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Objective: Recent work has shown that people with common epilepsies have characteristic patterns of cortical thinning, and that these changes may be progressive over time. Leveraging a large multicenter cross‐sectional cohort, we investigated whether regional morphometric changes occur in a sequential manner, and whether these changes in people with mesial temporal lobe epilepsy and hippocampal sclerosis (MTLE‐HS) correlate with clinical features. Methods: We extracted regional measures of cortical thickness, surface area, and subcortical brain volumes from T1‐weighted (T1W) magnetic resonance imaging (MRI) scans collected by the ENIGMA‐Epilepsy consortium, comprising 804 people with MTLE‐HS and 1625 healthy controls from 25 centers. Features with a moderate case–control effect size (Cohen d ≥ .5) were used to train an event‐based model (EBM), which estimates a sequence of disease‐specific biomarker changes from cross‐sectional data and assigns a biomarker‐based fine‐grained disease stage to individual patients. We tested for associations between EBM disease stage and duration of epilepsy, age at onset, and antiseizure medicine (ASM) resistance. Results: In MTLE‐HS, decrease in ipsilateral hippocampal volume along with increased asymmetry in hippocampal volume was followed by reduced thickness in neocortical regions, reduction in ipsilateral thalamus volume, and finally, increase in ipsilateral lateral ventricle volume. EBM stage was correlated with duration of illness (Spearman ρ = .293, p = 7.03 × 10−16), age at onset (ρ = −.18, p = 9.82 × 10−7), and ASM resistance (area under the curve = .59, p = .043, Mann–Whitney U test). However, associations were driven by cases assigned to EBM Stage 0, which represents MTLE‐HS with mild or nondetectable abnormality on T1W MRI. Significance: From cross‐sectional MRI, we reconstructed a disease progression model that highlights a sequence of MRI changes that aligns with previous longitudinal studies. This model could be used to stage MTLE‐HS subjects in other cohorts and help establish connections between imaging‐based progression staging and clinical features.

The study aimed to identify distinct phenotypes within nonconvulsive status epilepticus (NCSE). Consecutive episodes of NCSE in patients at least 14 years old were included. The level of consciousness was assessed through the Glasgow Coma Scale (GCS). Etiology of NCSE was defined as symptomatic (acute, remote, progressive) or unknown. Electroencephalographic (EEG) recordings were searched for lateralized periodic discharges (LPDs), generalized sharply and/or triphasic periodic potentials (GPDs), and spontaneous burst suppression (BS). According to treatment response, NCSE was classified as responsive, refractory, or superrefractory. Average linkage hierarchical cluster analysis was performed with Pearson correlation as similarity measure. Two hundred twenty‐nine episodes of NCSE were included. Three clusters were identified. The first cluster linked GCS score 3–8, presence of spontaneous BS on EEG, acute symptomatic etiology, and treatment superrefractoriness. The second cluster gathered GCS score 9–12, presence of LPDs or GPDs on EEG, unknown etiology, and treatment refractoriness. The third cluster associated GCS score 13–15, absence of LPDs, GPDs, and spontaneous BS on EEG, and progressive and remote symptomatic etiology with treatment responsiveness. Phenotyping the heterogeneity of NCSE into electroclinical clusters can contribute to understanding correlations between pathologic and clinical domains, assessing the intrinsic severity of NCSE episodes, and estimating the likelihood of treatment responsiveness.

This study was undertaken to validate the accuracy of the Epidemiology-Based Mortality Score in Status Epilepticus (EMSE) in predicting the risk of death at 30 days in a large cohort of patients with status epilepticus (SE) using a machine learning system.We included consecutive patients with SE admitted from 2013 to 2021 at Modena Academic Hospital. A decision tree analysis was performed using the 30-day mortality as a dependent variable and the EMSE predictors as input variables. We evaluated the accuracy of EMSE in predicting 30-day mortality using the area under the receiver operating characteristic curve (AUC ROC), with 95% confidence interval (CI). We performed a subgroup analysis on nonhypoxic SE.A total of 698 patients with SE were included, with a 30-day mortality of 28.9% (202/698). The mean EMSE value in the entire population was 57.1 (SD = 36.3); it was lower in surviving compared to deceased patients (47.1, SD = 31.7 vs. 81.9, SD = 34.8; p .001). The EMSE was accurate in predicting 30-day mortality, with an AUC ROC of .782 (95% CI = .747-.816). Etiology was the most relevant predictor, followed by age, electroencephalogram (EEG), and EMSE comorbidity group B. The decision tree analysis using EMSE variables correctly predicted the risk of mortality in 77.9% of cases; the prediction was accurate in 85.7% of surviving and in 58.9% of deceased patients within 30 days after SE. In nonhypoxic SE, the most relevant predictor was age, followed by EEG, and EMSE comorbidity group B; the prediction was correct in 78.9% of all cases (89.6% in survivors and 46.1% in nonsurvivors).This validation study using a machine learning analysis shows that the EMSE is a valuable prognostic tool, and appears particularly accurate and effective in identifying patients with 30-day survival, whereas its performance in predicting 30-day mortality is lower and needs to be further improved.

