Effects Of Status Epilepticus Research Articles

Management of Status Epilepticus, Refractory Status Epilepticus, and Super-refractory Status Epilepticus.

Status epilepticus is a serious condition caused by disorders and diseases that affect the central nervous system. In status epilepticus, hypersynchronous epileptic activity lasts longer than the usual duration of isolated self-limited seizures (time t1), which causes neuronal damage or alteration of neuronal networks at a certain time point (time t2), depending on the type of and duration of status epilepticus. The successful management of status epilepticus includes both the early termination of seizure activity and the earliest possible identification of a causative etiology, which may require independent acute treatment. In nonconvulsive status epilepticus, patients present only with subtle clinical signs or even without any visible clinical manifestations. In these cases, EEG allows for the assessment of cerebral function and identification of patterns in need of urgent treatment. In 2015, the International League Against Epilepsy proposed a new definition and classification of status epilepticus, encompassing four axes: symptomatology, etiology, EEG, and age. Various validation studies determined the practical usefulness of EEG criteria to identify nonconvulsive status epilepticus. The American Clinical Neurophysiology Society has incorporated these criteria into their most recent critical care EEG terminology in 2021. Etiology, age, symptomatology, and the metabolic demand associated with an increasing duration of status epilepticus are the most important determinants of prognosis. The consequences of status epilepticus can be visualized in vivo by MRI studies. The current knowledge about status epilepticus allows for a more reliable diagnosis, earlier treatment, and improved cerebral imaging of its consequences. Outcome prediction is a soft tool for estimating the need for intensive care resources.

P-EP024. Prevalence and clinical characteristics of pediatric haemorrhagic stroke complicated with seizure in Sardjito Hospital, Yogyakarta, Indonesia

Introduction. Intracerebral haemorrhage (ICH) is a condition of brain parenchymal haemorrhage with or without intraventricular bleeding. Although rare, ICH remains the most common cause of stroke in pediatric population. Previous study showed that prognosis of ICH in pediatric population is better than elderly, however neurologic sequelae should be considered, including seizure that may progress to epilepsy. Objective of this study is to determine the incidence of seizure in pediatric patients with intracranial haemorrhage. Methods. Retrospective cross-sectional study of children with ICH in Sardjito Hospital during 5 years period (January 2014 – December 2019). Results. There was 94 total ICH patient complicated with seizure, 36 (38.29%) of them are children (aged <18 years old). Approximately half of them suffered from status epilepticus, accounted for 15 children. Mean age of children with ICH complicated by stroke was 60.58 months, while those complicated with status epilepticus were older than non-status epilepticus, 84 months and 47.8 months respectively. Mortality rate of children population (66.67%) in this study was higher than adults (48%), which mainly as a consequence of status epilepticus which has mortality rate of 50%. Children with status epilepticus also had prolonged length of stay, around 19.92 days. Eleven children had hematologic disorder with thrombocytopenia, such as ALL (6), AML (1), hemophilia (1), thalassemia (1), anemia apalastic (1), and ITP (1), while congenital malformation was only in two children. Almost half of sample had multiple ICH, and can be a combination of parenchymal, SAH, EDH, and SDH. Only two children complicated with hypertension. Conclusion. Mortality rate among pediatric ICH with seizure was high, especially when complicated with status epilepticus. Multifocal hemorrhagic lesion was prominent in this studied population, therefore further study is needed to evaluate this associations with seizure symptoms.

Epileptologists infrequently discuss the risk of intubation with patients with epilepsy in the United States.

