Late-onset temporal lobe epilepsy: insights from brain atrophy and Alzheimer's disease biomarkers.

Considering the growing age of the world population, the incidence of epilepsy in older adults is expected to increase significantly. It has been suggested that late-onset temporal lobe epilepsy (LO-TLE) may be neurodegenerative in origin and overlap with Alzheimer's Disease (AD). Herein, we aimed to characterize the pattern of cortical atrophy and cerebrospinal fluid (CSF) biomarkers of AD (total and phosphorylated tau, and ß-amyloid) in a selected population of LO-TLE of unknown origin. We prospectively enrolled individuals with temporal lobe epilepsy onset after the age of 50 and no cognitive impairment. They underwent a structural MRI scan and CSF biomarkers measurement. Imaging and biomarkers data were compared to three retrospectively collected groups: (i) age-sex-matched healthy controls, (ii) patients with Mild Cognitive Impairment (MCI) and abnormal CSF AD biomarkers (MCI-AD), and (iii) patients with MCI and normal CSF AD biomarkers (MCI-noAD). From a pool of 52 patients, twenty consecutive eligible LO-TLE patients with a mean disease duration of 1.8 years were recruited. As control populations, 25 patients with MCI-AD, 25 patients with MCI-noAD, and 25 healthy controls were enrolled. CSF biomarkers returned normal values in LO-TLE, significantly different from patients with MCI due to AD. There were no differences in cortico-subcortical atrophy between epilepsy patients and healthy controls, while patients with MCI demonstrated widespread injuries of cortico-subcortical structures. Individuals with a late-onset form of temporal lobe epilepsy, characterized by short disease duration and normal CSF ß-amyloid and tau protein levels, showed patterns of cortical thickness and subcortical volumes not significantly different from healthy controls, but highly different from patients with MCI, either due to Alzheimer's Disease or not.

The risk of unprovoked seizure occurrence after status epilepticus in adults.

OBJECTIVE: Status epilepticus (SE) may lead to long-term consequences. This study evaluated the risk and predictors of seizure occurrence after SE, with a focus on SE due to acute symptomatic etiologies. METHODS: Prospectively collected data about adults surviving a first non-hypoxic SE were reviewed. The outcome was the occurrence of unprovoked seizures during the follow-up. Kaplan-Meier survival curve analysis and log-rank test were used to analyze the time to seizure occurrence and determine the statistical significance between etiological groups. Three subcategories within acute etiology were considered according to the presence of the following: (1) structural lesion (acute-primary); (2) brain involvement during systemic disorders (acute-secondary); and (3) drug or alcohol intoxication/withdrawal (acute-toxic). Cox proportional hazards model was adopted to estimate hazard ratios (HRs) with the 95% confidence intervals (CIs). RESULTS: Two hundreds fifty-seven individuals were included. Fifty-four subjects (21.0%) developed seizures after a median of 9.9 (interquartile range 4.3-21.7) months after SE. The estimated 1-, 2-, and 5-year rates of seizure occurrence according to acute SE etiologies were 19.4%, 23.4%, and 30.1%, respectively, for acute-primary central nervous system (CNS) pathology; 2.2%, 2.2%, and 8.7%, respectively, for acute-secondary CNS pathology; and 0%, 9.1%, and 9.1%, respectively, for acute-toxic causes. Five-year rates of seizure occurrence for non-acute SE causes were 33.9% for remote, 65.7% for progressive, and 25.9% for unknown etiologies. In multivariate Cox regression model, progressive etiology (adjusted HR [adjHR] 2.27, 95% CI 1.12-4.58), SE with prominent motor phenomena evolving in non-convulsive SE (adjHR 3.17, 95% CI 1.38-7.25), and non-convulsive SE (adjHR 2.38, 95% CI 1.16-4.90) were independently associated with higher hazards of unprovoked seizures. Older people (adjHR .98, 95% CI .96-.99) and people with SE due to acute-secondary CNS pathology (adjHR .18, 95% CI .04-.82) were at decreased risk of seizure occurrence. SIGNIFICANCE: SE carries a risk of subsequent seizures. Both the underlying cause and epileptogenic effects of SE are likely to contribute.

