The Role of Early Intubation in Status Epilepticus with Out-of-Hospital Onset: A Large Prospective Observational Study.

Background: this study aimed to evaluate the role of early airway management and intubation in status epilepticus (SE) with out-of-hospital onset. Methods: We included all patients with out-of-hospital SE onset referred to the emergency department of the Academic Hospital of Modena between 2013 and 2021. Patients were compared according to out-of-hospital airway management (intubation versus non-intubation) and a propensity score was performed for clinical variables unevenly distributed between the two groups. Results: We evaluated 711 patients with SE. A total of 397 patients with out-of-hospital SE onset were eventually included; of these, 20.4% (81/397) were intubated before arrival at the hospital. No difference was found in the clinical characteristics of patients after propensity score matching. The 30-day mortality in the propensity group was 19.4% (14/72), and no difference was found between intubated (7/36, 19.4%) and non-intubated (7/36, 19.4%) patients. No difference was found in SE cessation. Compared to non-intubated patients, those who underwent out-of-hospital intubation had a higher risk of progression to refractory or super-refractory SE, greater worsening of mRS values between hospital discharge and admission, and lower probability of returning to baseline condition at 30 days after SE onset. Conclusions: Early intubation for out-of-hospital SE onset is not associated with improved patient survival even after balancing for possible confounders. Further studies should evaluate the timing of intubation and its association with first-line treatments for SE and their efficacy. In addition, they should focus on the settings and the exact reasons leading to intubation to better inform early management of SE with out-of-hospital onset.

Electrographic seizure duration and inter-seizure intervals in focal status epilepticus.

OBJECTIVE: To characterize the duration of seizures and inter-seizure intervals in focal status epilepticus (SE). METHODS: We reviewed consecutive scalp EEG recordings from adult patients who were admitted for a first episode of focal status epilepticus. We identified electrographic seizure duration and inter-seizure intervals in the first diagnostic pretreatment EEG. We also reviewed isolated focal self-limiting seizures in epilepsy patients, as a comparison group for seizure duration. RESULTS: We recorded 307 focal seizures in 100 consecutive focal SE episodes, with a median seizure duration of 107 s (IQR: 54-186), and 134 isolated focal self-limiting seizures in 42 epilepsy patients, with a median duration of 59 s (IQR: 30-90; p < .001). The only clinical feature of SE that significantly increased seizure duration was acute symptomatic etiology. In SE, 15% and 7% of seizures lasted longer than 300 and 600 s, respectively (t1 of the actual definition for tonic-clonic and focal SE), while only 1% of self-limiting seizures lasted longer than 300 s, and none lasted longer than 600 s. The analysis of inter-seizure intervals in SE with multiple seizures showed that 50% of the inter-seizure periods were shorter than 60 s, and 95% were shorter than 540 s (9 min). Patients who had an increase in seizure duration (last versus first) of at least 1.4 times showed an increased 30-day mortality. SIGNIFICANCE: Focal seizures within a SE episode showed a wide range of duration, partly overlapping with the duration of focal self-limiting seizures but with a longer median duration. Inter-seizure intervals within an episode of SE were shorter than 1 min in 50% of the seizures and never lasted more than 10 min. Finally, an increase in seizure duration could represent an "electrophysiological biomarker" of a more severe SE episode, which may require more aggressive and rapid treatment.

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.

Predicting the progression to super-refractory status epilepticus: A machine-learning study.

AIM: Super-refractory status epilepticus (SRSE) is a status epilepticus (SE) that continues or recurs ≥24 h after the onset of anesthesia. We aimed to identify the predictors of progression to SRSE and the risk of 30-day mortality in patients with SRSE by using a machine learning technique. METHODS: We reviewed consecutive SE episodes in patients aged ≥14 years at Baggiovara Civil Hospital (Modena, Italy) from 2013 to 2021. A classification and regression tree analysis was performed to develop a predictive model of progression to SRSE in SE patients. In SRSE patients, a multivariate analysis was conducted to identify predictors of 30-day mortality. RESULTS: We included 705 patients, 16% of whom (113/705) progressed to SRSE. Acute symptomatic hypoxic etiology and age ≤ 68.5 years predicted the highest risk (87.1%) of progression to SRSE. Etiology other than acute symptomatic hypoxic and absence of NCSE predicted the lowest risk (3.6%) of progression to SRSE. The predictive model was accurate in 96.1% of patients not evolving to SRSE and in 48.7% of those evolving to SRSE. Among patients with SRSE, 46.9% (53/113) died within 30 days compared to 25.2% (149/592) of patients without SRSE (p < 0.001). Among patients with SRSE, older age was associated with increased 30-day mortality (odds ratio 1.075; 95% confidence interval: 1.031-1.112; p = 0.001). CONCLUSIONS: Acute symptomatic hypoxic etiology and younger age are major predictors of progression to SRSE. In patients with SRSE, older age is associated with increased risk of short-term mortality.

