Search Results (10)

Status epilepticus (SE) is a neurological emergency. Current evidence dictates a step-by-step approach with a first line of therapy consisting of benzodiazepines (BDZs). In many situations, the currently approved approach does not terminate a BDZ-resistant SE. This happens in Stage 1 Plus, a framework designed by the author to recognize cases of probable benzodiazepine-resistant status epilepticus even before treatment initiation. These cases include Prolonged SE (SE lasting > 10 min), the absence of prominent motor phenomena, and acute etiology (primary central nervous system etiologies most of all). BDZ-refractory SE cases (Stage 1 Plus) might require a different approach, one targeting the unresponsive GABA signaling state mediated by NMDA/AMPA receptors, such as combined polytherapy with Ketamine from the start. These considerations stem from the receptor trafficking hypotheses: in prolonged seizure activity and primary central nervous system etiologies, GABA receptors get internalized and move away from synapses, and therefore, SE becomes resistant to BDZ. A rational polytherapy that might restore the unresponsiveness to BDZ in SE should include NMDA antagonists, such as Ketamine. Ketamine has proven effective in many experimental models of status epilepticus, and much evidence is gathering supporting its use in humans, especially in refractory and super-refractory SE. We lack studies evaluating combined polytherapy in SE, especially in the early phases. The author suggests here that Ketamine should be used along with first-line BDZ in the early SE stage falling in the category of Stage 1 Plus and as a first-line anesthetic infusion drug in refractory SE, especially in cases progressing from Stage 1 Plus, eventually adding continuous midazolam/propofol infusion in later phases. This systematic review’s objective is to summarize the presently available evidence of the early use of combined polytherapy that includes Ketamine, along with the currently available evidence of Ketamine use in early, established, and refractory SE. Nine studies were included. Boluses of Ketamine and Midazolam are effective in pediatric convulsive Stage 1 Plus SE. The results show that earlier Ketamine administration (especially within 12 h of SE onset) was significantly associated with improved seizure control, with a more favorable safety profile than Midazolam in refractory SE. Notably, a dosage of less than 0.9 mg/kg/h proves ineffective in terminating SE. Ketamine has the advantage of preventing intubation, possibly shortening the length of stay in the intensive care unit. Full article

Stage 1 Plus is defined here as a naïve, previously untreated, status epilepticus (SE) that is probably refractory to Benzodiazepines (BDZ). These cases include not only prolonged SE as previously proposed by the author (SE lasting > 10 min) but also other cases notoriously associated with BDZ refractoriness such as the absence of prominent motor phenomena and acute etiology (especially primary central nervous system etiology). Interestingly, the absence of prominent motor phenomena as is the case of non convulsive SE might implicitly fall in the category of prolonged SE due to the delay in recognition and treatment. Future studies should help identify other factors associated with BDZ refractoriness, therefore widening the definition of Stage 1 Plus. The appropriate timing for defining prolonged SE may also differ depending on different etiology. Consequently, in future tailored models of SE, the definition of prolonged SE could be enhanced by defining it for a longer duration than Tx, a time point that changes based on different etiologies (x), Tx being much shorter than 10 min in acute etiologies. These cases of naïve probably BDZ refractory SE (Stage 1 Plus) might require a different approach: combined polytherapy from the start. The objective of this review is to provide pathophysiological and pre-clinical evidence, mostly from animal studies, for the different approach of combined polytherapy from the start for those cases of SE falling in the definition of Stage 1 Plus. Full article

Background: Status epilepticus is a life-threatening condition that is defined as refractory (RSE) when the seizure activity continues despite treatment with benzodiazepine and a second appropriate treatment. Super refractory status epilepticus (SRSE) is an RSE that persists or recurs for ≥24 h. Few papers have reported the outcomes of pediatric patients affected by RSE and SRSE and treated with neuromodulation therapies. Vagus nerve stimulation (VNS) is an approved treatment for drug-resistant epilepsy. We present our findings of pediatric patients treated with VNS for RSE/SRSE. Methods: We present a case series of seven consecutive pediatric patients treated with VNS for SRSE since 2012 by a single surgeon in Monza and Padua. A rapid titration was started soon after implantation. We considered electroclinical data before and after VNS implantation and at the last follow-up. Results: We achieved the resolution of SRSE in five out of seven patients in a mean time of two weeks. At the last follow-up, these patients had a significant reduction of seizure burden without any relapse of SE. Discussion and Conclusions: Based on our limited findings, we discuss the potential role of VNS therapy in similar but distinct clinical contexts. For patients with drug-resistant epilepsy and RSE/SRSE, prompt VNS consideration is suggested, offering rapid responses and potentially reducing pharmacological load. Meanwhile, in NORSE/FIRES, we suggest early neuromodulation during the acute phase if standard treatments prove ineffective or not tolerated. This approach may leverage VNS’s potential anti-inflammatory effects and neuromodulation, enhancing patient-specific treatments. Expanding case studies and prolonged follow-ups are recommended to strengthen these clinical insights. Full article