FADD gene pathogenic variants causing recurrent febrile infection-related epilepsy syndrome: Case report and literature review.

FIRES and NORSE are clinical presentations of disease processes that, to date, remain unexplained without an established etiology in many cases. Neuroinflammation is thought to have paramount importance in the genesis of these conditions. We hereby report the clinical, EEG, brain MRI, and genetic findings of a nuclear family with recurrent febrile-related encephalopathy with refractory de novo Status Epilepticus. Whole-exome sequencing (WES) revealed a homozygous p.C105W pathogenic variant of FADD gene (FAS-associated protein with death domain, FADD), known to cause ultrarare forms of autosomal recessive immunodeficiency that could be associated with variable degrees of lymphoproliferation, cerebral atrophy, and cardiac abnormalities. The FADD-related conditions disrupt FAS-mediated apoptosis and can cause a clinical picture with the characteristics of FIRES. This observation is important because, on one hand, it increases the number of reported patients with FADD deficiency, showing that this disorder may present variable expressivity, and on the other hand, it demonstrates a genetic cause of FIRES involving a cell-mediated inflammation regulatory pathway. This finding supports early treatment with immunomodulatory therapy and could represent a new avenue of research in the field of new onset refractory status epilepticus and related conditions.

Clinical practice guidelines on the management of status epilepticus in adults: A systematic review.

OBJECTIVE: Status epilepticus (SE) is the second most common neurological emergency in adults. Despite improvements in the management of acute neurological conditions over the last decade, mortality is still durably high. Because a gap has emerged between SE management based on clinical practice guidelines (CPGs) and actual clinical practice, we conducted a systematic review of CPGs, assessing their quality, outlining commonalities and discrepancies in recommendations, and highlighting research gaps. METHODS: We searched the PubMed and EMBASE databases and other gray literature sources (nine among guideline registries, evidence-based medicine databases, point-of-care tools; seven websites of governmental organizations and international neurologic societies) in December 2021 (updated in November 2023). The units of analysis were CPGs that included recommendations on the diagnostic and/or therapeutic management of SE in adults. The quality of the CPGs was assessed using the AGREE II tool. RESULTS: Fifteen CPGs were included. The "Applicability" domain was assigned the lowest median score of 10%. The domains "Stakeholder Involvement", "Rigor of Development," and "Editorial Independence" were as well generally underrated. Recommendations on general and diagnostic management and on organizational interventions were fragmented and scattered. Recommendations on pre-hospital and hospital treatment of early-onset and refractory SE were broadly agreed, whereas there was less agreement on the treatment model and medications for established SE and super-refractory SE. SIGNIFICANCE: The CPGs for the management of SE developed in recent years are flawed by several methodological issues and discrepancies in the coverage of important topics. The gap between CPG-based management of SE and actual clinical practice may be due in part to the inherent limitations of the CPGs produced so far.

Prediction of epilepsy after stroke: Proposal of a modified SeLECT 2.0 score based on posttreatment stroke outcome.

OBJECTIVE: The SeLECT 2.0 score is a prognostic model of epilepsy after ischemic stroke. We explored whether replacing the severity of stroke at admission with the severity of stroke after treatment at 72 h from onset could improve the predictive accuracy of the score. METHODS: We retrospectively identified consecutive adults with acute first-ever neuroimaging-confirmed ischemic stroke who were admitted to the Stroke Unit of the Ospedale Civile Baggiovara (Modena, Italy) and treated with intravenous thrombolysis and/or endovascular treatment. Study outcome was the occurrence of at least one unprovoked seizure presenting >7 days after stroke. RESULTS: Participants included in the analysis numbered 1094. The median age of the subjects was 74 (interquartile range [IQR] = 64-81) years, and 595 (54.4%) were males. Sixty-five (5.9%) subjects developed unprovoked seizures a median of 10 (IQR = 6-27) months after stroke. The median values of the original and modified SeLECT2.0 scores were 3 (IQR = 2-4) and 2 (IQR = 1-3). The modified SeLECT 2.0 score showed better discrimination for the prediction of poststroke epilepsy at 36, 48, and 60 months after stroke compared to the original score according to the area under time-dependent receiver operating characteristic curves. The modified SeLECT 2.0 score had higher values of Harrell C and Somers D parameters and lower values of Akaike and Bayesian information criteria than the original score. The modified SeLECT 2.0 score produced more accurate risk predictions compared to the SeLECT 2.0 score at all evaluated time points from 12 to 60 months after stroke according to the Net Reclassification Index. SIGNIFICANCE: Replacing baseline with posttreatment stroke severity may improve the ability of the SeLECT 2.0 score to predict poststroke epilepsy.