The aim of this study was to assess how frequently epileptologists discuss advance directives regarding intubation and mechanical ventilation with patients with epilepsy. A secondary aim was to understand the attitudes of neurologists toward discussion and implementation of such advance directives in epilepsy care. An online study survey was developed and distributed by email invitation to 210 neurologists at academic epilepsy and neurophysiology programs in the United States in December 2018. Seventy-seven neurologists, 95% with a clinical practice focus of epilepsy in adults, participated in the study (37% response rate). Three percent reported discussion of risk of intubation with "every" or a "majority" of patients newly diagnosed with epilepsy. Seventy-seven percent indicated a neurologist was the "most appropriate provider to have discussions concerning mechanical ventilation with patients with epilepsy." Twenty-five percent "strongly agreed" that "every patient with epilepsy should have an advance directive specifying their preferences concerning mechanical ventilation in the setting of treatment for seizures." A majority favored overriding a hypothetical patient's advance directive specifying no intubation in the context of airway compromise as a consequence of status epilepticus and its treatment. Epileptologists infrequently discuss the risk of intubation and mechanical ventilation with patients with epilepsy. Many felt that such discussions are unnecessary with most patients, but also best led by a neurologist. Neurologists with expertise in epilepsy may favor overriding advance directives in the setting of status epilepticus. Further data is needed surrounding discussion and implementation of advance care planning in patients with epilepsy.

Decreased Cerebrospinal Fluid Orexin-A (Hypocretin-1) Concentrations in Patients after Generalized Convulsive Status Epilepticus.

The effects of status epilepticus on the orexin/hypocretin system have yet to be investigated. The present study aimed to assay orexin-A/hypocretin-1 in the cerebrospinal fluid (CSF) of patients after generalized convulsive status epilepticus (GCSE). The study groups included 20 GCSE patients, 24 patients diagnosed with epilepsy but remaining in remission (ER), and 25 normal controls (CTR). Diagnostic lumbar puncture was performed in GCSE patients within 3–10 days of seizure cessation, as well as in the ER and to CTR subjects. Among all GCSE patients, the outcome was graded according to the modified Rankin Scale (mRS) at 1-month follow-up. Orexin-A levels were measured in unextracted CSF samples, using a commercial radioimmunoassay. There was a significant overall difference in median CSF orexin-A concentrations between GCSE, RE, and CTR patients (p < 0.001). The lowest concentrations were noted in the GCSE group compared to ER (p < 0.001) or CTR (p < 0.001). CSF orexin-A levels in GCSE patients inversely correlated with clinical outcome as assessed on the mRS at 1-month follow-up (r = −0.55; p = 0.1). In conclusion, CSF orexin-A levels may serve as a biomarker of increased turn-over of the peptide or post-SE neuronal damage, and implicates the orexin system in the pathogenesis of SE.

Clinical outcomes and treatments effectiveness in status epilepticus resolved by antiepileptic drugs: A five-year observational study.

ObjectiveTo evaluate clinical outcomes and treatment effectiveness of status epilepticus finally resolved by nonbenzodiazepine antiepileptic drugs (AEDs).MethodsAll consecutive SE episodes observed from September 1, 2013, to September 1, 2018, and resolved by AEDs were considered. Diagnosis and classification of SE followed the 2015 ILAE proposal. Nonconvulsive status (NCSE) diagnosis was confirmed according to the Salzburg EEG criteria. The modified Rankin Scale and deaths at 30 days from onset were used to evaluate outcomes.ResultsA total of 277 status episodes (mean age 71 years; 61% female) were treated and resolved by antiepileptic drugs after 382 treatment trials. 68% of the SE resolved after AED use as first/second treatment line, while subsequent trials with AEDs gave an additional 32% resolution. A return to baseline conditions was observed in 48% of the patients, while overall mortality was 19% without significant changes across the study years. Mortality was higher in NCSE than in convulsive SE (22.5% vs 12.9%; P < .05), while mortality did not differ in SE episodes resolved by a first/second AED trial (17.2%) versus SE resolved by successive treatment trials (18.9%). The resolution rate of intravenous AEDs was 82% for valproate, 77% for lacosamide, 71% for phenytoin, and 62% for levetiracetam. No significant differences were found in head‐to‐head comparison, but for the valproate‐levetiracetam one that was related to NCSE episodes in which valproate resulted to be effective in 86% of the trials while levetiracetam in 62% (P < .002).SignificanceA high short‐term mortality, stable over time, was observed in SE despite resolution of seizures, especially in SE with nonconvulsive semiology. Comparative AED efficacy showed no significant differences except for higher resolution rate for valproate versus levetiracetam in NCSE.

When the brain hurts the heart: status epilepticus inducing tako-tsubo cardiomyopathy.

