Onset Of Status Epilepticus Research Articles

Thyroid hormones and prognosis in adults with status epilepticus: a retrospective study

ObjectivesThyroid hormone levels have been indicated to be associated with the functional outcome in critical illness. However, the studies on thyroid hormones and status epilepticus (SE) are rare. This study aimed to evaluate the predictive value of serum thyroid hormone levels on admission for unfavorable outcome in adult patients with SE.MethodsWe investigated and validated the predictive value of serum thyroid hormone levels on admission for the prognosis of adult SE patients. We extracted the clinical information and outcomes of patients. Modified Rankin scale (mRS) scores were applied to assess the patients’ functional outcome, and mortality at 30 days after SE onset was identified. Serum levels of thyroid hormones including free thyroxin (FT4), free triiodothyronine (FT3) and thyroid-stimulating hormone (TSH) were detected on admission.ResultsWe first analyzed the discovery cohort of 87 patients with SE. We found that 35.6% (31/87) of the patients had a poor outcome at discharge, and 18.4% (16/87) of the patients died during hospital stay and at 30-day follow up. The serum FT3 levels in the non-survivors group were significantly lower than those in the survivors group. Low T3 syndrome occurred in 29.9% (26/87) of SE cases and patients with low T3 syndrome were more likely to have unfavorable outcomes. Furthermore, we observed similar results in the external cohort, which validated our findings.ConclusionsSerum FT3 levels measured on admission are independently associated with 30-day mortality in SE patients. Additionally, low T3 syndrome may be a promising candidate for predicting SE prognosis.

Optogenetic stimulation of dorsal striatum bidirectionally controls seizures.

Engagement of the striatum (caudate/putamen) and other basal ganglia nuclei during seizures was first observed over 75 years ago. Basal ganglia output nuclei, and the substantia nigra pars reticulata, in particular, have well-established anti-seizure effects across a large array of experimental models. However, striatal control of seizures is understudied. To address this gap, we used optogenetic approaches to activate and inactivate neurons in the dorsal striatum of Sprague-Dawley rats submitted to the gamma-butyrolactone (GBL) model of absence epilepsy, amygdala kindling model of temporal lobe epilepsy, and pilocarpine-induced Status Epilepticus (SE). All tests were performed on a within-subject basis. Animals were tested in two different light frequencies (5 Hz and 100 Hz). Open-loop (continuous light delivery) optogenetic activation of the dorsal striatal neurons robustly suppressed seizures in all models. On the other hand, optogenetic silencing of the dorsal striatal neurons increased absence seizure expression and facilitated SE onset but had no effect on kindled limbic seizures. In the GBL model, we also verified if the closed- loop strategy (light delivery in response to seizure detection) would be enough to induce antiseizure effects. On-demand light delivery in ChR2-expressing animals reduced SWD duration, while the same approach in ArchT-expressing animals increased SWD duration. These results demonstrated previously unrecognized anti-absence effects associated with striatal continuous and on-demand neuromodulation. Together, these findings document a robust, bidirectional role of the dorsal striatum in the control of seizure generation and propagation in a variety of seizure models, including focal seizure onset and generalized seizures.

New onset status epilepticus and its long-term outcome: A cohort study

PurposeNew onset status epilepticus (NOSE), a subtype of status epilepticus, is a neurological emergency associated with significant morbidity and mortality. This study aimed to analyze the phenotypic spectrum and outcomes of patients presenting with NOSE. MethodsThis prospective and retrospective descriptive study included patients presenting with NOSE over a 10-year period. Data collected included patient demographics, phenotypic characteristics of SE and its etiology, Status Epilepticus Severity Score (STESS), SE classification Axis-II, and Modified Rankin Scale (mRS) scores at admission and discharge. Functional outcomes and seizure status were assessed at least 6 months post-discharge. Prognostic factors for mortality and the development of epilepsy were also analyzed. ResultsA total of 208 patients were included, with a mean age of 41.97 ± 21.66 years, and a male predominance (57.1 %). Focal to bilateral tonic-clonic seizures were observed in 47.5 % of patients. The etiology was acute symptomatic in 35.57 % and remote symptomatic in 24 %. The median hospital stay was 4 days (range: 2.25–10.75 days). The mortality rate was 26.5 %, and 23 % of patients developed epilepsy with a median follow-up of 9 months. Higher age (≥ 50 years), elevated STESS, ICU admission, use of anesthetic agents, refractory status epilepticus (RSE), and new-onset refractory status epilepticus (NORSE) were significant risk factors for mortality (p<0.05). The development of epilepsy was associated with a higher number of antiseizure medications (ASM) at discharge, ICU admission, use of anesthetic agents, RSE, and NORSE (p<0.05). ConclusionNOSE is a neurological emergency with a variable etiology and significant long-term consequences. Approximately one-fourth of patients presenting with NOSE died, and another quarter developed epilepsy during a median follow-up of 9 months. Identifying and addressing the predictors of mortality and epilepsy development following NOSE may improve long-term outcomes.