Remote seizures and drug-resistant epilepsy after a first status epilepticus in adults.

BACKGROUND AND PURPOSE: Long-term consequences after status epilepticus (SE) represent an unsettled issue. We investigated the incidence of remote unprovoked seizures (RS) and drug-resistant epilepsy (DRE) in a cohort of first-ever SE survivors. METHODS: A retrospective, observational, and monocentric study was conducted on adult patients (age ≥ 14 years) with first SE who were consecutively admitted to the Modena Academic Hospital, Italy (September 2013-March 2022). Kaplan-Meier survival analyses were used to calculate the probability of seizure freedom following the index event, whereas Cox proportional hazard regression models were used to identify outcome predictors. RESULTS: A total of 279 patients were included, 57 of whom (20.4%) developed RS (mean follow-up = 32.4 months). Cumulative probability of seizure freedom was 85%, 78%, and 68% respectively at 12 months, 2 years, and 5 years. In 45 of 57 patients (81%), the first relapse occurred within 2 years after SE. The risk of RS was higher in the case of structural brain damage (hazard ratio [HR] = 2.1, 95% confidence interval [CI] = 1.06-4.01), progressive symptomatic etiology (HR = 2.7, 95% CI = 1.44-5.16), and occurrence of nonconvulsive evolution in the semiological sequence of SE (HR = 2.9, 95% CI = 1.37-6.37). Eighteen of 57 patients (32%) developed DRE; the risk was higher in the case of super-refractory (p = 0.006) and non-convulsive SE evolution (p = 0.008). CONCLUSIONS: The overall risk of RS was moderate, temporally confined within 2 years after the index event, and driven by specific etiologies and SE semiology. Treatment super-refractoriness and non-convulsive SE evolution were associated with DRE development.

Progression to refractory status epilepticus: A machine learning analysis by means of classification and regression tree analysis.

BACKGROUND AND OBJECTIVES: to identify predictors of progression to refractory status epilepticus (RSE) using a machine learning technique. METHODS: Consecutive patients aged ≥ 14 years with SE registered in a 9-years period at Modena Academic Hospital were included in the analysis. We evaluated the risk of progression to RSE using logistic regression and a machine learning analysis by means of classification and regression tree analysis (CART) to develop a predictive model of progression to RSE. RESULTS: 705 patients with SE were included in the study; of those, 33 % (233/705) evolved to RSE. The progression to RSE was an independent risk factor for 30-day mortality, with an OR adjusted for previously identified possible univariate confounders of 4.086 (CI 95 % 2.390-6.985; p < 0.001). According to CART the most important variable predicting evolution to RSE was the impaired consciousness before treatment, followed by acute symptomatic hypoxic etiology and periodic EEG patterns. The decision tree identified 14 nodes with a risk of evolution to RSE ranging from 1.5 % to 90.8 %. The overall percentage of success in classifying patients of the decision tree was 79.4 %; the percentage of accurate prediction was high, 94.1 %, for those patients not progressing to RSE and moderate, 49.8 %, for patients evolving to RSE. CONCLUSIONS: Decision-tree analysis provided a meaningful risk stratification based on few variables that are easily obtained at SE first evaluation: consciousness before treatment, etiology, and severe EEG patterns. CART models must be viewed as potential new method for the stratification RSE at single subject level deserving further exploration and validation.

The Epilepsy Surgery Satisfaction Questionnaire (ESSQ-19): Italian language translation and validation.