Tako-tsubo cardiomyopathy (TTC) is a transient myocardial dysfunction mainly affecting the left ventricle, mimicking an acute coronary syndrome. This condition can be precipitated either by psychological/physical stressful events or by a number of medical conditions among which are seizures and status epilepticus (SE). The evolution is mostly favourable but sometimes TTC can evolve into life-threatening conditions. We searched for cases of TTC among all consecutive SE episodes observed at our department during the period 2013-2018. In addition, we searched MEDLINE (accessed through PubMed from inception to August 31, 2018) to identify reports of patients with TTC associated with an SE episode. Three TTC cases among 392 SE episodes were identified. Adding our cases to those previously reported, overall, we identified 45 cases of TTC induced by SE. The majority were females of around 60 years of age experiencing a first episode of SE with prominent motor phenomena, mostly in the context of remote aetiology. The most frequent presenting symptom was mild hypotension but cases with a severe presentation were also reported. The overall evolution was positive in all cases but some severe complications such as pulmonary oedema, cardiogenic shock, ventricular fibrillation, and a giant apical thrombus were also reported (19%). TTC may be a rare potentially life-threatening consequence of SE. It is frequently unrecognized, and therefore underdiagnosed. Clinicians dealing with SE should be aware of this entity.

The effect of status epilepticus on autonomic regulation of the heart and its functional capabilities in different postictal periods

To study the postictal changes in the autonomic regulation of the heart rhythm and its functional capabilities in different periods after epistatus and to assess the risk of life-threatening arrhythmias. The study was conducted on Wistar rats after epileptic status (ES). Telemonitoring of EEG and ECG was performed in the online mode using the system of the company 'ADInstruments'. Functional stress test with dobutamine was used. ES leads to a long-lasting disturbance of autonomic regulation (AR) of the heart and reduces its functional capabilities. The heart's AR balance is shifted towards sympathetic tonus 5 days after ES. This increases the predictors of life-threatening arrhythmias. The decrease in SWD activity increases the activity of parasympathetic tonus 10 days after ES. However, this is due to the tension of regulation mechanisms and the risk of life-threatening arrhythmias. The high degree of seizure activity of the brain in the ES predetermines prolonged postictal disorders of the AR heart, which reduce its functional capabilities and increase the risk of life-threatening arrhythmias.

Effect of status epilepticus on expression of brain UDP-glucuronosyltransferase 1a in rats.

Status epilepticus (SE) involves severe epileptic seizures that cause oxidative stress in the brain. Oxidative stress is known to influence uridine 5'-diposphate-glucuronosyltransferase (UGT) 1A expression. The present study aimed at elucidating the effect of SE on Ugt1a1, Ugt1a6 and Ugt1a7 expression in the rat brain. Kainic acid was used to create an animal model of SE. Sprague-Dawley rats were treated intraperitoneally with 10mg/kg kainic acid. Ugt1a1 and Ugt1a7 mRNA levels were increased by SE in the cortex and hippocampus (Ugt1a1: 4.0- and 5.3-fold, respectively; Ugt1a7: 2.8- and 2.5-fold, respectively). Moreover, the induction degree of heme oxygenase-1 mRNA, an oxidative stress marker, was high in these regions, suggesting that oxidative stress could be involved in Ugt1a1 and Ugt1a7 induction. Ugt1a6 was elevated by 1.8-fold in the cortex in both SE and non-response (non-epileptic seizure response) rats, implying that Ugt1a6 induction may be independent from SE. An intraperitoneal single administration of 25mg/kg diazepam (DZP) for the treatment of SE could attenuate heme oxygenase-1 induction in the cortex, whereas Ugt1a1 was decreased in the hippocampus, but not in the cortex, suggesting that there likely exists an alternative mechanism for Ugt1a1 reduction by DZP treatment. Continuous 14-day administration of DZP inhibited Ugt1a1 induction in the cortex, but did not have an effect on Ugt1a7 induction. This study indicated that SE altered the expression of brain Ugt1a1 and Ugt1a7, which could alter glucuronidation in the brain.