Amygdala subnuclear volumes in temporal lobe epilepsy with hippocampal sclerosis and in non-lesional patients.

Together with hippocampus, the amygdala is important in the epileptogenic network of patients with temporal lobe epilepsy. Recently, an increase in amygdala volumes (i.e. amygdala enlargement) has been proposed as morphological biomarker of a subtype of temporal lobe epilepsy patients without MRI abnormalities, although other data suggest that this finding might be unspecific and not exclusive to temporal lobe epilepsy. In these studies, the amygdala is treated as a single entity, while instead it is composed of different nuclei, each with peculiar function and connection. By adopting a recently developed methodology of amygdala's subnuclei parcellation based of high-resolution T1-weighted image, this study aims to map specific amygdalar subnuclei participation in temporal lobe epilepsy due to hippocampal sclerosis (n = 24) and non-lesional temporal lobe epilepsy (n = 24) with respect to patients with focal extratemporal lobe epilepsies (n = 20) and healthy controls (n = 30). The volumes of amygdala subnuclei were compared between groups adopting multivariate analyses of covariance and correlated with clinical variables. Additionally, a logistic regression analysis on the nuclei resulting statistically different across groups was performed. Compared with other populations, temporal lobe epilepsy with hippocampal sclerosis showed a significant atrophy of the whole amygdala (p Bonferroni = 0.040), particularly the basolateral complex (p Bonferroni = 0.033), while the non-lesional temporal lobe epilepsy group demonstrated an isolated hypertrophy of the medial nucleus (p Bonferroni = 0.012). In both scenarios, the involved amygdala was ipsilateral to the epileptic focus. The medial nucleus demonstrated a volume increase even in extratemporal lobe epilepsies although contralateral to the seizure onset hemisphere (p Bonferroni = 0.037). Non-lesional patients with psychiatric comorbidities showed a larger ipsilateral lateral nucleus compared with those without psychiatric disorders. This exploratory study corroborates the involvement of the amygdala in temporal lobe epilepsy, particularly in mesial temporal lobe epilepsy and suggests a different amygdala subnuclei engagement depending on the aetiology and lateralization of epilepsy. Furthermore, the logistic regression analysis indicated that the basolateral complex and the medial nucleus of amygdala can be helpful to differentiate temporal lobe epilepsy with hippocampal sclerosis and with MRI negative, respectively, versus controls with a consequent potential clinical yield. Finally, the present results contribute to the literature about the amygdala enlargement in temporal lobe epilepsy, suggesting that the increased volume of amygdala can be regarded as epilepsy-related structural changes common across different syndromes whose meaning should be clarified.

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.

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.

Recurrent status epilepticus: Clinical features and recurrence risk in an adult population.

BACKGROUND: Knowledge regarding consequences among status epilepticus (SE) survivors is still scarce. We assessed the risk of recurrence in a cohort of first-ever adult SE survivors, comparing the clinical features of patients with recurrent and incident events. METHODS: We reviewed our prospective register of consecutive SE patients, from September 1st 2013 to September 1st 2020. We excluded post-anoxic events and those patients with a SE prior the study period. We examined the effect of clinical predictors on the risk of subsequent SE through Cox proportional hazard regression, while the risk of recurrence was estimated through a survival analysis. RESULTS: 430 patients were considered (mean follow-up: 23.3 months). 44 patients experienced SE recurrence, whereas 386 patients presented an isolated event. The highest risk of recurrence was observed within 6 months from the index event (7.9%), whereas the cumulative recurrence rate was 9.5%, 13%, and 20.5% at 6 months, 1 year, and 4-years respectively. SE recurrence was independently associated to remote (HR 2.8 - 95% CI 1.4 to 6.0) or progressive symptomatic etiologies (HR 3.9 - 95% CI 1.8 to 8.7) and it was higher for Super-Refractory SE (SRSE) cases (HR 3.3 - 95% CI 1.4 to 7.8). High STESS values (p = 0.01) and SE refractoriness (p = 0.01) were associated with early relapses (within 6 months from the index event). CONCLUSIONS: SE recurrence involved a significantly proportion of our cohort. Etiology other than acute symptomatic and SRSE were independently associated with a higher risk of recurrence, in particular within 6 months from the index event.

Case Report: Ictal Central Apnea as First and Overlooked Symptom in Temporal Lobe Seizures.