OBJECTIVE: Epilepsy surgery can be proposed as a treatment option in people with focal epilepsy, however satisfaction with epilepsy surgery in Italy remains unknown. We aimed to validate in Italy an instrument to measure patient satisfaction with epilepsy surgery, the 19-item Epilepsy Surgery Satisfaction Questionnaire (ESSQ-19). METHODS: Consecutive patients with epilepsy who received epilepsy surgery between the years 2018-2021 at Modena Academic Hospital were recruited and provided clinical and demographic data. The Italian version of the ESSQ-19 and other three questionnaires were completed to assess construct validity. To evaluate the validity and reliability of the tool Spearman's rank correlation, and internal consistency analysis were performed. RESULTS: 66 out of 79 eligible patients participated in the study (22 females; median age 37 years). The mean values of satisfaction for each domain of the IT-ESSQ-19 were: seizure control 83.4; (SD 16.7), psychosocial functioning 79.3 (SD 17.1), surgical complications 90.8 (SD 14.9), and recovery from surgery 81.4 (SD 16.9). The mean summary score was 83.7 (SD 13.3). The questionnaire was shown to have high internal consistency in the four domains (Cronbach's alpha = 0.82-0.93), and no significant floor/ceiling effects of the summary score. The ESSQ-19 scores significantly correlated with other instruments to support construct validity. It also demonstrated good discriminant validity for being seizure free [AUC 0.72; 95% CI = 0.56-0.88], and to endorse depression [AUC 0.76, 95% CI = 0.56-0.96]. SIGNIFICANCE: The Italian version of the ESSQ-19 is a reliable and valid self-reported questionnaire for assessing patient satisfaction with epilepsy surgery.

Acute symptomatic status epilepticus: Splitting or lumping? A proposal of classification based on real-world data.

This study aimed to group acute symptomatic etiologies of consecutive episodes of status epilepticus (SE) into different subcategories and explore their associations with clinical outcome. Etiologies were first categorized as "acute," "remote," "progressive," "SE in defined electroclinical syndromes," and "unknown." Four subcategories of acute etiologies were then defined: (1) withdrawal, low levels, or inappropriate prescription of antiseizure medications, or sleep deprivation in patients with pre-existing epilepsy; (2) acute insults to central nervous system (CNS; "acute-primary CNS"); (3) CNS pathology secondary to metabolic disturbances, systemic infection, or fever ("acute-secondary CNS"); and (4) drug/alcohol intoxication or withdrawal. Poor outcome at discharge, defined as worsening of clinical conditions (modified Rankin Scale [mRS] at discharge higher than mRS at baseline), was reported in 55.6% of cases. The etiological categories of acute-primary CNS (odds ratio [OR] = 3.61, 95% confidence interval [CI] = 2.11-6.18), acute-secondary CNS (OR = 1.80, 95% CI = 1.11-2.91), and progressive SE (OR = 2.65, 95% CI = 1.57-4.47), age (OR = 1.05, 95% CI = 1.04-1.06), nonconvulsive semiology with coma (OR = 3.06, 95% CI = 1.52-6.17), and refractoriness (OR = 4.31, 95% CI = 2.39-7.77) and superrefractoriness to treatment (OR = 8.24, 95% CI = 3.51-19.36) increased the odds of poor outcome. Heterogeneity exists within the spectrum of acute symptomatic causes of SE, and distinct etiological subcategories may inform about the clinical outcome.

Comparison of the status epilepticus severity score and the epidemiology-based mortality score in predicting 30-day mortality and status epilepticus cessation.