Identification of etiologies according to baseline clinical features of pediatric new-onset refractory status epilepticus in single center retrospective study

PurposeNew-onset refractory status epilepticus (NORSE) is defined as a state of prolonged seizure activity that does not improve despite the appropriate administration of medications, with underlying causes unknown after the initial diagnosis of status epilepticus. Because episodes of NORSE are accompanied by severe complications and a high risk of mortality, the prompt identification of the underlying cause is crucial for effective treatment and outcome prediction. This study assessed the relationship of NORSE etiologies with baseline clinical features in pediatric population. MethodsSeventy-one pediatric patients, under 18 years of age at the initial diagnosis (4.50 ± 4.04, mean ± standard deviation), who experienced at least one episode of NORSE and underwent a comprehensive diagnostic evaluation between January 2005 and June 2020 at our center, were retrospectively selected. We reviewed clinical features at disease onset and long-term follow-up data. Uniform manifold approximation and projection (UMAP) was used to distinguish etiological clusters according to baseline clinical characteristics, and further analysis was performed based on underlying etiologies. ResultsTwo distinct etiological groups—genetic and non-genetic—were identified based on the UMAP of clinical characteristics. Dravet syndrome (12/15, 80%) was more predominant in patients with a genetic diagnosis, whereas cryptogenic NORSE and encephalitis were prevalent in patients without a genetic diagnosis. The analysis of etiological categories revealed that age at the onset of status epilepticus (P=0.021) and progression to super refractory status epilepticus (SRSE) (P=0.038) were independently associated with differences in etiologies. ConclusionSeveral clinical features in patients with NORSE, including the age of onset and the development of SRSE, can help identify underlying causes, which necessitate prompt and adequate treatment.

Trends in management of patients with new-onset refractory status epilepticus (NORSE) from 2016 to 2023: An interim analysis.

In response to the evolving treatment landscape for new-onset refractory status epilepticus (NORSE) and the publication of consensus recommendations in 2022, we conducted a comparative analysis of NORSE management over time. Seventy-seven patients were enrolled by 32 centers, from July 2016 to August 2023, in the NORSE/FIRES biorepository at Yale. Immunotherapy was administered to 88% of patients after a median of 3 days, with 52% receiving second-line immunotherapy after a median of 12 days (anakinra 29%, rituximab 25%, and tocilizumab 19%). There was an increase in the use of second-line immunotherapies (odds ratio [OR] = 1.4, 95% CI = 1.1-1.8) and ketogenic diet (OR = 1.8, 95% CI = 1.3-2.6) over time. Specifically, patients from 2022 to 2023 more frequently received second-line immunotherapy (69% vs 40%; OR = 3.3; 95% CI = 1.3-8.9)-particularly anakinra (50% vs 13%; OR = 6.5; 95% CI = 2.3-21.0), and the ketogenic diet (OR = 6.8; 95% CI = 2.5-20.1)-than those before 2022. Among the 27 patients who received anakinra and/or tocilizumab, earlier administration after status epilepticus onset correlated with a shorter duration of status epilepticus (ρ = .519, p = .005). Our findings indicate an evolution in NORSE management, emphasizing the increasing use of second-line immunotherapies and the ketogenic diet. Future research will clarify the impact of these treatments and their timing on patient outcomes.