Status epilepticus in dogs and cats, part 1: etiopathogenesis, epidemiology, and diagnosis.

To review current knowledge of the etiopathogenesis, diagnosis, and consequences of status epilepticus (SE) in veterinary patients. Human and veterinary literature, including clinical and laboratory research and reviews. Status epilepticus is a common emergency in dogs and cats, and may be the first manifestation of a seizure disorder. It results from the failure of termination of an isolated seizure. Multiple factors are involved in SE, including initiation and maintenance of neuronal excitability, neuronal network synchronization, and brain microenvironmental contributions to ictogenesis. Underlying etiologies of epilepsy and SE in dogs and cats are generally classified as genetic (idiopathic), structural-metabolic, or unknown. Diagnosis of convulsive SE is usually made based on historical information and the nature of the seizures. Patient specific variables, such as the history, age of seizure onset, and physical and interictal neurological examination findings can help hone the rule out list, and are used to guide selection and prioritization of diagnostic tests. Electroencephalographic monitoring is routinely used in people to diagnose SE and guide patient care decisions, but is infrequently performed in veterinary medicine. Nonconvulsive status epilepticus has been recognized in veterinary patients; routine electroencephalography would aid in the diagnosis of this phenomenon in dogs and cats. Status epilepticus is a medical emergency that can result in life-threatening complications involving the brain and systemic organs. Status epilepticus often requires comprehensive diagnostic testing, treatment with multiple anticonvulsant agents, and intensive supportive care.

Expression regulation and targeting of the peroxisome proliferator-activated receptor γ following electrically-induced status epilepticus

The neuroprotective and anti-inflammatory effects of the peroxisome proliferator-activated receptor γ (PPARγ) agonist rosiglitazone are of particular interest for disease-modifying and antiepileptogenic approaches. We studied the expression of PPARγ and the impact of rosiglitazone on the consequences of status epilepticus (SE) in a rat post-SE model. Immunohistochemical analysis revealed a selective overexpression of PPARγ in the piriform cortex of rats with spontaneous seizures. Rosiglitazone administration initiated following SE failed to exert relevant effects on the development of spontaneous seizures and neuronal cell loss. Whereas spatial learning in the Morris water maze was delayed in SE animals with vehicle administration, the learning curve of rosiglitazone-treated SE rats showed no significant difference to that of controls. The study provides first evidence arguing against a robust antiepileptogenic effect. However, the findings in the spatial learning paradigm indicate disease-modifying effects.

Ischemic-hypoxic mechanisms leading to hippocampal dysfunction as a consequence of status epilepticus.

Status epilepticus (SE) is one of the recognized primary precipitating events that can lead to temporal lobe epilepsy (TLE) associated with hippocampal sclerosis. This type of epilepsy is characterized by poor response to drug treatment, often requiring surgical intervention to remove the mesial temporal regions involved in the seizure onset. However, even neurosurgery may not be completely successful. Thus, the prevention of hippocampal damage and epileptogenesis is currently evaluated as a possible alternative therapeutic approach to prevent the development of pharmacoresistant TLE. Lines of evidence suggest that ischemic-hypoxic lesions might occur in different brain regions, including the hippocampus, during SE. Especially in the hippocampal CA3 region, an ischemic-like lesion develops in the stratum lacunosum-moleculare and is mainly characterized by a loss of astrocytes and neuronal processes and increased immunostaining of pimonidazole which probes areas exposed to hypoxia. Interestingly, these mechanisms can contribute to neuronal cell loss and may be counteracted by drugs that can afford vascular protection, as in the case of ligands of the ghrelin receptor. Notably, some of the ghrelin receptor ligands possess a double edge effect, since they are anticonvulsant and vascular-protective, thus, potentially representing new tools to counteract the consequences of SE. This article is part of a Special Issue entitled "Status Epilepticus".

Consequences of status epilepticus in the intensive care unit: what we know and what we need to know.

Consequences of status epilepticus in the intensive care unit: what we know and what we need to know.

G328(P) A UK-wide review of deaths in children and young people with epilepsies

ObjectiveTo review cases of mortality in 1–18 year olds with epilepsies, in order to identify and learn from clinical and organisational management or personal issues that contributed to adverse outcomes...