OBJECTIVE: To evaluate the role of the Status Epilepticus Severity Score (STESS) and the Epidemiology-based Mortality score (EMSE) in predicting 30-day mortality and SE (Status epilepticus) cessation, and their prognostic performance in subgroups of patients with specific characteristics. METHODS: We reviewed consecutive episodes of SE occurring in patients aged ≥14 years at Baggiovara Civil Hospital (Modena, Italy) from 2013 to 2021. We evaluated the predictive accuracy of EMSE and STESS for 30-day mortality and SE cessation through stepwise regression binary logistic models adjusted for possible univariate clinical confounders. RESULTS: Seven hundred and eleven patients were enrolled. The mean value of STESS was 3.2 (SD 1.7) and of EMSE was 80.1 (SD 52.6). Within 30 days of the onset of SE, 28.4% of patients (202/711) died. EMSE had higher discriminatory ability for 30-day mortality compared with STESS (AUROC: 0.799; 95% CI: 0.765-0.832 versus 0.727; 95% CI: 0.686-0.766, respectively; p = 0.014). SE cessation within 1 h for convulsive SE and within 12 h for nonconvulsive SE was achieved in 35.3% (251/711) of patients. No significant difference was found between EMSE and STESS in discriminatory ability for SE cessation (AUROC: 0.516; 95% CI: 0.488-0.561 and 0.518; 95% CI: 0.473-0.563, respectively; p = 0.929). EMSE was superior to STESS in predicting 30-day mortality in patients with specific characteristics. No difference between the two scores was found in predicting SE cessation in subgroups of patients with specific characteristics. CONCLUSIONS: EMSE seems superior to STESS in predicting 30-day mortality, particularly in specific patient categories. Conversely, there is no difference in the ability of these scores in predicting SE cessation, which is overall rather low.

Exploring the relationship between amygdala subnuclei volumes and cognitive performance in left-lateralized temporal lobe epilepsy with and without hippocampal sclerosis.

Cognitive disruption is a debilitating comorbidity in Temporal Lobe Epilepsy (TLE). Despite recent advances, the amygdala is often neglected in studies that explore cognition in TLE. Amygdala subnuclei are differently engaged in TLE with hippocampal sclerosis (TLE-HS) compared to non-lesional TLE (TLE-MRIneg), with predominant atrophy in the first and increased volume in the latter. Herein, we aim to explore the relationship between the volumes of the amygdala and its substructures with respect to cognitive performances in a population of left-lateralized TLE with and without HS. Twenty-nine TLEs were recruited (14 TLE-HS; 15 TLE-MRIneg). After investigating the differences in the subcortical amygdalae and hippocampal volumes compared to a matched healthy control population, we explored the associations between the subnuclei of the amygdala and the hippocampal subfields with the cognitive scores in TLE patients, according to their etiology. In TLE-HS, a reduced volume of the basolateral and cortical amygdala complexes joined with whole hippocampal atrophy, was related to poorer scores in verbal memory tasks, while in TLE-MRIneg, poorer performances in attention and processing speed tasks were associated with a generalized amygdala enlargement, particularly of the basolateral and central complexes. The present findings extend our knowledge of amygdala involvement in cognition and suggest structural amygdala abnormalities as useful disease biomarkers in TLE.

Neuro-glial degeneration in Status Epilepticus: Exploring the role of serum levels of Neurofilament light chains and S100B as prognostic biomarkers for short-term functional outcome.

BACKGROUND: The last ILAE definition of Status Epilepticus (SE) highlights that the persistence of the epileptic activity per se could determine irreversible brain damages that could be responsible for long-term consequences. The measurement of neuro-glial injury biomarkers could help in the identification of those patients who will eventually develop short- and long-term consequences of SE. At present none of the already studied biomarkers has been validated to be used in everyday clinical practice. In this study, we explore the role of NfL and S100B as a prognostic biomarkers to identify patients who will develop short-term disability after an episode of SE. METHODS: This is a retrospective assessment of the serum levels of both NfL and S100B in a cohort of 87 adult patients with SE prospectively collected in our SE registry (Modena Status Epilepticus Registry - MoSER -) at Baggiovara Civil Hospital (Modena, Italy). All samples were acquired during SE within 72 hours of SE diagnosis. The comparison groups were: healthy controls (HC, n = 27) and patients with epilepsy (PWE, n = 30). Demographic, clinical, and therapeutical information and thirty-days follow-up information regarding disability development were acquired for every included patient and analyzed in relation to NfL and S100B values. RESULTS: Serum levels of NfL were significantly higher in SE compared to those of PWE (median 7.35 pg/ml, IQR 6.4, p < 0.001) and HC (median 6.57 pg/ml, IQR 9.1, p < 0.001); S100B serum levels were higher in SE (median 0.11 ug/L, IQR 0.18) compared to PWE (median 0.03 ug/L, IQR 0.03, p < 0.001) and HC (median 0.02 ug/L, IQR 0.008, p < 0.001). However, only NfL serum levels were found to be an independent predictor of 30 days functional outcome whereas S100B levels did not. CONCLUSIONS: Our results suggest that NfL measurement in serum during SE could help predict the short-term functional outcome. This paper was presented at the 8th London-Innsbruck Colloquium on Status Epilepticus and Acute Seizures held in September 2022.