Status epilepticus in POLG disease: a large multinational study

We aimed to provide a detailed phenotypic description of status epilepticus (SE) in a large cohort of patients with POLG disease and identify prognostic biomarkers to improve the management of this life-threatening condition. In a multinational, retrospective study with data on patients with POLG disease from seven European countries, we identified those who had SE. The age of SE onset, accompanying clinical, laboratory, imaging and genetic findings were analysed. One hundred and ninety-five patients with genetically confirmed POLG disease were recruited, of whom 67% (130/194) had epilepsy. SE was identified in 77% (97/126), with a median age of SE onset of 7 years. SE was the presenting symptom of the disease in 43% (40/93) of those with SE, while 57% (53/93) developed SE during the disease course. Convulsive SE was reported in 97% (91/94) followed by epilepsia partialis continua in 67% (56/84). Liver impairment 78% (74/95), ataxia 69% (60/87), stroke-like episodes 57% (50/88), were the major comorbidities. In the majority (66%; 57/86) with SE this became refractory or super-refractory. The presence of seizures was associated with significantly higher mortality compared to those without (P ≤ 0.001). The median time from SE debut to death was 5 months. SE is a major clinical feature of POLG disease in early and juvenile to adult-onset disease and can be the presenting feature or arise as part of a multisystem disease. It is associated with high morbidity and mortality, with the majority of patients with SE going on to develop refractory or super-refractory SE.

The influence of biological rhythms on the initial onset of status epilepticus in critically ill inpatients and the study of its predictive Model

ABSTRACT This study aims to explore the relationship between the circadian rhythms of critically ill patients and the incidence of Status Epilepticus (SE), and to develop a predictive model based on circadian rhythm indicators and clinical factors. We conducted a diurnal rhythm analysis of vital sign data from 4413 patients, discovering significant differences in the circadian rhythms of body temperature, blood oxygen saturation, and heart rate between the SE and non-SE groups, which were correlated with the incidence of SE. We also employed various machine learning algorithms to identify the ten most significant variables and developed a predictive model with strong performance and clinical applicability. Our research provides a new perspective and methodology for the study of biological rhythms in critically ill patients, offering new evidence and tools for the prevention and treatment of SE. Our findings are consistent or similar to some in the literature, while differing from or supplementing others. We observed significant differences in the vital signs of epileptic patients at different times of the day across various diagnostic time groups, reflecting the regulatory effects of circadian rhythms. We suggest heightened monitoring and intervention of vital signs in critically ill patients, especially during late night to early morning hours, to reduce the risk of SE and provide more personalized treatment plans.

Parvalbumin Regulates GAD Expression through Calcium Ion Concentration to Affect the Balance of Glu-GABA and Improve KA-Induced Status Epilepticus in PV-Cre Transgenic Mice.

Aims: the study aimed to (i) use adeno-associated virus technology to modulate parvalbumin (PV) gene expression, both through overexpression and silencing, within the hippocampus of male mice and (ii) assess the impact of PV on the metabolic pathway of glutamate and γ-aminobutyric acid (GABA). Methods: a status epilepticus (SE) mouse model was established by injecting kainic acid into the hippocampus of transgenic mice. When the seizures of mice reached SE, the mice were killed at that time point and 30 min after the onset of SE. Hippocampal tissues were extracted and the mRNA and protein levels of PV and the 65 kDa (GAD65) and 67 kDa (GAD67) isoforms of glutamate decarboxylase were assessed using real-time quantitative polymerase chain reaction and Western blot, respectively. The concentrations of glutamate and GABA were detected with high-performance liquid chromatography (HPLC), and the intracellular calcium concentration was detected using flow cytometry. Results: we demonstrate that the expression of PV is associated with GAD65 and GAD67 and that PV regulates the levels of GAD65 and GAD67. PV was correlated with calcium concentration and GAD expression. Interestingly, PV overexpression resulted in a reduction in calcium ion concentration, upregulation of GAD65 and GAD67, elevation of GABA concentration, reduction in glutamate concentration, and an extension of seizure latency. Conversely, PV silencing induced the opposite effects. Conclusion: parvalbumin may affect the expression of GAD65 and GAD67 by regulating calcium ion concentration, thereby affecting the metabolic pathways associated with glutamate and GABA. In turn, this contributes to the regulation of seizure activity.