Summary Objective In 2015, the International League Against Epilepsy (ILAE) proposed a new definition of status epilepticus (SE): 5 minutes of ongoing seizure activity to diagnose convulsive SE (CSE, ie, bilateral tonic–clonic SE) and 10 minutes for focal SE and absence SE, rather than the earlier criterion of 30 minutes. Based on semiology, several types of SE with prominent motor phenomena at any time (including CSE) were distinguished from those without (ie, nonconvulsive SE, NCSE). We present the first population‐based incidence study applying the new 2015 ILAE definition and classification of SE and report the impact of the evolution of semiology and level of consciousness (LOC) on outcome. Methods We conducted a retrospective population‐based incidence study of all adult patients with SE residing in the city of Salzburg between January 2011 and December 2015. Patients with hypoxic encephalopathy were excluded. SE was defined and classified according to the ILAE 2015. Results We identified 221 patients with a median age of 69 years (range 20‐99 years). The age‐ and sex‐adjusted incidence of a first episode of SE, NCSE, and SE with prominent motor phenomena (including CSE) was 36.1 (95% confidence interval [CI] 26.2‐48.5), 12.1 (95% CI 6.8‐20.0), and 24.0 (95% CI 16.0‐34.5; including CSE 15.8 [95% CI 9.4‐24.8]) per 100 000 adults per year, respectively. None of the patients whose SE ended with or consisted of only bilateral tonic–clonic activity died. In all other clinical presentations, case fatality was lower in awake patients (8.2%) compared with patients with impaired consciousness (33%). Significance This first population‐based study using the ILAE 2015 definition and classification of SE found an increase of incidence of 10% compared to previous definitions. We also provide epidemiologic evidence that different patterns of status evolution and LOCs have strong prognostic implications.

Magnetic resonance imaging (MRI) provides an opportunity for identifying peri-ictal MRI abnormalities (PMAs) related to status epilepticus (SE). Extremely variable MRI alterations have been reported previously during or after SE, mainly in small selected populations. In a retrospective monocentric study, we analyzed brain MRI changes observed in the ictal/postictal periods of SE in an adult population. We included all consecutive patients observed in a 5-year period with an electroclinical diagnosis of SE and an MRI performed within 30 days from the beginning of SE. We identified 277 patients. Among them, 32 (12%) showed PMAs related to SE. The duration of SE was strongly associated with MRI alterations, showing a mean duration of 6 days vs 2 days (P = .011) in the group with and without MRI alterations, respectively. Focal electroencephalography (EEG) abnormalities (P = .00003) and in particular, lateralized periodic discharges (LPDs) (P < .0001) were strongly associated with PMAs. MRI alterations were unilateral (23 patients, 72%), located in multiple brain structures (19 patients, 59%), and involving mesiotemporal structures (17 patients, 53%). Sixteen patients (50%) had good spatial correspondence between cortical PMAs and the focal EEG pattern; 12 patients (38%) with focal EEG pattern showed cortical PMAs plus MRI signal changes also involving subcortical structures. A follow-up MRI was available for 14 of 32 patients (44%): 10 patients presented a disappearance of PMAs, whereas in 4, PMAs were still present. This study demonstrates that a long duration SE and the presence of certain EEG patterns (LPDs) are associated with the occurrence of PMAs. A good spatial concordance was observed between cortical PMA location and the EEG focus.