Retrospective External Validation of the Status Epilepticus Severity Score (STESS) to Predict In-hospital Mortality in Adults with Nonhypoxic Status Epilepticus: A Machine Learning Analysis.

BACKGROUND: The objective of this study was to validate the value of the Status Epilepticus Severity Score (STESS) in the prediction of the risk of in-hospital mortality in patients with nonhypoxic status epilepticus (SE) using a machine learning analysis. METHODS: We included consecutive patients with nonhypoxic SE (aged ≥ 16 years) admitted from 2013 to 2021 at the Modena Academic Hospital. A decision tree analysis was performed using in-hospital mortality as a dependent variable and the STESS predictors as input variables. We evaluated the accuracy of STESS in predicting in-hospital mortality using the area under the receiver operating characteristic curve (AUROC) with 95% confidence interval (CI). RESULTS: Among 629 patients with SE, the in-hospital mortality rate was 23.4% (147 of 629). The median STESS in the entire cohort was 2.9 (SD 1.6); it was lower in surviving compared with deceased patients (2.7, SD 1.5 versus 3.9, SD 1.6; p < 0.001). Of deceased patients, 82.3% (121 of 147) had scores of 3-6, whereas 17.7% (26 of 147) had scores of 0-2 (p < 0.001). STESS was accurate in predicting mortality, with an AUROC of 0.688 (95% CI 0.641-0.734) only slightly reduced after bootstrap resampling. The most significant predictor was the seizure type, followed by age and level of consciousness at SE onset. Nonconvulsive SE in coma and age ≥ 65 years predicted a higher risk of mortality, whereas generalized convulsive SE and age < 65 years were associated with a lower risk of death. The decision tree analysis using STESS variables correctly classified 90% of survivors and 34% of nonsurvivors after the SE, with an overall risk of error of 23.1%. CONCLUSIONS: This validation study using a machine learning system showed that STESS is a valuable prognostic tool. The score appears particularly accurate and effective in identifying patients who are alive at discharge (high negative predictive value), whereas it has a lower predictive value for in-hospital mortality.

Fluid Biomarkers of Neuro-Glial Injury in Human Status Epilepticus: A Systematic Review.

As per the latest ILAE definition, status epilepticus (SE) may lead to long-term irreversible consequences, such as neuronal death, neuronal injury, and alterations in neuronal networks. Consequently, there is growing interest in identifying biomarkers that can demonstrate and quantify the extent of neuronal and glial injury. Despite numerous studies conducted on animal models of status epilepticus, which clearly indicate seizure-induced neuronal and glial injury, as well as signs of atrophy and gliosis, evidence in humans remains limited to case reports and small case series. The implications of identifying such biomarkers in clinical practice are significant, including improved prognostic stratification of patients and the early identification of those at high risk of developing irreversible complications. Moreover, the clinical validation of these biomarkers could be crucial in promoting neuroprotective strategies in addition to antiseizure medications. In this study, we present a systematic review of research on biomarkers of neuro-glial injury in patients with status epilepticus.

Epileptic phenotypes in autoimmune encephalitis: from acute symptomatic seizures to autoimmune-associated epilepsy.

