollar la revision. Conclusiones. En el edema pulmonar postictal, el tipo de crisis mas frecuentemente comunicada es la tonicoclonica generalizada. Las manifestaciones clinicas mas habituales fueron disnea y taquicardia de aparicion en los minutos posteriores a la crisis. En los paraclinicos, el hallazgo mas frecuente fue leucocitosis. En general se encontro un buen pronostico en la mayoria de los casos, con mejoria del edema entre las 12 y las 96 horas. Unicamente dos de los 21 pacientes comunicados fallecieron. Ademas, en un estudio clinico de patologia en pacientes con SUDEP, el edema pulmonar aparecio en la mayoria de los casos.

Asynchronous, bilateral, and biphasic temporally unstructured electrical stimulation of amygdalae enhances the suppression of pentylenetetrazole-induced seizures in rats.

A promising alternative for the treatment of refractory epilepsy is electrical stimulation (ES) of the central nervous system. Based on the premise that epilepsy is a result of neural hypersynchronization, we have previously demonstrated that a novel non-standard form of electrical stimulation with randomized inter-pulse intervals, termed non-periodic stimulation (NPS), applied to the amygdala is robustly anticonvulsant. This investigation also suggested that NPS attains its therapeutic effect by desynchronization of epileptiform activity. Here, we further explored the desynchronization hypothesis by testing how the efficacy of NPS in the suppression of convulsive behaviors depends on morphological, spatial, and temporal parameters of stimulus. For this purpose, we varied the number of pulse phases (monopolar versus bipolar square pulses), side of stimulation (right versus left), number of application hemispheres (unilateral versus bilateral), and interhemispheric temporal synchronicity (synchronous versus asynchronous), while measuring the impact on the anticonvulsant action of NPS. Wistar rats received a controlled infusion of the convulsant agent pentylenetetrazole (PTZ, 10 mg/min), together with one of six variations of NPS applied to the amygdala. A stimulated PTZ-free group of animals was also performed as a positive control. Latency to convulsive behavior was used to measure seizure threshold. Animals receiving NPS displayed significant higher threshold for forelimb clonus and generalized tonic-clonic seizures for all patterns. Thresholds seemed to increase gradually from mono to biphasic, unilateral to bilateral, and synchronous to asynchronous stimuli. Thus, combined biphasic, bilateral, and asynchronous stimulation resulted in the greatest seizure threshold. PTZ free animals did not develop any observable convulsive behavior or other uncommon motor activity. These results confirm that NPS has anticonvulsant properties and that biphasic, bilateral, and asynchronous stimulation enhances its efficacy. The fact that lack of synchronism between stimuli of each hemisphere maximizes NPS anticonvulsant power is evidence to desynchronization as tool for suppression of seizures.

Detection of generalized tonic-clonic seizures using surface electromyographic monitoring.

OBJECTIVE: A prospective multicenter phase III trial was undertaken to evaluate the performance and tolerability in the epilepsy monitoring unit (EMU) of an investigational wearable surface electromyographic (sEMG) monitoring system for the detection of generalized tonic-clonic seizures (GTCSs). METHODS: One hundred ninety-nine patients with a history of GTCSs who were admitted to the EMU in 11 level IV epilepsy centers for clinically indicated video-electroencephalographic monitoring also received sEMG monitoring with a wearable device that was worn on the arm over the biceps muscle. All recorded sEMG data were processed at a central site using a previously developed detection algorithm. Detected GTCSs were compared to events verified by a majority of three expert reviewers. RESULTS: For all subjects, the detection algorithm detected 35 of 46 (76%, 95% confidence interval [CI] = 0.61-0.87) of the GTCSs, with a positive predictive value (PPV) of 0.03 and a mean false alarm rate (FAR) of 2.52 per 24 h. For data recorded while the device was placed over the midline of the biceps muscle, the system detected 29 of 29 GTCSs (100%, 95% CI = 0.88-1.00), with a detection delay averaging 7.70 s, a PPV of 6.2%, and a mean FAR of 1.44 per 24 h. Mild to moderate adverse events were reported in 28% (55 of 199) of subjects and led to study withdrawal in 9% (17 of 199). These adverse events consisted mostly of skin irritation caused by the electrode patch that resolved without treatment. No serious adverse events were reported. SIGNIFICANCE: Detection of GTCSs using an sEMG monitoring device on the biceps is feasible. Proper positioning of this device is important for accuracy, and for some patients, minimizing the number of false positives may be challenging.