Summary Neuroactive steroids are increasingly considered as relevant modulators of neuronal activity. Especially allopregnanolone (AP) and pregnenolone sulfate (PS) have been shown to possess, respectively, anticonvulsant or proconvulsant properties. In view of the potential role of these steroids, we aimed at evaluating AP and PS levels in cerebrospinal fluid (CSF) and blood samples obtained from patients with status epilepticus (SE). To this purpose, we enrolled 41 patients affected by SE and 41 subjects investigated for nonepileptic neurologic disorders. Liquid chromatographic procedures coupled with electrospray tandem mass spectrometry and routine laboratory investigations were performed. Significantly lower AP levels were found in the CSF of patients affected by SE (−30%; p < 0.05, Mann-Whitney test). Notably, AP was not detectable in 28 of 41 patients affected by SE (p < 0.01 vs. controls, Fisher's exact test). In serum, AP levels did not differ in the two considered groups. Conversely, PS was present at similar levels in the investigated groups. Finally, differences in AP levels could not be explained by a variation in CSF albumin content. These findings indicate that AP is defective in the CSF of patients affected by SE. This phenomenon was not dependent on carriers for steroids, such as albumin.

Summary Objective Although many studies have attempted to describe treatment outcomes in patients with drug‐resistant epilepsy, results are often limited by the adoption of nonhomogeneous criteria and different definitions of seizure freedom. We sought to evaluate treatment outcomes with a newly administered antiepileptic drug (AED) in a large population of adults with drug‐resistant focal epilepsy according to the International League Against Epilepsy (ILAE) outcome criteria. Methods This is a multicenter, observational, prospective study of 1053 patients with focal epilepsy diagnosed as drug‐resistant by the investigators. Patients were assessed at baseline and 6, 12, and 18 months, for up to a maximum of 34 months after introducing another AED into their treatment regimen. Drug resistance status and treatment outcomes were rated according to ILAE criteria by the investigators and by at least two independent members of an external expert panel (EP). Results A seizure‐free outcome after a newly administered AED according to ILAE criteria ranged from 11.8% after two failed drugs to 2.6% for more than six failures. Significantly fewer patients were rated by the EP as having a “treatment failure” as compared to the judgment of the investigator (46.7% vs 62.9%, P

SummaryObjective Periventricular nodular heterotopias (PNHs) are malformations of cortical development related to neuronal migration disorders, frequently associated with drug-resistant epilepsy (DRE). Stereo-electroencephalography (SEEG) is considered a very effective step of the presurgical evaluation, providing the recognition of the epileptogenic zone (EZ). At the same time, via the intracerebral electrodes it is possible to perform radiofrequency thermocoagulation (SEEG-guided RF-TC) with the aim of ablating and/or disrupting the EZ. The purpose of this study was to evaluate both the relationships between PNH and the EZ, and the efficacy of SEEG-guided RF-TC. Methods Twenty patients with DRE related to PNHs were studied. Inclusion criteria were the following: (1) patients with epilepsy and PNHs (unilateral or bilateral, single or multiple nodules) diagnosed on brain magnetic resonance imaging (MRI); (2) SEEG recordings available as part of the presurgical investigations, with at least one intracerebral electrode inside the heterotopia; (3) complete surgical workup with SEEG-guided RF-TC and/or with traditional neurosurgery, with a follow-up of at least 12 months. Results Complex and heterogenic epileptic networks were found in these patients. SEEG-guided RF-TC both into the nodules and/or the cortex was efficacious in the 76% of patients. Single or multiple, unilateral or bilateral PNHs are the most suitable for this procedure, whereas patients with PNHs associated with complex cortical malformations obtained excellent outcome only with traditional resective surgery. Significance Each patient had a specific epileptogenic network, independent from the number, size, or location of nodules and from the cortical malformation associated with. SEEG-guided RF-TC appears as a new and very effective diagnostic and therapeutic approach for DRE related to PNHs.

SUMMARY Studies in animal models and patients with epilepsy have suggested that basal ganglia circuits may control epileptic seizures and that striatal dopaminergic transmission may play a role in seizure modulation and interruption. Chromosome 20 [r(20)] syndrome is a well-defined chromosomal disorder characterized by epilepsy, mildto-moderate mental retardation, and lack of recognizable dysmorphic features. Epilepsy is often the most important clinical manifestation of the syndrome, with prolonged episodes of nonconvulsive status epilepticus suggesting dysfunction in the seizure control system. We present the ictal blood oxygen level‐dependent (BOLD) changes in brief seizures recorded by means of electroencephalography‐functional magnetic resonance imaging (EEG-fMRI) coregistration in a patient with [r(20)] syndrome. We observed ictal BOLD increments in a cortical-subcortical network involving substantia nigrastriatum and frontal cortex. At present, this is the first functional neuroimaging evidence of the involvement of the nigrostriatal system during ictal EEG discharges in [r(20)] syndrome supporting a role of the basal ganglia circuits in human epileptic seizures.