Effect of lithium-pilocarpine-induced status epilepticus on ultrasonic vocalizations in the infant rat pup

Evidence shows that febrile convulsions induced in rat pups increase ultrasonic vocalizations (USVs); however, the effect of status epilepticus (SE) induced in developing rats on USVs has not been fully investigated. The goal of this study was to analyze USVs following lithium-pilocarpine-induced SE in fourteen-day-old (P14) rat pups. The rat pups were given 3-mEq/kg lithium chloride i.p. on the day before the induction of SE, which was carried out at P14 by subcutaneous injection of 100-mg/kg pilocarpine hydrochloride; control animals were given an equal volume of lithium chloride and saline on P13 and P14, respectively. Ultrasonic vocalizations were monitored at P15, P16, and P21 with a Mini 3 Bat Detector Ultra Sound Advice (15kHz–160kHz) set at 40±4kHz and digitally recorded in WAV format using the Audacity 1.3 beta software. A clear box (60×40×30cm) split down the middle with a holed wall was used; each pup was placed alone in one compartment, whereas its dam was placed on the other cage side at room temperature. Vocalizations were recorded over a 5-minute period, converted to sonograms and spectrograms, and analyzed using the Raven software. Parameters evaluated were as follows: USV frequency, latency to the first USV, and mean USV duration. There was a significant decrease in the latency (35.5±6.9s) and duration (50.8±8.6s) of USVs after SE compared with the control group (81.9±10.8s and 78.1±9.9s, respectively). Status epilepticus affected male and female rats differentially.

Design, synthesis and anticonvulsant properties of new N-Mannich bases derived from 3-phenylpyrrolidine-2,5-diones

The synthesis and anticonvulsant properties of new N-Mannich bases of 3-phenyl- (9a–d), 3-(2-chlorophenyl)- (10a–d), 3-(3-chlorophenyl)- (11a–d) and 3-(4-chlorophenyl)-pyrrolidine-2,5-diones (12a–d) were described. The key synthetic strategies involve the formation of 3-substituted pyrrolidine-2,5-diones (5–8), and then aminoalkylation reaction (Mannich-type) with formaldehyde and corresponding secondary amines, which let to obtain the final compounds 9a–d, 10a–d, 11a–d and 12a–d in good yields. Initial anticonvulsant screening was performed in mice (ip) using the maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) seizures tests. The most effective compounds in mice were tested after oral administration in rats. The acute neurological toxicity was determined applying the minimal motor impairment rotarod test. The in vivo results revealed that numerous compounds were effective especially in the MES test (model of human tonic-clonic seizures). The most active in the MES seizures in rats was 1-[(4-benzyl-1-piperidyl)methyl]-3-(2-chlorophenyl)pyrrolidine-2,5-dione (10c) which showed ED50 value of 37.64mg/kg. It should be stressed that this molecule along with 9a, 9d and 10d showed protection in the psychomotor seizure test (6-Hz), which is known as an animal model of therapy-resistant epilepsy. Furthermore compounds 9a, 9d and 10d were also tested in the pilocarpine-induced status prevention (PISP) test to assess their potential effectiveness in status epilepticus. For the most promising molecule 9d an influence on human CYP3A4 isoform of P-450 cytochrome was studied in vitro.

Developmental outcome after a single episode of status epilepticus

Consequences of status epilepticus (SE) on psychomotor development and the specific impact of the convulsive event on emerging executive functions remain controversial. Infants treated for a single episode of SE, those treated for a single febrile seizure, and healthy infants were tested with respect to motor development, language, personal, and social skills and self-regulation. The children were divided into two age groups to investigate the impact of the convulsive event at different windows of brain maturation. We found that infants who had had SE were inferior to healthy controls on the development scales. Age differentiated SE impact on visuomotor development versus sociolinguistic development. Children who had been treated for SE had significantly more difficulties delaying a response to an attractive stimulus in one of the long-delay conditions. A single episode of SE can interfere with psychomotor and cognitive development in children without previous developmental delay, and it seems that the functions that are emerging at the time of insult are most vulnerable.