EEG Patterns Predicting Clobazam Response in Refractory Status Epilepticus in Adults

Summary Background Seizure resolution is often difficult to attain promptly in status epilepticus (SE). Clobazam (CLB) is structurally different from typical benzodiazepines with an affinity to the α2 subunit of GABA-A receptors, rendering unique efficacy in seizure termination. Aim To assess the response of clobazam in refractory status epilepticus (RSE) and to correlate this response with EEG patterns. Materials and Methods This was a single-center retrospective study conducted at a neurocritical care unit between January 2018 and June 2023. The study included fifty consecutive patients with RSE, out of which sixteen adult patients had continuous EEG monitoring both before and during treatment with clobazam until the resolution of RSE. Patients for whom clobazam was the last anti-seizure medication (ASM) used were included in the study. Thirty-four patients were excluded for various reasons, like lack of continuous EEG monitoring (cEEG), status post cardiac arrest, exclusion of clobazam due to medical issues or adverse events, or admission to the hospice floor. Results Out of the sixteen patients included in the study, twelve (75%) had focal nonconvulsive RSE on cEEG and four had focal convulsive RSE when clobazam was administered. Thirteen out of sixteen patients (81.25%) responded successfully to clobazam, with an average time of 23.5 hours since starting the medication. On average, three other ASMs were tried before clobazam, initiated at a mean time of 27 hours since SE onset. The study identified EEG patterns correlated with the use of clobazam :1) lateralised periodic discharges that evolved from 1–1.5 Hz to 2–3 Hz, then evolved to rhythmic theta/delta activity with embedded LPDs; 2) repetitive spikes that evolved to theta and delta frequencies (good responders to CLB), and iii) low voltage faster frequencies and evolved to theta delta frequencies (less responders to CLB). Conclusion Rapid pharmacoresistance to first-line benzodiazepines and ASM occurs as seizures persist during SE. Our study provides EEG correlates to the successful use of CLB in RSE based on its unique targeting of the GABA-A subtype receptors involved in postsynaptic phasic inhibition.

Neuroprotective effects of chlorogenic acid against oxidative stress in rats subjected to lithium-pilocarpine-induced status epilepticus.

Epilepsy is a condition marked by sudden, self-sustained, and recurring brain events, showcasing unique electro-clinical and neuropathological phenomena that can alter the structure and functioning of the brain, resulting in diverse manifestations. Antiepileptic drugs (AEDs) can be very effective in 30% of patients in controlling seizures. Several factors contribute to this: drug resistance, individual variability, side effects, complexity of epilepsy, incomplete understanding, comorbidities, drug interactions, and no adherence to treatment. Therefore, research into new AEDs is important for several reasons such as improved efficacy, reduced side effects, expanded treatment options, treatment for drug-resistant epilepsy, improved safety profiles, targeted therapies, and innovation and progress. Animal models serve as crucial biological tools for comprehending neuronal damage and aiding in the discovery of more effective new AEDs. The utilization of antioxidant agents that act on the central nervous system may serve as a supplementary approach in the secondary prevention of epilepsy, both in laboratory animals and potentially in humans. Chlorogenic acid (CGA) is a significant compound, widely prevalent in numerous medicinal and food plants, exhibiting an extensive spectrum of biological activities such as neuroprotection, antioxidant, anti-inflammatory, and analgesic effects, among others. In this research, we assessed the neuroprotective effects of commercially available CGA in Wistar rats submitted to lithium-pilocarpine-induced status epilepticus (SE) model. After 72-h induction of SE, rats received thiopental and were treated for three consecutive days (1st, 2nd, and 3rd doses). Next, brains were collected and studied histologically for viable cells in the hippocampus with staining for cresyl-violet (Nissl staining) and for degenerating cells with Fluoro-Jade C (FJC) staining. Moreover, to evaluate oxidative stress, the presence of malondialdehyde (MDA) and superoxide dismutase (SOD) was quantified. Rats administered with CGA (30 mg/kg) demonstrated a significant decrease of 59% in the number of hippocampal cell loss in the CA3, and of 48% in the hilus layers after SE. A significant reduction of 75% in the cell loss in the CA3, shown by FJC+ staining, was also observed with the administration of CGA (30 mg/kg). Furthermore, significant decreases of 49% in MDA production and 72% in the activity of SOD were seen, when compared to animals subjected to SE that received vehicle. This study introduces a novel finding: the administration of CGA at a dosage of 30 mg/kg effectively reduced oxidative stress induced by lithium-pilocarpine, with its effects lasting until the peak of neural damage 72 h following the onset of SE. Overall, the research and development of new AEDs are essential for advancing epilepsy treatment, improving patient outcomes, and ultimately enhancing the quality of life for individuals living with epilepsy.

Second-line immunotherapy in new onset refractory status epilepticus.