Impairments of cingulated cortex in the generalized tonic-clonic seizure epilepsy by combining morphological and functional connectivity magnetic resonance imaging.

Previous studies suggested that the patients with generalized tonic-clonic seizure had structural abnormalities in the thalamus, cingulated cortex and some other specific brain regions. Concurrently, the abnormality in thalamocortical network and basal ganglia network has been found in idiopathic generalized epilepsy. The cingulated cortex, a nexus of information processing and regulation in human brain, is implicated in the propagation of generalized spike in IGE and the previous studies have suggested that the structural features and functional connectivity of the cingulated cortex have been changed. The aim of this study was to demonstrate the alterations in the cingulated cortex in generalized tonic-clonic seizure by combining morphological and functional connectivity magnetic resonance imaging. 19 patients with generalized tonic-clonic seizure and 19 age-and gender-matched healthy controls were involved in the study. The three-dimensional high-resolution T1-weighted magnetic resonance imaging data were acquired for voxel-based morphometry analysis, two-sample t-test run on the T1-weighted structural images revealed clusters exhibiting significant decreases in grey-matter volume in the generalized tonic-clonic seizure group, located within the cingulated cortex, thalamus, frontal lobe, temporal lobe, and cerebellum. The decreased gray matter volume in the cingulated cortex indicating that the cingulated cortex has structural impairments in generalized tonic-clonic seizure patients. The bilateral cingulated cortex, as detected with decreased gray matter volume in patients with generalized tonic-clonic seizure through voxel-based morphometry analysis, was selected as seed regions for functional connectivity analysis. Compared with controls, we found decreased functional connectivity to left anterior cingulated cortex (ROI1) in the cuneus, frontal lobe and precentral gyrus. There was no significant result when seeding at the right anterior cingulum gyrus (ROI2). The results of the ROI3 (left middle cingulum) revealed the significantly decreased functional connectivity in the parietal lobe and frontal lobe. Seeding at the ROI4 (right middle cingulum), decreased functional connectivity showed in the occipital lobe, temporal lobe, frontal lobe. Seeding at the ROI5 (left posterior cingulum), decreased functional connectivity showed in the temporal lobe and frontal lobe. Seeding at the ROI6 (right posterior cingulum), decreased functional connectivity showed in the cuneus and frontal lobe. We did not find any increased functional connectivity of the posterior cingulated cortex (ROI3-ROI6) for the generalized tonic-clonic seizure patients in comparison to the controls (p<0.001). Our findings demonstrated that the abnormalities of the functional connectivity were likely to be related to the decreased gray matter volume in the cingulated cortex.

Brain-responsive neurostimulation in patients with medically intractable seizures arising from eloquent and other neocortical areas.

OBJECTIVE: Evaluate the seizure-reduction response and safety of brain-responsive stimulation in adults with medically intractable partial-onset seizures of neocortical origin. METHODS: Patients with partial seizures of neocortical origin were identified from prospective clinical trials of a brain-responsive neurostimulator (RNS System, NeuroPace). The seizure reduction over years 2-6 postimplantation was calculated by assessing the seizure frequency compared to a preimplantation baseline. Safety was assessed based on reported adverse events. Additional analyses considered safety and seizure reduction according to lobe and functional area (e.g., eloquent cortex) of seizure onset. RESULTS: There were 126 patients with seizures of neocortical onset. The average follow-up was 6.1 implant years. The median percent seizure reduction was 70% in patients with frontal and parietal seizure onsets, 58% in those with temporal neocortical onsets, and 51% in those with multilobar onsets (last observation carried forward [LOCF] analysis). Twenty-six percent of patients experienced at least one seizure-free period of 6 months or longer and 14% experienced at least one seizure-free period of 1 year or longer. Patients with lesions on magnetic resonance imaging (MRI; 77% reduction, LOCF) and those with normal MRI findings (45% reduction, LOCF) benefitted, although the treatment response was more robust in patients with an MRI lesion (p = 0.02, generalized estimating equation [GEE]). There were no differences in the seizure reduction in patients with and without prior epilepsy surgery or vagus nerve stimulation. Stimulation parameters used for treatment did not cause acute or chronic neurologic deficits, even in eloquent cortical areas. The rates of infection (0.017 per patient implant year) and perioperative hemorrhage (0.8%) were not greater than with other neurostimulation devices. SIGNIFICANCE: Brain-responsive stimulation represents a safe and effective treatment option for patients with medically intractable epilepsy, including adults with seizures of neocortical onset, and those with onsets from eloquent cortex.