Status epilepticus (SE) is a neurological emergency with a high mortality rate. When compared to chronic epilepsy, it is distinguished by the durability of seizures and frequent resistance to benzodiazepine (BZD). The Receptor Trafficking Hypothesis, which suggests that the downregulation of γ-Aminobutyric acid type A (GABAA) receptors, and upregulation of N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors play major roles in the establishment of SE is the most widely accepted hypothesis underlying BZD resistance. NMDA and AMPA are ionotropic glutamate receptor families that have important excitatory roles in the central nervous system (CNS). They are both essential in maintaining the normal function of the brain and are involved in a variety of neuropsychiatric diseases, including epilepsy. Based on animal and human studies, antagonists of NMDA and AMPA receptors have a significant impact in ending SE; albeit most of them are not yet approved to be in clinically therapeutic guidelines, due to their psychomimetic adverse effects. Although there is still a dearth of randomized, prospective research, NMDA antagonists such as ketamine, magnesium sulfate, and the AMPA antagonist, perampanel, are regarded to be reasonable optional adjuvant therapies in controlling SE, refractory SE (RSE) or super-refractory SE (SRSE), though there are still a lack of randomized, prospective studies. This review seeks to summarize and update knowledge on the SE development hypothesis, as well as clinical trials using NMDA and AMPA antagonists in animal and human studies of SE investigations. Full article

We aimed to evaluate the current management of status epilepticus (SE) in intensive care units (ICUs) in Germany, depending on the different hospital levels of care and the ICU specialty. We performed a nationwide web-based anonymized survey, including all German ICUs registered with the German Society for Neurointensive and Emergency Care (Deutsche Gesellschaft für Neurointensiv- und Notfallmedizin; DGNI). The response rate was 83/232 (36%). Continuous EEG monitoring (cEEG) was available in 86% of ICUs. Regular written cEEG reports were obtained in only 50%. Drug management was homogeneous with a general consensus regarding substance order: benzodiazepines—anticonvulsants—sedatives. Thereunder first choice substances were lorazepam (90%), levetiracetam (91%), and propofol (73%). Data suggest that network structures for super-refractory SE are not permeable, as 75% did not transfer SE patients. Our survey provides “real world data” concerning the current management of SE in Germany. Uniform standards in the implementation of cEEG could help further improve the overall quality. Initial therapy management is standardized. For super-refractory SE, a concentration of highly specialized centers establishing network structures analogous to neurovascular diseases seems desirable to apply rescue therapies with low evidence carefully, ideally collecting data on this rare condition in registries and clinical trials. Full article

Refractory and super-refractory status epilepticus (RSE and SRSE) are life-threatening conditions requiring prompt initiation of appropriate treatment to avoid permanent neurological damage and reduce morbidity and mortality. RSE is defined as status epilepticus that persists despite administering at least two appropriately dosed parenteral medications, including a benzodiazepine. SRSE is status epilepticus that persists at least 24 h after adding at least one appropriately dosed continuous anesthetic (i.e., midazolam, propofol, pentobarbital, and ketamine). Other therapeutic interventions include immunotherapy, neuromodulation, ketogenic diet, or even surgical intervention in certain cases. Continuous electroencephalogram is an essential monitoring tool for diagnosis and treatment. In this review, we focus on the diagnosis and treatment of RSE and SRSE. Full article

Dravet Syndrome (DS) is burdened by high epilepsy-related premature mortality due to status epilepticus (SE). We surveyed centres within Europe through the Dravet Italia Onlus and EpiCARE network (European Reference Network for Rare and Complex Epilepsies). We collated responses on seven DS SCN1A+ patients who died following refractory SE (mean age 6.9 year, range 1.3–23.4 year); six were on valproate, clobazam, and stiripentol. All patients had previous SE. Fatal SE was always triggered by fever: either respiratory infection or one case of hexavalent vaccination. SE lasted between 80 min and 9 h and all patients received IV benzodiazepines. Four patients died during or within hours of SE; in three patients, SE was followed by coma with death occurring after 13–60 days. Our survey supports the hypothesis that unresponsive fever is a core characteristic feature of acute encephalopathy. We highlight the need for management protocols for prolonged seizures and SE in DS. Full article