Several pieces of evidence suggest immune dysregulation could trigger the onset and modulate sequelae of new onset refractory status epilepticus (NORSE), including its subtype with prior fever known as febrile infection-related epilepsy syndrome (FIRES). Consensus-driven recommendations have been established to guide the initiation of first- and second-line immunotherapies in these patients. Here, we review the literature to date on second-line immunotherapy for NORSE/FIRES, presenting results from 28 case reports and series describing the use of anakinra, tocilizumab, or intrathecal dexamethasone in 75 patients with NORSE. Among them, 52 patients were managed with anakinra, 21 with tocilizumab, and eight with intrathecal dexamethasone. Most had elevated serum or cerebrospinal fluid cytokine levels at treatment initiation. Treatments were predominantly initiated during the acute phase of the disease (92%) and resulted, within the first 2 weeks, in seizure control for up to 73% of patients with anakinra, 70% with tocilizumab, and 50% with intrathecal dexamethasone. Cytokine levels decreased after treatment for most patients. Anakinra and intrathecal dexamethasone were mainly initiated in children with FIRES, whereas tocilizumab was more frequently prescribed for adults, with or without a prior febrile infection. There was no clear correlation between the response to treatment and the time to initiate the treatment. Most patients experienced long-term disability and drug-resistant post-NORSE epilepsy. Initiation of second-line immunotherapies during status epilepticus (SE) had no clear effect on the emergence of post-NORSE epilepsy or long-term functional outcomes. In a small number of cases, the initiation of anakinra or tocilizumab several years after SE onset resulted in a reduction of seizure frequency for 67% of patients. These data highlight the potential utility of anakinra, tocilizumab, and intrathecal dexamethasone in patients with NORSE. There continues to be interest in the utilization of early cytokine measurements to guide treatment selection and response. Prospective studies are necessary to understand the role of early immunomodulation and its associations with epilepsy and functional outcomes.

Ivermectin Exerts Anticonvulsant Effects Against Status Epilepticus Induced by Lithium-Pilocarpine in Rats via GABAA Receptor and Neuroinflammation Modulation: Possible Interaction of Opioidergic Pathways and KATP Channel with Nitrergic System.

Status epilepticus (SE) is a critical medical emergency marked by persistent or rapidly repeating seizures, posing a threat to life. Using the lithium-pilocarpine-induced SE model, we decide to evaluate the anti-seizure effects of ivermectin as a positive allosteric modulator of GABAA receptor and the underlying mechanisms involved. Lithium chloride was injected intraperitoneally at a dose of 127 mg/kg, followed by the administration of pilocarpine at a dose of 60 mg/kg after a 20-h interval in order to induce SE. Subsequently, the rats received varying amounts of ivermectin (0.3, 1, 3, 5, and 10 mg/kg, i.p.) 30 min before the onset of SE. To study the underlying molecular mechanisms, we had pharmacological interventions of diazepam (1 mg/kg), glibenclamide and nicorandil as ATP-sensitive potassium channel blocker and opener (both 1 mg/kg, i.p.), naltrexone and morphine, as opioid receptor antagonist and agonist (1 mg/kg and 0.5 mg/kg, i.p., respectively). In addition, three nitric oxide inhibitors, namely, L-NAME (10 mg/kg, i.p.), 7-NI (30 mg/kg, i.p.), and aminoguanidine (100 mg/kg, i.p.), were administered to the rats in the experiment. Finally, we use ELISA and western blotting, respectively, to examine the amounts of pro-inflammatory cytokines (TNF-α and IL-1β), nitrite, and GABAA receptors in the rat hippocampal tissue. The study found that ivermectin, at doses of 3, 5, and 10 mg/kg, exerts anti-seizure effects and decrease Racine's scale SE score. Interestingly glibenclamide and naltrexone reduced the anti-seizure effects of ivermectin, and from other hand diazepam, nicorandil, morphine, L-NAME, 7-NI, and aminoguanidine, enhance the effects when co-administrated with subeffective dose of ivermectin. Additionally, the study found that ivermectin decreased the elevated levels of TNF-α and IL-1β following SE, while increased the reduced expression of GABAA receptors. Overall, these findings suggest that ivermectin has anti-seizure effects in a SE seizure which may be mediated by the modulation of GABAergic, opioidergic, and nitrergic pathways and KATP channels.