[Epileptic syndromes in childhood associated with secondary generalized tonic-clonic seizures]. / Épilepticheskie sindromy v detskom vozraste, assotsiirovannye s vtorichno-generalizovannymi sudorozhnymi pristupami.

AIM: To study a group of patients with secondary generalized tonic-clonic seizures (SGTCS) in view of nosology, medical history, clinical, electroencephalographic and neuroimaging features. MATERIAL AND METHODS: The study included 471 patients, 244 (51.8%) men and 227 (48.2%) women. RESULTS: SGTCS were observed in many epileptic syndromes. The most frequent were symptomatic focal epilepsy (33.8%), cryptogenic focal epilepsy (23.8%), rolandic epilepsy (12.6%), FEBL-BEDC syndrome (12.3%). Other forms of epilepsy were less frequent. The onset of epilepsy ranged over a wide age range from the first month of life to 18 years. The average age of onset was 5.7±4.96 years. SGTCS as the only type of paroxysms were observed in 28.3% of cases. Two or more types of seizures were observed in 71.7% of patients, three or more types in 39.3%. Epileptiform activity on EEG during long VEM was detected in 91.3% of patients with SGTCS. In 37.2% of patients, benign epileptiform discharges of childhood were recorded. Treatment with antiepileptic drugs (AEP) led to complete remission in 57.1% of cases of epilepsy associated with SGTCS. A reduction of the frequency of seizures by 50% or more was found in 33.6% of patients treated with AEP. No effect was observed in 9.3% of patients. CONCLUSION: Significant differences in the prognosis and therapeutic approaches to specific epileptic syndromes associated with SGTCS necessitate the use of the entire spectrum of diagnostic measures, which should include careful history taking, clinical examination, video-EEG monitoring with the inclusion of sleep dynamics, MRI / CT brain, genetic testing.

Hand postures in primary and secondary generalized tonic-clonic seizures.

OBJECTIVE: To evaluate and identify the frequency of hand postures during generalized convulsions in patients with genetic generalized epilepsy (GGE), localization-related epilepsy (LRE), and nonepileptic attacks (NEA). METHODS: We retrospectively analyzed 98 consecutive videos of generalized convulsions in 62 patients who were admitted for diagnostic video-EEG monitoring. Demographics were recorded, and hand postures were subdivided into fanning, fisting, index-finger pointing (IFP), clawing, and flaccid posturing. Hand postures were then compared between patients with GGE, LRE, and NEA for each stage of the convulsion and for the whole event. RESULTS: In patients with LRE, 96% had IFP, where fanning occurred in 91.3% of GGE (and only at onset), and the flaccid hand posture occurred in 56.0% of NEA. Fisting, fanning, and IFP postures all occurred significantly more frequently during epileptic seizures than during NEA (74.0% vs 32.0%, p = 0.0003; 60.3% vs 20.0%, p = 0.0005; 83.6% vs 12.0%, p < 0.0001). The claw hand posture was present only during NEA, and the flaccid posture occurred significantly more frequently during NEA than during epileptic seizures (56.0% vs 15.1%, p = 0.0001). CONCLUSIONS: Distinct ictal hand or finger posturing is present in patients with GGE, LRE, and NEA. The presence of any fisting, fanning, clawing, IFP, or flaccid hand posturing can help distinguish epileptic seizures from NEA. IFP suggests LRE while fanning with evolution suggests GGE. Overall, hand posturing during seizures provides unique information and aids in the differential diagnosis and classification of epilepsy.

Long-term outcome characteristics in mesial temporal lobe epilepsy with and without associated cortical dysplasia.