Ictal respiratory changes have been mainly described following generalized tonic-clonic seizures and recently considered to be a biomarker to assess the risk of sudden unexplained death in epilepsy (SUDEP). Nonetheless, modification of respiratory pattern can be related also to focal seizures, especially arising from the temporal lobe. Changes in cardiac function such as tachycardia or bradycardia could be often associated. We report a short case series of four patients with temporal lobe epilepsy admitted to our Epilepsy Monitoring Unit (EMU) presenting with an ictal central apnea as the first clinical manifestation of their seizures. None of these patients was aware of the occurrence of respiratory arrest. Age at onset ranged from 15 to 29 years. One patient had seizures with prolonged central apnea accompanied by a significant decrease in oxygen saturation. Neuroimaging in two patients showed alterations of mesial temporal lobe structures, including the amygdala. Recent neurophysiological studies supported the existence of a cortical network involving the limbic system that modulates downstream brainstem respiratory centers. Monitoring for respiratory changes and oxygen saturation in focal seizures is warranted for their potential value in identifying the epileptogenic zone and for a better understanding of ictal respiratory changes that could potentially define a subgroup of patients with high risk of seizure-related autonomic changes.

Cortical and thalamic hyper-perfusion in non-convulsive status epilepticus. Relationship between perfusion CT patterns and Salzburg EEG criteria.

INTRODUCTION: Status epilepticus (SE) is a neurological emergency and in particular nonconvulsive SE (NCSE) represents a diagnostic challenge. To improve clinical decision-making, cerebral perfusion-computed tomography (PCT) has been shown as a helpful tool to support the diagnosis of focal NCSE. MATERIALS AND METHODS: This is a monocentric retrospective study. Among the 602 cases of SE observed between September 2013 and April 2020 we included 21 patients that were studied with PCT. The perfusion maps were first visually analysed then a quantitative analysis (by regions of interest, ROI) was obtained. For each patient, the diagnostic EEG was reviewed and classified in accordance to the Salzburg Criteria for NCSE (SCC) as definite (D-NCSE) and possible (P-NCSE). Finally, we analysed the relationship between PCT and EEG patterns. RESULTS: Hyper-perfusion was observed in 18 patients (86%), while in the remaining 3 (14%) a normo-perfused pattern was present. Hyper-perfusion was observed in 14 of the D-NCSE group (88%) and in the two patients with a P-NCSE (100%). No one among the patients with a P-NCSE had a thalamic hyper-perfusion, while among the 6 patients with continuous sustained epileptiform discharges > 2.5 Hz (pattern 1 of SCC), 4 (67%) showed cortical plus thalamic hyper-perfusion. CONCLUSIONS: PCT could facilitate the differential diagnosis and speed-up the diagnostic process of NCSE in emergency situations. Finding cortical multi-lobar hyper-perfusion, especially if present together with homolateral thalamic hyper-perfusion in a patient with an acute-onset of motor/sensory/language deficits is highly suggestive for the presence of NCSE and is particularly related to continuous/sustained ictal patterns.

Intravenous brivaracetam in status epilepticus: A multicentric retrospective study in Italy.

PURPOSE: to evaluate the use, effectiveness, and adverse events of intravenous brivaracetam (BRV) in status epilepticus (SE). METHODS: a retrospective multicentric study involving 24 Italian neurology units was performed from March 2018 to June 2020. A shared case report form was used across participating centres to limit biases of retrospective data collection. Diagnosis and classification of SE followed the 2015 ILAE proposal. We considered a trial with BRV a success when it was the last administered drug prior the clinical and/or EEG resolution of seizures, and the SE did not recur during hospital observation. In addition, we considered cases with early response, defined as SE resolved within 6 h after BRV administration. RESULTS: 56 patients were included (mean age 62 years; 57 % male). A previous diagnosis of epilepsy was present in 21 (38 %). Regarding SE etiology classification 46 % were acute symptomatic, 18 % remote and 16 % progressive symptomatic. SE episodes with prominent motor features were the majority (80 %). BRV was administered as first drug after benzodiazepine failure in 21 % episodes, while it was used as the second or the third (or more) drug in the 38 % and 38 % of episodes respectively. The median loading dose was 100 mg (range 50-300 mg). BRV was effective in 32 cases (57 %). An early response was documented in 22 patients (39 % of the whole sample). The use of the BRV within 6 h from SE onset was independently associated to an early SE resolution (OR 32; 95 % CI 3.39-202; p = 0.002). No severe treatment emergent adverse events were observed. CONCLUSION: BRV proved to be useful and safe for the treatment of SE. Time to seizures resolution appears shorter when it is administered in the early phases of SE.