Status epilepticus is the most severe form of epilepsy, with a high mortality rate and high health care costs. Status epilepticus is divided into four stages: early, established, refractory, and super-refractory. While initial treatment with benzodiazepines has become standard of care for early status epilepticus, treatment after benzodiazepine failure (established status epilepticus (ESE)) is incompletely studied. Effective treatment of ESE is critical as morbidity and mortality increases dramatically the longer convulsive status epilepticus persists. Phenytoin/fosphenytoin, valproic acid, levetiracetam, phenobarbital, and lacosamide are the most frequently prescribed antiseizure medications for treatment of ESE. To date there are no class 1 data to support pharmacologic recommendations of one agent over another. We review each of these medications, their pharmacology, the scientific evidence in support and against each in the available literature, adverse effects and safety profiles, dosing recommendations, and limitations of the available evidence. We also discuss future directions including the established status epilepticus treatment trial (ESETT). Substantial further research is urgently needed to identify these patients (particularly those with non-convulsive status epilepticus), elucidate the most efficacious antiseizure treatment with head-to-head randomized prospective trials, and determine whether this differs for convulsive vs. non-convulsive ESE. Full article

This article describes current experimental models of status epilepticus (SE) and neuronal injury for use in the screening of new therapeutic agents. Epilepsy is a common neurological disorder characterized by recurrent unprovoked seizures. SE is an emergency condition associated with continuous seizures lasting more than 30 min. It causes significant mortality and morbidity. SE can cause devastating damage to the brain leading to cognitive impairment and increased risk of epilepsy. Benzodiazepines are the first-line drugs for the treatment of SE, however, many people exhibit partial or complete resistance due to a breakdown of GABA inhibition. Therefore, new drugs with neuroprotective effects against the SE-induced neuronal injury and degeneration are desirable. Animal models are used to study the pathophysiology of SE and for the discovery of newer anticonvulsants. In SE paradigms, seizures are induced in rodents by chemical agents or by electrical stimulation of brain structures. Electrical stimulation includes perforant path and self-sustaining stimulation models. Pharmacological models include kainic acid, pilocarpine, flurothyl, organophosphates and other convulsants that induce SE in rodents. Neuronal injury occurs within the initial SE episode, and animals exhibit cognitive dysfunction and spontaneous seizures several weeks after this precipitating event. Current SE models have potential applications but have some limitations. In general, the experimental SE model should be analogous to the human seizure state and it should share very similar neuropathological mechanisms. The pilocarpine and diisopropylfluorophosphate models are associated with prolonged, diazepam-insensitive seizures and neurodegeneration and therefore represent paradigms of refractory SE. Novel mechanism-based or clinically relevant models are essential to identify new therapies for SE and neuroprotective interventions. Full article

The aim of this article – to review the causes, clinical signs, pathophysiology, consequences, and treatment of seizures and status epilepticus in critically ill patients. Only 25% of people, who have seizures and status epilepticus, have epilepsy as well. In the intensive care settings, seizures and status epilepticus are a common neurologic complication, which is attributable to primary neurologic pathology (stroke, hemorrhage, tumor, central nervous system infection, head trauma) or secondary to critical illness (anoxic brain damage, intoxications, metabolic abnormalities) and clinical management. There are three main subtypes of status epilepticus in intensive care units: generalized convulsive status epilepticus, focal motor status epilepticus, and nonconvulsive status epilepticus. A seizure is a consequence of electrical neurological derangement because of sudden imbalance between the inhibitory and excitatory forces within the network of cortical neurons. The main inhibiting neurotransmitter in the brain is gamma-aminobutyric acid (GABA), which binds to GABA-A and GABA-B receptors. The main excitatory neurotransmitter is glutamate, which binds to N-methyl-D-aspartate receptors. Different ions (Cl^–, K⁺, Na⁺, Ca²⁺) also play a role in the pathophysiology of seizures. Prolonged status epilepticus may lead to different systemic and neurologic consequences. Generalized convulsive status epilepticus is one of the most common emergencies encountered in clinical practice, which requires immediate treatment. The first-line drugs are benzodiazepines (lorazepam, diazepam), the second-line ones – phenytoin and fosphenytoin. For the treatment of refractory status epilepticus, barbiturates (phenobarbital, pentobarbital, thiopental), valproate, midazolam, propofol, and isoflurane are used. The dosage of drugs and parameters to monitor are referred in the article. The mortality from generalized convulsive status epilepticus is 15–50%; the main factors, influencing prognosis, are the cause and the duration of status epilepticus and age of a patient. Full article