OBJECTIVE: To describe the clinical and paraclinical findings, treatment options and long-term outcomes in autoimmune encephalitis (AE), with a close look to epilepsy. METHODS: In this retrospective observational cohort study, we enrolled patients with new-onset seizures in the context of AE. We compared clinical and paraclinical findings in patients with and without evidence of antibodies. RESULTS: Overall, 263 patients (138 females; median age 55 years, range 4-86) were followed up for a median time of 30 months (range 12-120). Antineuronal antibodies were detected in 63.50%.Antibody-positive patients had multiple seizure types (p=0.01) and prevalent involvement of temporal regions (p=0.02). A higher prevalence of episodes of SE was found in the antibody-negative group (p<0.001).Immunotherapy was prescribed in 88.60%, and effective in 61.80%. Independent predictors of favourable outcome of the AE were early immunotherapy (p<0.001) and the detection of antineuronal surface antibodies (p=0.01).Autoimmune-associated epilepsy was the long-term sequela in 43.73%, associated with cognitive and psychiatric disturbances in 81.73%. Independent predictors of developing epilepsy were difficult to treat seizures at onset (p=0.04), a high number of antiseizure medications (p<0.001), persisting interictal epileptiform discharges at follow-up (p<0.001) and poor response to immunotherapy during the acute phase (p<0.001). CONCLUSIONS: The recognition of seizures secondary to AE represents a rare chance for aetiology-driven seizures management. Early recognition and treatment at the pathogenic level may reduce the risk of long-term irreversible sequelae. However, the severity of seizures at onset is the major risk factor for the development of chronic epilepsy.This study provides class IV evidence for management recommendations.

Serum neurofilament light as biomarker of seizure-related neuronal injury in status epilepticus.

Biomarkers of neuronal damage in status epilepticus (SE) would be of great relevance for clinical and research purposes. In a retrospective cross-sectional study, serum neurofilament light chain (NfL) levels were measured in patients with SE (30 subjects), patients with drug-resistant epilepsy (30 subjects), and healthy controls (30 subjects). Serum NfL levels were higher in patients with SE (median = 26.15 pg/ml) compared to both epilepsy patients (median = 7.35 pg/ml) and healthy controls (median = 6.81 pg/ml; p < .001). In patients with SE, serum NfL levels showed a high correlation with cerebrospinal fluid (CSF) NfL (τ = .68, p < .001) as well as with CSF total tau (t-tau) levels (τ = .627, p < .001); they were higher in SE lasting >24 h (p = .013), in refractory/superrefractory SE (p = .004), and in patients who died within 30 days or who presented a worsening of clinical conditions (p = .001). Values of >28.8 pg/ml predicted 30-day clinical worsening or death (odds ratio [OR] = 10.83, 95% confidence interval [CI] = 1.96-59.83, p = .006) and SE refractoriness (OR = 9.33, 95% CI = 1.51-57.65, p = .016). In conclusion, serum NfL levels are increased in SE and correlate with SE treatment response, duration, and outcomes, therefore representing a promising biomarker of seizure-related neuronal damage.

Machine learning validation through decision tree analysis of the Epidemiology-Based Mortality Score in Status Epilepticus.

OBJECTIVE: 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. METHODS: 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. RESULTS: 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). SIGNIFICANCE: 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.

Out-of-hospital versus in-hospital status epilepticus: The role of etiology and comorbidities.

BACKGROUND AND PURPOSE: Our objectives were to identify differences in clinical characteristics between patients with out-of-hospital and in-hospital status epilepticus (SE) onset, and to evaluate the influence of SE onset setting on 30-day mortality and SE cessation. METHODS: We included consecutive patients with SE admitted from 2013-2021 at Modena Academic Hospital. A propensity score was obtained with clinical variables unevenly distributed between the two groups. RESULTS: Seven hundred eleven patients were included; 55.8% (397/711) with out-of-hospital and 44.2% (314/711) with in-hospital onset. Patients with in-hospital SE onset were older and had a higher frequency of comorbidities, acute and/or potentially fatal etiologies, impaired consciousness before treatment, and nonconvulsive or myoclonic SE. No difference was found in SE cessation between the groups. Patients with in-hospital SE had higher 30-day mortality (127/314, 62.9% vs. 75/397, 37.1%; p < 0.001). In-hospital onset was an independent risk factor for 30-day mortality (adjusted odds ratio = 1.720; 95% confidence interval = 1.107-2.674; p = 0.016). In the propensity group (n = 244), no difference was found in 30-day mortality and SE cessation between out-of-hospital and in-hospital SE onset groups (36/122, 29.5% vs. 34/122, 27.9%; p = 0.888; and 47/122, 38.5% vs. 39/122; 32%; p = 0.347, respectively). CONCLUSIONS: In-hospital SE is associated with higher 30-day mortality without difference in SE cessation. The two groups differ considerably for age, acute and possibly fatal etiologies, comorbidities, and SE semiology. The patient location at SE onset is an important prognostic predictor. However, the increased mortality is probably unrelated to the setting of SE onset and reflects intrinsic prognostic predictors.