We postulate that "system epilepsies" (SystE) are due to an enduring propensity to generate seizures of functionally characterized brain systems. Data supporting this hypothesis-that some types of epilepsy depend on the dysfunction of specific neural systems-are reviewed. The SystE hypothesis may drive pathophysiologic and clinical studies that can advance our understanding of epilepsies and can open up new therapeutic perspectives.

Summary Purpose: Electroencephalography–functional magnetic resonance imaging (EEG-fMRI) coregistration has recently revealed that several brain structures are involved in generalized spike and wave discharges (GSWDs) in idiopathic generalized epilepsies (IGEs). In particular, deactivations and activations have been observed within the so-called brain default mode network (DMN) and thalamus, respectively. In the present study we analyzed the dynamic time course of blood oxygen level–dependent (BOLD) changes preceding and following 3 Hz GSWDs in a group of adolescent and adult patients with IGE who presented with absence seizures (AS). Our aim was to evaluate cortical BOLD changes before, during, and after GSWD onset. Methods: Twenty-one patients with IGE underwent EEG-fMRI coregistration. EEG-related analyses were run both at the single-subject and at group level (random effect). The time-course analysis was conducted for 3 s time windows before, during, and after GSWDs, and they were included until no further BOLD signal changes were observed. Key Findings: Fifteen patients (nine female, mean age 28 years) had GSWDs during EEG-fMRI coregistration (262 total events, mean duration 4 s). Time-course group analysis showed BOLD increments starting approximately 10 s before GSWD onset located in frontal and parietal cortical areas, and especially in the precuneus-posterior cingulate region. At GSWD onset, BOLD increments were located in thalamus, cerebellum, and anterior cingulate gyrus, whereas BOLD decrements were observed in the DMN regions persisting until 9 s after onset. Significance: Hemodynamic changes (BOLD increments) occurred in specific cortical areas, namely the precuneus/posterior cingulate, lateral parietal, and frontal cortices, several seconds before EEG onset of GSWD. A dysfunction of these brain regions, some of which belongs to the DMN, may be crucial in generating GSWDs in patients with IGE.

SUMMARY Purpose: To evaluate facial emotion recognition (FER) in a cohort of 176 patients with chronic temporal lobe epilepsy (TLE). Methods: FER was tested by matching facial expressions with the verbal labels for the following basic emotions: happiness, sadness, fear, disgust, and anger. Emotion recognition performances were analyzed in medial (n = 140) and lateral (n = 36) TLE groups. Fifty healthy subjects served as controls. The clinical and neuroradiologic variables potentially affecting the ability to recognize facial expressions were taken into account. Results: The medial TLE (MTLE) group showed impaired FER (86% correct recognition) compared to both the lateral TLE patients (FER = 93.5%) and the controls (FER = 96.4%), with 42% of MTLE patients recording rates of FER that were lower [by at least 2 standard deviations (SDs)] than the control mean. The MTLE group was impaired compared to the healthy controls in the recognition of all basic facial expressions except happiness. The patients with bilateral MTLE were the most severely impaired, followed by the right and then the left MTLE patients. FER was not affected by type of lesion, number of antiepileptic drugs (AEDs), aura semiology, or gender. Conversely, the early onset of seizures/ epilepsy was related to FER deficits. These deficits were already established in young adulthood, with no evidence of progression in older MTLE patients. Conclusion: These results on a large cohort of TLE patients demonstrate that emotion recognition deficits are common in MTLE patients and widespread across negative emotions. We confirm that early onset seizures with right or bilateral medial temporal dysfunction lead to severe deficits in recognizing facial expressions of emotions.