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.

Ketamine in the treatment of refractory and super-refractory status epilepticus: Experience from two centres

PurposeThere is insufficient evidence on the management of refractory status epilepticus (RSE) and super-RSE (SRSE). Ketamine is a N-methyl-d-aspartate receptor antagonist in the treatment of these entities. Our objectives were to study the effectiveness and safety of ketamine in the treatment of adult patients with RSE and SRSE, to determine the factors that can influence the response to ketamine, and to explore its use in patients without mechanical ventilation. MethodsAdult patients who had received intravenous ketamine for the treatment of RSE or SRSE at Hospital Universitario Clínico San Carlos (Madrid, Spain) or Hospital Universitari Vall d'Hebron (Barcelona, Spain) from 2017 to 2023 were retrospectively analysed. ResultsThis study included 58 adult patients, mean (standard deviation) age 60.2 (15.7) years, of whom 41 (70.7 %) were male; 33 (56.9 %) patients responded to ketamine without recurrence, with a low rate of adverse effects (8.6 %). The presence of SRSE at the time of ketamine initiation (OR 0.287, p = 0.028) and the time elapsed between status epilepticus onset and ketamine administration (OR 0.991, p = 0.034) were associated with worse response to ketamine. Patients treated without mechanical ventilation had similar rates of response without recurrence (62.5% vs 56.9 %) and lower mortality (37.5% vs 53.5 %) compared to the overall group. ConclusionKetamine is an effective drug with few adverse effects. Prompt administration should be considered in patients with RSE requiring anaesthesia, in patients with SRSE, and in patients with RSE who do not respond to standard antiseizure drugs and in whom mechanical ventilation is not advised.

Assessing the Role of Status Epilepticus Severity Score in Predicting Outcome in Patients with Convulsive Status Epilepticus: A Cross-sectional Study

Introduction: Status Epilepticus (SE) is a neurological emergency that necessitates prompt intervention and treatment. The Status Epilepticus Severity Score (STESS) is a clinical tool developed to assess the mortality rate among patients diagnosed with Convulsive Status Epilepticus (CSE). Aim: To assess the accuracy of STESS in predicting the outcome of CSE. Materials and Methods: This cross-sectional study was conducted at Jawaharlal Nehru Medical College, Aligarh, Uttar Pradesh, India from December 2020 to November 2022, involving 110 patients aged more than 15 years presenting with CSE lasting more than five minutes. Age, gender, seizure type, history of epilepsy, Glasgow Coma Scale (GCS), and STESS at presentation were assessed and associated with the outcome. Results: Among the 110 patients included in the study, there was a higher number of male patients compared to female patients. The mean age of the patients was 35.77±17.9 years. The most prevalent type of seizure observed was generalised tonic-clonic seizures, accounting for 65.45% of the cases, 9.09% of the patients expired, 89% of the patients had a STESS below 2. The Receiver-Operating Characteristic (ROC) curve for STESS at presentation to predict in-hospital mortality had an area under the curve of 0.859, 95% Confidence Interval (CI) from 0.780 to 0.918, and p-value&lt;0.0001. It had a sensitivity of 70%, specificity of 95%, Positive Predictive Value (PPV) of 58.3%, Negative Predictive Value (NPV) of 96.9%, and diagnostic accuracy of 92.73%. Conclusion: Assessment of in-hospital mortality at the onset of SE was reliably determined by STESS and is an useful clinical score. To fully comprehend the reasons for the high overall mortality rate following SE and potential prognostic factors, more research is required.

PICU Admission of Children for Status Epilepticus: Is There a Different Approach Between Referral and Second-Level Hospitals in an Italian Region?

Appropriate status epilepticus (SE) management is key to minimize admission to the pediatric intensive care unit (PICU). We retrospectively describe 115 children admitted to the PICU of the tertiary-care referral hospital of Padova for seizures, SE, and SE-related complications (59% from second-level hospitals, 41% from the referral hospital) and compare SE management among hospitals. Compared with the referral center, in second-level hospitals, anesthetics were more often administered as first/second drug (P < .001), and intubation was more frequent (P < .001). Intubation was significantly associated with SE onset at home (P = .045) and benzodiazepine-associated respiratory depression (P = .044). There was no association between intubation and SE duration, etiology, PICU length of stay, and morbidity at discharge. In conclusion, adherence to treatment protocols on SE management after the first-line drug differs between referral center and second-level hospitals. Lack of association with SE characteristics and patient's outcome suggests PICU admission could be due to inappropriate invasive management.