Ictal apnea: A prospective monocentric study in patients with epilepsy.

BACKGROUND AND PURPOSE: Ictal respiratory disturbances have increasingly been reported, in both generalized and focal seizures, especially involving the temporal lobe. Recognition of ictal breathing impairment has gained importance for the risk of sudden unexpected death in epilepsy (SUDEP). The aim of this study was to evaluate the incidence of ictal apnea (IA) and related hypoxemia during seizures. METHODS: We collected and analyzed electroclinical data from consecutive patients undergoing long-term video-electroencephalographic (video-EEG) monitoring with cardiorespiratory polygraphy. Patients were recruited at the epilepsy monitoring unit of the Civil Hospital of Baggiovara, Modena Academic Hospital, from April 2020 to February 2022. RESULTS: A total of 552 seizures were recorded in 63 patients. IA was observed in 57 of 552 (10.3%) seizures in 16 of 63 (25.4%) patients. Thirteen (81.2%) patients had focal seizures, and 11 of 16 patients showing IA had a diagnosis of temporal lobe epilepsy; two had a diagnosis of frontal lobe epilepsy and three of epileptic encephalopathy. Apnea agnosia was reported in all seizure types. Hypoxemia was observed in 25 of 57 (43.9%) seizures with IA, and the severity of hypoxemia was related to apnea duration. Apnea duration was significantly associated with epilepsy of unknown etiology (magnetic resonance imaging negative) and with older age at epilepsy onset (p < 0.001). CONCLUSIONS: Ictal respiratory changes are a frequent clinical phenomenon, more likely to occur in focal epilepsies, although detected even in patients with epileptic encephalopathy. Our findings emphasize the need for respiratory polygraphy during long-term video-EEG monitoring for diagnostic and prognostic purposes, as well as in relation to the potential link of ictal apnea with the SUDEP risk.

Development and Validation of a Nomogram Based on the Epidemiology-Based Mortality Score in Status Epilepticus (EMSE) Parameters to Predict 30-day Mortality in Status Epilepticus.

BACKGROUND: To develop a nomogram using the parameters of the Epidemiology-Based Mortality Score in Status Epilepticus (EMSE) and to evaluate its accuracy compared with the EMSE alone in the prediction of 30-day mortality in patients with status epilepticus (SE). METHODS: We included a cohort of patients with SE aged ≥ 21 years admitted from 2013 to 2021. Regression coefficients from the multivariable logistic regression model were used to generate a nomogram predicting the risk of 30-day mortality. Discrimination of the nomogram was evaluated using the area under the receiver operating characteristic curve (AUCROC) with 95% confidence interval. Internal validation was performed by bootstrap resampling. RESULTS: Among 698 patients with SE, the 30-day mortality rate was 28.9% (202 of 698). On the multivariable analysis, all EMSE parameters (except for the comorbidity group including metastatic solid tumor or AIDS) were associated with a significantly higher risk of 30-day mortality and were included in the nomogram. The discriminatory capability of the nomogram with bootstrap resampling (5000 resamples) had an AUCROC of 0.830 (95% confidence interval 0.798-0.862). Conversely, the AUCROC of the EMSE was 0.777 (95% confidence interval 0.742-0.813). Thus, the probability that a patient who died within 30 days from SE had a higher score than a patient who survived was 83%, indicating good discriminatory power of the nomogram. Conversely, the risk predicted using the EMSE alone was 77%. The nomogram was well calibrated. CONCLUSIONS: A nomogram based on EMSE parameters appears superior to the EMSE in predicting the risk of 30-day mortality after SE. The discrimination and calibration of the nomogram shows a better predictive accuracy than the EMSE alone.