To present new information on the semiology and short-term evolution of seizures associated with primary brain tumors (PBTs) in a prospective study.This study is a section of the PERNO study--Project of Emilia Romagna Region on Neuro-Oncology, the main aim of which is to collect prospectively all cases of PBTs occurring in the Emilia-Romagna region, northeast Italy (3,983,346 population) from January 2009 to December 2011, to allow epidemiologic, clinical, and biomolecular studies. The epilepsy section of the PERNO study included all the patients who experienced seizures, either as first symptom of the tumor or appearing during the course of the disease. Each patient was interviewed by the referring neurologist with a specific interest in epilepsy. The patients who entered the study were followed up with visits on a quarterly basis.We collected 100 cases with full clinical, neuroradiologic, and pathologic data. The majority (79\%) had high grade PBTs (glioblastoma in 50 cases), whereas the remaining patients had low-grade gliomas, mostly localized in the frontal (60\%), temporal (38\%), and parietal (28\%) lobes. Seizures were the first symptom of the tumor in 72 cases. Overall, the initial seizures were tonic-clonic (48\%) (without clear initial focal signs in more than half of the patients), focal motor (26\%), complex partial (10\%), and somatosensitive (8\%). The majority of cases (60\%) had isolated seizures or a low seizure frequency at the onset of the disease, whereas a high seizure frequency or status epilepticus was observed in 18\% and 12\% of cases, respectively. Ninety-two patients underwent surgical removal of the tumor, which was either radical (38\%) or partial (53\%). Seven patients underwent only cerebral biopsy. In the 72 patients in whom seizures were the first symptom, the mean time to the surgical treatment was 174 days, with a significant difference between high grade (95 days) and low grade (481 days) gliomas. At the time of our first observation, the majority of patients (69\%) had already undergone surgical removal, with a mean follow-up of 3 months after the procedure. Overall, 39 patients (56\%) were seizure free after tumor removal. The good outcome did not depend on presurgical seizure frequency or tumor type, although there was a trend for better results with low-grade PBTs.These data provide evidence that seizures are strictly linked to the tumoral lesion: They are the initial symptom of the tumor, reflect the tumor location and type, are usually resistant to antiepileptic treatment, and may disappear after the treatment of the lesion.

Summary: Purpose: To assess the quality and frequency of emotions induced by intracerebral electrical stimulation of the temporal lobe. Methods: Behavioral responses were obtained by electrical stimulation in 74 patients undergoing presurgical video-stereo-EEG monitoring for drug-resistant epilepsy. Intracerebral electrical stimulation was performed by delivering trains of electrical stimuli of alternating polarity; the intensity could vary from 0.2 to 3 mA. Stimulation frequency was 1 Hz or 50 Hz. Nine hundred thirty-eight stimulation procedures were performed. Results: Seventy-nine emotional responses (ERs) were obtained (8.4%). Of these, 67 were “'fear responses.” Sad feelings were evoked 3 times, happy-pleasant feelings 9 times. Anger and disgust were never observed. The following variables affected the incidence of ER: (a) Anatomical site of stimulation. ERs (always fear) were maximal at the amygdala (12%) and minimal for lateral neocortical stimulation (3%, p < 0.01). (b) Pathology. Stimulation of a temporal lobe with hippocampal sclerosis was associated with a lower frequency of ERs compared with stimulation of a temporal lobe with no evidence of atrophy in the medial temporal structures. (c) Stimulation frequency. ERs were 12% at 50 Hz versus 6.0% at 1 Hz (p < 0.01). (d) Gender. In women fear responses were 16% compared with 3% in men (p < 0.01). There were no gender differences when analyzing nonemotional responses. Conclusions: These data confirm the role of the medial temporal lobe region in the expression of emotions, especially fear-related behaviors. Fear was observed more frequently in the absence of medial temporal sclerosis, supporting the hypothesis that emotional behaviors induced by stimulation are positive phenomena, strictly related to the physiological function of these regions. Further investigations should address why women express fear behaviors more frequently than men.

Summary: Purpose: To describe the semiologic features of aggressive behaviors observed in human epileptic seizures with particular reference to the act of biting a conspecific. Methods: We analyzed the biting behavior (BB) and other aggressive gestures occurring in a group of 11 patients retrospectively selected from >1,000 patients subjected to videoEEG/SEEG monitoring for presurgical evaluation of drugresistant seizures. Results: Patients displaying BB showed (a) a male sex predominance, (b) heterogeneous etiologies and lesion locations, and (c) seizures involving the frontotemporal regions of both hemispheres. The act of biting was a rapid motor action, lasting ∼600 ms, occurring in the context of strong emotional arousal, fear, and anger, with various bodily gestures with aggressive connotation. BB was mainly a “reflexive” behavior, in that biting acts were evoked (both during and after seizures) by actions of people in close contact with the patient. The sole intrusion of the examiner’s hand in the space near the patient’s face was effective in triggering BB. Rarely, self-directed or object-directed biting acts were not triggered by external stimuli. Intracranial data (SEEG) obtained in one subject showed that the amygdala/hippocampal region plus the orbitomedial prefrontal cortex had to be involved by ictal activity to observe BB. Conclusions: Anatomic and electrophysiologic data in our patients suggest that a model of dual—temporal and frontal— dysfunction could account for the occurrence of ictal/postictal BB. Behavioral data suggest also that BB and related aggressive gestures can be considered as the emergence of instinctive behaviors with an adaptative significance of defense of the peripersonal space. Ke yW ords: Epilepsy—Aggression— Biting—Peripersonal space—Prefrontal cortex.