Risk assessment of long-term epilepsy after de novo status epilepticus with clinical and electroencephalographic biomarkers: The AFTER score

BackgroundThe risk of developing epilepsy after de novo status epilepticus (SE) is nonnegligible. The individualized management of patients with high risk of subsequent epilepsy could improve long-term quality of life and cognitive impairment. We aimed to ascertain potential biomarkers of subsequent epilepsy and to construct a scoring system possessing predictive value for the diagnosis of post-SE epilepsy during follow-up. MethodsThe study data were obtained from a prospective registry of all SE episodes occurring in patients over 16 years attended in our tertiary center from February 2011 to April 2022. Clinical data, electroencephalography findings, treatment, and long-term clinical data were prospectively recorded. We selected SE patients at risk of developing epilepsy (acute symptomatic and cryptogenic etiologies with no previous history of epilepsy) and analyzed the risk of developing subsequent epilepsy. ResultsWe included 230 patients. Median age was 65 years ± 16.9 SD and 112/230 (48.7 %) were women. One-hundred ninety-eight patients (86.1 %) had an acute symptomatic SE, whereas 32 patients (13.9 %) presented with a cryptogenic SE.A total of 55 patients (23.9 %) developed an unprovoked remote seizure and were diagnosed with epilepsy. After adjusting for identifiable confounders in a multivariable Cox regression analysis cryptogenic etiology (HR 2.24 [1.13–4.46], p = 0.022), first-line treatment initiation ≥1 h (HR 2.12 [1.03–4.36], p = 0.041], RDA/LPD/GPD EEG patterns (HR 1.88 [1.07–3.32], p = 0.028), and super-refractoriness (HR 2.90 [1.40–5.99], p = 0.004) emerged as independent predictors of post-SE epilepsy. Based on these findings, we constructed the AFTER score (1 point for each item) with a robust capability to predict post-SE epilepsy at 5 years (AUC 74.3 %, 95 %CI 64.3–84.3 %, p < 0.001). ConclusionsThe AFTER score is a robust predictor of the development of epilepsy after new onset SE using clinical and electroencephalographic biomarkers (such as etiology, time to first-line treatment initiation, EEG pattern and super-refractoriness). Prospective studies are warranted to validate the score in other populations.

Preventing Long-Term Brain Damage by Nerve Agent-Induced Status Epilepticus in Rat Models Applicable to Infants: Significant Neuroprotection by Tezampanel Combined with Caramiphen but Not by Midazolam Treatment.

Acute exposure to nerve agents induces a peripheral cholinergic crisis and prolonged status epilepticus (SE), causing death or long-term brain damage. To provide preclinical data pertinent to the protection of infants and newborns, we compared the antiseizure and neuroprotective effects of treating soman-induced SE with midazolam (MDZ) versus tezampanel (LY293558) in combination with caramiphen (CRM) in 12- and 7-day-old rats. The anticonvulsants were administered 1 hour after soman exposure; neuropathology data were collected up to 6 months postexposure. In both ages, the total duration of SE within 24 hours after soman exposure was significantly shorter in the LY293558 plus CRM groups compared with the MDZ groups. Neuronal degeneration was substantial in the MDZ-treated groups but absent or minimal in the groups treated with LY293558 plus CRM. Loss of neurons and interneurons in the basolateral amygdala and CA1 hippocampal area was significant in the MDZ-treated groups but virtually absent in the LY293558 plus CRM groups. Atrophy of the amygdala and hippocampus occurred only in MDZ-treated groups. Neuronal/interneuronal loss and atrophy of the amygdala and hippocampus deteriorated over time. Reduction of inhibitory activity in the basolateral amygdala and increased anxiety were found only in MDZ groups. Spontaneous recurrent seizures developed in the MDZ groups, deteriorating over time; a small percentage of rats from the LY293558 plus CRM groups also developed seizures. These results suggest that brain damage can be long lasting or permanent if nerve agent-induced SE in infant victims is treated with midazolam at a delayed timepoint after SE onset, whereas antiglutamatergic treatment with tezampanel and caramiphen provides significant neuroprotection. SIGNIFICANCE STATEMENT: To protect the brain and the lives of infants in a mass exposure to nerve agents, an anticonvulsant treatment must be administered that will effectively stop seizures and prevent neuropathology, even if offered with a relative delay after seizure onset. The present study shows that midazolam, which was recently approved by the Food and Drug Administration for the treatment of nerve agent-induced status epilepticus, is not an effective neuroprotectant, whereas brain damage can be prevented by targeting glutamate receptors.