OBJECT: The intention of our study was to identify predictive characteristics for long-term seizure control and running down phenomenon after surgical treatment of pharmacoresistant mesiotemporal lobe epilepsy (mTLE) with and without associated cortical dysplasia. MATERIALS AND METHODS: Our study comprises a consecutive series of 458 patients who underwent surgical treatment for intractable mTLE at the Epilepsy Center Freiburg. Data evaluated included semiology, duration and frequency of seizures, results of presurgical diagnostics including video-EEG monitoring, MRI, PET and SPECT as well as postoperative seizure outcome. Results were evaluated forming two groups: Group A consisted of isolated mesiotemporal lesions. Group B comprised patients with mTLE and additional focal cortical dysplasia (FCD). Statistical evaluation was based on the Kaplan Meier survival analysis, using log-rank-tests and a multivariate regression model. Postoperative running down phenomenon was defined as seizure freedom after a period of gradual reduction of postoperative seizure frequency. This was compared to patients with ongoing epilepsy. RESULTS: Complete seizure freedom was achieved in 65.0% of investigated patients at 1year and in 56.5% at long-term follow-up of ≥5 years after surgery. Corresponding results were 64.2% and 56.8% at 1 and ≥5 years, respectively in group A and 66.4% and 56.0%, respectively in group B. Predictive for favorable postoperative outcome in the total group were younger age at surgery, shorter duration of epilepsy, absence of secondarily generalized tonic-clonic seizures (SGTCS), presence of strictly ipsilateral temporal interictal epileptiform discharges (IEDs), complete resection of the lesion as well as absence of postoperative epileptiform activity and of early postoperative seizures. In subgroup analyses, patients of group A demonstrated longer postoperative seizure-free intervals with adolescent age at surgery, short duration of epilepsy before surgery and absence of SGTCS, whereas in patients of group B ipsilateral temporal seizure onset and strictly unilateral IEDs in EEG as well as complete resection were predictors for favorable seizure outcome. Furthermore, absence of early postoperative seizures and of spikes in EEG were predictive factors for long-term seizure-freedom in both subgroups. The running down phenomenon was found in 33 (7.2%) patients. None of the parameters evaluated demonstrated significant predictive power. Only late seizure onset and neoplastic lesions showed a trend for postoperative gradual seizure reduction in multivariate analyses. CONCLUSION: Depending on the presence or absence of focal cortical dysplasia in addition to mesiotemporal structural alterations, predictors of long-term seizure control differed regarding the relevant clinical and electrophysiological features. This is important for specific patient counseling in respective groups.

Electroresponsive Nanoparticles Improve Antiseizure Effect of Phenytoin in Generalized Tonic-Clonic Seizures.

Previously, we developed electroresponsive hydrogel nanoparticles (ERHNPs) modified with angiopep-2 (ANG) to facilitate the delivery of the antiseizure drug phenytoin sodium (PHT). However, the electroresponsive characteristics were not verified directly in epileptic mice and the optimal preparation formula for electroresponsive ability is still unclear. Here, we further synthesized PHT-loaded ANG-ERHNPs (ANG-PHT-HNPs) and PHT-loaded nonelectroresponsive hydrogel nanoparticles (ANG-PHT-HNPs) by changing the content of sodium 4-vinylbenzene sulfonate in the preparation formulae. In vivo microdialysis analysis showed that ANG-PHT-ERHNPs not only have the characteristics of a higher distribution in the central nervous system, but also have electroresponsive ability, which resulted in a strong release of nonprotein-bound PHT during seizures. In both electrical- (maximal electrical shock) and chemical-induced (pentylenetetrazole and pilocarpine) seizure models, ANG-PHT-ERHNPs lowered the effective therapeutic doses of PHT and demonstrated the improved antiseizure effects compared with ANG-PHT-HNPs or PHT solution. These results demonstrate that ANG-ERHNPs are able to transport PHT into the brain efficiently and release them when epileptiform activity occurred, which is due to the content of sodium 4-vinylbenzene sulfonate in formula. This may change the therapeutic paradigm of existing drug treatment for epilepsy into a type of on-demand control for epilepsy in the future.