Kainic acid-induced early genes activation and neuronal death in the medial extended amygdala of rats

The medial extended amygdala modulates pheromonal perception, influencing emotional and social behavior. As the amygdala is part of neuronal circuits that are very sensitive to excitability, its neurons are targets of seizures in temporal lobe epilepsy. It has been suggested that the hippocampus is strongly involved this pathology. There is less consistent information, however, on the effects of this disease in the amygdala. The effects of status epilepticus on the medial extended amygdala were analyzed by immunohistochemistry for neural stress and by the amino-cupric-silver technique for neuronal death in rats after kainic acid (KA) administration. Sixty adult Wistar male rats were used. Thirty animals received an injection of KA, and 30 were injected with saline. After 2, 4, 12, 24 and 48 h survival the brains were stained for Fos and FosB and for neuronal death. In the present study we show that KA induces Fos and FosB expression in neurons of the medial extended amygdala after 2, 4–48 h, with time courses that are different between them and from control animals. While Fos-IR peaks at 2–4 h post KA and then decreases, FosB-IR increases in the same period reaching its highest expression at 24–48 h. Moreover, KA injection produced massive neuronal death with a peak at 24 h. This neurodegeneration paralleled FosB-IR protein expression. These findings show that KA produces neuronal stress and activation of early genes and neuronal death in the medial extended amygdala, demonstrating the vulnerability of its neurons to the epileptogenic effects of KA.

What is animal experimentation telling us about new drug treatments of status epilepticus?

Basic research is mostly focused on the consequences of status epilepticus (SE) in terms of neuronal loss, behavior, epileptogenesis or disease-modifying effects such as preventing epilepsy or reducing seizure severity. Among the drugs tested, several were able to trigger neuroprotection but only a few had disease-modifying effects. At this point, many data are still missing, namely which drugs could efficiently stop SE or which mechanisms of action should be searched for to prevent the harmful consequences of SE.

Age‐Dependent Consequences of Status Epilepticus: Animal Models

Status epilepticus (SE) is a significant neurological emergency that occurs most commonly in children. Although SE has been associated with an elevated risk of brain injury, it is unclear from clinical studies in whom and under what circumstances brain injury will occur. The purpose of this review is to evaluate the effects of age on the consequences of SE. In this review, we focus mainly on the animal data that describe the consequences of a single episode of SE induced in the adult and immature rat brain. The experimental data suggest that the risk of developing SE-induced brain damage, subsequent epilepsy and cognitive deficits in large part depends on the age in which the SE occurs. Younger rats are more resistant to seizure-induced brain damage than older rats; however, when SE occurs in immature rats with abnormal brains, there is an increase in the severity of seizure-induced brain injury. Better understanding of the pathophysiologic mechanisms underlying the age-specific alterations to the brain induced by SE will lead to the development of novel and effective strategies to improve the deleterious consequences.

Effects of status epilepticus on hippocampal GABA A receptors are age-dependent

Long-term GABA A receptor alterations occur in hippocampal dentate granule neurons of rats that develop epilepsy after status epilepticus in adulthood. Hippocampal GABA A receptor expression undergoes marked reorganization during the postnatal period, however, and the effects of neonatal status epilepticus on subsequent GABA A receptor development are unknown. In the current study, we utilize single cell electrophysiology and antisense mRNA amplification to determine the effect of status-epilepticus induced by lithium-pilocarpine in postnatal day 10 rat pups on GABA A receptor subunit expression and function in hippocampal dentate granule neurons. We find that rats subjected to lithium-pilocarpine-induced status epilepticus at postnatal day 10 show long-term GABA A receptor changes including a two-fold increase in α1 subunit expression (compared with lithium-injected controls) and enhanced type I benzodiazepine augmentation that are opposite of those seen after status epilepticus in adulthood and may serve to enhance dentate gyrus inhibition. Further, unlike adult rats, postnatal day 10 rats subjected to status epilepticus do not become epileptic. These findings suggest age-dependent differences in the effects of status epilepticus on hippocampal GABA A receptors that could contribute to the selective resistance of the immature brain to epileptogenesis.