Effect of U50488, a selective kappa opioid receptor agonist and levetiracetam against lithium-pilocarpine-induced status epilepticus, spontaneous convulsive seizures and related cognitive impairment

PurposeKappa opioid receptor (KOR) agonists have anticonvulsant effect but their antiepileptogenic effect is unknown. U50488, a selective KOR agonist is used to determine its effect on status epilepticus (SE), spontaneous convulsive seizures (SS) and cognitive impairment in rat lithium-pilocarpine SE model. Effect of an antiepileptic drug levetiracetam is also studied. MethodMale Wistar rats with SE were divided into three groups namely, LiP, LiP + U50488 (10 mg/kg, i.p.) and LiP + levetiracetam (400 mg/kg, i.p.) group. SE was terminated after 90 min of its onset with diazepam (15 mg/kg, i.p.) and phenobarbitone (25 mg/kg, i.p.). Drug treatment was started after 15 min of onset of SE and repeated once after 4 h. Rats were video monitored 12 h daily (9 AM to 9 PM) to determine severity of SE using modified Racine scale and onset and frequency of SS from day 0 to day 21. Morris water maze (MWM) test was done at baseline i.e. day −1 (before lithium administration) and day 22, to assess cognitive impairment. ResultsAs compared to LiP, U50488 decreased the severity of SE (1.98 ± 0.13 vs 2.95 ± 0.12; p-value < 0.0001) but not levetiracetam (2.62 ± 0.09; p-value = 0.3112). Survival increased with both U50488 (90%, n = 10) and levetiracetam (81.8%, n = 11) as compared to NS (56.2%, n = 16). No effect on onset and frequency of SS was found in U50488/levetiracetam group. U50488 improved seizures-induced cognitive impairment. Levetiracetam group showed thigmotactic (wall hugging) behaviour in MWM in 8 out of 9 rats. ConclusionAcute treatment with U50488, a kappa opioid receptor agonist has a beneficial effect on SE, SE-related mortality and memory impairment. The dual protective effect of U50488 on seizures and related cognitive impairment is advantageous over currently used antiseizure drugs which are known to cause cognitive impairment.

Chronic Epilepsy and Mossy Fiber Sprouting Following Organophosphate-Induced Status Epilepticus in Rats.

Organophosphate (OP) compounds are highly toxic and include pesticides and chemical warfare nerve agents. OP exposure inhibits the acetylcholinesterase enzyme, causing cholinergic overstimulation that can evolve into status epilepticus (SE) and produce lethality. Furthermore, OP-induced SE survival is associated with mood and memory dysfunction and spontaneous recurrent seizures (SRS). In male Sprague-Dawley rats, we assessed hippocampal pathology and chronic SRS following SE induced by administration of OP agents paraoxon (2 mg/kg, s.c.), diisopropyl fluorophosphate (4 mg/kg, s.c.), or O-isopropyl methylphosphonofluoridate (GB; sarin) (2 mg/kg, s.c.), immediately followed by atropine and 2-PAM. At 1-hour post-OP-induced SE onset, midazolam was administered to control SE. Approximately 6 months after OP-induced SE, SRS were evaluated using video and electroencephalography monitoring. Histopathology was conducted using hematoxylin and eosin (H&E), while silver sulfide (Timm) staining was used to assess mossy fiber sprouting (MFS). Across all the OP agents, over 60% of rats that survived OP-induced SE developed chronic SRS. H&E staining revealed a significant hippocampal neuronal loss, while Timm staining revealed extensive MFS within the inner molecular region of the dentate gyrus. This study demonstrates that OP-induced SE is associated with hippocampal neuronal loss, extensive MFS, and the development of SRS, all hallmarks of chronic epilepsy. SIGNIFICANCE STATEMENT: Models of organophosphate (OP)-induced SE offer a unique resource to identify molecular mechanisms contributing to neuropathology and the development of chronic OP morbidities. These models could allow the screening of targeted therapeutics for efficacious treatment strategies for OP toxicities.